Post Traumatic

Stress Disorder
Diagnosis, Management,
and Treatment
Second Edition

Edited by
David J Nutt
Murray B Stein
Joseph Zohar
Posttraumatic Stress
Disorder
Diagnosis, Management, and Treatment
Second Edition

Edited by

David J Nutt, PhD, MA, DM, FRCP, FRCPsych, FMedSci

Department of Neuropsychopharmacology and Molecular Imaging
Imperial College London
Hammersmith Hospital
London
United Kingdom
Murray B Stein, MD, FRCPC, MPH
Department of Psychiatry
University of California at San Diego
La Jolla, California
United States of America

and

Joseph Zohar, MD
Division of Psychiatry
Chaim Sheba Medical School
Tel Hashomer
and Sackler School of Medicine
Tel Aviv University
Tel Aviv
Israel
© 2009 Informa UK

First published in 2009 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ. Informa
Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH.
Registered in England and Wales number 1072954.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted,
in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior
permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or
under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham
Court Road, London W1P 0LP.

Although every effort has been made to ensure that all owners of copyright material have been acknowledged in
this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our
attention.

A CIP record for this book is available from the British Library.
Library of Congress Cataloging-in-Publication Data

Data available on application

ISBN-13: 9780415395717

Distributed in North and South America by

Taylor & Francis

6000 Broken Sound Parkway, NW (Suite 300)
Boca Raton, FL 33487, USA

Within Continental USA

Tel: 1 (800) 272 7737; Fax: 1 (800) 374 3401

Outside Continental USA

Tel: 1-859-727-5000
Fax: 1-859-647-4028
E-mail: orders@taylorandfrancis.com

Orders in the rest of the world

Informa Healthcare
Sheepen Place
Colchester
Essex CO3 3LP
UK

Telephone: +44 (0)20 7017 5540

Email: CSDhealthcarebooks@informa.com

Typeset byC&M Digitals (P) Ltd, Chennai, India

Printed and bound in Great Britain by MPG Books Ltd, Bodmin, Cornwall, UK
 Contents

List of contributors v
Foreword vii
Simon Wessely
  1 Posttraumatic stress disorder: Diagnosis, history, and longitudinal course 1
Arieh Y Shalev
  2 Epidemiology of traumatic events and posttraumatic stress disorder 12
Tracie O Afifi, Gordon JG Asmundson, and Jitender Sareen
  3 Diagnostic dilemmas in assessing posttraumatic stress disorder 25
Berthold PR Gersons and Miranda Olff
  4 Neuroimaging and posttraumatic stress disorder 36
  Sarah N Garfinkel and Israel Liberzon
  5 Brain circuits in posttraumatic stress disorder 51
Eric Vermetten and Ruth Lanius
  6 The genetics of posttraumatic stress disorder 70
Eduard Maron and Jakov Shlik
  7 Setting apart the affected: A novel animal model for posttraumatic
stress disorder and its translational perspective 88
Joseph Zohar, Michael Matar, and Hagit Cohen
  8 Psychosocial treatments of posttraumatic stress disorder 99
Kerry J Ressler and Barbara O Rothbaum
  9 Pharmacotherapy of posttraumatic stress disorder 116
Lakshmi N Ravindran and Murray B Stein
10 Early interventions following traumatic events 127
Jonathan I Bisson, Arieh Y Shalev, and Joseph Zohar
11 Traumatic stress disorders in children 147
Soraya Seedat
12 Ethnocultural issues 163
Alexander McFarlane and Devon Hinton
13 Posttraumatic stress disorder after disasters 176
Andrea R Maxwell and Sandro Galea
14 Symptom exaggeration in posttraumatic stress disorder 187
Alzbeta Juven-Wetzler, Rachel Sonnino, Danit Bar-Ziv, and Joseph Zohar
15 Future directions 195
Joseph Zohar, Murray B Stein, and David Nutt
Index 201
 List of contributors

Tracie O Afifi Devon Hinton

Anxiety and Illness Behaviors Laboratory Harvard Medical School
University of Regina Boston, Massachusetts, USA
Regina, Saskatchewan, Canada
Alzbeta Juven-Wetzler
Gordon JG Asmundson Chaim Sheba Medical Center
Anxiety and Illness Behaviors Tel Hashomer, Israel
Laboratory
Department of Psychology Ruth Lanius
University of Regina Department of Psychiatry
Regina, Saskatchewan, Canada University of Western Ontario
London, Ontario, Canada
Danit Bar-Ziv
Chaim Sheba Medical Center Israel Liberzon
Tel Hashomer, Israel Department of Psychiatry
University of Michigan
Jonathan I Bisson and Ann Arbor VA Medical Center
School of Medicine Ann Arbor, Michigan, USA
Cardiff University
Cardiff, UK Eduard Maron
Department of Mental Health
Hagit Cohen The North Estonian Regional Hospital
Israel Ministry of Health Mental Health Psychiatry Clinic
Center Tallinn, Estonia
and and Department of Psychiatry
Anxiety and Stress Research Unit University of Tartu
Faculty of Health Sciences Tartu, Estonia
Ben-Gurion University of the Negev
Beer-Sheva, Israel Michael Matar
Israel Ministry of Health Mental Health
Sandro Galea Center
Medical School and Anxiety and Stress Research Unit
School of Public Health Faculty of Health Sciences
Institute for Social Research Ben-Gurion University of the Negev
University of Michigan Beer-Sheva, Israel
Ann Arbor, Michigan, USA
Andrea R Maxwell
Sarah N Garfinkel Department of Epidemiology
Department of Psychiatry University of Michigan School of Public
University of Michigan Health
Ann Arbor, Michigan, USA Ann Arbor, Michigan, USA

Berthold PR Gersons Alexander McFarlane

Department of Psychiatry The Centre for Military and Veterans’ Health
Amsterdam Medical Center The University of Adelaide,
Amsterdam, The Netherlands Adelaide, Australia
vi List of contributors

David J Nutt Arieh Y Shalev

Department of Neuropsychopharmacology Department of Psychiatry
and Molecular Imaging Hadassah University Hospital
Imperial College London Jerusalem, Israel
Hammersmith Hospital
London, UK Jakov Shlik
Department of Psychiatry
Miranda Olff University of Ottawa
Center for Psychological Trauma and
Department of Psychiatry Anxiety Disorders Program
Academic Medical Center Royal Ottawa Mental Health Centre
University of Amsterdam Ottawa, Ontario, Canada
Amsterdam, The Netherlands
Rachel Sonnino
Lakshmi N Ravindran Chaim Sheba Medical Center
Mood and Anxiety Program Tel Hashomer, Israel
Centre for Addiction and Mental Health
Toronto, ON, Canada Murray B Stein
Department of Psychiatry
Kerry Ressler University of California at San Diego
Department of Psychiatry and Behavioral La Jolla, California, USA
Sciences
Yerkes Research Center Eric Vermetten
Emory University Military Mental Health Center
Atlanta, Georgia, USA and
Rudolf Magnus Institute of Neurosciences
Barbara O Rothbaum, University Medical Center
Trauma and Anxiety Recovery Program Utrecht, The Netherlands
Department of Psychiatry
Emory University School of Medicine Simon Wessely
Atlanta, Georgia, USA King’s Centre for Military Health Research
Institute of Psychiatry
Jitender Sareen King’s College London
Department of Psychiatry London, UK
and
Department of Community Health Sciences Joseph Zohar
University of Manitoba Chaim Sheba Medical Center
Winnipeg, Manitoba, Canada Tel Hashomer
Sackler School of Medicine
Soraya Seedat Tel Aviv University
Department of Psychiatry Tel Aviv, Israel
University of Stellenbosch
Cape Town, South Africa
 Foreword

When writing an introduction to an already established text the easiest option is to turn to the
first edition and see what has changed over the years. And so never one to turn down the easy
route, that is what I have done.
Many things remain much the same, which is reassuring, as one sign of a maturing field is
stability. Some problems have not been solved. Diagnostic dilemmas remain, both as a chapter,
and as a problem. Neuroscience was the great prospect in 2000, and remains a great prospect
today. The sense of optimism conveyed in the final chapters in 2000 is undiminished, and indeed
some progress has been made. Neuroimaging has delivered at least some goods, although the
hope that this would translate into treatment advances expressed ten years ago remains a hope
today. Nevertheless, Vermetten is able to highlight for example a study in which long-term treat-
ment of PTSD with paroxetine increased hippocampal volume, suggesting some neurogenerating
actions of 5HT, which if replicated represents a genuine advance. Likewise, using the tryptophan
depletion paradigm Professor Nutt’s team have elegantly shown that 5HT might be critical to
restraining the expression of anxiety in PTSD when treated with SSRIs, although this in turn also
takes us back to the issue of comorbidity and whether PTSD is just another shuffling of the anxi-
ety disorder cards, rather than a unique diagnostic and biological entity.
A new and impressive addition is an authoritative chapter on genetics. The concept that
hereditary factors might play a role in the etiology of PTSD was a baby thrown out with the
1980 bathwater when they sat down to redraft the DSM and turned their backs on the previous
half century of thinking on predisposition, so it is good to see it back in there.
And what about treatment? The chapter on debriefing has gone, now incorporated into a
general discussion of early interventions. The reawakening of interest into the older literature
that suggested that ordinary people are and remain fairly resilient is starting to influence our
approaches and reminds us that sometimes in this area we go round and round, and not always
forwards. We have rediscovered what was known a generation ago—that the best immediate
mental health interventions in the hours and days after a disaster concern issues such as shel-
ter, safety, information, and communication. It is not necessary to immediately ask, “How was
it for you?” while the smoke and dust are literally and metaphorically still settling—because
the answers might be curt and unprintable. There are also signs of a more sensible public men-
tal health approach gaining ground—not wasting money on immediate treatments of large
numbers of people who are going to get better anyway (and who, as study after study shows,
vote with their feet in rejecting formal mental health interventions at that stage), but instead
concentrating a few weeks later on the smaller numbers who are still in trouble—the policy of
“watchful waiting” followed by “screen and treat” advocated in the UK NICE Guidelines and
used to good effect in the aftermath of the London bombs.(1)
So how should we be treating the smaller numbers of those who are still in trouble per-
haps some months after the event? The book reflects the fact that differences of opinion still
exist here. The final chapter, in which the editors use their prerogative to give their own views,
have not changed much over the decade. In 2000 SSRIs are the first-line treatment, and remain
so in 2009. But in the equally scholarly psychological treatment chapter Ressler and Rothbaum
draw attention to the recent statements from the respected US Institute of Medicine that expo-
sure-based psychotherapy remains the best validated treatment, and just like our own NICE
Guidelines, are less taken with the evidence for medications.
In truth most people don’t get very much anyway. In our studies of UK veterans with
mental health problems the majority never get near a doctor, and when they do they tend to
get given antidepressants, followed by counseling.(2) Only a very few will receive the NICE- or
IOM-approved “best practice” of trauma-focused therapy. Getting any decent treatment is the
challenge.
Perhaps the most challenging chapter comes from Professor McFarlane, writing alone in
2000 but now joined by Devon Hinton, who brings his experience of working in Cambodia to
viii Foreword

the table. I thoroughly commend this chapter to the reader because it is a thoughtful and wide-
ranging contribution that does not duck some difficult questions. For example, the authors use
Robert Hughes’s “Culture of Complaint,” one of my favorite books (3) to suggest that how soci-
ety conceptualizes personal responsibility is dramatically influenced by the adversarial tradition.
But Hughes also goes on to reflect about the cultural role of the victim, of a person defined not
by what he or she does, but by what was done to him or her, and identifies the growth of what
he called “victim culture” as a source of concern. Hughes is not alone in having these concerns—
influential sociologist Frank Furedi, for example, goes even further.(4) As a specialty we have
perhaps had a tendency to ignore views that run counter to our own narrative, so it is refreshing
for McFarlane and Hinton to be joining in this debate, as well as reminding us of the need to take
a broader historical perspective on what we have done and are doing.
If I have a personal hobby horse (and of course I do), it is to take issue with the view that
in the field of posttraumatic stress disorder, we are following an upward trajectory, always
moving along the path of knowledge in a Whiggish progress from ignorance to enlightenment.
My reading of the historical literature suggests that while this is partly true, it is also true that
we have also moved in a more circular trajectory during the past 100 years.
It is a great pity that there is still no real intellectual synthesis of trauma in the 20th
century—nor how and why the culture of trauma was transformed in the past two or three
decades of the last century. Too often trauma studies that delve into history rely on literature
as a primary sources, rather than history. The experiences of Sassoon and Owen were hardly
typical of the management of psychiatric injury in the First World War, and their accounts in
fiction or poetry were little known the immediate postwar years. Captain W E Johns, the inven-
tor of Biggles, was far more popular and gave a heroic narrative that people wanted to hear.
Field Marshall Haig was genuinely mourned when he died, and the fact that he still seats on his
horse at the top of Whitehall, looking down on the Cenotaph is not an example of postmodern
irony, but a mark of the fact that he was credited with masterminding Britain’s military victory.
When the now classic First World War play, “Journey’s End” was premiered in 1928 its author,
RC Sherriff, was shocked when he realized that the production was going to be “antiwar,” pro-
testing that he had never intended it to be anything of the sort.(5, 6, 7)
True, the publication of “All Quiet on the Western Front” in Germany in 1929 and then in
Britain the following signaled the start of a change. Lloyd George’s memoirs started the trash-
ing of Haig’s reputation in the 1930s, but the real turning point came in the 1950s and 1960s
with Alan Clark’s “The Donkeys” followed by the premier of “Oh What a Lovely War” in 1963.
The way was then clear for the apotheosis of our current views of the Great War in the person
of arguably its now most famous participant, Captain Edmond Blackadder, and in particular
the poignant last episode, recently voted the nation’s most favorite TV episode.
Our own views on our history have I would suggest also been influenced by the same
narratives changes that influenced Richard Curtis and Ben Elton when they created Captain
Blackadder. It is time for historians not comedy script writers to reclaim the history of trauma
and for us as practitioners and researchers to engage with the real history of PTSD, one free
from our own modern conceptions of how it “should have been,” but instead how it was. How
do we account for the very different view of children’s resilience in war time given by Melanie
Klein to that of our modern commentators? What about the work of pioneering sociologists
such as Quarantarelli whose findings on the outcome of disasters reads so differently from
our own? Why, for example, did studies from the First World War seem to report that prison-
ers of war were largely free from anxiety symptoms, whereas now the same group are seen as
particularly at risk?
Just before Ben Shephard published his history of war and psychiatry (8) he agreed to
talk about it at a major conference on psychological trauma. I recall the buzz of anticipation
before he spoke and then the almost palpable shock once the audience started to realize that he
was “not one of us.” True, he isn’t—but the field needs to engage with historians such as Ben
Shephard and Mark Micale (9) just as much as with neuroscientists.
One more new chapter deserves mention. Presumably in response to increasing concerns
about the increasing scope and spread of PTSD, and/or its increasingly prominence in the
Courts, the editors have requested a new chapter on symptom exaggeration, and a very good
one it is. But by focusing on exaggeration, inevitably the agenda has to reflect what are often
Foreword ix

overstated concerns about the malingering of PTSD (not unknown, but not common either) at
the expense of the more interesting and relevant topic of the influences on symptom reporting,
both positive and negative.
For example, whenever I interview a soldier, there are always contextual effects on what
he, or occasionally she, is prepared to admit to at any given time. On my first trip to an opera-
tional theatre I witnessed a Royal Marine trying to board the flight with a broken leg and con-
tinuing to deny there was anything wrong even when rumbled. He was a rather more blatant
example of the symptom minimization that we encounter each time we visit a base shortly
before a deployment to administer health questionnaires. Most soldiers have joined the mod-
ern professional armies of the developed world because they want to deploy—for the excite-
ment, challenge, and desire to put their training into reality, and also if they have any career
ambitions. It is in their interest to minimize any symptom or problem that might result in them
being refused permission to deploy, one more reason why predeployment screening for mental
health problems is doomed to fail.(10)
We also see minimization of symptoms if personnel are screened directly on their return
from deployment. Military personnel are not stupid, and know that if they endorse too many
symptoms then they will be held back in order to be interviewed by a psychologist or psy-
chiatrist, and thus miss their postoperational tour leave. So why should we surprised that in
another circumstance, perhaps a year later, when they are planning on leaving the military
and/or not wanting to return to Iraq or wherever (been there, done that, time to move on), their
thoughts now turn to what happens next and how they might guarantee future health care.
In each and every instance, context is intervening to decide what symptoms will be
endorsed, when, to whom, and for what purpose. Soldiers, like everyone else, are not disinter-
ested academic observers of their own condition.(11)
It is evidence like this that calls into question one assumption that underlies a few chap-
ters—that there exists the “real” or “true” level of symptoms, which can be determined either
with sophisticated questionnaires now or neuroimaging and/or neurophysiology in the future.
I am doubtful if this is possible. Not just reporting, but perhaps even experiencing symptoms
might be better understood as a pair of scales, in which there are factors promoting expression,
and factors promoting suppression, and what happens at any given time is the result of the
balance of the forces operating at any given moment. The fact that that rear-end shunts cause
whiplash in Sweden but not in Lithuania is also of relevance to PTSD.(12)
And what about the future? As in the first edition, the editors point to promising avenues
of research in the neurosciences and to the prospects of new pharmacological agents. However,
a new departure is the discussion of possible pharmacological prevention, as opposed to treat-
ment, of PTSD. This is a topic in which the “man in the street” (at least if journalists are to
be believed) expresses doubts, usually because of concerns that this in some way diminishes
our humanity, often linked to vague analogies with “Brave New World.” If the man in the
street knew more about epidemiology and public health he might also point out the differ-
ences between treating those who clearly have psychiatric disorders and have come forward
for treatment, and treating those who have been exposed to a trauma, most of whom won’t
develop psychiatric disorder, especially when we as yet we have no robust way of separat-
ing out that majority from the minority who will. The balance between risk and harm is very
different, something which this author believes will take a long time and some pretty heavy
evidence to change. Talk of the “golden hour” in major trauma or stroke care needs to done
cautiously, as the analogy is far from exact.
Anyway, the reader who opens this volume can be guaranteed a fascinating, scholarly
but still accessible account of PTSD in 2010. A warm welcome then for the second edition, a
brief rest for the editors, but then it will be time to start on the third.

Professor Simon Wessely

King’s Centre for Military Health Research
Department of Psychological Medicine
Institute of Psychiatry
King’s College London
x Foreword

References

  1. Brewin CR, Scragg P, Robertson M et al. Promoting mental health following the London bombings: a
screen and treat approach. J Trauma Stress 2008; 21(1): 3–8.
  2. Iversen A, Dyson C, Smith N et al. “Goodbye and Good Luck”; the mental health needs and treatment
experiences of British Veterans. submitted for publication. Br J Psychiatry 2005; 186: 480-486
  3. Wessely S. Ten Books. Britsh J Psychiatry 2002; 181: 81–4.
  4. Furedi F. Therapy Culture: Cultivating Vulnerability In An Anxious Age. Routledge, 2003.
  5. Bond B. The Unquiet Western Front: Britain’s Role in Literature and History. Cambridge: Cambridge
University Press; 2002.
  6. Todman D. “San Peur and Sans Reproche”: The retirement, death and mourning of Sir Douglas Haig:
1918–1928. J Mil Hist 2003; 67: 1083–106.
  7. Sheffield G. ‘Oh! What a Futile War: Perceptions of the First World War in Modern British Media
and Culture’, in War, culture and the media: representations of the military in 20th century Britain,
S. Carruthers, Stewart I, ed. Flicks Books: Wiltshire, 1996: 54–74.
  8. Shephard B. A War of Nerves, Soldiers and Psychiatrists 1914-1994. London: Jonathan Cape; 2000.
  9. Micale M, Lerner P, eds. Traumatic Pasts: History, Psychiatry and Trauma in the Modern Age, 1860-
1930. Cambridge University Press: Cambridge, 2001: 140–71.
10. Rona RJ, Hooper R, Jones M et al. Mental health screening in armed forces before the Iraq war and
prevention of subsequent psychological morbidity: follow-up study. BMJ 2006; 333(7576): 991.
11. Wessely S. War Stories. British J Psychiatry 2005; 186: 473–5.
12. Schrader H, Obelieniene D, Bovim G et al. Natural evolution of late whiplash syndrome outside the
medicolegal context. Lancet 1996; 347: 1207–11.
 1 Posttraumatic stress disorder: Diagnosis,
history, and longitudinal course
Arieh Y Shalev

What is posttraumatic stress disorder?

Posttraumatic stress disorder (PTSD) is an anxiety disorder defined by the co-occurrence in sur-
vivors of extreme adversity reexperiencing avoidance and hyperarousal symptoms.(1) Unlike
most other mental disorders, the diagnosis of PTSD relies on associating concurrent symptoms
with a previous “traumatic” event. The association is both chronological (symptoms starting
after the event) and content related: PTSD reexperiencing and avoidance symptoms involve
recollections and reminders of the traumatic event. Individuals who suffer from PTSD continu-
ously and uncontrollably relive the very distressing elements of the traumatic event in the form
of intrusive recollection and a sense of permanent threat. They avoid places, situations, and
mental states that can evoke such recollections.
The image of men and women condemned to repeatedly relive a traumatic event has
always captured human imagination. It was immortalized in ancient legends, such as that of
Lot’s wife, petrified into a column of salt, as she looked backward to the chaos of Sodom. This
metaphor of being frozen by looking back at the trauma served as inspiration for generations
of artists (see adjacent figures)
More recent expressions depict combat soldiers as ones for
whom “the war does not end when the shooting stops” (2) or the
holocaust survivors who experience the components of the horror
decades after liberation.(3)
Beyond reminders of the traumatic event, PTSD symptoms
include pervasive alterations in one’s emotional life, in the form
of depressed mood, tension, restlessness, and irritability (Box 1.1).
PTSD, therefore, encompasses trauma-related symptoms, anxiety
symptoms and symptoms otherwise found in depression. PTSD
is also the common outcome of all types of traumatic events,
from most horrifying and protracted (e.g., child abuse) to shorter
events or incidents (e.g., rape, assault, combat event, accidents).
The latter have been referred to as Type I Trauma, whereas the
former, or Type II Trauma, have been associated with complex
PTSD and other psychological difficulties (e.g., mistrust, subjec-
tive sense of emptiness, relational difficulties). The construct of
PTSD has replaced, in fact, several event-related syndromes that
preexisted its definition (e.g., “concentration camp syndrome,”
“war neurosis” or “rape victim syndrome”). The configuration
of PTSD symptoms is the same in all these occurrences, whereas
the specific mental content differs, reflecting the particularities of
each person’s experience.
PTSD is not seen in every survivor of a potentially traumatic
event. Exposure, therefore, is not a sufficient cause of the disorder.
Instead, the traumatic event is currently viewed as “triggering” a
reaction, to which prior and posterior (postevent) factors contrib-
ute at least as much (4–6 and see below).
2 Shalev

Box 1.1  DSM-IV diagnostic criteria for posttraumatic stress

disorder (PTSD).

2 Posttraumatic stress disorder

A. The person has been exposed to a traumatic event in which both of the following
were present:
(1) The person experienced, witnessed, or was confronted with an event or events
that involved actual or threatened death or serious injury, or a threat to the
physical integrity of self or others.
(2) The person’s response involved intense fear, helplessness, or horror.
B. The traumatic event is persistently reexperienced in one (or more) of the following
ways:
(1) Recurrent and intrusive distressing recollections of the event, including images,
thoughts, and perceptions;
(2) Recurrent distressing dreams of the event;
(3) Acting or feeling as if the traumatic event were recurring;
(4) Intense psychological distress at exposure to internal or external cues that
symbolize or resemble an aspect of the traumatic event;
(5) Physiological reactivity on exposure to internal or external cues that symbolize
or resemble an aspect of the traumatic event.
C. Avoidance of stimuli associated with the trauma and numbing of general respon­
siveness (not present before the trauma) as indicated by three (or more) of the
following:
(1) Efforts to avoid thoughts, feelings, or conversations associated with the trauma;
(2) Efforts to avoid activities, places, or people that arouse recollections of the trauma;
(3) Inability to recall an important aspect of the trauma;
(4) Markedly diminished interest or participation in significant activities;
(5) Feeling of detachment or estrangement from others;
(6) Restricted range of affect (e.g., unable to have loving feelings);
(7) Sense of a foreshortened future (e.g., does not expect to have a career, marriage,
children, or a normal life span).
D. Persistent symptoms of increased arousal (not present before the trauma) as indicated
by two (or more) of the following:
(1) Difficulty falling or staying asleep
(2) Irritability or outbursts of anger
(3) Difficulty concentrating
(4) Hypervigilance
(5) Exaggerated startle response
E. Duration of the disturbance (symptoms in criteria B, C, and D) is more than one month.
F. The disturbance causes clinically significant distress or impairment in social
occupational or other important areas of functioning

DIAGNOSIS, HISTORY, AND LIFE COURSE

Along with other novel diagnostic entities (e.g., panic disorder), PTSD was first defined and
included in the American Psychiatric Association’s third Diagnostic and Statistical Manual
(DSM-III; (7)). Though received with significant scepticism, the disorder has nonetheless won
a central place in the current discourse on life stresses and mental disorders. Among the many
reasons for such a “success” are (a) the growing attention to nonpsychotic disorders in modern
psychiatry; (b) increased social awareness of, and aversion for, human rights violations, war,
Posttraumatic stress disorder 3

and violence; and (c) the growing interest, by neurobehavioral scientists, in emotions, memory,
brain plasticity, and gene environment interaction. Triggered by an external event, and involv-
ing both emotional deregulation and memory disturbance, PTSD is the prototype of environ-
mentally induced disorder.
As with other disorders in DSM-III, PTSD was essentially defined by its overt and reli-
ably observable expressions (as opposed to mental dispositions, psychological conflicts, or pat-
terns of subjective experiences). DSM-III attempted to increase the reliability of psychiatric
diagnoses by defining mandatory “diagnostic criteria” for each disorder. These criteria are
states of mind, activities, and dispositions that the patient can readily communicate and the cli-
nician can rather easily recognize and confirm. Trauma survivors often report other symptoms
(e.g., a sense of inner change, loneliness, despair), but these do not count for the diagnosis of
PTSD. Numerous rating scales and structured interviews have been validated for PTSD and
are routinely used in studies of this disorder.
It has been argued, though, that some PTSD symptoms might be too easily perceived and
communicated and thus may create an impression of an “epidemic of PTSD” following major,
spectacular, and socially contagious events. Studies of the prevalence of PTSD following the
September 11, 2001 attacks on the Twin Towers in New York have been criticized for overes-
timating the rate of PTSD on the basis of commonly reported symptoms (e.g., (8)). Most such
cases of PTSD have, in fact, recovered within few months of the attacks (9).
Nevertheless, the definition of PTSD has enabled an ever-growing stream of empirical
studies of comparable groups of trauma survivors. Thus, while the boundaries of PTSD and
the accuracy of the diagnosis made shortly after a traumatic event are a still matter of debate,
it is currently clear that this “man-made” definition of the disorder is a good enough object for
scientific enquiry. Clinicians, however, should be aware of the significant variability of indi-
vidual experiences and symptoms within this diagnostic entity and of the major role of the
particularities of each trauma in shaping survivors behaviour and recovery paths.
Despite the link to a traumatic event, DSM IV and the related World Health Organization’s
10th edition of International Classification of Diseases (10) do not posit a pathogenic mechanism
for PTSD. Putative mechanisms have been proposed for PTSD others, including “fear condition-
ing,” an abnormality of “fear processing,” or “shattered cognitive assumptions.”(11–13) These the-
ories established a basis for theory-based interventions for PTSD, such as cognitive-behavioural
therapy (CBT) or pharmacotherapy by agents that interfere with the early stress responses.
This chapter will address the disorder’s boundaries, that is, its frequent coexistence with
major depression and other mental disorders, and the difficulties to discern PTSD from a normal
response to traumatic events at the early aftermath of the latter. It will also present arguments for
and against assuming a complex PTSD resulting from Type II trauma. As a starter, the chapter
will briefly examine the history of PTSD, evaluate the evidence for the syndrome’s reliability and
validity, and discuss the changes in the definition of PTSD over time. A detailed historical review
of trauma-related disorders before 1980 is beyond the scope of this chapter (but see 14–16).

A brief history
Traumatic syndromes resembling PTSD have been described and harshly debated during the
20th century. Rescuers of survivors of ship explosions in Toulon in 1907 and 1911, for example,
exhibited “recapitulation of the scene, terrifying dreams, diffuse anxiety, fatigue, and various
minor phobias” ((14) p. 247). A debate concerning the nature and the therapy of “shell shock”
raged during most of World War I, at which time three different approaches to treating the dis-
order were used: (a) a social environment approach, exemplified by treating soldiers in military
installations, close to the frontline, and expecting their full return to military duty (17); (b) a
behaviouristic approach, exemplified by directly addressing avoidance and bodily (i.e., conver-
sion) symptoms (e.g., (18)); and (c) a psychotherapeutic approach, exemplified by exploring the
content and the personal meaning of traumatic experienced as a means of recovery (e.g., (19)).
The burden of compensation for World War I–combat neuroses resulted in restrictive
administrative decisions, such as not to compensate financially for battle shock during World
War II (in the United Kingdom), or to use the neutral term “battle fatigue” for stress disorders
among combatants of the U.S. army, instead of implying a mental disorder.(14)
Under such different titles, the clinical observations repeated themselves quite systemati-
cally. Symptoms of “operational fatigue” included (16) irritability, fatigue, difficulties falling
4 Shalev

asleep, startle reaction, depression, tremor and evidences of sympathetic overreactivity, diffi-
culties in concentration and mental confusion, preoccupation with combat experiences, night-
mares and battle dreams, phobias, personality changes, and increased alcoholism. (p. 210).
A “traumatic neurosis” (11) comprised “Fixation on the trauma, typical dream life, contraction
of general level of functioning, irritability and proclivity to explosive aggressive reactions”
(p. 86). These descriptions clearly resemble those currently used for PTSD.
Despite clinical observations during World War I and II, traumatic stress disorders were
not included in DSM-I (1952-1968) and DSM-II (1968-1980). DSM I included a category of
“gross stress reaction” of a maximum duration of two months, thereby implying that genu-
ine reactions to major stressors are transient, and prolonged illness reflects more basic distur-
bances. Those who remain chronically ill after a traumatic exposure essentially express another
underlying disorder (e.g., childhood neurosis, depressive illness) possibly revealed by trauma.
DSM-II eliminated the gross stress reaction category altogether and provided no alternative
diagnosis for reactions to major stressors.
The introduction of PTSD into DSM-III followed the realization of the profound psy-
chological effect of the Vietnam War, (20, 21) and concurrent studies of rape victims. A major
force behind the delineation of PTSD was Vietnam Veterans Working Group (VVWG), a
heterogeneous association of professionals and activists formed in 1974 and supported
by the American Orthopsychiatric Association and the National Council of Churches. The
VVWG drew the attention of the American Psychiatric Association (APA) Task Force on
Nomenclature (the DSM-III Task Force) to the need for stress-related syndromes to be rec-
ognized. It further compiled 724 observations of psychologically disabled veterans and pro-
vided a tentative list of syndrome, closely resembling Kardiner’s description of “traumatic
neuroses” among World War I veterans. These and other observations were submitted to the
Committee of Reactive Disorders appointed by the APA task force and the latter decided to
include PTSD in DSM-III as one based on “consensus” rather than “empirically validated”
disorder.(20)
Empirical findings have somewhat refined PTSD diagnostic criteria in subsequent edi-
tions of the DSM. The definition of a “traumatic event” (PTSD criterion A) was modified (see
the following). A requirement for a minimal one-month duration was included. Survivor guilt,
which appeared in DSM-III, was omitted because studies have shown that it was infrequent.
The item “physiological reaction to reminders of the trauma” was moved from the “hyperar-
ousal” (D) criterion to the “intrusion” (B) criterion. Finally DSM-IV has introduced a require-
ment for clinically significant distress or impairment (Criterion F). DSM-IV (1994) also added
an associated syndrome—acute stress disorder (ASD) that will be discussed as follows.

The syndrome
The current (DSM-IV) diagnostic criteria for PTSD differ from those originally included in
DSM-III in several ways. Unlike DSM-III, DSM-IV definition of a traumatic event does not
require an outstanding stressor that “would evoke significant symptoms of distress in almost
everyone.” Milder and more common stressors, such as road traffic accidents or sudden trau-
matic loss, have been shown to induce prolonged PTSD symptoms in a proportion of survi-
vors.(22–28) Accordingly, traumatic events occur quite frequently, with different proportions
of survivors developing PTSD after each trauma type. Table 1.1 summarizes the likelihood of
being exposed to a traumatic event, as recorded in several studies of civilian adults.
Traumatic events in DSM-IV also include instances of witnessing trauma to others
(such as witnessing an execution or being involved in rescue operations). The requirement
of direct exposure to the stressful event is not required any more: suffice it to be confronted
with an event. The definition of the event currently includes an emotional reaction while
exposed. The latter involves intense fear, helplessness, or horror. In U.S. studies using the
liberal DSM-IV “trauma” criteria (7, 23–25) the probability of experiencing a traumatic event
during one’s life is very high indeed, reaching 97% of male adults. Interestingly, the rates
of exposure to a traumatic event and subsequent PTSD were found to be much lower in a
European and an Australian study.(26, 27)
The World Health Organization’s ICD-10 has kept the original perception of a trau-
matic event as outstanding and universally distressing: “event or situation (either short or
long lasting) of an exceptionally threatening or catastrophic nature, which is likely to cause
Posttraumatic stress disorder 5

Table 1.1  Likelihood of exposure to traumatic events in the general population.

Author &
publication Study PTSD among PTSD among
year Population (n) Sample Males (%) Females (%) Trauma type

Kessler et al., USA (5877) General 61% 51% Any trauma

1995 population
Breslau et al., USA (1007) Young adults 43% 37% Any trauma
1991 (age=21–30)
Norris et al., USA (1000) Adults 74% 65% Ten selected events
1992
Stein et al., Canada (1000) Adults 81% 74% List of traumatic events
1997
Breslau et al., USA (2181) Adults 97% 87% DSM IV events
1998
Perkonigg et al., Europe (3021) Adults Male = 26% Male = 1% Any trauma
2000 Female = 17.7% Female = 2.2%

pervasive distress in almost anyone.” Virtually, all current studies of PTSD use DSM-IV diagnostic
criteria, thereby including in their sample survivors of an array of major and minor events, the
major defining element of which has become the subjective reaction to the event rather than its
“objective” appearance.

Consistency of PTSD Symptoms

PTSD symptoms may be seen within hours of a traumatic event.(29) At the other end, night-
mares and intrusive recollections can be found, decades after exposure, in survivors of pro-
longed adversities who are minimally disturbed. Avoidance alone may develop as well, in the
form of specific phobia, reluctance to evoke specific topics, or avoidance of places and activities
without the associated hyperarousal and intrusive recollections. It is typical of phobic subjects
not to be distressed as long as they can successfully avoid the object of their phobia. Irritability
can also be an isolated outcome of a trauma, particularly upon homecoming from military con-
flicts. Abnormal irritability is often felt by survivors families and may lead misuse of alcohol
as a “tranquilizer.”
Partial PTSD is a subthreshold condition in which some but not all PTSD symptoms
criteria are formally met. Partial PTSD is often as frequent as PTSD (30) and similarly unre-
mitting.(31, 32) Not meeting the PTSD Criterion C (avoidance) is the most frequent reason
for having partial PTSD. As can be seen in Box 1.1 one has to experience at least three symp-
toms in order to meet the C criterion (compared with one reexperiencing symptom and two
hyperarousal symptoms). Moreover, only three of Criterion C’s seven items (Items one to
three) are directly related to avoiding reminders of the traumatic event. The other four items
(diminished interest, detachment and estrangement, restricted range of affect, and sense of
foreshortened future) reflect “psychological numbing,” a construct borrowed from the litera-
ture on grief and bereavement. More important, the four numbing symptoms resemble those
seen in depression (e.g., anhedonia)—a disorder that frequently co-occurs with PTSD.
PTSD Criterion D includes several expressions of increased arousal (insomnia, irritabil-
ity, bursts of anger) and exaggerated startle response. Exaggerated startle has been described
among trauma survivors throughout history. For example, ‘”stragglers” who ceased to func-
tion as soldiers during the American Civil War were “trembling, staring into the middle
distance and jumping at any loud noise.”(33) Kardiner (11) similarly recognized “auditory
hypersensitiveness” as one of the core features of traumatic neurosis in World War I veterans
(p. 95). Startle reaction was among the frequent symptoms seen in airmen with “operational
fatigue” ((16); p. 210). Exaggerated startle is reported by up to 88% of PTSD patients.(34)
Several studies evaluated the construct validity of PTSD (e.g., (22, 35, 36)) and found it
to be very good and generally matching the subdivision into reexperiencing, avoidance, and
hyperarousal. Despite somewhat fluctuating longitudinal trajectories in individuals, symptom
severity in cohorts of chronic PTSD patients remains stable over time.(37)
6 Shalev

The time course of PTSD

PTSD symptoms are very frequently in the immediate aftermath of trauma exposure (e.g.,
in 94% of rape victims, within a week of the trauma; 38). PTSD symptoms decrease with
time in most of those who initially express them—and so does the prevalence of diagnos-
able PTSD (e.g., 39%, 17% at six months and 10% at one year on a cohort of Israeli civilians
admitted to a general hospital ER (e.g., (39)). In a seminal epidemiological study, Kessler
et al. (40) described 60% recovery in trauma survivors with early PTSD. The National Vietnam
Veterans Readjustment Study (NVVRS) showed 30% lifetime prevalence and 15.2% point
prevalence of PTSD, more than 20 years after the war.(41) A reanalyses of the NVVRS study,
in which combat exposure was independently ascertained, from military records, yielded
lower lifetime (18.7%) and point prevalence (9.7%) of PTSD, (42) but similar ratio of lifetime
to chronic PTSD.
Most cases of spontaneous recovery occur within a year from the traumatic event.(40)
Survivors who recover later often have partial PTSD and are vulnerable to subsequent expo-
sure to analogous events.(43, 44)
Because they frequently decline, early PTSD symptoms should be seen as sensitive and
nonspecific predictors of the chronic disorder.(43) Indeed, the negative predictive value of
early symptoms (i.e., the likelihood that someone who does not have symptoms will develop
PTSD) is more reliable than their positive predictive value. The clinician’s dilemma, therefore,
is to identify, among those who express high levels of symptom, those at risk of keeping these
symptoms.
The presence of early dissociation symptoms, such as detachment, time distortion, feel-
ing “on automatic pilot” or out-of-the-body experience or frank episodes of dissociation sig-
nal a high risk for chronic PTSD.(4) Similarly early and severe depression (44) and elevated
heart rate levels shortly after the traumatic event (45) have been linked with higher risk
of PTSD. Past history of mental illness, previous traumatic experiences, and dysfunctional
families also contribute to PTSD. Finally, events and conditions that follow the traumatic
event have a major effect on the likelihood of recovery from early symptoms.(46) The sub-
jective appraisals of the event, and of one’s reactions to the event, contribute significantly
to the persistence of PTSD symptoms (e.g., (47)) as do societies responses, where people
close to the victim provide support; for example, family friends can be protective. Cognitive-
behavioural therapies specifically address these distortions and hence are effective as treat-
ments for PTSD.(48–50)

Severity and Comorbidity

The severity of chronic PTSD is subject to fluctuations.(37) Exacerbations in the severity of
PTSD symptoms are often due to life pressures, exposure to reminders of the traumatic event,
or failure in an area of living (e.g., family or work). Thus, many PTSD sufferers see their symp-
toms exacerbated when they retire from work, develop serious illness, or lose stabilizing ele-
ments of their lives.
PTSD patients are very sensitive to ongoing stressors, to which they often react by becom-
ing distraught, angry, or inappropriately using sedatives or alcohol. For the clinician, this fea-
ture of PTSD suggests that the environment within which chronic PTSD patients live should be
a target for monitoring and intervening. It is somewhat easier to help a recovered PTSD patient
keep his or her work, by guidance and advice, than to medically or psychologically address the
symptoms and the complications of a severe recurrence of symptoms. While such “tertiary”
prevention is recommended for most chronic mental illnesses, PTSD patients should be seen
as particularly reactive to stressors and negative events, and especially lonely, frustrated, and
isolated.
PTSD often co-occurs with other mental disorders, particularly with major depression,
anxiety disorders, and substance abuse. The U.S. National Comorbidity Study, for example
(41), has shown that 88.3% of male PTSD subjects and 79% of women with PTSD have at least
one other mental disorder. Depression was experienced by about one-half of all PTSD subjects
(48.5% in women and 47.9% in men). Anxiety disorders were seen in more than one-third, and
drug and alcohol abuse by a third of all women and half of all men. Other studies (51–55) have
confirmed the frequent co-occurrence of PTSD and depression—at levels between 34% to 51%
(current) and 95% (lifetime).
Posttraumatic stress disorder 7

Boundaries and subtypes

Acute stress disorder
In an attempt better to differentiate the early and normal responses to traumatic events from
“pathological” ones, DSM-IV proposed a diagnostic category of acute stress disorder (ASD;
Box 1.2). ASD includes PTSD symptoms and symptoms of dissociation, appearing immediately
after a traumatic event and up to four weeks later. ASD is a robust predictor of chronic PTSD,
yet most PTSD patients do not have an initial ASD.

Box 1.2 Symptom Criteria for Acute Stress Disorder.

A. A traumatic event—as in PTSD

B. Dissociative symptoms (at least three required):

1. A subjective sense of numbing, detachment, or absence of emotional
responsiveness;
2. A reduction in awareness of his or her surroundings (e.g., “being in a daze”);
3. Derealization;
4. Depersonalization;
5. Dissociative amnesia (i.e., inability to recall an important aspect of the trauma).

C. The traumatic event is persistently reexperienced in at least one of the following ways:
recurrent images, thoughts, dreams, illusions, flashback episodes or a sense of reliving
the experience or distress on exposure to reminders of the traumatic event.
D. Marked avoidance of stimuli that arouse recollections of the trauma (e.g., thoughts,
feelings, conversations, activities, places, people).

E. Marked symptoms of anxiety or increased arousal (e.g., difficulty sleeping, irritability,

poor concentration, hypervigilance, exaggerated startle response, motor restlessness).

F. The disturbance causes clinically significant distress or impairment in social,

occupational, or other important areas of functioning or impairs the individual’s ability
to pursue some necessary task, such as obtaining necessary assistance or mobilizing
personal resources by telling family members about the traumatic experience.
G. The disturbance lasts for a minimum of two days and a maximum of four weeks and
occurs within four weeks of the traumatic event.

Dissociation symptoms do not significantly to improve predictions made from other early
symptoms. Moreover, numerous trauma survivors who do not show dissociation symptoms
and who do not qualify for the diagnosis of ASD develop PTSD. For these reasons, ASD has
been criticized as being of little value.(56) Nevertheless, when it can be diagnosed, ASD signals
a very high likelihood (between 34% and 72%) of developing chronic PTSD.(57, 58)
Clinicians may wish to use this diagnostic category with great caution and, specifically,
not to exclude individuals without ASD, and who are otherwise distressed, from receiving
early treatment. Interestingly, ICD-10 defines an acute response to stress as starting at the time
of the traumatic events and lasting for up to two or three days. ICD-10 acute response differs,
therefore, from ASD in that it only pertains to the very early reaction—and is not properly a
“disorder”—but rather a reaction.

Acute PTSD and chronic PTSD

Another controversial matter is the subdivision of PTSD into acute (duration of symptoms
less than three months) and chronic (duration of symptoms exceeds three months) subtypes.
The two subtypes are identical, save for the duration and timing. The “chronic” condition is
8 Shalev

diagnosed after three months, which is truly exceptional in psychiatry, and medicine in gen-
eral. Many of those with acute PTSD (60% e.g., 40) may recover with or without treatment.
Most important, both conditions require similar therapies. Clinicians may wish to identify and
treat survivors with high levels of early PTSD symptoms, anxiety, or depression without pay-
ing much attention to the current subdivisions.

Delayed-onset PTSD
This condition consists of delayed appearance of PTSD more than six months after a traumatic
event. Such delayed appearance has been linked with seeking compensation and malingering.
Yet one sometimes encounters individuals who have been coping well with the consequences of a
traumatic event and who developed PTSD at a distance from the traumatic event, often as a result
of another event. A systematic study of 150 combat veterans with delayed PTSD (first referral to
treatment between six months and six years following trauma (59) has shown that 90% of these
individuals had been symptomatic prior to seeking help. Some 40% of the cases were identified
as “delayed referral,” that is, subjects who suffered without seeking help; 33% had subsyndromal
PTSD since the traumatic event, 13% had reactivated previously recovered PTSD, and 4% had
been given other psychiatric diagnoses before being identified as suffering from PTSD.
Thought to be an exception, new data on American veterans of the war in Iraq and
Afghanistan (e.g., (60)) show a paradoxical increase in the prevalence of PTSD during the year
that follows deployment. These findings may reflect a growing concern about going back to
combat zone among those who remain in the force, a progressive realization of how one’s reac-
tions were abnormal during deployment (i.e., while being on a survival mode of living) or an
increased saliency of symptoms in a context of nonmilitary life (e.g., troubles concentrating
and irritability may become very obvious when one has to go back to work—or play with one’s
children). It is also possible that the delayed expression of PTSD is more typical of survivors of
prolonged adversities (e.g., captivity, abuse) who fail to adjust to the highly competitive society
within which most of us live.

Trauma-induced personality changes

Survivors of Type 2 trauma may show a particularly severe form of PTSD, associated with pro-
found personality changes. The degree to which traumatic events can affect personality struc-
tures has been the subject of a heated debate, which ended by not including in the DSM-IV the
diagnostic category of “disorders of stress not otherwise specified” (DESNOS, DSM-IV draft
criteria, 1991). DESNOS was found to be consistently associated with PTSD, and therefore, was
not granted an independent status in DSM-IV. Interestingly, ICD-10 recognizes enduring per-
sonality changes resulting from exposure to “catastrophic stress” such as concentration camp
experiences, torture, or hostage situation. Traumatic personality changes must be present for at
least two years and include the following symptoms: permanent hostile or distressful attitude
toward the world, social withdrawal, feeling of emptiness, enduring feeling of being “on edge”
and estrangement (a permanent feeling of being changed or being different from others).
Clearly, the discussion of trauma-induced personality change is hampered by our cur-
rent view of mental disorders. Specifically, the boundary between “personality” and the very
chronic mental disorders is not well traced. Moreover, PTSD symptoms of pervasive avoidance,
irritability, increased stimulus response, and restriction to one’s life are very likely to be per-
ceived, by the patient and by the family, as involving permanent personality changes. Indeed,
one of the most frequent complaints of PTSD patients is “I am not the same.” Understandably,
childhood trauma, abuse, and neglect may lead to severe developmental difficulties, which
often present as personality disorders.

Conclusion

The uniqueness of PTSD among mental disorders is that this condition develops after salient
events, and therefore, can be detected at an early stage and, to some extent, prevented. Despite
its “political” origins and despite the admixture of various symptoms in this manmade syn-
drome, PTSD has proved to be robust, persistent, reliably diagnosable, and clearly linked with
Posttraumatic stress disorder 9

substantial distress and dysfunction. Indeed, similar constellations of symptoms have been
described in trauma survivors throughout history. Biologically, the disorder has been associ-
ated with consistent, converging, and replicable findings, particularly in the areas of startle
physiology and neuroendocrinology and some recent brainimaging studies. Several recent
treatment studies, including pharmacology and psychological therapies, are quickly reversing
a previous image of a hopeless condition. PTSD, therefore, is a story of success.
Yet PTSD is also a matter of debate, mainly because the disorder is used and abused in
compensation claims, in ideological debates (e.g., the false memory debate) and in introducing
some of the worse forms of therapies to the clinical arena. The main threat to the survival of
this condition is, therefore, its misuse and overextension to include any and all illnesses that
follow trauma. Intrinsic inconsistencies, however, do exist. First, the co-occurrence of PTSD
and depression is a major area for future research—particularly when the contribution of early
depression to chronic PTSD is considered. Second, the boundary with normal reactions to trau-
matic stress, particularly at the early aftermath of traumatic events, needs better definition.
Finally, the complex causation of chronic PTSD, and particularly the role of postevent factors
in maintaining the disorder, should make us rethink about the nature of the link between the
triggering traumatic event and the subsequent psychological, biological, and genomic events.
PTSD, therefore, faces an exciting future as subject of clinical and scientific investigation. PTSD
is also likely to be at the center of future debates concerning human nature, human resilience to
stress, and the role of culture in defining what is disordered and what is not.

References

  1. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th edition
(DSM-IV) (American Psychiatric Press: Washington, DC, 1994).
  2. Solomon Z, Combat Stress Reaction: The Enduring Toll of War (Plenum: New York, 1993).
  3. Eitinger L, Concentration Camp Survivors in Norway and Israel (Allen & Unwin: London, 1964).
  4. Shalev AY, Peri T, Canneti L, Schreiber S, Predictors of PTSD in recent trauma survivors: a prospective
study, Am J Psychiatry (1992) 153:219–25.
  5. King LA, King DW, Fairbank JA et al, Resilience and recovery factors in post-traumatic stress disorder
among female and male Vietnam veterans: hardiness, postwar social support, and additional stressful
life events, J Pers Soc Psychol (1998) 74:420–34
  6. Yehuda R, McFarlane AC, Conflict between current knowledge about posttraumatic stress disorder
and its original conceptual basis, Am J Psychiatry (1995) 152:1705–13.
  7. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 3rd edn
(DSM-III) (American Psychiatric Press: Washington, DC, 1980).
  8. North CS, Pfefferbaum B, Research on the Mental Health Effects of Terrorism JAMA. 2002;288:633-636.
  9. Galea S, Vlahov D, Resnick H, Ahern J, Susser E, Gold J, Bucuvalas M, Kilpatrick D. Trends of
probable post-traumatic stress disorder in New York City after the September 11 terrorist attacks. Am
J Epidemiol. 5:158:514-524, 2003
10. World Health Organization, The ICD 10 Classification of Mental and Behavioural Disorders:
Diagnostic Criteria for Research (WHO: Geneva, 1993).
11. Kardiner A, The Traumatic Neuroses of War (Hoeber: New York, 1941).
12. Pitman RK, Post-traumatic stress disorder, conditioning, and network theory, Psychiatric Annals,
18:182–9.
13. Janoff Bulman R, The aftermath of victimization: rebuilding shattered assumptions. In: Figley CR, ed,
Trauma and its Wake, the Study and Treatment of Post-traumatic Stress Disorder (Brunner-Mazel:
New York, 1985) 15–36.
14. Trimble MR. Posttraumatic Neurosis. From Railway Spine to the Whiplash. John Wiley: Chichester; 1981.
15. Merskey H. Shell shock. In: Berrios EG, Freedman H, eds. 150 years of British Psychiatry. Gaskell:
London; 1991.
16. Grinker RR, Spiegel JP. Men under stress. Backiston: Philadelphia; 1945.
17. Salmon TW. The care and treatment of mental diseases and war neuroses (‘shell shock’) in the British
Army. Ment Hyg 1917; 1: 509–47.
18. Jones E, Thomas A, Ironside S. Shell shock: an outcome study of a First World War ‘PIE’ unit. Psychol
Med 2007; 37: 215–23.
19. Rivers WHR. The repression of war experiences. Proc R Soc Med 1918; 11: 1–20.
20. Bloom SL. Our hearts and our hopes are turned to peace: origins of the International Society for
traumatic stress. In: Shalev AY, Yehuda R, McFarlane AC, eds. International Handbook of Human
Response to Trauma. Kluwer Academic/Plenum: New York, 2000: 27–50.
10 Shalev

21. Young A. An alternative history of traumatic stress. In: Shalev AY, Yehuda R, McFarlane AC, eds.
International Handbook of Human Response to Trauma. Kluwer Academic/Plenum: New York;
2000.
22. Keane TM. Symptomatology of Vietnam veterans with posttraumatic stress disorder. In: Davidson
JRT, Foa E, eds. Posttraumatic Stress Disorder: DSM IV and Beyond. American Psychiatric Press:
Washington, DC, 1993: 99–111.
23. Breslau N, Davis GC. Posttraumatic stress disorder: the etiologic specificity of wartime stressors. Am
J Psychiatry 1988; 144: 578–83.
24. Breslau N, Davis GC, Andreski P, Peterson E. Traumatic events and posttraumatic stress disorder in
an urban population of young adults. Arch Gen Psychiatry 1991; 48: 216–22.
25. Breslau N, Kessler RC, Chilcoat HD et al. Trauma and posttraumatic stress disorder in the community:
the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry 1998; 55: 626–32.
26. Perkonigg A, Kessler RC, Storz S, Wittchen HU. Traumatic events and posttraumatic stress disorder in
the community: prevalence, risk factors and comorbidity. Acta Psychiatr Scand 2000; 101(1): 46–59.
27. Creamer M, Burgess P, McFarlane AC. Posttraumatic stress disorder: findings from the Australian
National Survey of mental health and well-being. Psychol Med 2001; 31(7): 1237–47.
28. Resnick HS, Kilpatrick DG, Dansky BS et al. Prevalence of civilian trauma and posttraumatic stress
disorder in a representative national sample of women. J Consult Clin Psychol 1993; 61: 984–91.
29. Norris FH. Epidemiology of trauma: frequency and impact of different potentially traumatic events
on different demographic groups. J Consult Clin Psychol 1992; 60: 409–18.
30. Stein MB, Walker JR, Hazen AL, Forde DR. Full and partial posttraumatic stress disorder: findings
from a community survey. Am J Psychiatry 1997; 154: 1114–9.
31. Carlier IV, Lamberts RD, Fouwels AJ, Gersons BP. PTSD in relation to dissociation in traumatized
police officers. Am J Psychiatry 1996; 153: 1325–8.
32. Carlier IV, Gersons BPR. Partial posttraumatic stress disorder (PTSD): the issue of psychological scars
and the occurrence of PTSD symptoms. J Nerv Ment Dis 1995; 183: 107–9.
33. Marlowe DH. Psychological and psycho-social consequences of combat and deployment with special
emphasis on the Gulf War. Rand: Santa Monica, CA; in press.
34. Davidson JRT, Kudler HS, Smith RD. Assessment and pharmacotherapy of posttraumatic stress
disorder. In: Giller EL, ed. Biological Assessment and Treatment of Posttraumatic Stress Disorder.
American Psychiatric Press: Washington, DC, 1990; 203–21.
35. Fawzi MC, Pham T, Lin L et al. The validity of posttraumatic stress disorder among Vietnamese
refugees. J Trauma Stress 1997; 10: 101–8.
36. Kilpatrick DG, Resnick HS. Posttraumatic stress disorder associated with exposure to criminal
victimization in clinical and community populations. In: Davidson JRT, Foa E, eds. Posttraumatic
Stress Disorder: DSM IV and Beyond. American Psychiatric Press: Washington, DC, 1993; 113–43.
37. Niles BL, Newman E, Fisher LM. Obstacles to assessment of PTSD in longitudinal research. In: Shalev
AY, Yehuda R, McFarlane AC, eds. International Handbook of Human Response to Trauma. Kluwer
Academic/Plenum: New York, 2000; 213–22.
38. Rothbaum BO, Foa EB, Riggs DS, Murdock T, Walsh WA: prospective examination of post-traumatic
stress disorder in rape victims. J Traumatic Stress, 1992;5:455–75.
39. Shalev AY, Freedman S, Brandes D et al. Predicting PTSD in civilian trauma survivors: prospective
evaluation of self report and clinician administered instruments. Br J Psychiatry 1997; 170: 558–64.
40. Kessler RC, Sonnega A, Bromet EJ et al. Posttraumatic stress disorder in the National Comorbidity
Survey. Arch Gen Psychiatry 1995; 52: 1048–60.
41. Kulka RA, Schlenger WE, Fairbank JA et al. Trauma and the Vietnam War generation: report of
findings from the National Vietnam Veterans readjustment study. Brunner/Mazel: New York; 1990.
42. Dohrenwend BP, Turner JB, Turse NA et al. The psychological risks of Vietnam for U.S. veterans: a
revisit with new data and methods. Science 2006; 313(5789): 979–82.
43. Freedman SA, Peri T, Brandes D, Shalev AY. Predictors of chronic PTSD – a prospective study. Br J
Psychiatry 1999; 174: 353–9.
44. Shalev AY, Freedman S, Peri T et al. Prospective study of posttraumatic stress disorder and depression
following trauma. Am J Psychiatry 1998; 155: 630–7.
45. Shalev AY, Sahar T, Freedman S et al. A prospective study of heart rate responses following trauma
and the subsequent development of PTSD. Arch Gen Psychiatry 1998; 55: 553–9.
46. Brewin CR, Andrews B, Valentine JD. Meta-analysis of risk factors for posttraumatic stress disorder
in trauma-exposed adults. J Consult Clin Psychol 2000; 68(5): 748–66.
47. Ehlers A, Mayou RA, Bryant B. Psychological predictors of chronic posttraumatic stress disorder after
motor vehicle accidents. J Abnorm Psychol 1998; 107: 508–19.
48. Bryant RA, Harvey AG, Dang ST et al. Treatment of acute stress disorder: a comparison of
cognitivebehavioral therapy and supportive counseling. J Consult Clin Psychol 1998; 66: 862–6.
49. Bryant RA, Sackville T, Dang S et al. Treatment of acute stress disorder: an evaluation of cognitive
behavioral therapy and supportive counseling techniques. Am J Psychiatry 1999; 156: 1780–6.
Posttraumatic stress disorder 11

50. National Collaborating Centre for Mental Health. Posttraumatic stress disorder: the management
of PTSD in adults and children in primary and secondary care. London (UK): National Institute for
Clinical Excellence (NICE), 2005: 167.
51. Green BL, Grace MC, Lindy JD et al. Risk factors for PTSD and other diagnoses in a general sample
of Vietnam veterans. Am J Psychiatry 1990; 147: 729–33.
52. Engdahl BE, Speed N, Eberly RE, Schwartz J. Comorbidity of psychiatric disorders and personality
profiles of American World War II prisoners of war. J Nerv Ment Dis 1991; 179: 181–91.
53. McFarlane AC, Papay P. Multiple diagnoses in posttraumatic stress disorder in the victims of a natural
disaster. J Nerv Ment Dis 1992; 180: 498–504.
54. North CS, Smith EM, Spitznagel EL. Posttraumatic stress disorder in survivors of a mass shooting.
Am J Psychiatry 1994; 151: 82–8.
55. Bleich A, Koslowsky M, Dolev A, Lerer B. Posttraumatic stress disorder and depression. An analysis
of comorbidity. Br J Psychiatry 1997; 170: 479–82.
56. Marshall RD, Spitzer R, Liebowitz MR. Review and critique of the new DSM-IV diagnosis of acute
stress disorder. Am J Psychiatry 1999; 156: 1677–85.
57. Bryant RA. Early predictors of posttraumatic stress disorder. Biol Psychiatry 2003; 53(9): 789–95.
58. Harvey AG, Bryant RA. The relationship between acute stress disorder and posttraumatic stress
disorder: a prospective evaluation of motor vehicle accident survivors. J Consult Clin Psychol 1998;
66: 507–12.
59. Solomon Z, Kotler M, Shalev A, Lin R. Delayed posttraumatic stress disorders, Psychiatry 1989; 52:
428–36.
60. Milliken CS, Auchterlonie JL, Hoge CW. Longitudinal assessment of mental health problems among
active and reserve component soldiers returning from the Iraq war. JAMA 2007; 298(18): 2141–8.
 2 Epidemiology of traumatic events and
posttraumatic stress disorder
Tracie O Afifi, Gordon JG Asmundson, and Jitender Sareen

Epidemiology of Traumatic Events and Posttraumatic Stress Disorder

Many people experience traumatic events through their lifetime. After an exposure to a trau-
matic event, some individuals may develop posttraumatic stress disorder (PTSD). Studies
using community samples provide information on the epidemiology of traumatic events and
PTSD in the general population. Using the current literature primarily on general population
samples, this chapter reviews: (a) definitions of traumatic events, (b) methods of assessing
traumatic events and PTSD in epidemiologic studies, (c) epidemiologic studies on traumatic
events and PTSD, (d) epidemiology of traumatic events, (e) epidemiology of PTSD, and (f)
mental and physical health comorbidities of PTSD.

Definitions of Traumatic Events

The Diagnostic and Statistical Manual of Mental Disorders’ (DSM) first criterion for PTSD requires
that a person be exposed to a traumatic event. DSM-III and DSM-III-R criteria defined a trau-
matic event as an event outside the range of usual human experience and one that would
be distressing for almost anyone.(1, 2) The definition of what constitutes a traumatic event
was expanded in the DSM-IV criteria. According to the current DSM-IV diagnostic criteria
for PTSD, a traumatic event is an event that is experienced or witnessed and involves the
actual or threatened death, serious injury, or threat of physical integrity of oneself or others
and invokes a response of fear, helplessness, or horror.(3) Many different types of traumatic
events are included under the DSM-IV definition such as war-related events, natural disasters,
physical assault, sexual assault or violence, threats with weapons, serious accidents, illness,
and the unexpected death of loved ones. Many individuals will experience a traumatic event
or several events throughout their lifetime. Some people who are exposed to a traumatic event
will develop symptoms of PTSD and may meet criteria for a PTSD diagnosis.

Methods of Assessing Traumatic Events and PTSD in Epidemiologic

General Population Studies

Several epidemiologic studies on traumatic events and PTSD have been conducted using gen-
eral population samples. Most of these studies have used samples from the United States. The
first studies were conducted in the 1980s using DSM-III and later DSM-III-R criteria. In the
mid-1990s, studies using DSM-IV criteria began to be published. The prevalence of exposure to
traumatic events and PTSD reported in epidemiologic studies varies depending on the method
and criteria used for assessing traumatic events.(4)
With regard to method, earlier studies using DSM-III criteria inquire about traumatic
events using a single question, while studies using DSM-IV criteria provide respondents with
a list of qualifying traumatic events. The list method and the use of longer versus shorter lists
results in higher prevalence estimates of exposure to traumatic events and number of traumatic
events experienced compared to a single-question method.(4) In addition, the expansion of the
definition of traumatic events in the DSM-IV criteria indicates that studies using DSM-IV crite-
ria include a greater number of qualifying traumatic events compared to earlier studies using
DSM-III or DSM-III-R criteria, which also has an impact on the prevalence of traumatic event
exposure and PTSD.(4, 5)
Epidemiology of Traumatic Events and Posttraumatic Stress Disorder 13

Methods in studies also differ when respondents endorse experiencing more than one
traumatic event. When respondents have experienced multiple traumatic events, some studies
will require the respondent to identify the worst traumatic event, while other studies will use a
random method to select a traumatic event for assessing PTSD symptoms. Kessler et al. (1995)
stated that studies using the worst event method will likely overestimate the associations of
that event with PTSD, while using a random method to select an event may provide more
accurate information regarding a trauma.(6) Direct comparison of both methods has indicated
that prevalence of PTSD based on the worst event method and random event method was
13.6% and 9.2%, respectively.(7) However, further investigation determined that both methods
provided similar findings with regard to identifying sex differences and traumatic events with
the highest likelihood of PTSD.(8)
In addition, studies have also differed in the year in which data were collected, location of
data collection, ages of the respondents, interviewing methods (face-to-face versus telephone
interviewing), and the representativeness of the community samples. All these factors may
play a role in why variation in the prevalence estimates of traumatic events and PTSD has been
reported in different epidemiologic studies and may limit comparability of estimates in some
studies. Also, because most of the earlier studies were conducted in the United States, results
may not be generalizable to other countries.

Epidemiologic General Population Studies on

Traumatic Events and PTSD

Details of epidemiologic surveys that assess traumatic events and the prevalence of PTSD
using general population samples have been summarized in Table 2.1. The first two large-scale
epidemiologic surveys on PTSD using DSM-III criteria and general population samples were
conducted in the early 1980s with data from St. Louis using the Epidemiologic Catchment
Area (ECA) survey (9) and the Piedmont region of North Carolina (10). In 1989, Breslau
et al. (1991) conducted the first investigation of traumatic events and PTSD using DSM-III-R
criteria in a community sample of young adults from southeast Michigan.(11) Following this
study, DSM-III-R criteria were used to assess traumatic events and PTSD in a U.S. sample from
Southeastern cities (Charleston, Greenville, Charlotte, and Savannah) (12), a national sample of
young adult females (13), the first nationally representative sample of males and females using
the National Comorbidity Survey (NCS) (6), a community sample of mothers from southeast
Michigan (14), and a community sample from three cities in Chile using the Chile Psychiatric
Prevalence Study (CPPS) (15).
Following these studies, DSM-IV criteria was used to assess traumatic events and PTSD
in several samples including a community sample from Winnipeg, Canada (16); a community
sample from Lubeck, Germany (17); a community sample from Detroit (7); a national sample
from Australia (18); a sample of older adults from the Netherlands (19); a community sample
from Mexico (20); a national sample from Sweden (21); a national sample from the United
States (22, 23); and a European study including six countries (Belgium, France, Germany, Italy,
the Netherlands, and Spain).(24) Details of the prevalence of exposure to traumatic events and
PTSD from each study will now be discussed.

Epidemiology of Traumatic Events

Prevalence of Traumatic Events

Epidemiologic research has indicated that experiencing a traumatic event in the general
population is not a rare occurrence. The first general population sample assessing traumatic
events conducted in 1989 was from southeast Michigan using a sample of young adults.(11)
The data indicated that 39.1% (95% CI = 36.1% to 42.2%) of the respondents reported expe-
riencing at least one traumatic event in their lifetime. The most common traumatic events
reported were sudden injury or serious accident (9.4%), physical assault (8.3%), seeing some-
one seriously hurt or killed (7.1%), and news of the sudden death or injury of a close friend
or relative (5.7%).
 14

Table 2.1  Lifetime and current prevalence of PTSD in the general population (Posttraumatic Stress Disorder).

Dataset and/or place of collection Year of Data n (response Lifetime

(Authors) Type of Sample Collection rate) Age in years Diagnostic Tools Current prevalence % prevalence %
(ECA) USA (Helzer et al) (9) Community sample 1981–1982 2,493 (67%) Adult DIS/DSM-III N/A 1.0%
North Carolina, USA (Davidson et al) (10) Community sample N/A 2,985 (79%) 18–95 DIS/DSM-III six month 0.44% 1.3%
Michigan, USA (Breslau et al) (11) Communty sample 1989 1,007 (84%) 21–30 DIS/DSM-III-R N/A 9.2%
Southeastern cities, USA (Norris et al) (12) Community sample 1990 1,000 (71%) 18+ TSS based on DSM-III-R 5.1% N/A
  
USA (Resnick et al) (13) National sample 1989 4,008 + only 18–34 DIS/DSM-III-R six month 4.6% (+) 12.3% (+)
(N/A)
(NCS) USA (Kessler et al) (6) National sample 1990–1992 5,877 (82.4%) 15–54 DIS/CIDI/DSM-III-R N/A 7.8%

Michigan, USA (Breslau et al) (14) Community sample 1990–1992 801 mothers Mean 33.1 DIS/DSM-III-R N/A 13.8%(+)
(75%)
(CPPS) Chile (Zlotnick et al) (15) Community sample 1992–1999 2,390 (90.3%) 15+ DIS/DSM-III-R N/A 4.4%

Winnipeg, Canada (Stein et al) (16) Community sample 1994 1,002 (72%) Modified PTSD one month 2.7 (+) 1.2 () N/A
Symptom Scale/DSM-IV
Detroit, USA (Breslau et al) (7) Commuity sample 1996 2,181 (86.8%) 18–45 DIS/CIDI/DSM-IV N/A 9.2%a
Lubeck Germany (Hapke et al) (17) Community sample 1996–1997 4.075 18–64 M-CIDI/SDM-IV 12 month 0.7% 1.4%
(NSMHWB) Australia (Creamer et al) (18) National sample 1997 10,641 (78%) 18+ CIDI/DSM-IV 12 month 1.33% N/A
(LASA) Netherlands (van Zelst et al) (19) National sample 1998–1999 422 (N/A) 61–95 CIDI-DSM-IV six month 0.9% N/A
Mexico (Norris et al) (20) Community sample 1999–2001 2,509 (79%) 18–92 CIDI/DSM-IV N/A 11.2%
Sweden (Frans et al) (21) National sample N/A 1,824 (60.8%) 18–70 DSM-IV N/A 5.6%
(NCS-R) USA (Kessler et at 2005) (22, 23) National sample 2001–2003 5,692 (70.9%) 18+ WHM-CIDI/DSM-IV 12 month 3.5% 6.8%
(ESEMeD) Europe (24) National sample 2001–2003 21,425 (61.2%) 18+ WMH-CIDI/DSM-IV 12 month 0.9% 1.9%
a
Conditional probability of PTSD after exposure.
N/A = Not available.
Afifi, Asmundson, AND Sareen
Epidemiology of Traumatic Events and Posttraumatic Stress Disorder 15

Another community sample from the United States assessing 10 traumatic events indi-
cated that 21% (SE = 1.3%) and 69% (SE = 1.5%) of the total sample had experienced any past
year and lifetime traumatic event, respectively.(12) The most commonly experienced traumatic
events were tragic death, robbery, and car accident. In a representative sample of females from
the United States, 69% reported experiencing a lifetime traumatic event with 36% of females
experiencing any crime-related event (e.g., sexual assault, physical assault, homicide of friend,
or family member) and 33% of females experiencing a noncrime event (e.g., accident, natural
disaster, fear of death or injury, witnessing death or injury) only.(13)
Using the NCS, Kessler (1995) found that exposure to traumatic events were high in the
general U.S. population with 60.7% of males and 51.2% of females endorsing any lifetime trau-
matic event.(6) In a community sample of mothers from southeast Michigan, the prevalence of
one or more traumatic events was 40%.(14) The prevalence of traumatic events was similar in
the sample from Chile, with 39.7% of the sample reporting a traumatic experience.(15) A rep-
resentative community sample from Detroit found the prevalence of lifetime traumatic events
to be much higher, with 89.6% (SE = 0.8%) of the sample endorsing experiencing a lifetime
traumatic event.(7) The most commonly experienced event in this study was the sudden unex-
pected death of a relative or friend.
Data from the Winnipeg community sample also found that many individuals had been
exposed to a lifetime traumatic event, with 74.2% endorsement among females and 81.3%
endorsement among males.(16) The violent death of a friend or family member and being phys-
ically attacked were the two most common traumatic events among both males and females.
The prevalence of traumatic events were also prevalent in the national sample from Australia,
with 64.6% of males and 49.5% of females reporting at least one traumatic event.(18) In the
community sample from Mexico, 76% of the sample reported experiencing a lifetime traumatic
event.(20) These data also indicated that traumatic bereavement, witnessing someone killed or
injured, and life-threatening accident were the three most common traumatic events among
males and females. Similarly, 80.8% of the national sample from Sweden reported experiencing
at least one traumatic event.(21)

Prevalence of Multiple Traumatic Events

Research has indicated that exposure to more than one traumatic event is also common in
the general population. A study by Breslau et al. (1991) indicated that out of all the young
adults from the community sample who were exposed to a traumatic event, 67.3% expe-
rienced one traumatic event, 23.3% experienced two traumatic events, and 9.4% experi-
enced three traumatic events.(11) Among the representative sample of females experiencing
crime-related traumatic events (rape, sexual assault, physical assault, homicide of a family
member), 67.5% reported experiencing one event, 23.7% reported experiencing two differ-
ent crime events, 8.8% experienced three or more different crime events, and 41% of those
experiencing a crime event experiencing multiple incidents of the same event.(13) The NCS
data indicated that 34.2% of males and 24.9% of females experienced two or more lifetime
traumatic events.(6) Canadian data using DSM-IV criteria found an even higher prevalence
of multiple lifetime traumatic events reported among males and females (55.4% among
males and 45.8% among females).(16) Finally, Breslau et al. (1998) reported a mean number
of 4.8 (SE = 0.1) distinct events among those experiencing trauma in the community sample
from Detroit.(7)
When assessing the prevalence of one or more lifetime traumatic events reported in gen-
eral population samples, studies using DSM-IV criteria tended to report higher estimates. As
previously mentioned, DSM-IV criteria expanded the definition of traumatic events, increasing
the number of events qualifying as trauma. This may partly explain the increased prevalence
in traumatic events reported in more recent studies. Differences in year and location of data
collection and age range of the sample may also influence the prevalence of traumatic events
reported within a sample.

Sex Differences in Exposure to Traumatic Events

Research has generally found that males are more likely to experience lifetime traumatic
events compared to females.(6, 11, 12, 16, 21) However, some sex differences have been found
16 Afifi, Asmundson, AND Sareen

when investigating specific traumatic events among males and females. For example, Breslau
et al. (1991) found that the traumatic experience of rape was only reported among females.
(11) Norris et al. (1992) found that males were more likely than females to be physically
assaulted, be in a motor vehicle crash, and be exposed to combat, while females were more
likely than males to be sexually assaulted.(12) No other sex differences were detected in
this study with regard to lifetime exposure to robbery, fire, other disaster or hazard, and
tragic death. Kessler et al. (1995) reported numerous sex differences with regard to lifetime
prevalence of traumatic events.(6) More specifically, males relative to females were more
likely to experience physical attack, combat, threat with a weapon, life-threatening acci-
dent, natural disaster with fire, and witnessing someone badly injured or killed. However,
females were more likely to experience rape, molestation, child physical abuse, and child-
hood neglect relative to males. Breslau et al. (1998) found similar results using a com-
munity sample from Detroit, which indicated that males compared to females were more
likely to be mugged or threatened with a weapon, shot or stabbed, and badly beaten, while
females relative to males were more likely to experience rape and other sexual assault.(7)
In the community sample from Germany, females were more likely to experience rape and
sexual abuse than were males, but when considering lifetime prevalence of any traumatic
event, gender differences were not found.(17) In the national sample from Australia, males
were significantly more likely to experience being physically attacked, threatened with a
weapon, and to be exposed to combat, while females were more likely to be exposed to
rape and sexual molestation.(18) Sex differences were also noted in the community sample
from Mexico, with males being more likely to experience traumatic bereavement, witness-
ing someone killed or injured, life-threatening accident, physical assault, being threatened
with a weapon, combat, and torture or terrorism, while females were more likely to experi-
ence sexual assault.(20)
The most consistent findings among all general population studies of traumatic events
with regard to sex differences is that females are more likely to experience sexual traumatiza-
tion involving sexual assault, rape, or molestation, while males are more likely to experience
combat and assaultive violence such as physical attacks and threats with a weapon. However,
comparing sex differences across studies is challenging because not all studies include the same
qualification for traumatic events.

Risk Factors for Traumatic Events

Some studies using general population samples have identified certain factors that increase
the risk for experiencing a traumatic event. In addition to sex being a risk factor for certain
traumatic events, as discussed above, other risk factors have been identified in the literature.
Norris et al. (1992) found race differences, with White respondents being significantly more
likely than Black respondents to experience lifetime traumatic events in a community sample
of Southeastern United States cities.(12) Contrary to this finding, Breslau et al. (1998) found in
a community sample from Detroit that being non-White was associated with increased odds of
assaultive violence and trauma to others compared to being White.(7) This research also indi-
cated that lower educational attainment and household income was associated with increased
odds of assaultive violence.
Among young adults from southeast Michigan, risk factors for exposure to traumatic
events included being male, having less than a college education, a history of three or more
early conduct problems, a family history or psychiatric problems, neuroticism, and extraver-
sion.(11) These young adults were reinterviewed three years later, and results revealed that
neuroticism and extraversion remained prospective predictors of exposure to traumatic events.
(25) Another prospective study from southeast Michigan that assessed externalizing problems,
anxiety, and intelligence at age six and exposure to traumatic events at age 17 found that high
externalizing problems increased the odds of exposure to assaultive violence, while IQ above
115 lowered the odds of exposure to assaultive and other types of trauma.(26) Only a few stud-
ies have assessed risk factors for traumatic events. However, results from these studies indicate
that such events are not random occurrences.(4) In fact, research using twin pairs from the gen-
eral population found that genetically based personality factors may increase the likelihood of
experiencing certain traumatic events.(27) More specifically, it was found that antisocial per-
sonality traits predicted exposure to violent assaultive traumatic events.
Epidemiology of Traumatic Events and Posttraumatic Stress Disorder 17

Epidemiology of Posttraumatic Stress Disorder

Prevalence of PTSD
Table 2.1 provides a summary of the lifetime and current (past one month, six months, 12 months)
prevalence rates of PTSD based on several general population samples. As previously mentioned,
differences in PTSD prevalence estimates reported in general population samples may be due to
the method and diagnostic criteria for assessing traumatic events and PTSD symptoms and dif-
ferences in study samples, including year and location of data collection, age of respondents, and
interviewing methods. Regardless of study differences, epidemiologic investigations are able to
provide estimates of how prevalent PTSD is in the general population.
The two earliest studies of PTSD conducted in the early 1980s using general population
samples and DSM-III criteria provided similar estimates of the prevalence of lifetime PTSD.
The first study using ECA data indicated that only 1% of the total sample met full DSM-III
criteria for a lifetime PTSD diagnosis.(9) However, 15% of males and 16% of females had a least
one PTSD symptom after experiencing a traumatic event. Similarly, data from a community
sample from North Carolina reported that 1.3% of the sample met DSM-III criteria for lifetime
PTSD.(10)
Later general population samples using DSM-III-R criteria produced larger prevalence
estimates for PTSD. The Breslau study (1991), using a sample of young adults from Michigan,
found that 9.2% (95% CI = 7.6% to 11.2%) of the total sample met criteria for lifetime PTSD.(11)
However, 23.6% of individuals exposed to traumatic events developed PTSD. Similarly, the
community sample from four Southeast United States cities found that 5.1% of the sample met
criteria for current PTSD.(12) In a national U.S. sample of females only, the lifetime and past
six-month prevalence of PTSD was 12.3% and 4.6%, respectively.(13) Similarly, results from a
community sample of mothers from southeast Michigan found the prevalence of lifetime PTSD
to be 13.8%.(14) The results from a national U.S. sample of males and females using NCS data
estimated lifetime prevalence of PTSD to be 7.8% (SE = 0.5%).(6) The prevalence of lifetime
PTSD in the representative sample from Chile was 4.4% (SE = 0.5%), slightly lower than figures
from the United States.(15)
Studies using general population samples and DSM-IV criteria also found higher PTSD
prevalence estimates. A Canadian study by Stein et al. found that 2.7% of females and 1.2% of
males met DSM-IV criteria for a past month diagnosis of PTSD.(16) The study also indicated
that an additional 3.4% of females and 0.3% of males had a past month subthreshold PTSD
diagnosis. Subthreshold or partial PTSD has been defined in different ways, but generally
speaking, it is applicable only when an individual lacks one or more specified criteria required
to meet the full DSM diagnosis. Breslau et al. (1998) reported the conditional probability of
PTSD after traumatic event exposure to be 9.2% in a community sample from Detroit.(7) The
community sample from Germany indicated that lifetime, past year, and conditional probabil-
ity of PTSD was 1.4% (SE = 0.18), 0.7% (SE = 0.13%), and 6.9% (SE = 0.89), respectively (17). The
national sample from Australia reported that 1.3% (SE = 0.12%) of the sample met criteria for
past 12-month diagnosis of PTSD.(18) A representative sample from the Netherlands reported
that 0.9% (95% CI = 0.7–1.1) of the older adult sample met criteria for a past six-month PTSD
diagnosis, while 13.1% (95% CI = 12.7–13.6) met criteria for subthreshold PTSD.(19) The preva-
lence of lifetime PTSD was 11.2% (SE = 0.6) in the community sample from Mexico.(20) Results
from the National Comorbidity Survey Replication (NCS-R), a nationally representative study
from the United States, indicated that past year and lifetime prevalence of PTSD was 3.5% (SE =
0.3%) and 6.8% (SE =0.4%), respectively.(22, 23) Findings from the study of six European coun-
tries reported a much lower prevalence of lifetime PTSD of only 1.9% (95% CI = 1.7–2.1).(24)
Collectively, studies dated from the early 1980s to the present indicate that the lifetime
prevalence of PTSD in general population samples of males and females ranges from 1% to 11%.
Factors decreasing comparability of studies, such as selected DSM criteria and study methods,
have already been mentioned. However, it should be noted that the large range of PTSD preva-
lence estimates may be partly explained by the studies being conducted in different cities and
in different countries. The prevalence of traumatic events, and thereby PTSD, may depend on
crime, poverty, politics, violence and other factors, which differ in different parts of the world.
For example, Zlonick et al. (2006) speculate that differences in the prevalence of PTSD found in
Mexico and Chile may in part be due to greater crime and poverty rates in Mexico compared to
18 Afifi, Asmundson, AND Sareen

Chile.(15) Regardless of the range in PTSD prevalence reported in general population samples,
findings from these epidemiologic studies have determined that PTSD is prevalent in the gen-
eral population and is considered an important public health concern.

Duration of PTSD Symptoms

PTSD has been found to be a chronic condition for many individuals. A standard definition of
PTSD chronicity does not exist in the research literature. However, many studies require that the
duration of PTSD symptoms must last at least six months to be considered a chronic case. ECA
data have indicated that, among individuals with PTSD symptoms, symptoms lasted less than six
months for 49% of individuals, but persisted for more than six years for one-third of symptom-
atic persons.(9) These data also indicated that long duration of symptoms occurred for males who
experienced combat and for females who were physically attacked. In the community sample from
North Carolina, approximately 50% of individuals with PTSD were considered to be chronic cases
as measured by symptoms lasting more than six months.(10) In the sample of young adults from
Detroit, 57% of those with PTSD had symptoms lasting for more than one year.(28) These data also
indicated that a family history of antisocial behavior and female sex were specific risk factors for
chronic PTSD. The nationally representative NCS data also found that PTSD is chronic, with one-
third of individuals not recovering from their symptoms even after many years and regardless of
treatment.(6) Breslau et al. (1998) found that 26% and 40% individuals with PTSD remitted after
six months and 12 months, respectively.(7) These data also indicated that duration of symptoms
lasted longer in females (median duration 48.1 months) compared to males (median duration 12.0
months). The community sample from Mexico indicated that 62% of those with PTSD had symp-
toms lasting longer than one year and were considered chronic PTSD cases.(20)
Results from a prospective longitudinal study of adolescents and young adults (aged
14–24 years) indicated that 48% of individuals with full or subthreshold PTSD at baseline con-
tinued to experience full or subthreshold PTSD during the two follow-up periods (approxi-
mately 20 and 42 months after baseline) and were classified as chronic PTSD cases.(29) Also, the
experience of new traumatic events after the baseline assessment, higher avoidant symptoms,
more help seeking, and lower self-competence were predictors of chronic PTSD in this sample.
In another study investigating predictors of chronic PTSD in the sample recruited from an
emergency room, depressive symptoms measured at one week, one month, and four months
after the traumatic event were the best predictors of chronicity.(30) Furthermore, a study of
monozygotic veteran pairs indicated that 15 years after the Vietnam War, the prevalence of
PTSD among the twin pair serving in the military in Southeast Asia remained substantially
increased compared to the nonserving twin pair.(31)

Sex Differences in Prevalence of PTSD

Epidemiologic investigations of PTSD have indicated that females are more likely than males
to develop PTSD after the exposure to a traumatic event.(6, 7, 9–11, 15, 16, 19, 20). More spe-
cifically, several studies report that PTSD is approximately twice as prevalent among females
compared to males.(6, 7, 11, 15, 16, 20) Breslau et al. (1997) examined sex differences of PTSD in
detail using the southeast Michigan community sample of young adults and found that males
and females did not differ on the cumulative incidence of traumatic events or the number of
traumatic exposures, yet females were two times more likely to experience PTSD after a trau-
matic event.(32) The risk factors that partially explained the sex differences in these data were
preexisting anxiety disorders or major depressive disorders and greater exposure to traumatic
events in childhood. Another study using a representative sample from Detroit of adults aged
18 to 45 years indicated that sex differences were primarily due to females’ risk of PTSD fol-
lowing exposure to assaultive violence (36%), compared to males (6%).(33, 34) These data also
indicated that assaultive trauma was associated with increased risk of PTSD following a later
traumatic event.(35) This trauma sensitization hypothesis finding was replicated in another
community sample of young adults from a mid-Atlantic U.S. city, indicating that when assault-
ive violence preceded a subsequent nonassaultive traumatic event the risk for PTSD increased
significantly among females (relative risk = 4.9, 95% CI =2.1–11.11), but not among males (rel-
ative risk = 1.6, 95% CI = 0.9–3.0).(36) The data from the Canadian sample from Winnipeg
showed that females did not experience a greater number of traumatic events compared to
Epidemiology of Traumatic Events and Posttraumatic Stress Disorder 19

males; however, females were more likely to experience full or subthreshold PTSD after expe-
riencing any trauma and nonsexual assaultive violence.(37)
It is noteworthy that sex differences have not been found in all epidemiological studies.
Results from the national sample in Australia indicated that the past 12-month prevalence of
PTSD among males and females was similar (1.2% versus 1.4%).(18) Also, data from the com-
munity sample from Germany indicated that the female gender was not an independent risk
factor for PTSD.(17) The authors suggest that the increased risk of PTSD among females may
be due to their greater likelihood of experiencing trauma events most associated with PTSD
(i.e., rape and sexual abuse) and having preexisting disorders associated with increased risk of
PTSD, compared to males. Generally speaking, however, females do not have a greater vulner-
ability to PTSD.
A review of 25 years of research does confirm the increased likelihood of females devel-
oping PTSD, compared to males, but indicates that females’ higher prevalence of PTSD is not
solely a result of higher exposure to sexual trauma.(38) The current literature seems to indi-
cate that the type of traumatic events, preexisting psychiatric disorders, and childhood events
may also account for some of the variance in the relationship between sex and PTSD. Further
research in this area is warranted.

Traumatic Events Exposure and PTSD

The prevalence of PTSD has been found to vary depending on the type of traumatic event experi-
enced. Also, males and females experience specific traumatic events at different rates, which has
an impact on the relationship between traumatic event exposure and the development of PTSD.
In the early study by Helzer et al. (1987), the only two experiences associated with PTSD among
males were combat and seeing someone hurt or die, while a serious accident, physical attack,
seeing someone hurt or die, and threat or close call were associated with PTSD among females.
(9) Of these traumatic events, PTSD was the most common among females who were physically
attacked. These data also indicated that experiencing a natural disaster did not account for any
of the PTSD cases among males or females. In the general sample of young adults from south-
east Michigan, the lowest rate of PTSD was associated with sudden injury or serious accident
(11.6%) and was significantly greater for threat of death (24.0%), seeing someone killed or seri-
ously hurt (23.6%), physical assault (22.6%), and news of sudden death or accident of a close
relative or friend (21.1%).(11) These data also indicated that 80% of females reporting rape (rape
only reported among females) met criteria for PTSD. Kessler et al. (1995) found that the trau-
matic events most commonly associated with PTSD among males were combat exposure (28.8%)
and witnessing someone badly injured or killed (24.3%), while rape (29.9%) and sexual molesta-
tion (19.1%) were the most common traumatic events associated with PTSD among females.(6)
However, this study also indicated that rape had the highest conditional probability associated
with PTSD for both males and females, with 65% of males and 46% of females meeting criteria
for PTSD when reporting rape as the most upsetting traumatic event. In the national U.S. sample
of females, the prevalence of PTSD was the highest among those reporting physical assault and
rape.(13) In the national Australian sample, sexual trauma (rape and molestation) was associated
with the greatest likelihood of developing PTSD among both males and females.(39)
Not all studies investigate the relationship between exposure to traumatic events and
prevalence of PTSD separately for males and females. In a combined sample of males and
females, Norris et al. (1992) found that the types of traumatic events with the highest asso-
ciation with PTSD were sexual assault (14%), physical assault (13%), and motor vehicle crash
(12%).(12) Breslau et al. (1998) found that 31% of all PTSD cases were attributable to the single
traumatic event of an unexpected death of a loved one, while collectively the traumatic event
category of assaultive violence accounted for 39.5% of PTSD cases.(7) When looking at the
combined male and female community sample from Mexico, sexual assault or molestation was
the most highly associated traumatic event with PTSD.(20) In a representative sample of active
Canadian military personnel (n = 8,441, age = 16 to 54 years), exposure to combat (adjusted odds
ratios = 2.10, 95% CI = 1.28–3.45), and witnessing atrocities or massacres (adjusted odds ratios
= 4.33, 95% CI = 2.79–6.72) were associated with increased odds of past year (DSM-IV) PTSD
(relative to no past year mental disorder) after adjusting for sex, age, marital status, income,
education, military rank, type of force, and other deployment-related traumatic events.(40)
20 Afifi, Asmundson, AND Sareen

Research has identified numerous traumatic events that are highly associated with
increased prevalence of PTSD. Arguably, the most consistent finding in the literature on expo-
sure to traumatic events and PTSD is the relationship between sexual violence leading to PTSD
among females and combat exposure leading to PTSD among males.

Risk Factors for PTSD

As previously mentioned, female sex is associated with a greater risk of PTSD. In addition,
research has identified other important risk factors that increase the likelihood of PTSD after the
exposure to a traumatic event. Childhood behavior problems (i.e., lying, vandalism, fighting)
before the age of 15 have been found to be associated with PTSD, which may reflect a greater like-
lihood of exposure to traumatic events and/or a predisposition to experiencing symptoms after
the trauma.(9) Other childhood and family factors were identified in another community sample,
which indicated that individuals with PTSD were more likely to have experienced childhood pov-
erty, family history of psychiatric illness, parental divorce or separation before the age of 10, and
child abuse.(10) A study using the NCS found that, after adjusting for individual type of trauma,
only a history of affective disorders among females and a history of anxiety disorders and paren-
tal mental disorder among males predicted PTSD.(41) In a study of young adults, PTSD was asso-
ciated with neuroticism, separation from parents in childhood, preexisting psychiatric anxiety
or depression, and a family history of anxiety or antisocial behavior.(11) Similarly, in a study of
older adults (61 years to 95 years), neuroticism and early adverse childhood events were found
to be risk factors for PTSD.(19) In a nationally representative U.S. sample using NCS data, neu-
roticism was found to be significantly associated with PTSD among females, while neuroticism
and self-criticism were associated with PTSD among males after adjusting for specific traumatic
events, lifetime anxiety disorders, and parental mental disorders.(42) Interestingly, in a prospec-
tive study from southeast Michigan, externalizing problems and anxiety at age six increased the
odds of PTSD following an exposure to a traumatic event at age 17, while IQ of greater than 115
at age six decreased the odds of PTSD.(26) Similarly, a longitudinal study using a New Zealand
birth cohort found that children’s externalizing disorders, family history of mental health diffi-
culties, family adversities, low IQ, and chronic environmental stressors assessed before the age of
11 were risk factors for PTSD up to the age of 32.(43) Similar results from a U.S. sample indicated
that high levels of depressed and anxious feelings reported in Grade 1 were associated with 1.5
times increased risk of developing PTSD after a traumatic event in early adulthood.(44)
A meta-analysis of 77 studies published between 1980 and 2000 identified 14 risk factors
for PTSD.(45) More specifically, the results of the meta-analysis collectively indicate that psy-
chiatric history, reported child abuse, and family psychiatric history are the most uniform risk
factors for predicting PTSD regardless of the study population and methods.

Mental and Physical Health Comorbidities of PTSD

Mental Health
Comorbidity of other psychiatric disorders is common among individuals with PTSD. Helzer
et al. (1987) found that individuals with PTSD were twice as likely to have a comorbid psy-
chiatric disorder, with obsessive-compulsive disorder (OCD), dysthymia, and manic-depres-
sive disorder being the most prevalent comorbid diagnoses.(9) Davidson et al. (1991) found
that when compared to individuals without PTSD individuals with PTSD were more likely to
have somatization disorder, schizophrenia, panic disorder, social phobia, OCD, drug abuse or
dependence, major depression, agoraphobia, simple phobia, and generalized anxiety disorder
(GAD).(10) Breslau et al. (1991) found in the general population sample of young adults that
82.8% of those with PTSD had one or more comorbid psychiatric disorders, including OCD,
agoraphobia, dysthymia, mania, panic, major depression, GAD, drug abuse or dependence,
and alcohol abuse or dependence.(11) Similarly, results from the NCS indicated that 88.3% of
males and 79% of females with PTSD had at least one other comorbid psychiatric diagnosis.
(6) The prevalence of comorbid lifetime mental disorders was equally as high in the Chilean
sample with 90.4% of individuals with PTSD reporting a comorbid mental health disorder.(15)
Results from the national Australian sample also found comorbidity of PTSD and other Axis I
disorder to be prevalent, with 85.2% of males and 79.7% of females with PTSD meeting criteria
Epidemiology of Traumatic Events and Posttraumatic Stress Disorder 21

for at least one other Axis I disorder.(18) Another study using the same data found that 34.4% of
individuals with PTSD also met criteria for a substance use disorder.(46) In a nationally repre-
sentative Canadian sample, PTSD (assessed using a single item asking whether the respondent
had been given a diagnosis of PTSD from a health care professional) was associated with major
depression, mania, panic attacks, agoraphobia, social phobia, alcohol dependence, and drug
dependence.(47) These data indicated that major depression was the comorbid disorder with
the largest effects.
Many PTSD studies do not assess order of onset of psychiatric disorders, either due to the
cross-sectional design of the study or the lack of data on age of onset of each disorder. However, in
a sample of mothers from southeast Michigan, it was determined that PTSD increased the risk of
first onset major depression and alcohol abuse/dependence and that preexisting major depression
increased the risk of experiencing trauma and vulnerability to PTSD following traumatic events.(14)
In addition, a survival analysis using NCS data indicated that individuals with a current diagnosis
of PTSD were more likely to develop secondary other anxiety, mood, and substance use disorder
compared to those without PTSD.(48) This increased risk was not found when PTSD was in remis-
sion. A review of the comorbidity literature indicates that PTSD may have a causal role in the onset
of some secondary psychiatric diagnoses, while preexisting psychiatric disorders may also increase
vulnerability of PTSD after exposure to a traumatic event.(49) Prospective studies on the PTSD and
comorbidity are necessary to further understand the temporal sequence of disorder onset and the
causal relationship among commonly comorbid psychiatric disorders.

Suicidal Behavior
Research has found a significant relationship between PTSD and suicidal ideation and attempts
using general population samples. An earlier study found that individuals with PTSD were
14.9 times (95% CI = 5.10–43.66) more likely to attempt suicide compared to individuals with-
out PTSD.(10) The odds ratios were attenuated when comorbidity of major depression was
controlled, yet the relationship between PTSD and suicide attempts remained statistically sig-
nificant (Adjusted odds ratio = 8.2, 95% CI = 5.49–12.21). Results from the NCS indicated that
PTSD was associated with increased odds of subsequent suicidal ideation (odds ratio = 5.1,
95% CI = 3.9–6.8) and suicide attempts (odd ratio = 6.0, 95% CI = 3.4–10.7) after controlling for
person–year and sociodemographic variables.(50) In another investigation of females using the
NCS data, PTSD was associated with 2.5 times greater odds of suicidal ideation after adjusting
for the effects of sociodemographic variables, sexual assault history, psychosocial characteris-
tics, alcohol symptoms, and depression.(51) Using a national Canadian sample, those with cur-
rent self-reported, physician-diagnosed PTSD were 2.35 times more likely to have attempted
suicide in the past year, even after controlling for sociodemographic variables, numerous
psychiatric disorders, and medical morbidity.(47) The current body of literature supports the
relationship between PTSD and increased likelihood of suicidal ideation and attempts, which
highlights the possible utility of screening those with PTSD for suicidal behavior.

Physical Health Conditions

PTSD has been found to have significant associations with physical health conditions. An early
community study found that individuals with PTSD compared to those without PTSD were
more likely to have bronchial asthma (13.5% versus 4.8%, p = 0.02), peptic ulcer (12.8% versus
4.1%, p = 0.02), and hypertension (31.4% versus 18.5%, p = 0.04).(10) These data did not reveal
any other significant relationships between PTSD and other physical health conditions assessed
(emphysema, diabetes, heart disease, arthritis, cerebrovascular disease, cancer, arteriosclerosis,
and neurological disorder). Chronic PTSD, defined as symptoms lasting at least one year, has
also been found to be associated with an increased likelihood of arthritis, bronchitis, migraine,
and gynecologic problems (among females) compared to nonchronic PTSD.(28) In a prospec-
tive study, it was found that PTSD at baseline was associated with more gastrointestinal, car-
diopulmonary, conversion or pseudoneurological, and sexual symptoms.(52) In addition, these
data indicated that those with PTSD reported more somatic symptoms compared to individu-
als with other psychiatric disorders. In a nationally representative sample using NCS data,
it was found that among anxiety disorders, PTSD had the strongest associations with physi-
cal disorders, including neurological conditions, vascular conditions, gastrointestinal disease,
22 Afifi, Asmundson, AND Sareen

metabolic/autoimmune conditions, and bone and joint conditions, after adjusting for socio-
demographic variables, major depression, dysthymia, bipolar disorder, alcohol use disorder,
substance use disorder, and other anxiety disorders.(53) Another study using NCS data found
that individuals with PTSD were more likely to report having a physical condition after adjust-
ing for sex, health perceptions, stress, health-related behaviors, insurance coverage, number
of trauma exposures, number of psychiatric disorders, and neuroticism.(54) In a national
Canadian sample, individuals with current self-reported, physician-diagnosed PTSD were
more likely to have a higher prevalence of all physical health problems assessed in the survey
compared to those reporting no PTSD diagnosis.(47) These data also indicated that PTSD was
associated with increased odds of respiratory diseases, cardiovascular diseases, chronic pain
conditions, gastrointestinal illnesses, cancer, chronic fatigue syndrome, and multiple chemical
sensitivities after adjusting for sociodemographic variables and psychiatric disorders. Research
has also indicated that PTSD commonly co-occurs with chronic pain, which may be due to
factors that predispose individuals to both conditions (shared vulnerability) and/or aspects of
chronic pain maintaining or complicating PTSD and vise versa (mutual maintenance).(55)
The relationship between PTSD and physical health has also been reported in military sam-
ples. In an American sample of Iraq war veterans, numerous physical health symptoms (i.e., pain
symptoms, dizziness, fainting, indigestion problems) were found to be more prevalent among
those with PTSD compared to those without PTSD one year after serving in Iraq.(56) In a sample
of female veterans, medical conditions were more prevalent in females with a history of PTSD
compared to females with depression or females reporting neither depression nor PTSD.(57)
Similarly, in a Canadian sample of male veterans, PTSD symptoms directly influenced diagnos-
able physical symptoms when controlling for the effects of depression and alcohol dependence
and indirectly influenced physical health symptoms through depression only.(58) In a popula-
tion-based survey of Gulf War veterans, those who screened positive for a PTSD diagnosis were
more likely to have more self-reported physical health symptoms and medical conditions com-
pared to those without PTSD.(59) More information on PTSD and the military can be found in a
later chapter of this book. Using several general population and military samples, research has
confirmed that a significantly association between PTSD and physical health problems exists.

Conclusions

Traumatic events and PTSD are prevalent in the general population. Research has identified
certain factors that increase the risk of exposure to traumatic events and vulnerability to PTSD.
PTSD is an important public health problem not only due to the high prevalence found in the
general population but also because of its morbidity and the significant relationships found
between PTSD and other psychiatric disorders, suicidal behavior, and physical health prob-
lems. Knowledge of the epidemiology of traumatic events and PTSD will help inform preven-
tion efforts and increased ability to screen for PTSD and its associated conditions in populations
that have been exposed to its known risk factors.

References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed.
Washington, DC: American Psychiatric Press, Inc; 1980.
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed.
Washington, DC: American Psychiatric Press, Inc; 1987.
  3. American Psychiatric Association. Diagnostic & Statistical Manual for Mental Disorders (DSM). 4th
ed. Washington, DC: American Psychiatric Press, Inc; 1994.
  4. Breslau N. Epidemiological studies of trauma, posttraumatic stress disorder, and other psychiatric
disorders. Can J Psychiatry 2002; 47: 923–9.
  5. Breslau N, Kessler RC. The stressor criterion in DSM-IV posttraumatic stress disorder: An empirical
investigation. Biol Psychiatry 2001; 50: 699–704.
  6. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the national
comorbidity survey. Arch Gen Psychiatry 1995; 52: 1048–60.
  7. Breslau N, Kessler RC, Chilcoat HD et al. Trauma and posttraumatic stress disorder in the community:
the 1996 Detroit area survey of trauma. Arch Gen Psychiatry 1998; 55: 626–32.
Epidemiology of Traumatic Events and Posttraumatic Stress Disorder 23

  8. Breslau N, Peterson EL, Poission M, Schultz LR, Lucia VC. Estimating post-traumatic stress disorder
in the community: lifetime perspective and the impact of typical traumatic events. Psychol Med 2004;
34: 889–98.
  9. Helzer J, Robins L, McEvoy L. Post-traumatic stress disorder in the general population: findings of
the epidemiologic catchment area survey. N Engl J Med 1987; 317: 1630–4.
10. Davidson JRT, Hughes D, Blazer D, George LK. Posttraumatic stress disorder in the community: an
epidemiological study. Psychol Med 1991; 21: 1–19.
11. Breslau N, Davis GC, Andreski P, Peterson EL. Traumatic events and posttraumatic stress disorder in
an urban population of young adults. Arch Gen Psychiatry 1991; 48: 216–22.
12. Norris FH. Epidemiology of trauma: Frequency and impact of different potentially traumatic events
on different demographic groups. J Consult Clin Psychol 1992; 60: 409–18.
13. Resnick HS, Kilpatrick DG, Dansky BS, Saunders BE, Best CL. Prevalence of civilian trauma and
posttraumatic stress disorder in a representative national sample of women. J Consult Clin Psychol
1993; 61: 984–91.
14. Breslau N, Davis GC, Peterson EL, Schultz L. Psychiatric sequelae of posttraumatic stress disorder in
women. Arch Gen Psychiatry 1997; 54: 81–7.
15. Zlotnick C, Johnson J, Kohn R et al. Epidemiology of trauma, post-traumatic stress disorder (PTSD)
and co-morbid disorders in Chile. Psychol Med 2006; 36: 1523–33.
16. Stein MB, Walker JR, Hazen AL, Forde DR. Full and partial posttraumatic stress disorder: findings
from a community survey. Am J Psychiatry 1997; 154: 1114–9.
17. Hapke U, Schumann A, Rumpf H-J, John U, Meyer C. Post-traumatic stress disorder: the role of trauma,
pre-existing psychitric disorders, and gender. Eur Arch Psychiatry Clin Neurosci 2006; 256: 299–306.
18. Creamer M, Burgess P, Mcfarlane AC. Post-traumatic stress disorder: findings from the Australian
national survey of mental health and well-being. Psychol Med 2001; 31: 1237–47.
19. Van Zelst W, De Beurs E, Beekman ATF, Deeg DJH, Van Dyck R. Prevalence and risk factors of
posttraumatic stress disorder in older adults. Psychother Psychosom 2003; 72: 333–42.
20. Norris FH, Murphy AD, Baker CK et al. Epidemiology of trauma and posttraumatic stress disorder
in Mexico. J Abnorm Psychol 2003; 112: 646–56.
21. Frans O, Rimmo PA, Aberg L, Fredrikson M. Trauma exposure and post-traumatic stress disorder in
the general population. Acta Psychiatr Scand 2005; 111: 291–9.
22. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-
IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry 2005; 62: 617–27.
23. Kessler RC, Berglund P, Demler O, Jin R, Walters EE. Lifetime prevalence and age-of-onset distributions
of DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry 2005; 62:
593–602.
24. Alonso J, Angermeyer MC, Bernert S et al. Prevalence of mental disorders in Europe: results from the
European study of the epidemiology of mental disorders (ESEMeD) project. Acta Psychiatr Scand
Suppl 2004; (420): 21–7.
25. Breslau N, Davis GC, Andreski P. Risk factors for PTSD-related traumatic events: a prospective study.
Am J Psychiatry 1995; 152: 529–35.
26. Breslau N, Lucia VC, Alvarado GF. Intelligence and other predisposing factors in exposure to trauma
and posttraumatic stress disorder. Arch Gen Psychiatry 2006; 63: 1238–45.
27. Jang KL, Stein MB, Taylor S, Asmundson GJG, Livesley WJ. Exposure to traumatic events and
experiences: aetiological relationships with personality function. Psychiatry Res 2003; 120: 61–9.
28. Breslau N, Davis GC. Posttraumatic stress disorder in an urban population of young adults: risk
factors for chronicity. Am J Psychiatry 1992; 149: 671–5.
29. Perkonigg A, Pfister H, Stein MB et al. Longitudinal course of posttraumatic stress disorder and
posttraumatic stress disorder symptoms in a community sample of adolescents and young adults.
Am J Psychiatry 2005; 162: 1320–7.
30. Freedman SA, Brandes D, Peri T, Shalev A. Predictors of chronic post-traumatic stress disorder. Br J
Psychiatry 1999; 174: 353–9.
31. Goldberg J, True WR, Eisen SA, Henderson WG. A twin study of the effects of the Vietnam War on
posttraumatic stress disorder. JAMA 1990; 263: 1227–32.
32. Breslau N, Davis GC, Andreski P, Peterson EL, Schultz LR. Sex differences in posttraumatic stress
disorder. Arch Gen Psychiatry 1997; 54(11): 1044–8.
33. Breslau N. Gender differences in trauma and posttraumatic stress disorder. J Gend Specif Med 2002;
5: 34–40.
34. Breslau N, Chilcoat HD, Kessler RC, Lucia VC. Vulnerability to assaultive violence: further
specification of the sex differences in post-traumatic stress disorder. Psychol Med 1999; 29: 813–21.
35. Breslau N, Chilcoat HD, Kessler RC, Davis CG. Previous exposure to trauma and PTSD effects of
subsequent trauma: results from the Detroit area survey of trauma. Am J Psychiatry 1999; 156: 902–7.
36. Breslau N, Anthony JC. Gender differences in the sensitivity to posttraumatic stress disorder: an
epidemiological study of urban young adults. J Abnorm Psychol 2007; 116: 607–11.
24 Afifi, Asmundson, AND Sareen

37. Stein MB, Walker JR, Forde DR. Gender differences in susceptibility to posttraumatic stress disorder.
Behav Res and Ther 2000; 38: 619–28.
38. Tolin DF, Foa EB. Sex differences in trauma and posttraumatic stress disorder: a quantitative review
of 25 years of research. Psychol Bull 2006; 132: 959–92.
39. Rosenman S. Trauma and posttraumatic stress disorder in Australia: findings in the population
sample of the Australian national survey of mental health and wellbeing. Aust N Z J Psychiatry 2002;
36: 515–20.
40. Sareen J, Cox BJ, Afifi TO et al. Combat and peacekeeping operations in relation to prevalence of
mental disorders and perceived need for mental health care: findings from a large representative
sample of military personnel. Arch Gen Psychiatry 2007; 64: 843–52.
41. Bromet E, Sonnega A, Kessler RC. Risk factors for DSM-III-R posttraumatic stress disorder: findings
from the national comorbidity survey. Am J Epidemiol 1998; 147(4): 353–61.
42. Cox BJ, MacPherson PSR, Enns MW, McWilliams LA. Neuroticism and self-criticism associated with
posttraumatic stress disorder in a nationally representative sample. Behav Res Ther 2004; 42: 105–14.
43. Koenen KC, Moffitt TE, Poulton R, Martin J, Caspi A. Early childhood factors associated with the
development of post-traumatic stress disorder: results from a longitudinal birth cohort. Psychol Med
2007; 37: 181–92.
44. Storr CL, Ialongo NS, Anthony JC, Breslau N. Childhood antecedents of exposure to traumatic events
and posttraumatic stress disorder. Am J Psychiatry 2007; 164: 119–25.
45. Brewin CR, Andrews B, Valentine JD. Meta-analysis of risk factors for posttraumatic stress disorder
in trauma-exposed adults. J Consult Clin Psychol 2000; 68(5): 748–66.
46. Mills KL, Teesson M, Ross J, Peters L. Trauma, PTSD, and substance use disorders: findings from the
Australian national survey of mental health and well-being. Am J Psychiatry 2006; 163: 651–8.
47. Sareen J, Cox BJ, Stein MB et al. Physical and mental comorbidity, disability, and suicidal behavior
associated with posttraumatic stress disorders in a large community sample. Psychosom Med 2007;
69: 242–8.
48. Kessler RC. Posttraumatic stress disorder: The burden to the individual and to society. J Clin Psychiatry
2000; 61: 4–12.
49. Brady KT, Killeen TK, Brewerton T, Lucerini S. Comorbidity of psychiatric disorders and posttraumatic
stress disorder. J Clin Psychiatry 2000; 61: 22–32.
50. Kessler RC, Borges G, Walters EE. Prevalence of and risk factors for lifetime suicide attempts in the
national comorbidity survey. Arch Gen Psychiatry 1999; 56(7): 617–26.
51. Ullman SE, Brecklin L. Sexual assault history and suicidal behavior in a national sample of women.
Suicide Life Threat Behav 2002; 32: 117–30.
52. Andreski P, Chilcoat H, Breslau N. Post-traumatic stress disorder and somatization symptoms: a
prospective study. Psychiatry Res 1998; 79: 131–8.
53. Sareen J, Cox BJ, Clara I, Asmundson GJG. The relationship between anxiety disorders and physical
disorders in the U.S. national comorbidity survey. Depress Anxiety 2005; 21: 193–202.
54. Lauterbach D, Vora R, Rakow M. The relationship between posttraumatic stress disorder and self-
reported health problems. Psychosom Med 2005; 67: 939–47.
55. Asmundson GJ, Coons MJ, Taylor S, Katz J. PTSD and the experience of pain: research and clinical
implications of shared vulnerability and mutual maintenance models. Can J Psychiatry 2002; 47(10):
930–7.
56. Hoge CW, Terhakopian A, Castro CA, Messer SC, Engel CC. Association of postraumatic stress
disorder with somatic symptoms, health care visits, and absenteeism among Iraq war veterans. Am J
Psychiatry 2007; 164: 150–3.
57. Frayne SM, Seaver MR, Loveland S et al. Burden of medical illness in women with depression and
posttraumatic stress disorder. Arch Intern Med 2004; 164(12): 1306–12.
58. Asmundson GJG, Stein MB, McCreary DR. Posttraumatic stress disorder symptoms influence health
status of deployed peacekeepers and nondeployed military personnel. J Nerv Ment Dis 2002; 190:
807–15.
59. Barrett DH, Doebbeling CC, Schwartz DA et al. Posttraumatic stress disorder and self-reported physical
health status among U.S. military personnel serving during the gulf war period. Psychosomatics
2002; 43: 195–205.
 3 Diagnostic dilemmas in assessing post
traumatic stress disorder
Berthold PR Gersons and Miranda Olff

Introduction

The introduction of the Third Diagnostic and Statistical Manual (DSM-III (1)), International
Classification of Diseases of the World Health Organization version 10 (ICD-10) (2) and Fourth
Diagnostic and Statistical Manual (DSM-IV (3)) has helped psychiatrists to become more precise
in assessing psychiatric disorders. In DSM-III the posttraumatic stress disorder (PTSD) has been
introduced for the first time in psychiatry as a coherent profile of signs and symptoms related
to the experience of a traumatic incident. Large epidemiological studies have contributed to the
validity of this disorder.(4, 5, 6) In the assessment of PTSD two flaws however can interfere with
the correct establishing of the diagnosis of PTSD. The first flaw is people do not tell easily about
their traumatic experiences and doctors do not like to hear the terrible details. The accuracy of the
information generated during the psychiatric interview concerning trauma depends on the level
of skills used to establish a trustful relationship with the patient and a willingness to listen to
horrifying details. Also, the patient is often unaware of any relationship between the symptoms
of PTSD and the experience of the trauma. As we know in psychiatry the accuracy of the informa-
tion that we get during the interview depends strongly on our willingness to listen. A nonjudg-
mental attitude in the interview is a necessary prerequisite. The second flaw in assessing PTSD
is the overwhelming affect that accompanies the report of someone who experienced trauma.
For the listener, therefore, it sometimes seems self-evident traumatic experiences must result in
some kind of disorder, especially PTSD. Asking about symptoms after listening to the details of a
traumatic incident can look like an unneeded burden. Here the epidemiology of PTSD (4, 5) helps
us enormously to understand the limited relationship between the experience of trauma and the
development of PTSD. While between 50% and 90% of the general population experience trauma
at least once during lifetime, the lifetime prevalence of PTSD lies between seven and eight (6, 7),
which still means a huge burden on society. Men and women differ in terms of risk to develop
PTSD after trauma; for men it is between 8% and 13%, and for women, between 20% and 30%.(6,
7) Differences in appraisal and coping mechanisms as well as psychobiological response patterns
have been related to these differences.(8)
The initial response to a trauma can be characterized as a “normal reaction” toward an
“abnormal” event that relates to sleep, nightmares, concentration, emotionality, and flashbacks.
“Watchful waiting” is recommended when symptoms are mild and have been present for less
than four weeks after the trauma. Early psychological intervention, often called debriefing, has
no effect in preventing PTSD (9)—despite the high satisfaction. Instead, public information on
psychological reactions and crisis intervention combined with practical support is useful for
people to regain control over their situation.
Treatment is needed when severe early posttraumatic symptoms arise or when the dis-
order of PTSD is diagnosed. It should be noted that other disorders like depression, anxiety,
or addictive disorders may also occur and are also often comorbid to PTSD. Before starting
treatment, it is essential first to assess the diagnosis of PTSD. It is equally necessary to evalu-
ate the effectiveness of the intervention after the treatment as well; here comes a dilemma: For
patients it is often already very satisfactory to have experienced the intense emotions related
to the trauma in the trusted setting with the therapist. The patient rarely judges the result
of the treatment by evaluating the disappearance of symptoms. Whereas, for the therapist,
sometimes the cathartic expression of emotions by the patient is often taken as proof of a well-
established working through the traumatic experience. Also therapists do not always evaluate
the treatment in a more objective fashion. Studies of debriefing after traumatic experiences,
for instance, have shown a high satisfaction by the debriefed patients and by the therapist
26 Gersons AND Olff

themselves (10, 11, 12, 13), and those who were debriefed showed higher symptom profiles
in the follow up compared to the nondebriefed.(14, 15) Therefore, the precise assessment of
symptoms is important for the assessment of PTSD. It also helps the patient to understand that
he or she is not only suffering from traumatic experiences but also from symptoms resulting
from the experience.
The assessment skill sets for PTSD consist of the skills to assess trauma in all its grue-
some details and to assess symptoms resulting from the traumatic incident(s). In this chap-
ter, we will first pay attention to the assessment of trauma and its pre- and post-treatment
dilemmas. Then we will continue with the symptoms of PTSD. There are specific structured
interviews and self-report instruments developed for the assessment of PTSD. The chapter
will only highlight these instruments but not discuss them in detail. There are also other
techniques to help to establish the diagnosis of PTSD with psychophysiologic measures and
neuroimaging and neurohormonal measures. These techniques will not be discussed here,
however. Then we will discuss the issue of the trauma-spectrum disorders and comorbidity
in PTSD.

Dilemmas in the assessment of trauma

In DSM-IV1 diagnostic criteria for PTSD trauma is described as follows:

The person has been exposed to a traumatic event in which both of the following were present:
(1) The person experienced, witnessed, or was confronted with an event or events that
involved actual or threatened death or serious injury, or a threat to the physical integrity of
self or others
(2) The person’s response involved intense fear, helplessness, or horror.

What follows from the definition is the distinction between the actual traumatic event and the
person’s reaction.

Traumatic event
The definition does not describe exactly what a traumatic event means. There are characteris-
tics concerning the actual role of the person involved in the event:
· The person must be exposed to an event.
· The event can be an experience of the person him or herself.
· The event can be an experience of others in which the person is a witness.
The conditions that result from the definition, for instance, give the following examples. A
person who has been a victim of an automobile accident and who lost consciousness for the
incident itself did not consciously experience the traumatic incident. However, for instance,
when the same person later on learns that her husband died in the incident and, as was the
case in our hospital, also experienced her leg was broken has to cope with two traumatic
events following the incident. This is important to understand because the reexperienced
symptoms of the event can only evolve when someone consciously went through the inci-
dent. Another example was a police officer who could not work because of illness at a spe-
cific day, and another officer who worked in her place for that day was killed in the police
car. She developed quite similar symptoms to PTSD and she tried to reconstruct the event.
She felt guilty because she thought she should have been the one to be killed and not her fel-
low police officer. This assessment of the actual involvement in the incident is important in
treatment when this implies imaginal exposure. It is another question if such exposure can
be helpful in such situations, but the nature of reexperiencing is essentially different. For the
assessment, it is important to analyze very precisely the actual involvement in the traumatic
situation with the patient.

1
Because DSM-IV favors a more precise description of symptoms compared to ICD-10 we will quote from the
DSM-IV definition of PTSD.
Diagnostic dilemmas in assessing post traumatic stress disorder 27

In the DSM-IV definition of trauma the examples mentioned are as follows:

· Actual death
· Threatened death
· Serious injury
· Threat to the physical integrity to self
· Threat to the physical integrity of others.
These events can become traumatic for the person who experienced, witnessed, or was confronted
with the event. From our police studies (16, 17) we, therefore, made the distinction between threat-
ening and depressive experiences. The threatening ones are those incidents in which the patient him
or herself is the victim. The depressive experiences are those events in which the patient witnesses
the traumatic incident. This distinction is important because it makes the traumatic experience very
different. In a threatening experience, one’s fight–flight stress responses are activated to reach safety.
This is important, for instance, for survivors of fires, robberies, and rapes. But in the same instances,
those who were not directly threatened but only witness the incident become overwhelmed by the
helplessness to see others hurt, die, or suffer any other trauma. Here also the fight–flight responses
can become activated but more to flee from the horrible experience and from the intense feeling of
helplessness. An 18-year-old girl witnessed a robbery in daylight. Her office manager asked her to
accompany her to put a cassette with the money of the day into the deposit box of the bank. The
box was located outside the bank. When they approached the bank one of the two boys put a gun
on the head of the office manager. She gave the cassette to the boy and the boys disappeared in the
crowd. The girl was not threatened at all by the boys who actually did not take notice of her. But
she witnessed the threat and later on started to get reexperiences of this scene. She was not used
at all to such events. Ursano (18), for instance, wrote about the risk factor for emergency workers,
for example, they seem to be more at risk to develop PTSD when the corpses resembled their fam-
ily or children. The confrontation with death and destruction is in itself a frequent experience for
rescue workers but when they associate the victims with their close ones the traumatic experience
can result in PTSD. Here we are reminded of an aspect of the definition of the stressor criterion
mentioned in the DSM-IIIR description of PTSD: “. . . an event outside the range of usual human
experience and that would be markedly distressing to almost anyone. . . .” This criterion has been
abandoned in DSM-IV because the stressors as we know from epidemiology are much more com-
mon human experiences, which is in contrast to what was thought before. However, it still is impor-
tant because even one usual experience can make the difference.
By focusing on the definition of (threatening) death or injury, too much attention is some-
times only paid to the result of some act. In fact in the reexperiencing we know that not only
the result of the act comes back in memory, for example, a dead body, but also the details of the
actual happenings themselves. A man survived an air crash. The plane crashed on the landing
lane because of storm. This was accompanied by an enormous noise. The plane turned around.
Then the walls of the cabin started to crumble. One of the stewardesses felt over him. So the
air crash in itself is of course a traumatic event. But the traumatic experiences, which can come
back as symptoms in PTSD, are these specific aspects of the threatening happening. In this case,
for instance, the trembling of the plane, the noise of the crash, the falling down of the steward-
ess, and the view of a crumbling cabin became the traumatic details. Also violent behavior of
someone else can become the reminder of the incident. Here also specific moments are often
reexperienced. This is also meant by the adjunctive serious to injury. Here the threat is the most
important aspect of the event. A significant aspect of an incident is often that it is unexpected.
A person driving came along an accident. He saw a tractor with a white stick behind it. A
moment later he found out it was someone’s leg with its flesh stripped of. Also, the adjec-
tive serious, in medical parlance, denotes the critical condition of the victim. To make a critical
inquiry into a traumatic experience and to make an effective assessment, it is mostly the unex-
pected, unwelcome details that are essential. For instance, someone tried reanimation to keep
an old man alive. However, under the pressure of the act, the rescuer had broken the ribs of the
person he was trying to save. In the reexperiencing, he relives the noise of the moment the ribs
broke, and the persons reaction—intense fear, helplessness, and horror.
In contrast to DSM-III not only the experience of a traumatic event is necessary for the
diagnosis but also the response of intense fear, helplessness, and horror. For instance, threat to
one’s physical integrity will specifically result in these intense reactions, for example, in rape,
28 Gersons AND Olff

sexual abuse in childhood, and torture of any kind. Rape is always accompanied by threat
and some kind of violence. Here also the reminders give a clue to the traumatic aspects of the
experience, like the use of a knife or the threat, “I will kill you when you tell someone else.”
Here fear also plays an important role in the aftermath of the event. Though not mentioned for
all traumatic events, shame is one factor that is usually very strongly felt in the three types of
events. Here the assessment skills are important. Questioning about trauma not only involves
facts but also extreme emotions associated with the incident. The traumatized person tries
often to suppress the intense emotional reminders. The victim also protects the interviewer
from being confronted with the repulsive details and the extreme emotions. For instance, a
woman who has been raped by a group of youngsters had lots of difficulties telling all the
terrible details of the experience. There had been moments that one of the boys had put the
gun into her vagina and at other moments to her head. It is extremely difficult to not only tell
these horrid details but also listen to them. These elements are most important in treatment.
However, for the patient, it is important that the therapist listens without hesitation to these
details. So one has to ask questions, for example, as given below:

· Did you feel fear?

· What were the most fearful experiences?
· Did you feel helpless?
· At which moments you felt most helpless?
· Did you feel horror?
· At which moments you felt most horror?
· Do you feel ashamed to tell these things?

Abuse in childhood is also often connected with violence and neglect. Here also shame and
helplessness play an important role in the traumatization of the person. A critical factor in the
assessment of sexual���������������������������������������������������������������������������
���������������������������������������������������������������������������������
traumas is the trust to be established between the patient and the thera-
pist. This is of course not self-evident. Judith Herman (19) calls our attention for a “stabilization
phase” in which the patient can test the therapist about the safety of the treatment situation. It
is good to realize the assessment phase can be complicated by the need for safety. The trauma-
tized person not only suffers from the event that resulted in his or her trauma but also from the
disappearance of trust he or she had in other human beings before the event. This is also the
case with torture victims, whereas the safety of the consulting room for other trauma victims
can resemble too much the torture room, disconnected from the outside world, sitting in the
consulting room. Basoglu et al. (20) has paid attention to the development of psychological
preparedness for torture. This office of the therapist can repeat this experience as well.
Horror is also an emotion that is often difficult to share. An example of such horror is
the following example: In 1992, in Amsterdam, a plane crashed on a neighborhood.(21) This
caused a fire as high as the apartment buildings that were struck by the plane. Eyewitnesses
not only experienced this unbelievable scene but also heard the shouting and crying of burning
people, some of them jumping off the balconies; thus, these details are horrible and difficult
to tell. Such extreme emotions are characteristic of traumatic experiences. Fear is often pre-
sented this way, “I felt the adrenaline flow through my body.” One remembers fear as a somatic
experience of increased heartbeat, the trembling of the legs, being rooted to the ground, being
unable to speak, cold hands, and so on.
For the therapist, there are risks connected to the listening about the events, especially
when confronted with having to observe the extreme emotions of the patient in session. This is
called secondary traumatization or vicarious traumatization.(22) It is well known in psychiatry,
and it is also essential for a good interview that an empathic, understanding relationship with
the patient is developed . The patient tells his or her story and details of symptoms only when
he or she can trust the therapist. The right attitude, therefore, is one of willingness to listen and
of acceptance. Such attitudes stimulate the patient to continue to tell; however, with trauma
histories, this is much more complicated. The patient might worry that the interviewer will
not take his or her story and the complaints serious or be afraid that the disclosure of grue-
some details of the traumatic incident could scare the therapist him or herself. For instance,
after listening to the story of burning people jumping from the balconies, even the therapist
might be prone to dreaming about it. Treatment of a survivor of a plane crash can make the
Diagnostic dilemmas in assessing post traumatic stress disorder 29

therapist fearful of flying. Secondary traumatizing refers to a sort of ‘infectious’ effect of listen-
ing to trauma stories. One feels saddened and helpless. Especially the listening to the details
can cause the interviewer to develop nightmares of such incidents. So PTSD can endanger the
mental health of the interviewer. It is, therefore, advised to limit the number of trauma patients
one has to interview or to treat. Also regular intervision between trauma-therapists is highly
recommended to limit their risk of secondary traumatisation.
Another dilemma lies in the discussion on whether the emotional response (A2 criterion)
to trauma should get more weight than the type of event (A1).(23)
While some have argued that this definition is too narrowly defined and should be
broadened to even include experiences that are distressing, but not necessarily directly associ-
ated with physical threat or injury (23, 24), others have been critical, stating that this definition
is too inclusive.(25) The “conceptual bracket creep” (25) refers to the broadening of the stressor
criterion in DSM-IV, especially to the inclusion of “second-hand exposure,” such as learning
about the unexpected death of a close friend/relative or watching atrocities on television .
This seems to increase the eligible events by about 20%.(26) However, what is more important
in this case is the question addressed in DSM-IV, that is, “whether or not to include reactions
to the numerous stressors that are upsetting, but not life threatening or even to eliminate the
stressor criterion altogether.” The fear that more inclusive definitions will vastly increase the
frequency of the diagnosis seems to be unrealistic. More minor stressors simply will not result
in the other diagnostic criteria for PTSD.

Symptoms assessment

A variety of common symptoms are already covered in the assessment of the traumatic event.
The symptom profile of PTSD has been divided into three sections:
1 Reexperiencing symptoms
2 Avoidance symptoms
3 Hyperarousal symptoms.
In the interview, a person often realizes the reexperience symptoms are related to the traumatic
event. So they are more easily reported. The other two groups of symptoms are less well known
to the sufferer and, therefore, are connected to the experience of the event. In the context of
DSM-IV guidelines, a clear problem the therapist is faced with while asking about the different
symptoms is a lack of frequency and intensity of the symptom mentioned. In the structured
interviews for PTSD this is mostly better defined.

Reexperience symptoms
These are as follows:
B. The traumatic event is persistently reexperienced in one (or more) of the following
ways:
1 Recurrent and intrusive distressing recollections of the event, including images, thoughts,
or perceptions;
2 Recurrent distressing dreams of the event;
3 Acting or feeling as if the traumatic event were recurring (includes a sense of reliving the
experience, illusions, hallucinations, and dissociative flashback episodes, including those
that occur on awakening or when intoxicated);
4 Intense psychological distress during exposure to internal or external cues that symbolize
or resemble an aspect of the traumatic event;
5 Physiological reactivity on exposure to internal or external cues that symbolize or resemble
an aspect of the traumatic event.
In the reexperience symptoms there are some important characteristics:
· The person involved does not have control over the occurrence of the symptoms.
· The reexperience is a perceptional one that resemble actual experience.
· The perceptional quality of the remembrance is essentially different from telling a story.
30 Gersons AND Olff

When a symptom is regarded persistent it means that nearly every week it occurs, and it is quite
typical that the symptoms reoccur. Mostly specific episodes of the traumatic scene come back
again and again. At moments of rest, for example, before sleep, when someone is most relaxed,
he or she can be taken by surprise in reliving and seeing the terrible happening. They also come
back in dreams. For instance, the partner can tell the bedclothes were wet and disordered or
the person was talking and behaving in his sleep. The confrontations of cues that symbolize
or resemble an aspect of the traumatic event are characteristic. Someone who survived an air
crash bends down every time when a plane crosses the sky. After a rape by a colored person
every time a woman sees a colored person she feels frightened even when knowing there is no
real danger. Every element of the traumatic incident, such as sound, color, scene, and so on,
can act as the trigger of the conditioned fear response, which is accompanied by some kind of
reminder or reliving. It is hypothesized that this impaired extinction of fear conditioning may
lie at the core of the development of PTSD and other anxiety disorders.(27)
The physiological reactivity means that the confrontation with cues result in increased
heartbeat, transpiration, feeling cold, trembling, and so on. In psychobiological research trauma
scripts are often used to examine, for instance, the heart rate response or changes in brain acti-
vation in response to the patient’s own trauma story.(28, 29)

Avoidance symptoms
These are as follows:
C. Persistent avoidance of stimuli associated with the trauma and numbing of gen-
eral responsiveness (not present before the trauma) as indicated by three (or more) of the
following:

1 Efforts to avoid thoughts, feelings, or conversations associated with the trauma;

2 Efforts to avoid activities, places, or people that arouse recollections of the trauma;
3 Inability to recall an important aspect of the trauma;
4 Markedly diminished interest or participation in significant activities;
5 Feeling detachment or estrangement from others;
6 Restricted range of affect (e.g., unable to have love feelings)
7 Sense of a foreshortened future (e.g., does not expect to have career, marriage, children, or
a normal life span).

Here two kinds of reactions are described: actual avoidance or numbing of general responsive-
ness. These symptoms strongly relate to the general fight–flight response to stress. The numb-
ing seems related to a third kind of response, which is known from animals: acting as if one is
dead. In the interview one has to rigorously pursue and probe for avoidance behavior. Often a
patient is so used to the avoidance that it is not perceived as an active strategy. In fact much of
the normal activities before the traumatic events are not taking place anymore. Certain neigh-
borhoods will not be visited anymore. Those who suffered war and camps avoid the scenes
of endless streams of refugees on television. So in assessing avoidance symptoms one has to
understand that the traumatic cue brings back the perceptual remembrances of the trauma.
Also, the intense pain, grief, and helplessness are felt again. It feels like “an open wound.” The
wound will never completely close. Also fear is intense again, and behind it often extreme feel-
ings of aggression are hiding. The avoidance can also involve (like in C1) social withdrawal.
Here the following question helps: “Do others perceive you as being changed after the inci-
dent?” The answer is often this: “Yes, I was always actively involved but now I do not like to go
out.” An example of how complicated this can be is the following. An officer who shot a person
was complemented after returning to the police station. He was seen as a hero. However, he felt
terrible because he did not want to kill anybody. He felt guilty not withstanding the rightness
of the act in the terrible situation. He realized his colleagues had no idea about how lousy he
felt. They could not understand his withdrawal and in a certain way they did not like to see
their hero withdrawn. For the assessment of the inability to recall an important aspect of the
trauma one has to investigate very carefully the traumatic incident. The traumatized person
is not always aware of this symptom. A woman survived a killing in daylight while sitting
in good weather with friends outside a cafe. She could only remember seeing coming near a
group of men and then she remembers being in the hospital crying. She was not hurt herself.
Diagnostic dilemmas in assessing post traumatic stress disorder 31

But the actual traumatic moment has been lost because of dissociation. Another well-known
aspect of the remembrance of traumatic incidents is the fact the one involved feels very con-
vinced of the details of the happening. For instance I treated three persons who survived the
same crash; each presented a different version in terms of recounting the incident and present-
ing the details of the incident. But they felt threatened after being faced with the probability
their memory was not totally accurate. In the face of danger one must rely on few cues, which
activates the stress response. From the work of le Doux (30) we know our brains work to per-
ceive these threatening cues after which our fight–flight behavior becomes activated. Certain
details are not taken into consideration or are lost. This is also defined by what is called “tunnel
vision.” The perception is restricted to endangering elements.
The symptoms listed under C4, 5, 6, and 7 overlap strongly with symptoms of depres-
sion. The interest in initiating activities or participation in something can be lost. The world
that seemed normal and safe before the incident is no longer perceived that way and seems
far less important after the incident. Here we see that the appreciation of the world, of what is
important, can have changed tremendously. A UN military officer went to Bosnia to identify
the corpses of killed inhabitants. In one month he saw a 300 bodily remains of the dead in a
devastated surrounding complete with burned and destroyed houses. Before this, in his home-
land, the solder was an active participant in local activities in the area where he was living
with his family. After this trip, he felt everything was unimportant. He also felt detached from
his partner and even his children, which is a terrible feeling. In the treatment it became clear
as to what was the reason for this detachment; he felt he is no longer capable of safeguarding
his family and he internally anticipated the possibility of losing them. Also, this symptom of
detachment is difficult to express because the person involved feels very guilty about it. The
restricted range of affect also becomes clear from the fact that the “shine” of normal experience
has been lost. The sense of a foreshortened future relates to the loss of control over one’s life
and over the lives one feels responsible for.
A dilemma within the DSM IV classification is that research indicates that the avoidance
cluster may need to be split into two distinct factors.(31) The first factor consists of actively
avoiding thoughts or feelings about the event or doing things that remind the person of the
event. The second factor describes emotional numbing as in having difficulty enjoying things
or having sad or loving feelings, feeling distant from other people, or finding it hard to imagine
fulfilling future goals. Foa et al. (32) already suggested that avoidance and numbing represent
two separate factors reflecting different mechanisms. Previous models attempted to character-
ize PTSD based on the theoretical position that the clinical manifestations of PTSD follow a
pattern of oscillations.(32, 33) Avoidance would be an effortful and strategic process following
distress associated with intrusive thoughts or episodes of reexperiencing the traumatic event,
whereas numbing, that is, a lack of emotional responsiveness and social withdrawal, is a con-
sequence of uncontrollable arousal as in hypervigilance and anger.

Hyperarousal symptoms
These are as follows:
D. Persistent symptoms of increased arousal (not present before the trauma) as indicated
by two (or more) of the following:
1 Difficulty falling or staying asleep;
2 Irritability or outburst of anger;
3 Difficulty concentrating:
4 Hypervigilance;
5 Exaggerated, startled response.
These symptoms are more easy to assess. The sleeping problem can relate to the fear that the
traumatic incident can happen again. After the air crash in Amsterdam, we saw people who
could only sleep with the light and TV on. Here the stimuli came in place of the increased need
to scan the environment for endangering cues. Also waking up after two hours is common, as
it seems dangerous to be not awake. To have no control over one’s reactions becomes clear in
the symptom irritability or outburst of anger. A shopkeeper was robbed at gun point just before
closing time. He developed PTSD. One of the symptoms was his hypervigilance. He was afraid
the robbery would happen again. He had much difficulty in being patient with his clients. His
32 Gersons AND Olff

normal humor had faded away. People no longer liked to visit his cheese shop. This change
affected the family front as well; he became quite irritable toward his wife and children. He
changed, so partners often told us. Children suffered because of the irritability of their par-
ent. One can easily understand this irritability. The traumatized person seems to be constantly
distinguishing dangerous stimuli from “unimportant” stimuli. This is in fact the description of
hypervigilence. Also one sees this in the behavior. A person has taken the chair as close to the
wall as possible that his back was against the wall and to feel safe that no one can between him
and the wall. A person who had been attacked very violently constantly slowed down when
bicycling because he feared the persons bicycling behind him. Also normal stimuli like the clos-
ing of a door can startle the person extremely. The difficulty in concentrating corresponds also
to this “scanning behavior.” For example, recalling and describing the danger experienced is
not difficult; on the contrary, a person might actively recall all sorts of details associated with
the danger experienced. But if the same person were to read two pages of a book, he will likely
forget the contents and start all over again. One might forget to what to buy during shopping.
One needs to write down at home a list before going to the shop.
The hyperarousal symptoms are quite invalidating. Normal relations and normal activi-
ties become disordered. We see the person involved to cope with it in less adaptive ways by
avoiding and withdrawal.

Dissociative symptoms
Apart from the symptoms B3, “dissociative flashback episodes,” and C3, “inability to recall
an important aspect of the trauma,” dissociative symptoms are not very well specified in the
DSM-IV description of PTSD. Spiegel and others (34) have argued that PTSD is a disorder
of memory. From this viewpoint, more symptoms similar to the two mentioned above can
be seen as distorting normal memory functions like encoding, storage, and retrieval of trau-
matic memories. Bremner et al. (35) have argued that dissociation is the main mechanism in
the development of PTSD; an example is the lack of emotions while remembering traumatic
events. Without such accompanying emotions, the incident according to the definition is not
a traumatic one. Here we have a problem; dissociation could have negated such emotions.
Thus, the person remembers the incident but cannot remember the intense emotions he felt
while it happened. Brewin (36) has described different forms of memory: (1) verbally accessible
memory (VAM) involving explicit, conscious, and hippocampally dependent memories, such
as ordinary autobiographical memories, and (2) situational assessable memory systems (SAM),
which involve implicit, image-based, cue-dependent, and nonhippocampally dependent mem-
ories at the amygdala level as when sensory memories of the traumatic event are reexperienced
after being triggered by external cues. One of the aims of treatment is integrating the memories
of the trauma into the totality of a person’s memory system.
A specific accompanying symptom is often the depersonalization or derealization, which
are dissociative symptoms. Especially from sexual child abuse, it is well known that the trau-
matic incident can be forgotten. This is part of a heavy debate, especially because some accuse
that therapists “implant such memories.” One has to be very careful in the interview not to
suggest such experiences. But one cannot leave them out, particularly because when the thera-
pist detects long periods of amnesia during childhood phase, as becomes evident during the
session, the possibility that that there was a childhood trauma must indeed be taken seriously.
Marmar et al (37) has described a set of specific dissociative features of the traumatic
experience that are quite common. These symptoms are called peritraumatic dissociation.
These symptoms are part of the traumatic experience of a person and come back while remem-
bering the event. For instance, a traumatic situation feels “endless” in time, whereas it could
have lasted only for a short moment. Also the incident can be experienced as a “slow-motion”
scene in which the sound associated with the actual event can change or even be absent.
Peritraumatic dissociation describes the changes in perception, especially in time–space rela-
tion. A police officer who was sitting in his car shot through the windscreen at a man who took
a woman as the hostage. The window-screen splintered into thousand particles. He, however,
saw them falling down slowly, as if they were water drops. It sounded like “Christmas bells.”
The traumatic value of an incident can, therefore, change the perception; thus, the perception
concerning time, sound, place of the incident may not only vary but may instead regard the
incident as unreal, as if it never happened.
Diagnostic dilemmas in assessing post traumatic stress disorder 33

Structured Instruments

Structured interviews and self-report instruments have a definite advantage because they
don’t need much clinical skills while using them, as outlined before. Also they make the valid-
ity of assessment between groups better. Many instruments have been developed for epide-
miological purposes and for research on PTSD. We will summarize a few here. The Impact
of Events Scale (IES) of Horowitz et al (38) is not only well known but is also the oldest one
in its category. It is more often used because it gives a fine presentation of the reexperience
and avoidance characteristics. However, the disadvantage is it has been developed far before
the formulation of PTSD in DSM-III and IV and may not cover many of the symptoms as
presented in DSM-III and IV; for example, the hyperarousal symptoms are not part of this
scale. The revised version now includes these hyperarousal symptoms (IES-R), though. The
Structured Clinical Interview for DSM-IV (39)) is also available with a PTSD part. Furthermore,
in current research, the Clinician Administered PTSD Scale for DSM-IV (CAPS-DX) is also very
often used. (40) For epidemiological research with trained lay interviewers (not clinicians), the
Composite International Diagnostic Interview (41) is available for PTSD assessment. Breslau
et al. (42) reported about a 7-item symptom list to discover PTSD in the community and later
Brewin et al. (43) developed a 10-item instrument to screen for the presence of PTSD. Also,
self-report instruments have been used in research and are sometimes recommended for use in
clinical practice as well. These are the Davidson Trauma Scale (DTS) (44), the Self-Rating Scale
for PTSD (SRS-PTSD) (45), the Self-Rating Inventory for Posttraumatic Stress Disorder (SID)
(46) and the Posttraumatic Diagnostic Scale (PDS) (47). Most of the self-report instruments
have been developed for special trauma populations, like Vietnam veterans (CAPS), police and
disaster victims (46) and rape victims (47).

Trauma spectrum and Comorbidity

The ICD-10 classification (2) mentions that PTSD is often accompanied by anxiety, depres-
sion, or even obsessive–compulsive disorder. The consequence is that when a patient comes for
assessment, one should not restrict assessment to only focus on PTSD but must instead look
for other accompanying symptoms described previously. Comorbidity of PTSD with other
disorders, including the dissociative ones, is quite common. Therefore, some have argued for
the need of a so-called trauma spectrum of disorders (48, 49, 50). There are important over-
laps with depression, other anxiety disorders and with dissociative disorders. Also, PTSD can
become complicated by addiction. Acute stress disorder (ASD) has been recognized in DSM-IV
(3). There is also much interest in subtreshold manifestations of PTSD-symptoms described as
partial PTSD (51). Herman (52) and van der Kolk (53) have pleaded for adding complex PTSD
to DSM-IV items of measure. Much attention has been given to a partial relationship between
the borderline personality disorder and early trauma. Complex PTSD has been developed to
describe the long-term effect of PTSD on the personality.
For future research, it will be necessary to pay more attention to trauma spectrum disor-
ders, which, in the meantime, should not, however, stop clinicians from assessing PTSD alone.

Conclusion

In the assessment of the diagnosis of PTSD many dilemmas have been mentioned. Psychiatrists
are mostly familiar with the difficulty of assessing, for instance, psychotic symptoms because
having such skills is usually associated with one’s bearing a professionally accomplished
persona and professional pride, whereas for other doctors such assessment turns out to be
extremely difficult. The disorders like PTSD that are related to traumatic events may at first
seem more easy to detect. The improved classification of disorders in DSM and ICD over time
has tremendously increased the in between reliability of making diagnosis of different disor-
ders. However, behind the short descriptions, definitions, and sentences, much clinical exper-
tise is hidden, which helps with precise diagnosis of PTSD and other disorder. A special aspect
in the skills for assessing PTSD is the impact of any unpleasant stories divulged during the
34 Gersons AND Olff

diagnosis. It is important to understand that the patient often does not want to share his or her
terrible experiences with the therapist, which he or she feels acts sometimes as a protection
so that the therapist does not get bogged down with such details and extreme emotions. For
the clinician, it is, therefore, necessary to realize how one should be prepared with knowledge
and skills to start assessing PTSD. Those who argue for seeing PTSD as a dissociative disorder
help us to understand the symptoms from the view of a memory disorder. The use of struc-
tured instruments and self-rating inventories can be helpful, but to what extent is not yet well
known. The risk of secondary traumatization has to be taken very seriously.

References

  1. American Psychiatric Association. Diagnostic And Statistical Manual of Mental Disorders, third
edition (DSM-III). Washington, DC: APA; 1980.
  2. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders; Clinical
Descriptions and the Diagnostic Guidelines. Geneva; 1992.
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, fourth
edition (DSM-IV). Washington, DC: APA; 1994.
  4. Kessler, RC, Sonnega A, Bromet E, Nelson CB. Posttraumatic stress disorder in the national comorbidity
survey. Arch Gen Psychiatry 1995; 52, 1058–60.
  5. Breslau N, Kessler RC, Chilcoat HD et al. Trauma and posttraumatic stress disorder in the community;
the 1996 Detroit area survey of trauma. Arch Gen Psychiatry 1998; 55: 626–32.
  6. Olff M, de Vries G-J. The epidemiology of PTSD in the Netherlands. 9th European Conference on
Traumatic Stress, Stockholm. Stockholm: Sweden, 2005: 106.
  7. Breslau N, Davis GC, Andreski P, Peterson EL, Schultz LR. Sex differences in posttraumatic stress
disorder. Arch Gen Psychiatry 1997; 54(11): 1044–8.
  8. Olff M, Langeland W, Draijer N, Gersons BPR. Gender differences in posttraumatic stress disorder.
Psychol Bull 2007; 133(2): 183–204.
  9. National Institute for Clinical Excellence. The management of PTSD in primary and secondary care.
London: NICE; 2005.
10. Kenardy JA, Webster RA, Lewin TJ et al. Stress debriefing and patterns of recovery following a natural
disaster. J Trauma Stress 1996; 9: 37–50.
11. Bisson JI, Jenkins PL. Psychological debriefing for victims of acute burn trauma. Br J Psychiatry 1997;
171: 583.
12. Bisson JI, Jenkins PL, Alexander J, Bannister C. Randomized controlled trial of psychological
debriefing for victims of acute burn trauma. Br J Psychiatry 1997; 171: 78–81.
13. Carlier IVE, Van Uchelen JJ, Lamberts RD, Gersons BPR. Disaster-related posttraumatic stress in
police officers; a field study of the impact of debriefing. Stress Med 1998b; 14: 143–8.
14. van Emmerik AA, Kamphuis JH, Hulsbosch AM, Emmelkamp PM. Single session debriefing after
psychological trauma: a meta-analysis. Lancet 2002; 360: 766–71.
15. Sijbrandij EM, Olff M, Reitsma JB, Carlier IVE, Gersons BPR. Emotional or educational debriefing
after psychological trauma: Randomised controlled trial. Br J Psychiatry 2006; 189, 150–5.
16. Carlier IVE, Gersons BPR. Partial PTSD; the issue of psychological scars and the occurrence of the
PTSD symptoms. J Nerv Ment Dis 1995; 183, 107–9.
17. Carlier, I.V.E., Lamberts, R.D., Gersons, B.P.R., Risk factors for posttraumatic stress symptomatology
in police officers: a prospective analysis. J Nerv Ment Dis 185(8):498-506, 1997.
18. Ursano RJ, Fullerton CS, Vance K, Kao TC. Posttraumatic stress disorder and identification in disaster
workers. Am J Psychiatry 1999; 156, 353–9.
19. Herman J. Trauma and Recovery; the Aftermath of Violence - From Domestic Abuse to Political Terror.
Basic Books; 1992.
20. Basoglu M, Mineka S, Paker M et al. Psychological preparedness for trauma as a protective factor in
survivors of torture. Psychol Med 1997; 27: 1421–33.
21. Carlier IVE, Gersons BPR. Stress reaction in disaster victims following the Bijlmermeer plane crash.
J Trauma Stress 1997; 10: 329–35.
22. Figley CR. Compassion fatigue as secundary stress disorder: An overview. In: Figley CR, ed.
Compassion fatigue: Secundary Traumatic Stress Disorder in Treating the Traumatized. New York:
Brunner/Mazel, 1995: 1–20.
23. Avina C, O’Donohue W. Sexual harassment and PTSD: is sexual harassment diagnosable trauma?
J Trauma Stress 2002; 15: 69–75.
24. Olff M, Gersons BPR. What is a traumatic event? Br J Psychiatry 2005; 187, 189–90.
25. McNally RJ. Progress and controversy in the study of posttraumatic stress disorder. Annu Rev Psychol
2003; 54: 229–52.
Diagnostic dilemmas in assessing post traumatic stress disorder 35

26. Breslau N, Kessler RC. The stressor criterion in DSM^IV posttraumatic stress disorder, an empirical
investigation. Biol Psychiatry 2001; 50: 699–704.
27. Knight DC, Smith CN, Cheng DT, Stein EA, Helmstetter FJ. “Amygdala and hippocampal activity
during acquisition and extinction of human fear conditioning”, Cogn Affect Behav Neurosci 2004;
4(3): 317–25.
28. Lindauer RJL, Van Meijel EPM, Jalink M et al. Heart rate responsivity to script-driven imagery in
posttraumatic stress disorder: specificity of response and effects of psychotherapy. Psychosom Med
2006; 68(1); 33–40.
29. Lindauer RJL, Booij J, Habraken JBA et al. Cerebral blood flow changes during script-driven imagery
in police officers with posttraumatic stress disorder. Biol Psychiatry 2004; 56(11): 853–61.
30. LeDoux J. The emotional brain. The mysterious underpinnings of emotional life. New York: Simon
and Schuster; 1996.
31. Olff M, Sijbrandij M, Opmeer BC, Carlier IV, Gersons BP, The structure of acute posttraumatic stress
symptoms: ’Reexperiencing’, ’Active avoidance’, ’Dysphoria’, and ’Hyperarousal’, J Anxiety Disord,
2009 Jun;23(5):656-9.
32. Foa EB, Riggs DS, Gershuny BS. Arousal, numbing, and intrusion: symptom structure of PTSD
following assault. Am J Psychiatry 1995; 152(1): 116–20.
33. Litz BT. Emotional Numbing in combat-related posttraumatic-stress-disorder - a critical-review and
reformulation. Clin Psychol Rev 1992; 12(4): 417–32.
34. Butler LD, Spiegel D. Trauma and memory, in: American Psychiatric Press, Washington. Review of
Psychiatry 1997; 16(2): 13–53.
35. Bremner JD, Marmar CR. Trauma, memory, and dissociation. American Psychiatric Press, Washington;
1998.
36. Brewin CR. A cognitive neuroscience account of posttraumatic stress disorder and its treatment.
Behav Res Ther 2001; 39: 373–93.
37. Marmar CR, Weiss DS, Schlengen WE et al. Peritraumatic dissociation and posttraumatic stress in
male Vietnam theater veterans. Am J Psychiatry 1994; 151: 902–7.
38. Horowitz MJ, Wilner N, Alvarez W. Impact of event scale: a measure of subjective stress. Psychosom
Med 1979; 41: 209–18.
39. Spitzer RL, Williams JBW, Gibbon M. Structured clinical interview for DSM-III-R, Version NP-V. New
York: Biometrics Research Department, New York State Psychiatric Institute; 1987.
40. Blake D, Weathers F, Nagy D. A clinician administered PTSD scale for the assessing current and
lifetime PTSD: the CAPS-I. Behav Ther 1990; 18: 187–8.
41. Kessler RC, Andrews G, Mroczek D, Ustun B, Wittchen HU. The world health organization composite
international diagnostic interview short-form (CIDI-SF). Int J Methods in Psychiatry Res 1998; 7:
171–85.
42. Breslau N, Peterson EL, Kessler RC, Schultz LR. Short screening scale for DSM-IV posttraumatic
stress disorder. Am J Psychiatry 1999; 156: 908–11.
43. Brewin CR, Rose S, Andrews B et al. Brief screening instrument for post-traumatic stress disorder.
Br J Psychiatry 2002; 181: 158–62.
44. Davidson JR, Book SW, Colket JT et al. Assessment of a new self-rating scale for posttraumatic stress
disorder. Psychol Med 1997; 27: 153–60.
45. Carlier IVE, Lamberts RD, van Uchelen JJ, Gersons BPR. Clinical utility of a brief diagnostic test for
posttraumatic stress disorder. Psychosom Med 1998a; 60: 42–7.
46. Hovens JE, Van der Ploeg HM, Bramsen I. The development of the self-rating inventory for
posttraumatic stress disorder. Acta Psychiatrica Scandinavica 1994; 90: 172–83.
47. Foa EB, Hearst-Ikeda D, Perry KJ. Evaluation of a brief cognitive-behavioral program for the
prevention of chronic PTSD in recent assault victims. J Consult Clin Psychol 1995a; 63: 948–55.
48. Bremner JD. Editorial: Acute and chronic responses to psychological trauma: where do we go from
here? Am J Psychiatry 1999; 156(3): 349-351.
49. Horowitz MJ. Stress-response Syndromes (2nd ed.). Northvale, NJ: Jason Aronson; 1986.
50. Van der Kolk BA, McFarlane AC, Weiseath L, eds. Traumatic Stress: the Effects of Overwhelming
Experience on Mind, Body, and Society. New York: Guilford Press; 1996.
51. Carlier IVE, Gersons BPR. Partial posttraumatic stress disorder (PTSD): The issue of psychological
scars and the occurrence of PTSD symptoms, J Nerv Ment Dis 1995; 183(2): 107–9.
52. Herman JL. Sequelae of prolonged and repeated trauma: evidence for a complex posttraumatic
syndrome (DESNOS). In: Davidson JRT, Foa EB, eds. Posttraumatic Stress Disorder: DSM-IV and
Beyond. Washington, DC: APA; 1993.
53. Van der Kolk B.A, McFarlane AC, Weiseath L eds. Traumatic Stress: the Effects of Overwhelming
Experience on Mind, Body, and Society. New York: Guilford Press; 1996.
 4 Neuroimaging and posttraumatic stress
disorder
Sarah N Garfinkel and Israel Liberzon

Introduction

Neuroimaging provides a powerful way to investigate the structural and functional abnor-
malities associated with posttraumatic stress disorder (PTSD) and PTSD vulnerability. It can be
used to identify mechanisms that mediate emotional processing in healthy individuals as well
as the dysregulation of these processes in posttraumatic stress disorder (PTSD). Reviewed are
neuroimaging findings in PTSD, with a focus on studies utilizing symptom provocation, cog-
nitive activation, and functional connectivity. These studies identify neurocircuitry associated
with PTSD, highlighting the role of the medial prefrontal cortex (mPFC), insula, amygdala,
sublenticular extended amygdala (SLEA), and hippocampus, in mediating symptom formation
in PTSD. In addition, psychological processes presently emerging as new foci in neuroimaging
research relevant to PTSD, such as fear conditioning, habituation, extinction recall; cognitive–
emotional interactions are also discussed. Findings linking neurocircuitry subserving these
processes to the abnormalities associated with PTSD are highlighted, suggesting that mPFC is
implicated in a number of these processes. Finally, a section on receptor imaging will discuss
the differences in functional neurochemistry associated with PTSD.
The last decade saw the emergence of neurocircuitry models of PTSD, (1–3), which were
inspired by both basic animal research and a growing number of human neuroimaging studies. These
models conceptualize PTSD as a state of heightened responsivity to threatening stimuli and/or a state
of insufficient inhibitory control over exaggerated threat sensitivity. They emphasize the centrality of
threat-related processing in the pathophysiology of PTSD and hence account for the “hypersensitiv-
ity to threat” that is highly characteristic of PTSD (such as hypervigilence and hyperarousal). It is
becoming increasingly apparent, however, that the “hypersensitivity to threat” models do not fully
capture the full complexity of PTSD or the complexity of changes associated with, trauma exposure
and PTSD development. For instance, important phenomena associated with PTSD, such as intrusive
thoughts and memories, avoidance and numbing, generalization, vulnerability, and resilience factors,
all need to be further understood in terms of underlying psychological mechanisms and their neu-
robiological substrates. There is presently a growing appreciation that additional mechanisms, other
than hyperresponsivity to threat, must be involved in PTSD pathophysiology. Lines of research have
begun exploring neurobiological and psychological processes seemingly relevant to the develop-
ment, maintenance and/or recovery of PTSD, including conditioning, habituation, stimulus general-
ization, extinction resistance, and (impaired) extinction recall. In addition, processes (and underlying
neurocircuitry) involving higher order cognitive–emotional interactions, appraisal, reappraisal, and
metaawareness may also play an important role in PTSD vulnerability, pathophysiology, and resil-
ience. In recent years, a growing body of literature has examined these processes both in healthy
and PTSD subjects. This chapter will first review what is currently known on the basis of functional
neuroimaging in PTSD, with a particular emphasis on symptom provocation studies, cognitive acti-
vation studies and functional connectivity analyses. The second part of the chapter focuses on specific
psychological processes that have been implicated in PTSD symptom generation or pathophysiology.
These include neuroimaging studies of fear-conditioning phenomena (with a particular emphasis on
extinction and extinction recall) and also cognitive–emotional interactions. Finally, potential future
directions for PTSD research are discussed.

Part I: Neuroimaging studies in PTSD

Different neuroimaging modalities, such as single-photon emission tomography (SPECT), pos-

itron emission tomography (PET), and functional magnetic resonance imaging (fMRI), have
Neuroimaging and posttraumatic stress disorder 37

all been used in conjunction with PTSD research. This chapter will incorporate many of these
modalities, with a particular emphasis on fMRI.

Symptom provocation studies

Studies utilizing symptom provocation to investigate PTSD do so by employing autobiograph-
ical stimuli that are trauma related (e.g., narrative scripts of personal trauma) or alternatively
are more general in nature, employing generally evocative but not necessarily autobiographi-
cally relevant pictures and sounds. Such studies were the first to emerge, were the first to
provide relatively stable and replicable findings, and are still the most common studies in
the PTSD functional neuroimaging literature. In one of the first functional imaging symptom
provocation studies, Rauch and colleagues (4) used individualized trauma scripts and [15O]
H2O PET, in a small and heterogeneous group of eight PTSD subjects. They demonstrated
increased regional cerebral blood flow (rCBF) in anterior paralimbic (right posterior media-
lorbito frontal cortex [OFC], insular, anterior temporal polar, and medial temporal cortex) and
limbic structures (amygdala) in the provoked versus control contrast. In a following study, the
same group then used combat-related, emotionally negative and neutral pictures paired with
verbal descriptions (imagery) in combat veterans with and without PTSD. Combat veterans
with PTSD had increased rCBF in ventral anterior cingulated cortex (ACC) and right amygdala
when generating mental images of combat-related pictures but had deceased rCBF in the ACC
in the combat image viewing versus neutral image viewing contrast.(5) Though these early
studies had methodological limitations, such as a small and heterogeneous sample size, as well
as a lack of adequate control groups that limited the generalization of their findings, they set
the stage for more detailed studies into the neural substrate of the symptomatic PTSD state.
In an ensuing study, our group exposed three groups of subjects (14 combat PTSD sub-
jects, 11 combat-exposed subjects without PTSD, and 11 combat unexposed healthy subjects) to
combat sounds or white noise in two counterbalanced sessions and studied rCBF with 99mTc
hexamethylpropyleneamineoxime (HMPAO) SPECT. Only the PTSD group showed increased
rCBF in the left amygdaloid region.(6) Another study using combat-related pictures and
sounds and PET in 10 combat veterans with and 10 without PTSD, revealed decreased blood
flow in medial prefrontal cortex (mPFC) (Area 25) and other areas in response to traumatic
pictures and sounds in PTSD patients, while non-PTSD control subjects activated the anterior
cingulate (Area 24) to a greater degree than PTSD patients.(7) The same group also studied
childhood sexual abuse (CSA) subjects (22 women, 10 of whom had PTSD) with exposure to
traumatic and neutral scripts and PET. The PTSD group showed rCBF increases in posterior
cingulate (Area 31) and superior and middle frontal gyri bilaterally in Brodmann Areas 9 and
10. The PTSD group also showed deactivation in the subcallosal anterior cingulate (Area 25)
and decreased activation in an adjacent portion of anterior cingulate (Area 32).(7) Using PET
and script-driven imagery in 16 subjects with CSA (eight subjects with PTSD), Shin and col-
leagues also reported deactivation of the medial prefrontal and as well as left inferior frontal
(Broca’s) areas in the PTSD group.(8)
Lanius and colleagues reported two fMRI studies where they used a script-driven symp-
tom provocation paradigm. They also observed significantly decreased blood oxygen level–
dependent method (BOLD) signal in the ventral ACC (Brodmann’s area 32) and the thalamus in
the PTSD group to both the traumatic and nontraumatic emotional states conditions, suggest-
ing that the earlier neuroimaging findings related to these areas in PTSD may not be specific to
traumatic stimuli.(9, 10) Hendler and colleagues studied processing of repeated versus novel
visual presentations in an fMRI study of combat veterans with and without PTSD. Repeated
presentations resulted in less decrease in BOLD signal in the lateral occipital cortex in PTSD
subjects, interpreted as impaired visual habituation to trauma-related stimuli.(11) A more
recent PET script-driven imagery study of 17 Vietnam veterans with PTSD and 19 without
PTSD replicated rCBF decreases in the medial frontal gyrus in the PTSD group. This activity
was inversely correlated with rCBF changes in the left amygdala and the right amygdala–
periamygdaloid cortex. Interestingly, only the male subgroup showed increased rCBF in left
amygdale.(12) We recently reported the results of a [15O] H2O PET, script-driven imagery
study of emotionally evocative and neutral autobiographic events in 16 combat veterans with
PTSD (PTSD patients [PP], 15 combat veterans without PTSD (combat controls [CC]) and 14
healthy, age-matched, control subjects; (noncombat controls [NC]) that allow to isolate changes
38 Garfinkel AND Liberzon

that are trauma related (PP vs. NC and CC vs. NC) and PTSD specific (PTSD vs. CC). While
all subjects deactivated the mPFC and activated the insula for traumatic scripts, the PP deacti-
vated the rostral anterior cingulate cortex (rACC) more than both control groups (CC and NC)
but did not demonstrate ventromedial PFC (vmPFC) deactivation observed in controls. The
findings observed only in the PTSD group (deactivation of the rACC and higher vMPFC activ-
ity) may reflect neural substrates specific to PTSD.(13)
Neural activation in response to symptom provocation in PTSD has been shown to differ, in
part, as a function of comorbid depression.(14) In one recent study, 15 traumatized subjects with
PTSD and major depression (MDD), 11 traumatized subjects with PTSD and no MDD, and 16 sub-
jects who met criterion A for PTSD but did not reach full diagnosis, were subjected to script-driven
imagery (both traumatic and neutral scripts). Commonalities in brain activation between PTSD
subjects with and without MDD were revealed in the dorsal and ventral ACC, where reduced
activation was observed in response to traumatic scripts relative to traumatized control subjects.
In addition, reduced blood flow, relative to healthy controls, was also observed in the two PTSD
groups in the ventrolateral prefrontal cortex. After controlling for differences in PTSD severity,
the PTSD group with MDD displayed less activity than the PTSD group without MDD in the left
anterior insula (BA 13). PTSD group with MDD had increased activation in the anterior and poste-
rior cingulated gyri relative to the PTSD without MDD subjects. Given the frequent occurrence of
comorbidites, such as MDD, with PTSD, these latter findings highlight the necessity to delineate
what activation variations are a function of PTSD and what are attributable to comorbidities.(14)
To date, though the vast majority of studies have been performed in adult PTSD popula-
tions, only limited studies have been performed in children and/or adolescents with PTSD to
investigate the neural correlates induced by symptom provocation. One small study examined
brain responses during visual perception and imaginary recollection of traumatic reminders in
adolescents (aged 12–14 years) who developed PTSD versus those who did not after experienc-
ing an earthquake.(15) Sample size was limited (five with PTSD vs. six trauma exposed PTSD
negative individuals). During earthquake imagery (as compared with neural imagery), the
PTSD group was found to have activation in the bilateral visual cortex, bilarteral cerebellum,
and left parahippocampal gyrus, relative to the control group. During earthquake perception
relative to neutral perception, the control group showed activation of the ACC, but the PTSD
group did not. Additional analyses demonstrated that intergroup differences were significant,
providing preliminary evidence that neurobiological alternation of PTSD in adolescence are
similar to those occurring in adult PTSD populations.(15)

Correlation with Cross-sectional Symptom Severity

Another way of investigating symptom genesis in PTSD is to correlate imaging findings with
measures of symptom severity. Such an approach allows a quantitative assessment of whether
changes in brain function are related to the magnitude of specific PTSD symptoms. Osuch and
colleagues correlated rCBF response with flashback intensity in a personalized, script-driven
imagery PET paradigm in eight chronic PTSD subjects. rCBF correlated directly with flashback
intensity in the brain stem, insula, and hippocampus, and inversely in the prefrontal, right
fusiform, and medial temporal cortices.(16) Similarly, in an fMRI study, Lanius and colleagues
reported that seven CSA subjects with PTSD and concomitant dissociative responses to symp-
tom provocation by scripts had increased activation in the ACC, mPFC, and several other cor-
tical areas compared to 10 control subjects.(17) However, none of these activations correlated
with either dissociative or flashback intensity. The small samples and significant comorbid-
ity limit the interpretation of these findings. In a script-driven imagery and PET study (8),
Shin and colleagues reported that symptom severity in the PTSD group (as measured by the
total score on the clinician-administered PTSD scale [CAPS]) was positively related to rCBF
in the right amygdala and negatively related to rCBF in medial frontal gyrus after controlling
for depression severity score. In a recent block design fMRI study, investigators examined the
time course of amygdala responses to trauma-relevant negative words, panic-relevant negative
words (negative control condition), positive/safety words, and neutral words, in nine predom-
inantly sexual assault PTSD patients and 14 healthy controls.(18) The PTSD group showed an
increased left amygdala response to trauma-relevant negative versus neutral stimuli compared
to controls in the first two (but not last two) runs, and this response correlated with the symp-
tom severity (CAPS total score). Healthy controls showed the opposite pattern.
Neuroimaging and posttraumatic stress disorder 39

Hypoactive mPFC
(e.g. reduced mPFC responses
to overt fear vs. happy faces).

Impaired ACC
(e.g. reduced activation during
counting Stroop).

Hyperactive amygdala
(e.g. in response to subliminal fear faces).

Impaired hippocampal function

(e.g. Impaired spatial memory).

Figure 4.1  A summary of key functional neuroanatomical impairments associated with PTSD and examples of
cognitive activation paradigms that expose these deficits.

In summary, symptom provocation studies have implicated a number of structures in the

genesis of PTSD, particularly anterior paralimbic and limbic structures, such as the medial orbital
frontal cortex (OFC), the insula, and the medial temporal cortex. One of the more consistent and
reliable findings, is decreased or failure of activation in subregions of the mPFC and ACC, and this
was demonstrated by a number of studies, though was not universally found. Increased respon-
sivity of the amygdala has been observed in some studies, but has not been a consistent finding.
Design and/or methodological factors may contribute to these divergent findings, including the
method of symptom provocation (trauma imagery vs. external stimuli), experimental tasks (pas-
sive viewing vs. active recall), scanning methodology, and relatively small samples, all of which
may affect the ability to activate and/or detect amygdala response.

Cognitive activation studies

One way to assess specific impairments in neuronal processing associated with PTSD is via
cognitive activation studies. These studies utilize a neurocognitive task (a ‘‘probe’’) that is
expected to selectively activate neural circuits implicated in task-related processing. Selectively
activating a circuit without eliciting symptoms has a substantial advantage in that this over-
comes the confound of eliciting a large number of more general or nonspecific trauma-related
responses. Investigators have used cognitive activation strategies to further examine a number
of regions implicated in PTSD by symptom provocation studies, such as the mPFC, amygdala,
ACC, and hippocampus (see Figure 4.1).
The ACC is a region that has been implicated in PTSD, where symptom provocation
studies have revealed it to be hypofunctioning, or failing to activate, relative to unaffected
controls. The ACC is a region that has been activated by many functional neuroimaging studies
and has been implicated in different processes involving cognitive–emotional interactions. A
variety of evidence supports the existence of functional subdivisions in the ACC, with dorsal
ACC supporting cognitive control and error-related processing, while rACC is involved in the
assessment of salience of emotional information and the regulation of emotional responses.
(19) Bremner et al. (2004) used the modified Stroop task (color Stroop, emotional Stroop, and
control task) and [15O] H2O PET to probe ACC function in 12 women with early CSA-related
PTSD and nine CSA women without PTSD. The PTSD group demonstrated a relative decrease
in ACC blood flow during the emotional but not the color Stroop task, which elicited increased
40 Garfinkel AND Liberzon

rCBF in the ACC (BA 24 and 32) in both groups.(20) Shin et al. (2001) also investigated ACC
functioning in 16 Vietnam combat veterans (eight with PTSD) using fMRI and an emotional
counting Stroop paradigm. Subjects were asked to count the number of combat-related, gener-
ally negative, and neutral words while being scanned. In the comparison of combat-related
words with generally negative words, the non-PTSD group showed significant BOLD signal
increases in rACC but the PTSD group did not.(21) In addition, to assess interference process-
ing and inhibitory control, tasks commonly associated with ACC function, a version of the
counting Stroop task incorporating only affectively neutral words also demonstrated hypoac-
tivation of the ACC in patients with PTSD. This task requires participants to count the num-
ber of identical words presented on the screen and to press a button corresponding to the
correct number. In the interference condition, the presented word—a numerical value, is an
“incorrect” response (e.g., four words on the screen all read “two”); in the neutral condition,
the words do not include numbers (e.g., four words on the screen all read “cat”). This task was
performed in 26 trauma-exposed men, 13 of whom met diagnosis for PTSD. The PTSD group
exhibited less deactivation in subgenual ACC and more deactivation in the insula as compared
to controls during the interference minus neutral task.(22)
The amygdala is integral to the generation and maintenance of emotional responses,
and this has been shown in both animal and human studies.(23–25) The amygdala is a region
implicated in rapidly assessing the salience of emotional and especially threat-related stimuli.
(26) A number of studies have presented fearful faces to individuals with PTSD, using vari-
ous exposure durations, and these have converged upon increased amygdala responsivity
in PTSD (especially when stimulus presentation is rapid (27–29)). Rauch et al. (2000) com-
pared amygdala responses in nine PTSD subjects versus eight combat-exposed, non-PTSD
subjects using a previously validated masked emotional faces paradigm. Contrasting fearful
versus happy masked faces revealed exaggerated amygdala responses in the PTSD subjects.
Furthermore, the magnitude of these responses distinguished PTSD subjects with 75% sensi-
tivity and 100% specificity.(29) These findings suggest that PTSD is associated with increased
amygdala responsivity to threat-related (but not necessarily trauma-related) stimuli. Another
group used a similar masked emotional faces paradigm to examine 13 subjects with acute,
rather than chronic PTSD.(27) There was a positive correlation between the severity of PTSD
and the difference in amygdala responses between masked fearful and happy faces. These find-
ings suggest that functional abnormalities in brain responses to emotional stimuli observed in
chronic PTSD might be apparent already in the acute phase. In a recent study, Bryant et al.,
(2008) exposed 15 patients with PTSD and 15 age and sex-matched nontraumatized controls to
fearful stimuli (16.7 ms), followed by a 163.3 ms neutral mask. They found significantly greater
left amygdala activity in the PTSD relative to the control group.(30)
Regarding overt presentation of fearful faces, heightened amygdala activity does not
appear to be particularly robust during this type of processing of fear stimuli, though dif-
ferences have been obtained in some studies.(28) In one study, Shin et al. (2005) used overtly
presented emotional facial expressions and fMRI to compare BOLD responses in 13 men
with PTSD and 13 trauma-exposed men without PTSD. The PTSD group showed increased
amygdala responses and decreased mPFC responses to overt fearful (vs. happy) facial expres-
sions.(31) The amygdala is known to be involved with the rapid assessment of threat, and
hence it appears amydgala-related hypoactivation associated with PTSD is more sensitive to
subliminal exposure durations in the region of 12 to 30 ms. Overt, longer duration exposure
might lead to signal that integrates repeated stimulation and the habituation processes, and
thus it might be less sensitive in picking up changes involving a specific process.
Another region implicated in PTSD is the hippocampus, which plays a role in explicit mem-
ory processes as well as contextual learning.(32, 33) Individuals with PTSD perform poorly on
neuropsychological memory tasks.(34, 35) A number of structural MRI studies reported decreased
hippocampal volumes in individuals with PTSD (34, 36–39), and Magnetic resonance spectros-
copy (MRS) studies have reported decreased N-acetylaspartate (NAA) levels in the hippocam-
pus, interpreted as reflecting decreased neuronal integrity.(40, 41) Reductions in hippocampal
volumes have ranged from 5% to 26% and have tended to be found bilaterally across studies.(42)
It should be noted, however, that a number of studies have not replicated the finding of decreased
hippocampal volumes in PTSD.(43–45) These discrepancies suggests that smaller hippocampi
may be restricted to subgroups of PTSD, may be secondary to comorbid conditions, or that
Neuroimaging and posttraumatic stress disorder 41

hippocampal pathology may be subtle and not always detectable using standard morpho-
metric MRI procedures.(42) Furthermore, it has not been clear whether reported hippocampal
changes are acquired signs of PTSD or potential predisposing factors.
Work done in twin studies helps to clarify what are the predisposing factors relative
to acquired signs of PTSD. Gilbertson et al. (2002) studied monozygotic twins discordant for
trauma exposure, with and without PTSD, and found that both twins with PTSD and their
trauma-unexposed twin had smaller hippocampi relative to trauma-exposed, non-PTSD twins
and their cotwin.(46) Moreover, the same group, both PTSD and trauma–nonexposed cotwin,
showed impaired hippocampus-mediated spatial processing, using a cue configuration task.
(47) These findings offer compelling evidence for reduced hippocampal size and function serv-
ing as a vulnerability or predisposing factor for PTSD.
To investigate impaired hippocampal functioning associated with PTSD, Shin et al.
(2004) used PET in 16 firefighters (eight with PTSD) using a word stem completion task.
Subjects completed a three-letter word stem with deeply encoded/high-recall and shallow
encoded/low-recall words learned during a preceding training session. Somewhat surpris-
ingly the PTSD group demonstrated greater rCBF in the hippocampi (bilateral) across con-
ditions, and symptom severity was positively associated with rCBF in hippocampus and
parahippocampal gyrus. In the comparison of high- versus low-recall conditions, however,
PTSD showed smaller rCBF increases in the left hippocampus. This was interpreted as poten-
tially reflecting reduced efficiency of hippocampus during the performance of an explicit
memory task.(42)

Functional connectivity analyses

There is a growing awareness that complicated cognitive and emotional processes rely on the
orchestrated interactions of distributed brain networks, rather than, or at least in addition to,
activation of individual brain regions. Consequently, functional connectivity analysis, which
refers to the application of specific statistical methods to functional neuroimaging data sets to
identify correlated brain activity across various regions (48, 49), is a particularly relevant and
useful technique. Several recent studies have applied functional connectivity analysis to neu-
roimaging studies of PTSD. Gilboa et al. (2004) studied 20 individuals with a history of civil-
ian trauma (10 with PTSD), using symptom provocation (autobiographical trauma-related and
neutral scripts), and [15O] H2O PET. A multivariate analysis technique (partial least squares)
was used to identify brain regions whose activity covaried with two reference (‘‘seed’’) voxels,
one in right PFC (BA 10) and the other in right amygdala. Amygdala activity was found to sig-
nificantly influence activity in the visual cortex, subcallosal gyrus, and anterior cingulate in the
PTSD subjects but not in the trauma-exposed controls.(50) These findings indicate that blood
flow measures reflect influence of the amygdala on medial frontal regions in PTSD, rather than
a failure of mPFC inhibition of the amygdala. In addition, correlational analyses did not lend
support for the failure of inhibition of the ACC over the amygdala.
Lanius et al. (2004) used functional connectivity analyses on data gathered during fMRI
script-driven symptom provocation experiments in 11 subjects with PTSD from sexual abuse/
assault or motor vehicle accident (MVA) and 13 trauma-exposed subjects without PTSD. In the
case of PTSD subjects (vs. controls) connectivity maps for right ACC showed greater correla-
tions in the right posterior cingulate cortex (PCC) (BA 29), right caudate, right parietal lobe (BA
7 and 40), and right occipital lobe (BA 19). Subjects without PTSD had greater correlations of
ACC with left superior frontal gyrus (BA 9), left anterior ACC (BA 32), left striatum (caudate),
left parietal lobe (BA 40 and 43), and left insula (BA 13).(51) These findings are intriguing;
however, our understanding of functional neural networks both in health and disease is still
very limited. As methods for the analysis of functional connectivity continue to develop and
the knowledge base regarding coordinated activation of brain regions grows these approaches
will likely play an increasingly important role in delineating functional relationships between
regions implicated in the pathophysiology of PTSD.

Summary of functional neuroimaging studies in PTSD

The studies reviewed above involve different cohorts (combat and CSA-related PTSD), differ-
ent paradigms (symptom provocation vs. cognitive activation), and different modalities (fMRI,
42 Garfinkel AND Liberzon

fMRI

Imaging MRS
techniques
PET
Receptor imaging
(baseline)
SPECT

Symptom provocation

Paradigms

Cognitive activation

PTSD vs. control

group differences

Analysis
Functional connectivity
techniques

Correlate activity with

symptom severity

Figure 4.2  A summary of key imaging techniques, paradigms and analysis techniques discussed with in the
chapter that are used to study the functional neuroanatomy associated with PTSD.

PET, and SPECT) [See Figure 4.2 for examples of imaging techniques]. Taken together, they
lend tentative support to a neurocircuitry model that emphasizes the role of dysregulation in
threat-related processing in PTSD. According to this model, trauma exposure sets off a cascade
of neural changes that culminates in a state of amygdala hyperresponsivity to trauma-reminis-
cent and other threat-related stimuli that mediates symptoms of hyperarousal and vigilance
associated with PTSD. The model also proposes associated inadequate top-down control by
the mPFC that maintains and perpetuates the state of amygdala hyperresponsivity and also
helps mediates the failure to suppress attention to trauma-related stimuli. Consistent with this
model, several studies have demonstrated reduced activation of the mPFC (BA 10 and 11) and
ACC (BA 32) in PTSD subjects compared to traumatized controls.(8–10, 21, 52) Other studies
have reported increased responsivity of the amygdaloid region (4, 24, 29), though some have
not (8, 10, 52). While the conceptualization of PTSD-related pathophysiology that emphasizes
the role of threat-related processing has some empirical support, there is clearly a need for a
broader conceptualization of the processes implicated in the disorder. This is because deficits
in threat-related processing explain only some aspects of PTSD, and other significant mani-
festations of PTSD remain unexplained by this model. These include intrusive thoughts and
memories, emotional numbing, vulnerability and resilience factors, and generalization of vigi-
lance and avoidance from the initial traumatic event to other less closely related events. Thus
to understand these complex phenomena, additional relevant mechanisms that may assist in
understanding the complex phenomenology of PTSD need to be explored. The following sec-
tion includes a selective review of emerging neuroimaging research that focuses on a number
of mechanisms that are potentially relevant to the pathophysiology of PTSD, including fear
conditioning and cognitive–emotional interactions.
Neuroimaging and posttraumatic stress disorder 43

Part II: Processes implicated in PTSD and neuroimaging

Studies of threat-related processing (fear conditioning, habituation, extinction, and

extinction recall)
Studies using the fear-conditioning paradigm in rats over the past two decades have helped out-
line a specialized threat-related neurocircuitry with a number of functionally connected regions,
including subregions of the PFC, the amygdala, and the hippocampus. A conceptual framework
amalgamating their findings has been put forward, proposing the existence of two broad path-
ways in the processing of threat-related signals—a subcortical “fast” pathway that transmits fea-
tures of the stimulus rapidly, but with poor specificity, and a cortical “slow” pathway that involves
more integrated and detailed cognitive processing of stimulus characteristics.(53) Animal stud-
ies have identified the amygdaloid complex (central, lateral, and basolateral nuclei) as a crucial
substrate in the formation of stimulus response associations involved in fear conditioning and
aversive learning. Functional neuroimaging studies have used PET and fMRI to examine fear
conditioning in humans, confirming that similar regions identified in animal research subserve
fear conditioning in humans.(54) These usually examined classical conditioning to aversive stim-
uli, typically aversive tones, or mild electrical shocks. For example, Buchel and colleagues used
event-related fMRI to study the classical conditioning of faces paired with aversive tones in nine
healthy right-handed volunteers.(55) Comparison of the CS (+) condition to the CS (–) condition
revealed greater activation of the ACC and greater activation in the amygdala in only early trials,
suggesting a rapid habituation of the amygdala response in healthy volunteers.
There is also empirical work in healthy individuals indicating that the time course of
amygdala activation during aversive conditioning is modulated by attention. Straube et al.
(2007) demonstrated this empirically using stimulus processing to modulate attention. When
attention was directed toward differences between CS (+) and CS (–), increased responses of
the left amygdala to CS (+) versus CS (–) were rapidly established but absent at the end of con-
ditioning trials, while directing attention to similarities between the CS (+) and CS (–) resulted
in amygdala activation during the late but not early phase of conditioning.(56) This is signifi-
cant, as it demonstrates that attention allocation can affect amygdala activation and potentially
fear responding, implying that populations with aberrant patterns of attention allocation, such
as attentional biases, may exhibit different patterns of amygdala activation and fear responses
during conditioning.
Interestingly, studies designed to investigate the time course for amygdala response dem-
onstrated that individuals with PTSD fail to show the same patterns of habituation of amygdala
responding to negative stimuli, suggesting a possible longer maintenance of fear responses in
PTSD.(18) In general, habituation and extinction are two processes that involve a time compo-
nent that modulate conditioning and aversive learning and might be highly relevant to PTSD.
Habituation refers to the process by which repeated presentation of the same CS–US pairing
leads to a decreasing conditioned response (CR), while extinction refers to a reduction and
disappearance of a CR on account of learning about a new stimulus–response association (i.e.,
the CS is no longer associated with the US). These are adaptive processes for organisms as they
provide the organism with flexibility to reallocate critical resources to threat-related stimuli in
a constantly changing environment. The failure of habituation to trauma-related stimuli and/
or the failure of extinction have been hypothesized to contribute to the development or main-
tenance of PTSD (i.e., trauma plays the role of the conditioning event). These phenomena have
been extensively studied in animals and behaviorally in humans, but these processes have only
recently been the subject of neuroimaging investigations.
A number of neuroimaging studies have found that presentation of emotionally expressive
faces, presented both overtly as well as in a masked manner (fearful or happy faces masked with a
neutral face such that subjects consciously perceive only the neutral face) activates the amygdala,
a response that rapidly habituates with repeated presentation regardless of the mode of presen-
tation (overt or masked).(57, 58) Several studies reviewed above, in which a CS is repeatedly
paired with an aversive US, also found rapid habituation of the amygdala response.(55, 59, 60)
One recent fMRI study suggests that repeated presentation of emotionally expressive faces may
generate habituation in a regionally specific manner based on the valence of the facial stimulus.
In this study fearful and happy faces were repeatedly presented in two 2-min runs to eight right-
handed healthy men. Habituation was observed in the left dorsolateral prefrontal cortex (dlPFC)
44 Garfinkel AND Liberzon

and premotor cortex and the right amygdala. The left dlPFC showed increased habituation to
happy rather than fearful faces, the right amygdala exhibited greater habituation to emotionally
valenced stimuli, and the left amygdala responded significantly more to negatively versus posi-
tively valenced stimuli (relative to the right).(61) Our laboratory has also demonstrated rACC
habituation with repeated emotional picture (aversive minus neutral/ blank) presentation.(62)
These studies provide evidence for habituation in the dlPFC, ACC, and the amygdala, with
potentially differential habituation in prefrontal versus subcortical regions, or lateralized special-
ization. Interestingly, the only study that has specifically addressed the time course of amygdala
responses to trauma cues (trauma-relevant words) in PP and healthy controls found an increased
left amygdala response to trauma-relevant negative versus neutral stimuli in the first two but not
last two runs. This response correlated with the symptom severity (CAPS total score). However,
while sensitization to nontrauma negative words was seen in the PTSD group, failure of habitu-
ation to trauma-related words was not seen.(18)
The process of extinction has also been the subject of recent neuroimaging studies and it has
been suggested that a failure to adequately extinguish fear responses is the mechanism underlying
the maintenance of pathological fear in PTSD.(63) Phelps et al. (2004) used a simple discrimina-
tion, partial reinforcement, fear-conditioning paradigm with an event-related fMRI design. Colored
squares were used for conditioned Stimulus (CS) (+) and conditioned Stimulus (CS) (–) (blue and
yellow) and unconditioned stimulus (US) was a mild wrist shock. The study was conducted in
three phases, an acquisition phase in which subjects were exposed to reinforced presentations of
the CS, followed by Day 1 extinction and Day 2 extinction, in which subjects were exposed to unre-
inforced presentations of the CS. The authors reported that right amygdala activation predicted the
CR in the early acquisition (positive correlation) and Day 1 extinction phase (negative correlation).
The vmPFC (the subgenual anterior cingulate region of interest) response positively correlated with
the CR magnitude during Day 2 extinction.(64) Milad et al. (2007) studied recall of fear extinction
in healthy adults (N = 17). Context was manipulated, separating acquisition and extinction context,
and extinction recall took place the next day, in the extinction context. Significant bilateral activa-
tions in the vmPFC and left amygdala were identified during fear extinction and two distinct loci
within the vmPFC and bilateral hippocampi during extinction recall.(65)
Together, these findings appear to be consistent with those of animal research that impli-
cate the amygdala in acquisition and extinction and the vmPFC in the retention and recall
of the extinction learning process.(25, 64, 66–68) They are also intriguing in light of evidence
reviewed earlier from human neuroimaging studies of altered connectivity between medial
frontal regions and amygdala in PTSD. Thus, the evidence from human neuroimaging studies
implicates subregions of the mPFC and OFC; subdivisions of the ACC; the extended amygdala;
the hippocampus; and nuclei of the thalamus in the processes of fear conditioning, habitua-
tion, and extinction. The neuroimaging studies of these processes in healthy humans and also
extending these studies to patients with PTSD are needed to better understand the roles of fear
conditioning, habituation, and extinction in PTSD pathophysiology and symptom generation.

Cognitive–emotional interactions: appraisal, reappraisal, and

emotional regulation

Emotion regulation refers to the set of mental processes by which people amplify, attenuate, or
otherwise modulate emotion states.(69) Key features of PTSD include emotional numbing and
heightened and prolonged experience of fear, anxiety, and other negative affective states. While
it is possible that abnormal threat-processing drives some of these symptoms, it is also possible
that poor emotion regulation plays a key or complimentary role in this disorder and contrib-
utes significantly to behavioral dysfunction. If threat detection is a “bottom-up” process cogni-
tive–emotional interaction can be seen as “top-down” regulation. Abnormalities in either one
or in both of these processing streams can lead to similar outcomes, and in the case of PTSD, to
similar psychopathology. For the purposes of this discussion, emotion regulation is understood
in terms of a number of component processes that operate over different time scales. Appraisal
refers to the cognitive interpretation of emotion-relevant stimuli by higher cortical centers. An
increasing number of neuroimaging studies are providing evidence that cognitive appraisal
can modulate emotional responses, which is reflected in changes in the activity of emotion
Neuroimaging and posttraumatic stress disorder 45

processing areas. Cognitive reappraisal is a form of emotion regulation that involves volition-
ally reinterpreting the meaning of a stimulus to change one’s emotional response to it.
A number of studies have manipulated the extent to which subjects cognitively attend to
aspects of emotion-relevant stimuli. These studies suggest that even the simple process of apprais-
ing an emotion via labeling or rating can reduce the activity in structures that are responsive when
the emotional stimulus is passively viewed or experienced. Hariri and colleagues examined the
cognitive modulation of emotions by comparing the BOLD response in healthy subjects as they
performed three different tasks (match, label, and control). In the match task, subjects were asked to
match the affect of one of two faces to that of a simultaneously presented target face (angry or fear-
ful) whereas in the label task, they were asked to assign one of two simultaneously presented lin-
guistic labels (angry or afraid) to a target face. Matching was associated with increased activation in
both the right and left amygdale, whereas linguistically labeling the expression was associated with
a decreased activation in the amygdala. In addition, right PFC activity was inversely correlated
with left amygdala activity, interpreted as it being the neural substrate for the cognitive modulation
of emotion.(70) This finding has been replicated using threatening and fearful pictures as well.(71)
In our laboratory, we examined rCBF response in healthy subjects comparing a rating to a
passive viewing condition.(72) Subjects saw aversive and neutral pictures while they performed
a passive viewing and rating task. During passive viewing, subjects activated right amygdala/
insula and left insula, and rating was associated with increased activation of the dorsomedial
prefrontal cortex (dmPFC) and the ACC, and with reduced sadness and reduced activation of
the right amygdala/insula and left insula. These findings demonstrate the involvement of the
dmPFC and ACC in the cognitive rating task and suggest modulating effects of these structures
on emotion-related structures, such as the amygdala and insula. These results extend findings
from animal studies that have demonstrated the inhibitory influence of the mPFC over the
amygdale.(73) If indeed dmPFC/ACC dysfunction is present in PTSD, these findings could
suggest one explanation for exaggerated emotional responses of PTSD patients, as they are less
effectively modulated by cognitive appraisal.
The ability to cognitively modulate emotions refers to the efficacy of individuals to effort-
fully change their emotional reaction to a stimulus. Recently, several groups of researchers have
begun to investigate this empirically using imaging, adopting different strategies to induce cog-
nitive modulation. Cognitive reappraisal is one strategy, and this refers to volitional reinterpre-
tion of the meaning of a stimulus to modify one’s emotional response. This line of work is likely
very relevant to PTSD, where an inability to reinterpret the meaning of ambiguous stimuli might
contribute to emotional dysregulation. It is also of much interest in the investigation of brain
mechanisms of cognitive behavioral therapy, an effective treatment for some patients with PTSD.
Ochsner and colleagues used an event-related fMRI design and aversive pictures to study cogni-
tive reappraisal in healthy women. These women were asked to attend (be aware of feelings elic-
ited by the picture) or to reappraise (reinterpret the picture so that it no longer elicits a negative
emotional response) while being scanned.(74) Reappraising (vs. attending) was associated with
increased activation of the dorsal and ventral left lateral prefronal cortex, dmPFC, left temporal
pole, right supramarginal gyrus (SMG), and left lateral occipital cortex. Greater activation in the
right ACC and SMG correlated with greater decreases in negative affect (greater reappraisal suc-
cess); left ventral PFC activation during reappraisal was inversely correlated with activity in the
amygdala. Effective reappraisal resulted in increased activation in lateral PFC and mPFC regions
and in decreased activation of medial OFC and amygdala. Using a similar paradigm, Phan et al.
(2005) showed highly aversive and arousing pictures to healthy subjects, who were instructed
to either ‘‘maintain’’ (feel naturally) or ‘‘suppress’’ (by positive reframing or rationalizing) nega-
tive affect. Successful reduction of negative affect was associated with increasing activation of
dmPFC, dorsal ACC, dlPFC, lateral OFC, and ventrolateral PFC/inferior frontal gyrus, and with
decreasing activity in the left nucleus accumbens, left lateral PFC, and left extended amygdala. In
addition, right dorsal ACC, right anterior insula, bilateral dlPFC, and bilateral ventrolateral PFC
activity inversely correlated with the intensity of negative affect.(75)
These studies provide evidence for the emotion regulatory role of lateral PFC, dmPFC,
SMG, and ACC.(75) The observed difficulty among patients with PTSD to cognitively regulate
their emotions can be hypothesized to be a result of dysfunctional cognitive–emotional pro-
cesses (such as cognitive appraisal and reappraisal) subserved by some of these regions. The
therapeutic mechanisms of cognitive behavioral therapy in PTSD may also be related to these
46 Garfinkel AND Liberzon

processes and structures. There is, therefore, a need to extend these innovative paradigms to
the study of PTSD.

Receptor imaging

Insight into which regions differ in activity as a function of PTSD can be gauged with fMRI, as
the BOLD signal, a measure of the ratio of oxygenated to deoxygenated hemoglobin in the blood
across regions of the brain, is likely to reflect changes in neuronal firing or postsynaptic activity.
In contrast, differences that may exist in functional neurochemistry between those with and with-
out PTSD can be directly gauged with receptor imaging. To date, only a few studies have used
receptor imaging to investigate neurotransmitter abnormalities associated with PTSD. Previous
research in both animals and humans has implicated gamma-Aminobutyric acid (GABA), the
principle inhibitory neurotransmitter within the brain, to be involved in both the pathogenesis
and pathophysiology of PTSD.(76, 77) In a recent study, Geuze et al. (2008) used [11C]flumazenil
and PET to assess differences in the benzodiazepine–GABAA receptor complex in veterans with
and without PTSD.(78) They found reduced binding potential of [11C]flumazenil in veterans with
PTSD relative to control veterans without PTSD, specifically in the hippocampus, thalamus, and
throughout the cortex, including the frontal, temporal, parietal, and occipital cortex.(78) This
suggests that these specific regions may be associated with premorbid differences in the compo-
sition/expression of GABAA –benzodiazepines receptors in PTSD patients or a disease-induced
modulation and/or downregulation of the GABAA receptor complex. Consistent with this study
is a previous [123I]iomazenil SPECT study in Vietnam veterans that also found decreased volume
of distribution of [123I]iomazenil in the medial prefrontal cortex in Vietnam veterans with PTSD
relative to healthy controls.(79) It should be noted, however, that another study also using [123I]
iomazenil and SPECT was unable to find any differences in volume distribution of [123I]iomazenil
between Gulf War veterans with and without PTSD.(80)
In a recent study, our group investigated µ-opioid receptor binding in PTSD, using PET
and the selective µ-opioid radiotracer [11C] carfentanil.(81) We had previously demonstrated
endogenous opioids to be involved in inhibiting and modulating emotional responses in
healthy humans (82), and this was the first study to provide direct evidence of alterations
in µ-opioid receptor in vivo availability in PTSD. We demonstrated significant regional dif-
ferences in the binding of µ-opioid receptor between both the trauma-exposed groups and
normal controls, as well as between PTSD patients and trauma-exposed individuals who did
not develop PTSD. These differences between the groups indicate µ-opioid receptor alterations
arising from trauma that can be differentiated from those specifically associated with PTSD.
Changes were principally located in limbic forebrain and cortical regions known to be involved
in emotion regulation, which likely reflect adaptive changes resulting from trauma exposure or
stress, as well as maladaptive alterations associated with PTSD pathophysiology.(81)
Despite both receptor imaging and fMRI approaches implicating similar brain regions in the
pathophysiology of PTSD (e.g., prefrontal cortex and hippocampus), reconciling the findings of
these two methodologies poses a challenge. The receptor imaging data suggest decreased GABAA
receptor binding potential in prefrontal regions in PTSD, suggesting potentially lower inhibitory
tone, and therefore, enhanced reactivity. In contrast, the fMRI data indicate hypoactivation of cor-
tical regions (specifically mPFC) associated with PTSD. However, if the decreased GABA binding
potential reflects a decreased number of GABAA receptors on the inhibitory interneurons, this
could explain overall higher inhibitory tone in the mPFC. Furthermore, while BOLD activity
likely reflects overall neuronal activity within a particular region, changes both in inhibitory and
excitatory neurotransmission can contribute to the overall BOLD output. Thus, the changes in
one particular neurotransmitter system should not be interpreted as defining the overall changes
in BOLD signal. Moreover, given the complex interconnectivity of the PFC, its heterogeneity, and
its broad functionality, it is possible that PTSD is associated with both increased and decreased
activity within distinct regions of the PFC. To date, receptor imaging in PTSD has focused on
inhibitory systems (GABA and Opioids) and a focus for future research on glutamatergic (excit-
atory) systems, as well as other neurotransmitters/neuromodulators implicated in PTSD, such
as serotonin (83), central catecholamines (84), and corticotrophin-releasing hormone (85), will
further help elucidate the molecular basis of altered brain function associated with PTSD.
Neuroimaging and posttraumatic stress disorder 47

Summary and future directions

Neuroimaging studies of PTSD over the past decade have been based on a model that concep-
tualizes the disorder as a state of heightened responsivity to threatening stimuli and/or a state
of insufficient inhibitory control over exaggerated threat-sensitivity. Consistent with this model,
several studies have demonstrated reduced activation of the mPFC (BA 10 and 11) and ACC (BA
32) in PTSD subjects compared to traumatized controls. Other studies have reported increased
responsivity of the amygdaloid region, although these findings are not always consistent. Results
may be influenced by several methodological issues, such as small samples, heterogeneous pop-
ulations, presence or absence of comorbidities, and varying imaging methods that limit broad
generalization. More importantly, it is still not known what are acquired signs of the disorder
and what are its predisposing factors. Innovative imaging work in twins discordant for PTSD is
beginning to elucidate this issue, suggesting that reduced hippocampus size and function may
be a predisposing factor. Prospective neuroimaging studies are costly and challenging to employ,
though they are essential for the identification of endophenotypes indicative of PTSD vulner-
ability, as well as to effectively delineate what are the causes and consequence of PTSD in terms
of brain morphology and function. PTSD is a complex disorder, and despite the progress made,
existing models and findings are unable to fully capture the complexity of PTSD. Innovative par-
adigms being developed in cognitive and social neuroscience suggest novel directions for future
work that can broaden our understanding of a range of pathophysiological processes in PTSD.
Future directions of research include neuroimaging studies of fear conditioning, habitu-
ation, extinction, and extinction recall, as well as studies investigating emotion regulation pro-
cesses in PTSD. Complicated emotional and cognitive processes rely not only on the activation
of discrete brain regions but also upon the strength and nature of distributed brain networks.
Consequently, increased use of connectivity analyses will help illuminate how the relationship
between different neuronal regions is also impaired in PTSD. There is also a need for prospec-
tive studies, as well as studies that integrate different lines of inquiry, including genetic, neu-
roendocrine (HPA axis, catecholamines, etc.) and neurochemical receptor studies, and blood
flow parameters in PTSD. This research holds the exciting promise of helping to identify neu-
robiological factors that may confer vulnerability or resilience to PTSD and offer meaningful
clues to the pathophysiology of PTSD. This progress will be essential for the future develop-
ment of effective prevention and treatment strategies for this disorder.

References

  1. Liberzon I, Phan KL. Brain-imaging studies of posttraumatic stress disorder. CNS Spectr 2003; 8(9):
641–50.
  2. Pitman RK, Shin LM, Rauch SL. Investigating the pathogenesis of posttraumatic stress disorder with
neuroimaging. J Clin Psychiatry 2001; 62(Suppl 17): 47–54.
  3. Rauch SL, Shin LM. Functional neuroimaging studies in posttraumatic stress disorder. Ann N Y Acad
Sci. 1997; 821: 83–98.
  4. Rauch SL, van der Kolk BA, Fisler RE et al. A symptom provocation study of posttraumatic stress
disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry 1996;
53(5): 380–7.
  5. Shin LM, Kosslyn SM, McNally RJ et al. Visual imagery and perception in posttraumatic stress
disorder. A positron emission tomographic investigation. Arch Gen Psychiatry 1997; 54(3): 233–41.
  6. Liberzon I, Britton JC, Phan KL. Neural correlates of traumatic recall in posttraumatic stress disorder.
Stress 2003; 6(3): 151–6.
  7. Bremner JD, Narayan M, Staib LH et al. Neural correlates of memories of childhood sexual abuse in
women with and without posttraumatic stress disorder. Am J Psychiatry 1999; 156(11): 1787–95.
  8. Shin LM, McNally RJ, Kosslyn SM et al. Regional cerebral blood flow during script-driven imagery
in childhood sexual abuse-related PTSD: A PET investigation. Am J Psychiatry 1999; 156(4): 575–84.
  9. Lanius RA, Hopper JW, Menon RS. Individual differences in a husband and wife who developed PTSD
after a motor vehicle accident: a functional MRI case study. Am J Psychiatry 2003; 160(4): 667–9.
10. Lanius RA, Williamson PC, Densmore M et al. Neural correlates of traumatic memories in
posttraumatic stress disorder: a functional MRI investigation. Am J Psychiatry 2001; 158(11): 1920–2.
11. Hendler T, Rotshtein P, Hadar U. Emotion-perception interplay in the visual cortex: “the eyes follow
the heart”. Cell Mol Neurobiol 2001; 21(6): 733–52.
48 Garfinkel AND Liberzon

12. Shin LM, Orr SP, Carson MA et al. Regional cerebral blood flow in the amygdala and medial
prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch
Gen Psychiatry 2004; 61(2): 168–76.
13. Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I. Corticolimbic blood flow in posttraumatic stress
disorder during script-driven imagery. Biol Psychiatry 2005; 57(8): 832–40.
14. Lanius RA, Frewen PA, Girotti M et al. Neural correlates of trauma script-imagery in posttraumatic
stress disorder with and without comorbid major depression: a functional MRI investigation.
Psychiatry Res 2007; 155(1): 45–56.
15. Hsu CC, Chong MY, Yang P, Yen CF. Posttraumatic stress disorder among adolescent earthquake
victims in Taiwan. J Am Acad Child Adolesc Psychiatry 2002; 41(7): 875–81.
16. Osuch EA, Benson B, Geraci M et al. Regional cerebral blood flow correlated with flashback intensity
in patients with posttraumatic stress disorder. Biol Psychiatry 2001; 50(4): 246–53.
17. Lanius RA, Williamson PC, Boksman K et al. Brain activation during script-driven imagery induced
dissociative responses in PTSD: a functional magnetic resonance imaging investigation. Biol
Psychiatry 2002; 52(4): 305–11.
18. Protopopescu X, Pan H, Tuescher O et al. Differential time courses and specificity of amygdala
activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry 2005;
57(5): 464–73.
19. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends
Cogn Sci 2000; 4(6): 215–22.
20. Bremner JD, Vermetten E, Vythilingam M et al. Neural correlates of the classic color and emotional
stroop in women with abuse-related posttraumatic stress disorder. Biol Psychiatry 2004; 55(6): 612–20.
21. Shin LM, Whalen PJ, Pitman RK et al. An fMRI study of anterior cingulate function in posttraumatic
stress disorder. Biol Psychiatry 2001; 50(12): 932–42.
22. Shin LM, Bush G, Whalen PJ et al. Dorsal anterior cingulate function in posttraumatic stress disorder.
J Trauma Stress 2007; 20(5): 701–12.
23. Davis M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci 1992; 151: 353–75.
24. Liberzon I, Taylor SF, Amdur R et al. Brain activation in PTSD in response to trauma-related stimuli.
Biol Psychiatry 1999; 45(7): 817–26.
25. Morgan MA, LeDoux JE. Differential contribution of dorsal and ventral medial prefrontal cortex to
the acquisition and extinction of conditioned fear in rats. Behav Neurosci 1995; 109(4): 681–8.
26. Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol Psychiatry 2001; 6(1): 13–34.
27. Armony JL, Corbo V, Clement MH, Brunet A. Amygdala response in patients with acute PTSD to
masked and unmasked emotional facial expressions. Am J Psychiatry 2005; 162(10): 1961–3.
28. Bryant RA, Kemp AH, Felmingham KL et al. Enhanced amygdala and medial prefrontal activation
during nonconscious processing of fear in posttraumatic stress disorder: an fMRI study. Hum Brain
Mapp 2008; 29(5): 517–23.
29. Rauch SL, Whalen PJ, Shin LM et al. Exaggerated amygdala response to masked facial stimuli in
posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 2000; 47(9): 769–76.
30. Bryant RA, Kemp AH, Felmingham KL et al. Enhanced amygdala and medial prefrontal activation
during nonconscious processing of fear in posttraumatic stress disorder: an fMRI study. Hum Brain
Mapp 2008; 29(5): 517–23.
31. Shin LM, Wright CI, Cannistraro PA et al. A functional magnetic resonance imaging study of
amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic
stress disorder. Arch Gen Psychiatry 2005; 62(3): 273–81.
32. Corcoran KA, Maren S. Hippocampal inactivation disrupts contextual retrieval of fear memory after
extinction. J Neurosci 2001; 21(5): 1720–6.
33. Eichenbaum H. A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 2000; 1(1):
41–50.
34. Bremner JD, Randall P, Scott TM et al. MRI-based measurement of hippocampal volume in patients
with combat-related posttraumatic stress disorder. Am J Psychiatry 1995; 152(7): 973–81.
35. Bremner JD, Scott TM, Delaney RC et al. Deficits in short-term memory in posttraumatic stress
disorder. Am J Psychiatry 1993; 150(7): 1015–9.
36. Bremner JD, Randall P, Vermetten E et al. Magnetic resonance imaging-based measurement of
hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual
abuse--a preliminary report. Biol Psychiatry 1997; 41(1): 23–32.
37. Gurvits TV, Shenton ME, Hokama H et al. Magnetic resonance imaging study of hippocampal volume
in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 1996; 40(11): 1091–9.
38. Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B. Hippocampal volume in women victimized
by childhood sexual abuse. Psychol Med 1997; 27(4): 951–9.
39. Villarreal G, Hamilton DA, Petropoulos H et al. Reduced hippocampal volume and total white matter
volume in posttraumatic stress disorder. Biol Psychiatry 2002; 52(2): 119–25.
40. Schuff N, Neylan TC, Lenoci MA et al. Decreased hippocampal N-acetylaspartate in the absence of
atrophy in posttraumatic stress disorder. Biol Psychiatry 2001; 50(12): 952–9.
Neuroimaging and posttraumatic stress disorder 49

41. Villarreal G, Petropoulos H, Hamilton DA et al. Proton magnetic resonance spectroscopy of the hippocampus
and occipital white matter in PTSD: preliminary results. Can J Psychiatry 2002; 47(7): 666–70.
42. Shin LM, Shin PS, Heckers S et al. Hippocampal function in posttraumatic stress disorder.
Hippocampus 2004; 14(3): 292–300.
43. Bonne O, Brandes D, Gilboa A et al. Longitudinal MRI study of hippocampal volume in trauma
survivors with PTSD. Am J Psychiatry 2001; 158(8): 1248–51.
44. Carrion VG, Weems CF, Eliez S et al. Attenuation of frontal asymmetry in pediatric posttraumatic
stress disorder. Biol Psychiatry 2001; 50(12): 943–51.
45. De Bellis MD, Keshavan MS, Clark DB et al. A.E. Bennett Research Award. Developmental
traumatology. Part II: Brain development. Biol Psychiatry 1999; 45(10): 1271–84.
46. Gilbertson MW, Shenton ME, Ciszewski A et al. Smaller hippocampal volume predicts pathologic
vulnerability to psychological trauma. Nat Neurosci 2002; 5(11): 1242–7.
47. Gilbertson MW, Williston SK, Paulus LA et al. Configural cue performance in identical twins
discordant for posttraumatic stress disorder: theoretical implications for the role of hippocampal
function. Biol Psychiatry 2007; 62(5): 513–20.
48. Friston KJ, Frith CD, Fletcher P, Liddle PF, Frackowiak RS. Functional topography: multidimensional
scaling and functional connectivity in the brain. Cereb Cortex 1996; 6(2): 156–64.
49. Friston KJ, Frith CD, Liddle PF, Frackowiak RS. Functional connectivity: the principal-component
analysis of large (PET) data sets. J Cereb Blood Flow Metab 1993; 13(1): 5–14.
50. Gilboa A, Shalev AY, Laor L et al. Functional connectivity of the prefrontal cortex and the amygdala
in posttraumatic stress disorder. Biol Psychiatry 2004; 55(3): 263–72.
51. Lanius RA, Williamson PC, Densmore M et al. The nature of traumatic memories: a 4-T FMRI
functional connectivity analysis. Am J Psychiatry 2004; 161(1): 36–44.
52. Bremner JD, Staib LH, Kaloupek D et al. Neural correlates of exposure to traumatic pictures and
sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron
emission tomography study. Biol Psychiatry 1999; 45(7): 806–16.
53. LeDoux JE. Emotion Circuits in the Brain. Annu Rev Neurosci 2000; 23: 155–84.
54. Buchel C, Dolan RJ. Classical fear conditioning in functional neuroimaging. Curr Opin Neurobiol
2000; 10(2): 219–23.
55. Buchel C, Dolan RJ, Armony JL, Friston KJ. Amygdala-hippocampal involvement in human aversive
trace conditioning revealed through event-related functional magnetic resonance imaging. J Neurosci
1999; 19(24): 10869–76.
56. Straube T, Weiss T, Mentzel HJ, Miltner WH. Time course of amygdala activation during aversive
conditioning depends on attention. Neuroimage 2007; 34(1): 462–9.
57. Breiter HC, Etcoff NL, Whalen PJ et al. Response and habituation of the human amygdala during
visual processing of facial expression. Neuron 1996; 17(5): 875–87.
58. Whalen PJ, Rauch SL, Etcoff NL et al. Masked presentations of emotional facial expressions amygdala
activity without explicit knowledge. J Neurosci 1998; 18: 411–8.
59. Buchel C, Morris J, Dolan RJ, Friston KJ. Brain systems mediating aversive conditioning: an event-
related fMRI study. Neuron 1998; 20(5): 947–57.
60. LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation during
conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron 1998; 20(5): 937–45.
61. Wright CI, Fischer H, Whalen PJ et al. Differential prefrontal cortex and amygdala habituation to
repeatedly presented emotional stimuli. Neuroreport 2001; 12(2): 379–83.
62. Phan KL, Liberzon I, Welsh RC, Britton JC, Taylor SF. Habituation of rostral anterior cingulate cortex
to repeated emotionally salient pictures. Neuropsychopharmacology 2003; 28(7): 1344–50.
63. Charney DS, Deutch AY, Krystal JH, Southwick SM, Davis M. Psychobiologic mechanisms of
posttraumatic stress disorder. Arch Gen Psychiatry 1993; 50(4): 295–305.
64. Phelps EA, Delgado MR, Nearing KI, LeDoux JE. Extinction learning in humans: role of the amygdala
and vmPFC. Neuron 2004; 43(6): 897–905.
65. Milad MR, Wright CI, Orr SP et al. Recall of fear extinction in humans activates the ventromedial
prefrontal cortex and hippocampus in concert. Biol Psychiatry 2007; 62(5): 446–54.
66. Falls WA, Miserendino MJ, Davis M. Extinction of fear-potentiated startle: blockade by infusion of an
NMDA antagonist into the amygdala. J Neurosci 1992; 12(3): 854–63.
67. Morgan MA, Romanski LM, LeDoux JE. Extinction of emotional learning: contribution of medial
prefrontal cortex. Neurosci Lett 1993; 163(1): 109–13.
68. Morgan MA, Schulkin J, LeDoux JE. Ventral medial prefrontal cortex and emotional perseveration:
the memory for prior extinction training. Behav Brain Res 2003; 146(1–2): 121–30.
69. Gross JJ. Antecedent- and response-focused emotion regulation: divergent consequences for
experience, expression, and physiology. J Pers Soc Psychol 1998; 74(1): 224–37.
70. Hariri AR, Bookheimer SY, Mazziotta JC. Modulating emotional responses: effects of a neocortical
network on the limbic system. Neuroreport 2000; 11(1): 43–8.
71. Hariri AR, Mattay VS, Tessitore A, Fera F, Weinberger DR. Neocortical modulation of the amygdala
response to fearful stimuli. Biol Psychiatry 2003; 53(6): 494–501.
50 Garfinkel AND Liberzon

72. Taylor SF, Phan KL, Decker LR, Liberzon I. Subjective rating of emotionally salient stimuli modulates
neural activity. Neuroimage 2003; 18(3): 650–9.
73. Rosenkranz JA, Grace AA. Cellular mechanisms of infralimbic and prelimbic prefrontal cortical
inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J Neurosci 2002;
22(1): 324–37.
74. Ochsner KN, Bunge SA, Gross JJ, Gabrieli JD. Rethinking feelings: an FMRI study of the cognitive
regulation of emotion. J Cogn Neurosci 2002; 14(8): 1215–29.
75. Phan KL, Fitzgerald DA, Nathan PJ et al. Neural substrates for voluntary suppression of negative
affect: a functional magnetic resonance imaging study. Biol Psychiatry 2005; 57(3): 210–9.
76. Harvey BH, Oosthuizen F, Brand L, Wegener G, Stein DJ. Stress-restress evokes sustained iNOS
activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology
2004; 175: 494–502.
77. Vaiva G, Thomas P, Ducrocq F et al. Low posttrauma GABA plasma levels as a predictive factor in the
development of acute posttraumatic stress disorder. Biol Psychiatry 2004; 55(3): 250–4.
78. Geuze E, van Berckel BNM, Lammertsma AA et al. Reduced GABAA benzodiazepine receptor
binding in veterans with post-traumatic stress disorder. Mol Psychiatry 2008; 13: 74–83.
79. Bremner JD, Innis RB, Southwick SM et al. Decreased benzodiazepine receptor binding in prefrontal
cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 2000; 157(7): 1120–6.
80. Fujita M, Southwick SM, Denucci CC et al. Central type benzodiazepine receptors in Gulf War
veterans with posttaumatic stress disorder. Biol Psychiatry 2004; 56: 95–100.
81. Liberzon I, Taylor SF, Phan KL et al. Altered central mu-opiod binding after psychological trauma.
Biol Psychiatry 2007; 61(9): 1030–8.
82. Liberzon I, Zubieta JK, Fig LM et al. mu-Opioid receptors and limbic responses to aversive emotional
stimuli. Proc Natl Acad Sci U S A 2002; 99: 7084–9.
83. Southwick SM, Krystal JH, Bremner JD et al. Noradrenergic and serotonergic function in posttraumatic
stress disorder. Arch Gen Psychiatry 1997; 54(8): 749–58.
84. Yehuda R, Southwick SM, Giller EL, Ma XW, Mason JW. Urinary catecholamine excretion adn severity
of PTSD symptoms in vietnam combat veterans. J Nerv Ment Dis 1992; 180(5): 321–5.
85. Bremner JD, Licinio J, Darnell A et al. Elevated CSF corticotropin-releasing factor concentrations in
posttraumatic stress disorder. Am J Psychiatry 1997; 154(5): 624–9.
 5 Brain circuits in posttraumatic stress
disorder
Eric Vermetten and Ruth Lanius

Introduction

With the notion that the primary goal in research in the clinical neuroscience of stress-related disor-
ders is to apply findings related to the effects of stress on the brain in animals to patients with stress-
related disorders (e.g., posttraumatic stress disorder [PTSD]), a variety of different methods have
contributed to the working model of the neural circuitry of PTSD that is presented here. In addi-
tion to preclinical studies that look at brain tissue specificity to stress, in human studies the neural
circuitry can be studied by measuring volumes of key brain structures with structural neuroimag-
ing; the brain metabolic response to provocation of disease-specific symptoms in conjunction with
functional neuroimaging, using neuroimaging to measure neuroreceptors; or neurotransmitters
and hormone levels in blood, urine, and saliva, as well as assessing behavioral and biochemical
responses to pharmacological challenge to specific neurochemical systems. The composite of these
methods enables a definition of the circuitry that is involved in the pathophysiology of PTSD. As
such the circuitry is mediating symptoms of the wider trauma-related disorders (e.g., acute stress
disorders, dissociative disorders, pathological grief) [see also Liberman chapter].
Only since the last 10 years a model of PTSD could start to be validated with the newer
neuroimaging methods. The imaging facilities and also the studies that have contributed to the
model have improved over the past decade, mostly due to technical and software enhancements.
Spatial and temporal resolution of neuroimaging methods have improved much (Dickerson,
2007) that promise to reveal novel insights into the function of fine-scale neural circuitry of the
stress response. However, the findings of the various studies, research designs, methodologies,
and techniques that will be discussed in this chapter vary to a great extent, show incoherence,
or sometimes opposite results. Repeated studies across centers are an important prerequisite
to generate consensus for a model. The lack of coherency of findings between studies may
be accounted for by a large variety of parameters, among which standardization of the study
protocol, and imaging parameters are of key importance. This review first focuses on the basic
structures involved in the stress response and then moves on to discussing the compromised
neural circuits in PTSD that were revealed through functional neuroimaging research. It covers
various techniques (single positron emitted tomography (SPECT), positron emission tomogra-
phy (PET), and functional neuroimaging (fMRI) that use different paradigms (resting, active
tasks, stimulus presentation) and provides a global overview of the current findings of these
studies. New developments in the field are also discussed briefly in the last section.

A working model for a neural circuitry in PTSD

Based on studies of the effects of stress on animals and emerging work in clinical neuroscience of
PTSD, a working model for a neural circuitry of fear that is also applicable to PTSD can be described
(see Vermetten and Bremner, 2002). This model is based on work of Charney and Bremner (Bremner
et al. 1995, Charney et al. 1993). This work is ongoing and the models proposed may be subject to
modification and revision as our knowledge base in this area continues to expand.
The brain structures that constitute a neurological working model for traumatic stress
should have several features:
1 Sufficient afferent input should be provided to permit assessment of the fear-producing
nature of the event;
2 The neuronal interactions between the brain structures must be capable of incorporation of
a person’s prior experience into the cognitive appraisal of stimuli;
52 Vermetten AND Lanius

3 The ability to effectively lay down memory traces related to a potential threat;
4 Efferent projections from the brain that are able to mediate an individual’s neuroendo-
crine, autonomic, and motor responses.

Critical brain structures involved in mediating fear behavior resulting from traumatic stress are
locus coeruleus (LC), hippocampus, amygdala, prefrontal cortex, thalamus and hypothalamus,
and periaqueductal grey (PAG), which contribute to neural mechanisms of fear conditioning,
extinction, and behavioral sensitization in case of persistent symptoms of traumatic stress.
The model provides the neural circuitry that plays a role in describing how information
related to a threatening stimulus (e.g., being threatened by someone at gunpoint or witnessing a
deadly car accident) enters the primary senses (smell, sight, touch, hearing); is integrated into a
coherent image that is grounded in space and time; activates memory traces of prior similar expe-
riences with the appropriate emotional valence (necessary in order to evaluate the true threat
potential of the stimulus); triggers a stress response and subsequently triggers appropriate and
adaptive behavioral response, like defending yourself, running away, or calling for help.
Afferent sensory input enters through the eyes, ears, smell, touch, the body’s own visceral
information, or any combination of these. These sensory inputs are relayed through the dorsal thal-
amus to cortical brain areas, such as primary visual (occipital), auditory (temporal), or tactile (post-
central gyrus) cortical areas. Olfactory sensory input, however, has direct inputs to the amygdala
and entorhinal cortex (Turner et al. 1978). Input from peripheral visceral organs is relayed in the
brainstem to the LC, site of the majority of the brain’s noradrenergic neurons (see companion
paper), and from here to central brain areas. These brain areas have projections to multiple areas,
including amygdala, hippocampus, entorhinal cortex, orbitofrontal cortex, and cingulate, which
are involved in mediating memory and emotion (Van Hoesen et al. 1972) (Vogt & Miller 1983).
Cognitive appraisal of potential threat, which involves placing the threatening object in
space and time, is an important aspect of the stress response. Specific brain areas are involved
in these functions (like localizing objects in space, visuospatial processing, memory, cognition,
action, and planning). The anterior cingulate gyrus (Brodmann Area 32) is involved in selection
of responses for action as well as emotion (Devinsky et al. 1995). This area and other medial
portions of the prefrontal cortex, including Brodman’s Area 25 and orbitofrontal cortex (OFC),
modulate emotional and physiological responses to stress. If one is approached in a potentially
threatening situation, it will be important to determine whether the face of the person you see
is someone known to you or is a stranger who may be more threatening. Also, it is important
to place the situation in time and place. Entering a dark alleyway may trigger prior memories
of being robbed, with associated negative emotions and physiological arousal. These memo-
ries may have survival value in that the individual will avoid the situation where the previous
negative event took place, with arousal stimulated and eventual flight prepared. Retrieval of
prior memories of traumatic events has survival value for a true threatening situation; how-
ever, if retrieval occurs repeatedly in nonthreatening situations situation it can be maladaptive
and so lead to symptoms of PTSD.
It is critical to effectively lay down memory traces related to a potential threat in order to
prevent, defend against, or avoid types of threat in the future. The hippocampus and adjacent cor-
tex mediate declarative memory function (e.g., recall of facts and lists) and play an important role
in integration of memory elements at the time of retrieval and in assigning significance for events
within space and time (Squire & Zola-Morgan 1991). The hippocampus also regulates the neuroen-
docrine response to the stress by its role in glucocorticoid negative feedback. The function of the
amygdala in the processing of fear involves conditioning and addition of an emotional valence to
the situation. The amygdala also has direct connections that initiate motor responses to fear (Sarter
& Markowitsch 1985). It is most likely that fearful experiences will be stored in long-term memory.
However, (dissociative) amnesia for traumatic events, a widely debated issue regarding memories
for childhood abuse, is not an uncommon phenomenon in patients with trauma-related disorders
(Bremner et al. 1996) (Chu et al. 1999) (van der Hart et al. 2005) (Vermetten and Bremner, 2000).
With long-term storage, memories are felt to be shifted through hippocampal synaptic plasticity
by protein synthesis, from hippocampus to the neocortical areas where also the sensory impres-
sions are stored (Neves et al. 2008) (Bekinschtein et al. 2007).
In situations of extreme fear, a special category of memory is involved, which entails
the implicit (probably unconscious) learning and storage of information about the emotional
Brain Circuits in Posttraumatic Stress Disorder 53

significance of events. The neural system underlying emotional memory involves the amygdala
and structures with which it is connected. Afferent inputs from sensory processing areas of the
thalamus and cortex mediate emotional learning in situations involving specific sensory cues,
whereas learning about the emotional significance of more general, contextual cues involves
projections to the amygdala from the hippocampal formation (LeDoux 1993). Associative pro-
cesses can occur during the process of fear conditioning, and these may underlie the long-
term associative plasticity that constitutes memory of the conditioning experience (Rogan et
al. 1997). Fear conditioning to explicit and contextual cues has been proposed as a model for
intrusive memories that in a kindling-like process, are reactivated by trauma-related stimuli
and hyperarousal, respectively (Grillon et al. 1996). Clinicians often report that ‘traumatic cues’
such as a particular sight or sound reminiscent of the original traumatic event can trigger a cas-
cade of anxiety- and fear-related symptoms in a patient, not uncommonly without conscious
recall of the original traumatic event (Vermetten & Bremner 2003).
Frontal cortical areas modulate emotional responsiveness through inhibition of amygdala
function, and it has been hypothesized that dysfunction in these regions may underlie path-
ological emotional responses in patients with PTSD, and possibly other anxiety disorders.
Medial prefrontal cortex (mPFC) (area 24, 25 and 32) (incl. subcallosal gyrus) has projections
to the amygdala (Buchanan et al. 1994), which are involved in the suppression of amygdala
responsiveness to fearful cues. Dysfunction of this area may be responsible for the failure of
extinction to fearful cues, which is an important part of the anxiety response (Morgan et al.
1993) (Anderson & Insel 2006). In animal models of extinction, the aversive association in the
amygdala seems to be inhibited rather than removed; fear can be rapidly reinstated even long
after extinction either by the presentation of the conditioned stimulus in a different context
or by a single stimulus-shock pairing (Myers & Davis 2007). medial prefrontal cortex (MPF)
is involved in regulation of peripheral responses to stress, including heart rate, blood pres-
sure, and cortisol response (Roth et al. 1988). Finally, case studies of humans with brain lesions
(e.g., the famous case of Phineas Gage) have implicated mPFC (including orbitofrontal cortex,
Area 25, and anterior cingulate, Area 32) in “emotion” and socially appropriate interactions
(Damasio et al. 1994). Auditory association areas (temporal lobe) have also been implicated in
animal studies as mediating extinction to fear responses (Quirk et al. 1997). As reviewed later,
in PTSD patients, dysfunction of medial prefrontal cortex and auditory cortex during exposure
to traumatic reminders has been reported in several studies (Bremner et al. 1999, Bremner et al.
1999, Liberzon & Sripada 2008, Shin et al. 1997b).
A final component of the traumatic stress response involves preparation for a response to
potential threat. Preparation for responding to threat requires integration between brain areas
involved in assessing and interpreting the potentially threatening stimulus, and brain areas
involved in response. For instance, prefrontal cortex and anterior cingulate play an important
role in the planning of action and in holding multiple pieces of information in ‘working memory’
during the execution of a response (Goldman-Rakic 1988). Parietal cortex and posterior cingu-
late cortex are involved in visuospatial processing that is an important component of the stress
response. Motor cortex may represent the neural substrate of planning for action. The cerebellum
has a well-known role in motor movement, which would suggest that this region is involved in
planning for action; however, recent imaging studies are consistent with a role in cognition as
well (Katz & Steinmetz 2002). Connections between parietal and prefrontal cortex are required
in order to permit the organism to rapidly and efficiently execute motor responses to threat. It
is, therefore, not surprising that these areas have important innervations to precentral (motor)
cortex, which is responsible for skeletal motor responses to threat, which facilitate survival. The
striatum (caudate and putamen) modulates motor responses to stress. The dense innervation of
the striatum and prefrontal cortex by the amygdala indicates that the amygdala can regulate both
of these systems. These interactions between the amygdala and the extrapyramidal motor system
may be very important for generating motor responses to threatening stimuli, especially those
related to prior adverse experiences (Berretta 2005) (Charney & Deutch 1996).
The organism must also rapidly effect peripheral responses to threat, which are medi-
ated by the stress hormones, cortisol, and arganine vasopressine (AVP), and the sympathetic
and parasympathetic systems. Stimulation of the lateral hypothalamus results in sympathetic
system activation producing increases in blood pressure and heart rate, sweating, piloerec-
tion, and pupil dilatation. Stress stimulates the release of corticotropin reseasing factor (CRF)
54 Vermetten AND Lanius

from the hypothalamic periventricular nucleus (PVN), which in turn increases peripheral
adrenocorticotrophic hormone (ACTH) and cortisol levels. The medial prefrontal cortex, as
mentioned above, also mediates increased blood pressure and pulse as well as elevations in
cortisol in response to stress. Striatum, amygdala, and bed nucleus of the stria terminalis also
affect peripheral responses to threat through inputs to the lateral nucleus of the hypothamalus
(Walker et al. 2003) (Grillon 2008). The vagus and splanchnic nerves are major projections of
the parasympathetic nervous system. Afferents to the vagus include the lateral hypothalamus,
PVN, LC, and the amygdala. Efferent connections to the splanchnic nerves have been described
occurring from the LC (Clark & Proudfit 1991).

Formation of traumatic memories

The molecular basis and brain locations of certain memories are also now becoming better under-
stood. Storage of memories of stressful life events appears to involve changes in gene expression in
response to a traumatic stimulus. Genes can be in a state of active transcription in open chromatin
or kept in a silent state in condensed chromatin. Chromatin remodeling to allow gene transcription
is a crucial early step in the memory encoding process. N methyl D aspartase (NMDA) receptor
activation will lead to such chromatin modifications in a small subset of neurons in the dentate
gyrus of the hippocampus (less than 10,000 neurons for each memory-inducing stress event) (see
Chandramohan et al. 2008). These dentate neurons have a prominent role in the encoding of sen-
sory information for the formation of memory and possibly also thus further downstream struc-
tures. This could explain why stress memories can stay so very prominent for an extended period,
and at the same time it would open the possibility for intervention therapies, for example, NMDA
antagonists or glutamate depressing drugs initiated soon after trauma (Reul and Nutt, 2008).
Thus, the pathophysiology of PTSD can be linked to several neurobiological mechanisms
related to traumatic stress. Preclinical studies that investigated the effects of stress on neural
processes such as learning and memory retention were initially used to model PTSD as humans
experience it. These studies suggested that an altered fear response mechanism, behavioral
sensitization, and failure of the extinction of fear play an important role in the pathophysiology
of PTSD (Charney et al. 1993) (see Figure 5.1). These neuro- or psycho-biological mechanisms
will be briefly described below:

Behavioral Sensitization (enhanced stress sensitivity)

Insomnia, poor concentration, hypervigilance, and exaggerated startle response are traits related
to the increased susceptibility to stress of patients with PTSD (Vermetten & Bremner 2002).
‘‘Sensitization’’ may be defined as an increase in a certain response due to the presentation of
a specific stimulus. In military veterans with PTSD, for example, a traumatic event, or series of
events they witnessed, is thought to cause the onset of PTSD. Patients become more aroused and
hypervigilant, among other characteristics, than do healthy individuals when presented with
trauma-related stimuli. It is the experience or recurrent experience of traumas that facilitates or
sensitizes this process. It is, therefore, possible to state that PTSD is a certain type of behavioral
sensitization, in which trauma exposure causes the onset of increased stress sensitivity. Although
few human subject studies have investigated these symptoms on a neurobiological level, more
advances have been made in preclinical settings (Stam et al. 2000) (Stam 2007a, Stam 2007b).
The neural circuitry underlying the increased sensitivity to stress is not centralized to a
specific anatomical or functional neurological component because sensitization is a very broad
concept and even occurs at cellular levels throughout the body. In patients with PTSD, the (over)
sensitization is more vivid in the structures and mechanisms involved in the stress response, as
described earlier. An example of this, the glucocorticoid mechanism, is thought to be sensitized
in patients with PTSD, (Yehuda et al. 2004, Yehuda et al. 1991, Rohleder et al. 1994), making
them more susceptible to stress. However, some findings are in contrast with this model. De
Kloet et al. (2007) measured the effect of dexamethasone on the mitogen-induced proliferative
response and on pro- and anti-inflammatory cytokine secretion by PHA-stimulated phytohe-
magglutinin T cells. These results suggest that trauma exposure alone is sufficient to induce
changes in GR binding characteristics, whereas resistance of T cell proliferation to dexametha-
sone only occurs in PTSD (de Kloet et al. 2007).
Brain Circuits in Posttraumatic Stress Disorder 55

sensory
ce
sensory and cognitive associations re

x
r te
Bz to orginal trauma mo

br
Orbito p e-frontal co
tor
mediate fear conditioning

al
l
DA

nta
nguli

ro

c
serotonin
cy

o. f

or
s
/ r
DA

Gyru

tex
amygdala hippocampus

subsequent

m
PF
stress

C
thalamus
orbitoformal sensitisizes the
ento
inhabition rhin response
al c
of the amygdala or te hypothalamus
x

cereb
mediates
extinction CRF
LC
pituitary
el
NPG
lum
peripheral receptor cells of
exteroceptive, auditory, visual,
TRAUMA-STRESS somesthetic sensory systems, PAG
olfactory systems and visceral
afferent systems

Figure 5.1  A schematic model for the neural circuits involved in the afferent input of fear and anxiety-inducing
stimuli and the processing of the stimuli. The amygdala plays a pivotal role in the assessment of danger and the
response. The LC is a critical component in both afferent and efferent systems, mainly through the NE release.
The amygdala receives input from PAG, LC, thalamus, hippocampus, association cortices, entorhinal cortex,
and visceral pathways. Input form mPFC is involved in determining the significance of fear producing sen-
sory events, the choice and implementation and the type of behavior, and the extinction of conditioned fear
responses. States of stress and fear result in a rapid increase in firing of neurons in the LC, with release of
NE transmitter in different target sites in the brain. This results in an increase in attention and vigilance, as
well as enhancement of memory recall, which can be life saving in threatening situations. Patients with anxiety
disorder, however, develop long-term alterations in function of this system. The fear response is dependent on
previous experience, sensitization, fear conditioning and extinction of previous fear responses. (from Vermetten
and Bremner, 2002).

Fear Conditioning
Among the most characteristic feature of PTSD is that ‘anxiogenic’ memories (e.g., of the trau-
matic experience) can remain seemingly indelible for years or decades without causing prob-
lems and then can be reawakened by various sorts of stimuli and stressors. The strength of
traumatic memories relates, in part, to the degree to which certain neuromodulatory systems,
particularly catecholamines and glucocorticoids, are activated by the traumatic experience.
Release of these stress hormones promotes the encoding of memories of the stressful event.
Long-term alterations in these catecholaminergic and glucocorticoid systems may not only be
responsible for symptoms of fragmentation of memories but also for hypermnesia, amnesia,
deficits in declarative memory, delayed recall, and other aspects of the wide range of memory
distortions in anxiety- and traumatic stress–related disorders. Experimental and clinical inves-
tigations provide evidence that memory processes remain susceptible to modulating influences
after information has been acquired. The brain mechanisms by which sensory representations
(such as colors, objects, or individuals) are selected for episodic encoding are not fully under-
stood. It is thought that with long-term storage, memories are shifted from hippocampus to
the neocortical areas, as the neocortex gradually comes to support stable, long-term storage
(Murray et al. 2001; Wang et al. 2008). The shift in memory storage to the cortex may repre-
sent a shift from conscious representational memory to unconscious memory processes that
indirectly affect behavior. “Traumatic cues” such as a particular sight or sound reminiscent of
the original traumatic event will trigger a cascade of anxiety and fear-related symptoms will
ensue, often without conscious recall of the original traumatic event. In patients with PTSD,
56 Vermetten AND Lanius

however, the traumatic stimulus is always potentially identifiable. In contrast, in panic or

phobic disorder patients, symptoms of anxiety may be related to fear responses to a traumatic
cue (in individuals who are vulnerable to increased fear responsiveness, either through con-
stitution or previous experience), where there is no possibility that the original fear-inducing
stimulus will ever be identified.
Thus, patients with PTSD have symptoms that reflect a more or less continuous percep-
tion of threat with unconsciously processed fear responses (see Vermetten and Spiegel, 2007).
The animal model of contextual fear-conditioning represents a good model for these symp-
toms. Preclinical data suggest that the hippocampus (as well as bed nucleus striae terminals
(BNST) and periaquaeductal grey) plays an important role in the mediation of contextual fear
and that increased responding to conditioned stimuli (CS) is due to hippocampal dysfunction.
Hippocampal atrophy in PTSD, therefore, provides a possible neuroanatomical substrate for
abnormal, contextual fear conditioning and chronic symptoms of feeling of threat and anxiety.
Interestingly, in light of studies showing abnormal noradrenergic function in PTSD, the BNST
has some of the densest noradrenergic innervation of any area in the brain (Yamada et al. 2006).
The startle reflex has been the subject of the few fear-conditioning-specific studies in PTSD
that have been preformed in humans. Startle is a useful method for examining fear responding
in experimental studies involving both animals and humans that is mediated by the amygdala
and connected structures. Patients with combat-related PTSD were found to have elevated
baseline startle compared with controls in some studies but not others. In the patients group
these was asymmetry of baseline startle response (higher in patients) and increased heart
rate responses during measurement of startle. From other studies, it becomes quite clear that
unconscious emotional processes are involved in fear conditioning, for example, patients with
anxiety disorders have demonstrated greater resistance to extinction of conditioned responses
to angry facial expressions, but not to neutral facial expressions, compared with controls. In
the neural circuitry, damage to the amygdala does not prevent patients from learning the rela-
tionship between the CS and the unconditioned stimulus (UCS), but it abolishes conditioned
autonomic responses. In contrast, damage to the hippocampus does not affect conditioned
autonomic responses, but does prevent learning of the conditioned stimulus (CS)–US uncondi-
tioned stimulus association. Further evidence for unconscious processes stems from backward
masking techniques, which prevents conscious awareness of a stimulus. Using such a tech-
nique, fear conditioning to a certain class of stimuli called fear-relevant stimuli (e.g., spiders
and snakes) proves to be mediated by preattentive, automatic information-processing mecha-
nisms. These automatic mechanisms may be mediated in part by direct thalamic–amygdala
connections. These thalamo–mygdala pathways that bypass the cerebral cortex may trigger
conditioned responses before the stimulus reaches full awareness, providing an explanation
for unconscious conditioned phobic responses to fear-relevant stimuli (Katkin et al. 2001).

Failure of Extinction
The process of fear extinction is closely linked to the conditioning of fear. When a person is
exposed to a normally dangerous situation from which no aversive events result, this situ-
ation elicits a smaller fear response than before—a process which repeated leads to smaller
and smaller responses called extinction. In patients with PTSD, this process does not occur
efficiently, and fear of certain situations fails to extinguish. In military veterans this may be
identified by persistent, fearful responses to large, noisy crowds, fireworks, and doors slam-
ming, among other forms of traumatic recall. Therefore, some permanence in fear conditioning
in patients is due to a dysfunction in the extinction of fear. Ultimately, this can be the cause of
the persistence of the traumatic memories. The neural mechanisms involved in the extinction
of fear greatly overlap with those involved in fear acquisition, as just described.
The main structures involved in the extinction of fear are the medial prefrontal cortex and
the amygdalae (Quirk et al. 2006). NMDA receptors and voltage-gated calcium channels are
essential to extinction processes (Charney 2004). Other systems include the neurotransmitters
gamma-amino-butyric acid (GABA) (Berlau & McGaugh 2006), norepinephrine (Southwick
et al. 1999), and dopamine (Pezze & Feldon 2004). During a fearful response of the amygdala,
the mPFC is activated and attempts to regulate the initial response to the threat so that fear
is contained and managed appropriately. If this prefrontal activation is absent or occurs to a
lesser extent, the amygdala does not receive sufficient inhibitory feedback, resulting in higher
Brain Circuits in Posttraumatic Stress Disorder 57

autonomic arousal and exaggerated responses as we see in patients with PTSD. The amygdala–
mPFC connection (feedback process) is thought to be mediated by GABA interneurons, which
may be malfunctioning in PTSD (Berkowitz et al. 2007, Gilboa et al. 2004) as evidenced by a
reduction in GABA-A receptor binding in mPFC (Bremner et al. 2000; Geuze et al. 2007).

Memory performance in PTSD

A symptom that is common in PTSD patients that is negatively contributing to social and occupa-
tional function is forgetfulness (Geuze et al. 2008a). Patients with PTSD have showed significant defi-
cits in hippocampal-mediated declarative memory (Bremner et al. 1995, Bremner et al. 1993) (Golier
et al. 2002, Vasterling et al. 2002; see review Brewin et al. 2007). A large number of clinical studies have
reported alterations in learning and memory in patients with PTSD, which are consistent with both
deficits in encoding on explicit memory tasks, deficits in retrieval, as well as enhanced encoding or
retrieval for specific trauma-related material (Pitman 1989; Wolfe and Schlesinger 1997; Vasterling
et al. 1998; Bremner and Narayan 1998; Andrews et al. 2000; Buckley et al. 2000; Gilbertson et al.
2001; Roca and Freeman 2001). The majority of these studies found deficits in verbal memory, with a
relative absence of deficits in tasks of attention or visuospatial memory. The alterations varied from
self-reported difficulties in memory (Thygesen, 1970), to impairments of verbal declarative memory
(Sutker et al. 1991; Uddo, 1993; Bremner et al. 1993a; Yehuda et al. 1995; Bremner et al. 1995; Jenkins
et al. 1998; Moradi et al. 1999; Gilbertson et al. 2001). These studies, which involved heterogeneous
groups of trauma populations and comorbidity status, all reported specific deficits in explicit memory
function in PTSD (with no change in IQ). The memory impairments were not accounted for by atten-
tional disturbances or intellectual functioning (Gilbertson et al. 2001; Vasterling et al. 2002). While
attention and immediate memory is also associated with PTSD, some studies did not report verbal
declarative memory deficits (Dalton et al. 1989; Zalewski et al. 1994).
Alterations in memory are correlated with specific brain structures and functional path-
ways that may be altered and are, therefore, possibly dysfunctional in patients with PTSD
(Geuze et al. 2008c). Studies that look into the memory deficiencies in PTSD have found sig-
nificant associations with reductions in hippocampal volume (Geuze et al. 2005b). The hip-
pocampus has been linked to spatial and episodic memory, stress and emotional regulation,
and novelty processing. Lesions of the hippocampus have been found to result in deficiencies
of hippocampus-based learning and memory (Scoville & Milner 2000), 2000]. In conjunction
with the clinical observation that patients with PTSD have been found to perform significantly
more poorly on neuropsychological memory tasks, studies that have examined hippocampal
structure in this population have found smaller hippocampal volumes in patients who have
experienced combat trauma, physical and sexual abuse, and childhood sexual abuse. However,
the findings for hippocampal reductions vary greatly (5–26%) and are found in different areas
within this structure, depending on the methodology, (Geuze et al. 2005a) and are not specific
for PTSD (Geuze et al. 2005b). Moreover, in some studies, trauma-exposed persons without
PTSD also showed significantly smaller bilateral hippocampal compared to nonexposed con-
trols. A recent meta-analyses also found significantly smaller left amygdala volumes in adults
with PTSD compared with both healthy and trauma-exposed controls and significantly smaller
anterior cingulate cortex compared with trauma-exposed controls (Karl et al. 2006).
Although changes in hippocampal volume have been attributed to PTSD, a causal rela-
tionship between a traumatic stressor and hippocampal volume reductions is difficult to prove.
There are two current hypotheses about smaller hippocampal volume. One explanation for a
reduced hippocampal volume in PTSD is the neurotoxicity caused by elevated glucocorticoids,
reduced brain-derived neurotrophic factor (BDNF), and the inhibition of the regeneration of
damaged brain tissue (Vermetten et al. 2003, who also found that treatment for 9 months with
the selective serotonergic reuptake inhibitor (SSRI) paroxetine restored both the hippocampal
volume and memory function ). The second hypothesis is that people who have a smaller hip-
pocampus by birth are (genetically) more at risk to develop PTSD. A twin study that provided
some evidence for the latter hypothesis indicated that there is a negative correlation between
PTSD severity and hippocampal volume in both the patients and their healthy, trauma-unex-
posed twin’s hippocampi (Gilbertson et al. 2002). Furthermore, several studies suggested that
childhood abuse may be a significant contributor to disturbances in hippocampal volume in
58 Vermetten AND Lanius

patients with PTSD during a later stage in their lives. Ultimately, longitudinal studies in popu-
lations regularly exposed to traumatic events may provide evidence of whether hippocampal
volume reduces over time or is initially lower in people who get PTSD.

Functional neuroimaging studies in PTSD

The advent of modern, structural, and functional imaging techniques has opened a great window
of opportunity for conducting neurological research in human patients. In the past years, such
techniques have been used to reveal whether the hypotheses about changes in the brain in PTSD,
made in the 1990s by Charney et al. (1993) and Bremner et al. (1995), were accurate. In more
recent publications by the same authors, hypotheses supported by preclinical data are discussed
in relation to research findings in human subjects (Bremner 2003, Charney 2004). These updates
include neural structures, circuits, and functions that are altered in patients with PTSD. Although
there is no definitive pathophysiology for PTSD and its biological cause, many theories that have
been developed remain closely tied to the mechanisms from the preclinical findings.
Functional neuroimaging techniques are a relatively recent development in the field of
neurological research. There are various ways to measure the activity that takes place in the
brain, all based on different principles. Such techniques include SPECT, PET, and fMRI. These
three techniques derive brain function indirectly from physiological measures such as cerebral
blood flow, blood oxygen levels, and energy consumption. The assumption related to these
techniques is that glucose metabolism and blood flow, among other parameters, alter when
certain brain areas become activated or inhibited. When neural cells fire, their increase in activ-
ity requires a restoration of the energy they used. It is thought that the metabolic demands by
such neurons result in an increased blood flow to these areas (Jueptner & Weiller 1995). Hence,
these methods interpret physiological measures to deduce brain activity. Both SPECT and PET
make use of regional cerebral blood flow (rCBF) and neuroreceptor concentration, whereas
fMRI makes use of the blood oxygen level–dependent (BOLD) signal to show patterns of activ-
ity in the brain.

Functional neuroimaging paradigms

There are various types of strategies used in measuring functional activity of the brain. The
most straightforward way of measuring brain activity is by observing a subject at rest. In PTSD,
researchers have used both PET and SPECT to measure rCBF (Bonne et al. 2003) (Mirzaei et al.
2001) (Seedat et al. 2004), glucose metabolism (Bremner et al. 1997), and the binding potentials
for both benzodiazepine (Bremner et al. 2000, Fujita et al. 2004, Geuze et al. 2008) and serotonin
1A (Bonne et al. 2005) receptors. Cerebral blood flow, and both receptor availability and affin-
ity, are all indirect measures of activity, or potential activity, in the brain. Differences of these
variables in persons with PTSD may be helpful in describing the pathophysiology of the disor-
der. Activity in the brain can also be observed by having subjects participate in an active task
or by exposing them to certain stimuli. When a paradigm includes active tasks, subjects are
asked to perform certain activities that elicit a predicted brain response. These tasks are usually
designed so that they change neural activities in regions hypothesized to be dysfunctional in
PTSD. Such tasks include emotional recall tasks (Pavic et al. 2003), memory recall tasks (Shin
et al. 2004), memory encoding tasks (Bremner et al. 2003c), the counting Stroop task (Shin et
al. 2001b), the emotional Stroop task (Bremner et al. 2004), and the auditory continuous per-
formance task [auditory continuous performance task (ACPT); (Semple et al. 1996b, Semple
et al. 2000a)]. Each of these methods measures variables of how well a subject performs a task
and what actual neural activity is involved during these tasks. Ideally these two variables show
some kind of correlation so the brain activity can explain the performance of a task (Vermetten &
Bremner 2004). In the functional neuroimaging studies of PTSD, paradigms frequently consist
of exposure to visual or auditory stimuli related to a specific type of trauma. In this way, neural
activity can be studied when subjects are exposed to stimuli reminiscent of their traumatic past.
Studies of Vietnam combat veterans have used combat sounds (Bremner et al. 1999, Liberzon
et al. 1999, Pissiota et al. 2002, Zubieta et al. 1999) and combat slides (Bremner et al. 1999,
Brain Circuits in Posttraumatic Stress Disorder 59

Hendler et al. 2003) as well as olfactory cues (Vermetten et al. 2007) to induce trauma-related
stress by symptom provocation. Other studies that include victims of sexual assault or abuse
have used personal traumatic scripts (Britton et al. 2005, Gilboa et al. 2004, Lanius et al. 2002,
Lanius et al. 2003, Liberzon et al. 2003b, Rauch et al. 1996, Shin et al. 2004) to elicit an emotional
response. Although it is interesting to observe these patients during a state of traumatic recall,
it is important to have a baseline with which to compare this activity. This can be done intrap-
ersonally by also measuring activity during a neutral activity or stimulus, or interpersonally,
by having a healthy or trauma control group, or a combination of both.

Summary of current findings

MPFC and amygdala

The findings of the current studies indicate several trends in neural correlates of PTSD, per-
mitting us to create a model of this disorder. Two of the most recurrent findings in patients
with PTSD, using PET, fMRI, and SPECT are decreased medial prefrontal cortex and increased
amygdalar activation. On the other hand, inconsistent findings have been tied to regions such as
the hippocampus and the adjacent parahippocampal gyrus. These inconsistencies could be the
result of a wide variation of parameters in different studies and of the complex nature of PTSD.
Altered function in the amygdala is frequently discussed in the clinical presentation of PTSD.
Studies using symptom provocation paradigms and active tasks have both found an increased
amygdalar activation pattern in patients with PTSD compared to healthy controls. Symptom
provocation studies target the fear response mechanism in which the amygdala is thought to
play a pivotal role. Stimuli successfully used in these paradigms include combat sounds (e.g.,
Zubieta et al. 1999) and images (e.g., Hendler et al. 2003, Shin et al. 1997a), emotional faces
(e.g., Britton et al. 2008, Rauch et al. 2000, Shin et al. 2005), emotional words (e.g., Protopopescu
et al. 2005), and traumatic scripts (e.g., Lanius et al. 2001, Osuch et al. 2008). Furthermore, stud-
ies using active tasks found amygdala activation when subjects were instructed to perform an
auditory continuous performance task (Semple et al. 2000b), explicit memory recall tasks (Shin
et al. 2004), and active trauma recall (Driessen et al. 2004). On the whole, the amygdala appears
to be more responsive in patients with PTSD. This hyperactivation is thought to be the reason
for a failure of the extinction to fearful stimuli, a common component of the clinical presenta-
tion of PTSD (Vermetten & Bremner 2002). Another common finding in studies measuring
neural activity in PTSD is a hypoactivation of the mPFC, which includes the OFC (Brodmann’s
Area 11), the anterior cyngulated gyrus (ACC) (Brodmann’s Area 32), and mPFC proper
(Brodmann’s Areas 9 and 25). Symptom provocation paradigms that found this trend for the
latter two regions in patients with PTSD made use of traumatic sounds and images (Bremner
et al. 1999; Yang et al. 2004a), emotional faces (Britton et al. 2008, Shin et al. 2005), and traumatic
scripts (Bremner et al. 1999; Britton et al. 2005; Lanius et al. 2001; Lanius et al. 2003, Liberson
et al. 2003a, Lindauer et al. 2004, Shin et al. 1999, Shin et al. 2004) (Bremner et al. 1999, Britton
et al. 2005, Lanius et al. 2001, Lanius et al. 2003, Liberzon et al. 2003a, Lindauer et al. 2004,
Shin et al. 1999, Shin et al. 2004, Osuch et al. 2008). Furthermore, studies using active tasks found
relative mPFC deactivation when subjects were instructed to perform an auditory continuous
performance task (Semple et al. 2000b), memory tasks (Bremner et al. 2003b, Lanius et al. 2003),
or a counting Stroop task using combat words (Shin et al. 2001b). Similarly, studies using rest-
ing paradigms (Bremner et al. 1997), symptom provocation (Driessen et al. 2004, Lanius et al.
2001), and active memory tasks also found OFC dysfunction. Studies using SPECT to measure
benzodiazepine receptor-binding affinity have found both reductions (Bremner et al. 2000,
Geuze et al. 2008) and unchanged (Fujita et al. 2004) binding in the mPFC of war veterans. The
latter finding was related to Gulf War veterans, whereas the former included veterans from the
Vietnam era. Several studies have suggested a relationship or direct functional link between
the amygdala and the mPFC regions discussed here. In fact, four functional imaging studies
(Driessen et al. 2004, Semple et al. 2000b, Shin et al. 2004, Shin et al. 2005) have found a decrease
in mPFC activity and a simultaneous hyperactivation of the amygdala in patients with PTSD. It
is thought that the mPFC provides a system of negative feedback to the amygdala, regulating
its activation during emotional and fearful conditions: An increase in mPFC activity inhibits
activation of the amygdala, whereas a decrease in mPFC activity, as found in numerous imag-
ing studies in PTSD, seems to be connected to increased, or unchecked, amygdalar activity.
60 Vermetten AND Lanius

Although there is significant agreement about the connection of mPFC and amygdalar activity
among the functional imaging studies, some findings point in different directions. Gilboa et al.
(Gilboa et al. 2004) reported a parallel increase in mPFC and amygdalar activity, for example.
Conversely, another study reported parallel hypoactivation of these structures in a group of
combat veterans with PTSD (Liberzon et al. 2003a). Other PTSD studies report no changes in
amygdalar (Bremner et al. 1999, Bremner et al. 1999, Britton et al. 2005, Lanius et al. 2007, Lanius
et al. 2003a, Lanius et al. 2002, Lanius et al. 2001, Yang et al. 2004b) or mPFC (Bonne et al. 2005,
Semple et al. 1996b) activity. One possible explanation for the lack of amygdalar activation in
two of these studies (Britton et al. 2005, Lanius et al. 2001) is the use of traumatic scripts (inter-
nally generated stimuli as opposed to externally generated sounds or images). Yang et al. (Yang
et al. 2004a) attributed their lack of amygdalar activation to paradigm design and small sample
size (n = 11). The fact that Rauch et al. (2000) did not observe any mPFC changes is difficult
to explain. In a more recent symptom provocation study using the presentation of emotional
faces, activity in the mPFC was significantly reduced in patients with PTSD (Shin et al. 2005).
Furthermore, studies using combat pictures (Bremner et al. 1999) and slides related to natural
disaster (Yang et al. 2004a) found significantly reduced activation of the mPFC. One possibility
for the lack of results in the study by Rauch et al. (Rauch et al. 2000) could be the presentation of
masked emotional faces, a practice not employed by studies showing reduced mPFC activity.
Semple et al. (Semple et al. 1996a) also failed to find a difference in mPFC activity, yet they did
manage to do so in a more recent study using a similar auditory continuous performance task
paradigm. Finally, Lanius et al. (Lanius et al. 2002) found an increase in mPFC/ACC region,
as opposed to the decreased activation trend. A possible explanation for this is the exclusive
participation of subjects with dissociative responses to fearful stimuli, as we discuss further on.
In a SPECT study, Zubieta et al. (Zubieta et al. 1999) also reported an increased mPFC activity
and hypothesized hyperactive dysfunction of the mPFC.

Hippocampus and parahippocampus

Inconsistencies are not uncommon in neuroimaging studies of PTSD. For instance, findings in
the hippocampus and parahippocampus are highly inconsistent when considered both indi-
vidually and compared to each other. The parahippocampal gyrus, a region anatomically adja-
cent to the hippocampus, is liaison for many neocortical projections from the hippocampus and
also the source of most afferents to the hippocampus. Activity in these structures is, therefore,
related and can be compared to a certain extent. Despite their functional relationship in one of
the limbic pathways, results in functional imaging studies of PTSD appear to be altered regard-
ing these regions, because the majority of findings suggest a decrease in hippocampal function-
ing alongside increased parahippocampal activity. When we look at these results more closely,
however, it is possible to find trends of neural activity disruption in PTSD.
The hippocampus plays a critical role in the consolidation of novel memories of facts
and events. Several studies have shown that patients with chronic PTSD perform significantly
more poorly on hippocampal-based memory and learning tasks (Bremner et al. 1995, Bremner
et al. 1993). Starting from this premise, a multitude of studies have explored the hippocampal
structure of patients with PTSD. A recent review summarized the MRI-based hippocampal
volume reduction studies in PTSD as being inconsistent because both reductions and insig-
nificant differences were observed (Geuze et al. 2005b). Studies reporting differences in the
functional properties of the hippocampus have similarly presented consistency issues. Altered
hippocampal function was reported mostly in paradigms that employ memory to elicit hip-
pocampal activity. PET studies by Bremner et al. using declarative memory tasks (Bremner
et al. 2003a, Bremner et al. 2003c) and script-driven imagery (Bremner et al. 1999) have shown
a failure or reduced activation of the hippocampus. In addition, Shin et al. (2004) demonstrated
reduced hippocampal activation, using PET during a word-stem completion task. On the con-
trary, in the few fMRI studies to report hippocampal dysfunction, Shin et al. (Shin et al. 2001a)
found increased hippocampal activity during a counting Stroop task that used emotionally
valenced words. Some years earlier, using a resting paradigm, Bremner et al. (Bremner et al.
1997) observed reduced hippocampal functioning when administering the a2 receptor antago-
nist yohimbine. In conclusion, reduced activation of the hippocampus is found in patients with
PTSD during memory-related tasks, whereas studies using tasks with emotional content report
inconsistent findings.
Brain Circuits in Posttraumatic Stress Disorder 61

The parahippocampal gyrus is to a great extent functionally related to the hippocampus.

The majority of findings related to this structure show a trend of increased activity, which could
contradict the theory of memory deficits in PTSD. The parahippocampus is an extensive neural
structure with a large functional diversity. In analyzing the studies that specified the precise
location of altered parahippocampal functioning, we can attempt to derive several interesting
conclusions. The studies that suggest decreased parahippocampal functioning (Lanius et al.
2003b, Lanius et al. 2002) refer to more specific regions such as the entorhinal and perirhinal
cortices (Brodmann’s Areas 28 and 35, respectively). The entorhinal cortex has been found to
be one of the major afferents to the hippocampus. Results for these specific regions reported
a decrease in activity in patients with PTSD. Both regions are found to be functionally related
to emotion, memory, and association of these memories. Another region, anatomically differ-
ent but functionally similar to these areas, is the retrosplenial cortex, which is situated in the
posterior cingulate cortex (Brodmann’s Area 30). This region is also involved as an intermedi-
ary between the hippocampus and more cortical areas, and findings from the same studies
show reduced activation in patients with PTSD. On the other hand, three studies that reported
increases in parahippocampal activity referred more specifically to the more posterior-oriented
lingual gyrus (Brodmann’s Area 19; Bremner et al. 1999, Bremner et al. 1999, Shin et al. 2001a,
Yang et al. 2004b). This specific region has previously been linked to visuospatial processing
and visual association (Geuze et al. 2008b). A possible explanation for the increased activity of
this area, and perhaps other regions of the parahippocampus, is that it may facilitate or trigger
flashbacks and intrusive thoughts. The fact that some studies report the specific areas within a
region of interest enables us to make the distinctions found above. Other studies unfortunately
did not report their results in great detail, making it difficult to trace the trend within the
parahippocampus. It is therefore important to note that a future direction in the field of neu-
roimaging should be a common way of reporting results, paying close attention to the level of
detail. This includes a more specific categorization of parahippocampal structures and a better
understanding of the role these play in various networks.

Thalamus
A less documented finding in functional neuroimaging studies is the involvement of the thala-
mus in patients with PTSD even though thalamic dysfunction in PTSD has previously been
shown by several groups (Bremner et al. 1999; Liberzon et al. (1996/7); Lanius et al. 2001; 2003).
The thalamus has also been suggested to be involved in mediating the interaction between
attention and arousal (Portas et al. 1998), both of which are clearly relevant to the phenomenol-
ogy of traumatic stress syndromes. Moreover, the thalamus is an important relay station for
the transmission of external sensory information to different areas of the cerebral cortex and
limbic system where this information is processed. Target regions include the frontal cortex,
cingulated gyrus, amygdala, and hippocampus, all of which are closely related to the neural
networks hypothesized to be active in PTSD. Two studies by Lanius et al. (Lanius et al. 2001,
Lanius et al. 2004) using traumatic script-driven imagery and another using traumatic memory
recall (Lanius et al. 2003a) reported decreased thalamic activity. The disruption in thalamic
activity could lead to several of the traits displayed by the clinical presentation of PTSD. Due
to its functional nature, a disruption in activity of the thalamus could lead to the misinterpre-
tation of external stimuli. It is important to note, however, that the only research group that
found altered activity in PTSD with regard to the thalamus, used MRI as opposed to SPECT
or PET. Furthermore, this particular group uses a 4 Tesla MRI scanner as proposed to the more
conventional (and lower resolution) 1.5 and 3 Tesla scanners. Due to the importance of the
thalamus in relaying sensory information to higher cortical regions, it is a region of interest in
PTSD research that deserves and requires further investigation.

Precuneus
The role of the precuneus has been neglected in PTSD research. When male veterans with
and without PTSD (n = 12 per group) were subjected to fMRI during encoding of 12 neutral,
non–trauma-related word pairs, the precuneus was less activated in veterans with PTSD,
which correlated significantly with the severity of PTSD. Like frontotemporal regions the
precuneus is differentially activated during memory formation in veterans with PTSD (Geuze
et al. 2008b).
62 Vermetten AND Lanius

Default network

The notion that the brain has an intrinsic mode of functioning has received increasing atten-
tion over the past years, an idea that stems from observations that even when no explicit task
is performed a consistent network of brain areas shows high levels of activity—the “default”
network (Bruckner et al. 2008). In these studies the default network appeared to be more
active at rest than in a range of explicit tasks. Two opposing brain systems have been identi-
fied with opposing functions, dorsal attention, and hippocampal-cortical memory systems,
which are positioned anatomically to integrate information from the external world versus
internally directed mentation that involves long-term memory (Vincent et al. 2008). Bluhm
et al. have recently reported that at rest, spontaneous low-frequency activity in the posterior
cingulate/precuneus was more strongly correlated with activity in other areas of the default
network in healthy comparison subjects than in subjects with PTSD related to chronic child-
hood abuse. Direct comparison of the two groups showed that posterior cingulate/precu-
neus connectivity was also greater in healthy comparison subjects than in patients with PTSD
in a number of areas previously associated with PTSD, including the right amygdala and
the hippocampus/parahippocampal gyrus. In this patient population, the observed altera-
tions may be associated with the disturbances in self-referential processing often observed in
PTSD (Bluhm et al. 2008).

Heterogeneity of responses in PTSD

An emerging literature in PTSD has begun to examine the heterogeneity of response to trau-
matic reminders. Due to the different type of traumas that cause the onset of PTSD, the clinical
presentation of symptoms can vary between patients. Recently, it has been hypothesized that
there are two main categories of PTSD symptoms closely related to the criteria that make up the
disorder. Whereas some patients tend to be hyperaroused, others show numbing in response
to fearful situations. This latter often have moments of dissociation, as opposed to the former,
who tend to be hypervigilant and experience flashbacks of their trauma (Bremner, 1996). In a
study performed by Lanius et al. (Lanius et al. 2005), functional connectivity was measured
using fMRI in both dissociated and flashback PTSD groups. The findings indicate a different
neural connectivity between the two groups, with the dissociated group showing greater con-
nectivity in the left inferior frontal gyrus, an area previously found to be related to the determi-
nation of self-relevance of emotional statements (Lanius et al. 2006). Moreover, in a case report
of a married couple involved in a motor vehicle accident, Lanius et al. (Lanius et al. 2003a)
clearly presented a case for different types of PTSD. The husband responded to a traumatic
script about the accident in a state of hyperarousal, whereas his wife became numb and frozen.
Because there is a possible difference in brain activation patterns between the flashback and
dissociated PTSD groups, comparing these two groups of patients may lead to distortions in
the outcome of a study. We recently reviewed evidence that dissociation reflects frontal inhibi-
tion of limbic and other temporal lobe structures. Moreover, these dissociative response states
have been shown to be triggered by several classes of neurochemicals, including serotonergic
hallucinogens, NMDA antagonists, and opioid agonists, acting through the hippocampus and
other brain areas involved in memory and emotion.
The model of PTSD has focused on a model of hyperactivation of the noradrenergic sys-
tem, for example, the locus coeruleus. Irritability; increased heart rate; and ����������������������
blood�����������������
pressure associ-
ated with trauma reminders, flashbacks, and nightmares have been key symptoms targeted for
treatments such as exposure, cognitive restructuring, and coping skills training. However, the
neurobiology of these dissociative responses is a rapidly developing field as well. Different types
of dissociation, involving somatoform, cognitive, and affective cognitive components have been
identified, and brain mechanisms linking frontal cortical inhibition to amygdala and other limbic
hypoactivation have been identified (see Vermetten et al. 2008; Lanius et al. in review; Vermetten,
Dorahy, & Spiegel, 2007, Felmingham et al. 2008) as well. Thus, there is also potential to recog-
nize in DSM-V the dissociative component of trauma response in peritraumatic, acute, and post-
traumatic periods and symptomatology. A better integration of related disciplines may help to
provide a more coherent nosology regarding trauma response and its treatment.
Brain Circuits in Posttraumatic Stress Disorder 63

Summary and future directions

During the past decade, more than 60 studies were published that specifically used functional neu-
roimaging techniques in PTSD research. These studies make use of a wide range of methodologies:
measuring resting brain activity, presenting a wide range of stimuli, and using active tasks per-
formed by a subject. Within these main groupings, there are further distinctions to be made, such
as the type of stimulus (auditory, visual, trauma script, personal script), type of task (active recall,
counting Stroop task, auditory continuous performance task), and type of tracer used in PET or
SPECT studies. Due to this variation, difficulties arise when comparing data across different studies.
Another issue that confounds comparison is a wide array of subjects in specific studies and when
comparing different studies, including patients with a broad trauma spectrum and of different
sexes. It is important to distinguish between trauma types, such as trauma caused by motor vehicle
accident (MVAs), sexual assault, combat situations, natural disasters, and so on. This could be one
reason behind the inconsistency in hippocampal activation. Furthermore, studies have shown sig-
nificant differences in properties between the male and female brain (Goldstein et al. 2001). PTSD is
a complex disorder with foundations in an extensive neural circuitry (Rauch et al. 2006). By examin-
ing patients with a common traumatic history and sex, it is possible to analyze neural activity with
higher precision, and potential differences between the groups can be brought to light.
An interesting observation can also be drawn from the discrepancy in abnormalities
between functional versus structural neuroimaging. Although functional neuroimaging dem-
onstrates abnormalities in the mPFC (including ACC) and amygdalar circuit, structural MRI
studies have almost exclusively focused on the hippocampus and have only recently started to
examine the amygdale factor. Functional neuroimaging studies suggest that there are clear dif-
ferences in metabolic acticity in the mPFC–amygdale circuit; therefore, it would be interesting
to investigate further whether patients with PTSD show structural differences with respect to
their amygdalae (Karl et al. 2006) (Vermetten et al. 2006). As reported before, an important issue
that needs to be raised is that one may wonder whether the abnormalities found in structural
and functional neuroimaging studies are specific to PTSD. Similar findings have also been
reported in other studies, targeting other anxiety disorders, such as obsessive–compulsive dis-
order (Nakao et al. 2005), panic disorder (van den Heuvel et al. 2005), and generalized social
phobia (Phan et al. 2006). We must be careful, however, in assuming similarity with these other
anxiety disorders due to the specificity of the experimental designs. Studies that target patients
with PTSD use different experimental designs, with content specific to the disorder. For exam-
ple, script-driven imagery for patients with PTSD differs from that used for patients with other
anxiety disorders. In turn, this may elicit different, disease-specific brain activation patterns.
In conclusion, functional neuroimaging studies that use SPECT, PET, and fMRI have opened up a
new window to uncover the biobehavioral mechanisms in PTSD. The most consistent finding in many
research studies to date is a relative decrease in mPFC activity, in conjunction with an increased amygda-
lar activation. Although no conclusive evidence exists, a functional relationship between the two regions
is hypothesized, which is altered in PTSD. The role of the hippocampus and parahippocampal gyrus in
PTSD is ambiguous, despite several studies that support the involvement both in structural and func-
tional studies. The numerous variations between the studies discussed and the complexity of PTSD
symptomatology are potential causes for the inconsistent findings to date. More comprehensive meta-
analyses of the findings across functional imaging studies in PTSD could be benefited by paradigm
conformation. With a standard set of guidelines for subject inclusion, scanning procedures, stimulus
presentation, tasks and other variables, results may become more comparable. Correspondingly, setting
guidelines risks limiting novel methods and ultimately novel results, potentially impeding progress
in uncovering the neural mechanisms underlying PTSD. As the research base deepens, the number
of studies increases, facilitating comparison. Ultimately this may lead to more consistent trends. Even
though the increase in the number of neuroimaging studies has contributed much to the insight in the
neural circuits of PTSD, further research is imperative to fine-tune this model to better understand this
complex and diverse disorder.

List of abbreviations

BNST - bed nucleus striae terminals

CS - conditioned stimulus
64 Vermetten AND Lanius

DSM - diagnostic statistical manual

UCS - unconditioned stimulus
mPFC - medial prefrontal cortex
ACC - anterior cyngulated gyrus
NMDA - N methyl D aspartase
GABA – gamma amino butyric acid
BDNF – brain derived neurotrophic factor
SPECT - single positron emitted tomography
PET - positron emission tomography
MRI - magnetic resonance imaging
BOLD - blood oxygen level dependent
rCBF – regional cerebral blood flow
Tc-99m HMPAO - technetium-99m hexamethyl propylenamine oxime
ACPT - auditory continuous performance task
18
F-FCWAY - 18F-trans-4-Fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yllethyl]-N-(2-pyridyl)
cyclohexanecarboxamide
5HT1AR - Serotonin type 1A receptors
FDG - 18F-fluorodeoxyglucose
OFC – orbitofrontal gyrus
MVA – motor vehicle accident

References

   1. Anderson KC, Insel TR. The promise of extinction research for the prevention and treatment of
anxiety disorders. Biol Psychiatry 2006; 60(4): 319–21.
   2. Bekinschtein P, Cammarota M, Igaz LM et al. Persistence of long-term memory storage requires a late
protein synthesis- and BDNF- dependent phase in the hippocampus. Neuron 2007; 53(2): 261–77.
   3. Berkowitz RL, Coplan JD, Reddy DP, Gorman JM. The human dimension: how the prefrontal cortex
modulates the subcortical fear response. Rev Neurosci 2007; 18(3–4): 191–207.
   4. Berlau DJ, McGaugh JL. Enhancement of extinction memory consolidation: the role of the
noradrenergic and GABAergic systems within the basolateral amygdala. Neurobiol Learn Mem
2006; 86(2): 123–32.
   5. Berretta S. Cortico-amygdala circuits: role in the conditioned stress response. Stress 2005; 8(4): 221–32.
   6. Bluhm RL, Osuch EA, Lanius RA et al. Default mode network connectivity: effects of age, sex, and
analytic approach. Neuroreport 2008; 19(8): 887–91.
   7. Bonne O, Bain E, Neumeister A et al. No change in serotonin type 1A receptor binding in patients
with posttraumatic stress disorder. Am J Psychiatry 2005; 162(2): 383–5.
   8. Bonne O, Gilboa A, Louzoun Y et al. Resting regional cerebral perfusion in recent posttraumatic
stress disorder. Biol Psychiatry 2003; 54(10): 1077–86.
   9. Bremner JD. Functional neuroanatomical correlates of traumatic stress revisited 7 years later, this
time with data. Psychopharmacol Bull 2003; 37(2): 6–25.
  10. Bremner JD. Stress and brain atrophy. CNS Neurol Disord Drug Targets 2006; 5(5): 503–12.
  11. Bremner JD, Innis RB, Ng CK et al. Positron emission tomography measurement of cerebral metabolic
correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen
Psychiatry 1997; 54(3): 246–54.
  12. Bremner JD, Innis RB, Southwick SM et al. Decreased benzodiazepine receptor binding in prefrontal
cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 2000; 157(7): 1120–6.
  13. Bremner JD, Krystal JH, Charney DS, Southwick SM. Neural mechanisms in dissociative amnesia for
childhood abuse: relevance to the current controversy surrounding the “false memory syndrome”.
Am J Psychiatry 1996; 153(7): 71–82.
  14. Bremner JD, Krystal JH, Southwick SM, Charney DS. Functional neuroanatomical correlates of the
effects of stress on memory. J Trauma Stress 1995; 8(4): 527–53.
  15. Bremner JD, Narayan M, Staib LH et al. Neural correlates of memories of childhood sexual abuse in
women with and without posttraumatic stress disorder. Am J Psychiatry 1999; 156(11): 1787–95.
  16. Bremner JD, Randall P, Scott TM et al. Deficits in short-term memory in adult survivors of childhood
abuse. Psychiatry Res 1995; 59(1–2): 97–107.
  17. Bremner JD, Scott TM, Delaney RC et al. Deficits in short-term memory in posttraumatic stress
disorder. Am J Psychiatry 1993; 150(7): 1015–9.
  18. Bremner JD, Staib LH, Kaloupek D et al. Neural correlates of exposure to traumatic pictures and
sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron
emission tomography study. Biol Psychiatry 1999; 45(7): 806–16.
Brain Circuits in Posttraumatic Stress Disorder 65

  19. Bremner JD, Vermetten E, Vythilingam M et al. Neural correlates of the classic color and emotional stroop
in women with abuse-related posttraumatic stress disorder. Biol Psychiatry 2004; 55(6): 612–20.
  20. Bremner JD, Vythilingam M, Vermetten E et al. MRI and PET study of deficits in hippocampal
structure and function in women with childhood sexual abuse and posttraumatic stress disorder.
Am J Psychiatry 2003a; 160(5): 924–32.
  21. Bremner JD, Vythilingam M, Vermetten E et al. Neural correlates of declarative memory for
emotionally valenced words in women with posttraumatic stress disorder related to early childhood
sexual abuse. Biol Psychiatry 2003b; 53(10): 879–89.
  22. Bremner JD, Vythilingam M, Vermetten E et al. Neural correlates of declarative memory for
emotionally valenced words in women with posttraumatic stress disorder related to early childhood
sexual abuse. Biol Psychiatry 2003c; 53(10): 879–89.
  23. Brewin CR, Kleiner JS, Vasterling JJ, Field AP. Memory for emotionally neutral information in
posttraumatic stress disorder: A meta-analytic investigation. J Abnorm Psychol 2007; 116(3): 448–63.
  24. Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I. Corticolimbic blood flow in posttraumatic stress
disorder during script-driven imagery. Biol Psychiatry 2005; 57(8): 832–40.
  25. Britton JC, Shin LM, Barrett LF, Rauch SL, Wright CI. Amygdala and fusiform gyrus temporal
dynamics: responses to negative facial expressions. BMC Neurosci 2008; 9: 44.
  26. Buchanan SL, Thompson RH, Maxwell BL, Powell DA. Efferent connections of the medial prefrontal
cortex in the rabbit. Exp Brain Res 1994; 100(3): 469–83.
  27. Chandramohan Y, Droste SK, Arthur JS, Reul JM. The forced swimming-induced behavioural
immobility response involves histone H3 phospho-acetylation and c-Fos induction in dentate gyrus
granule neurons via activation of the N-methyl-D-aspartate/extracellular signal-regulated kinase/
mitogen- and stress-activated kinase signalling pathway. Eur J Neurosci 2008; 27(10): 2701–13.
  28. Charney DS. Psychobiological mechanisms of resilience and vulnerability: implications for successful
adaptation to extreme stress. Am J Psychiatry 2004; 161(2): 195–216.
  29. Charney DS, Deutch A. A functional neuroanatomy of anxiety and fear: implications for the
pathophysiology and treatment of anxiety disorders. Crit Rev Neurobiol 1996; 10(3–4): 419–46.
  30. Charney DS, Deutch AY, Krystal JH, Southwick SM, Davis M. Psychobiologic mechanisms of
posttraumatic stress disorder. Arch Gen Psychiatry 1993; 50(4): 295–305.
  31. Chu JA, Frey LM, Ganzel BL, Matthews JA. Memories of childhood abuse: dissociation, amnesia,
and corroboration. Am J Psychiatry 1999; 156(5): 749–55.
  32. Clark FM, Proudfit HK. The projection of locus coeruleus neurons to the spinal cord in the rat determined
by anterograde tracing combined with immunocytochemistry. Brain Res 1991; 538(2): 231–45.
  33. Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. The return of Phineas Gage: clues
about the brain from the skull of a famous patient. Science 1994; 264(5162): 1102–5.
  34. de Kloet CS, Vermetten E, Bikker A et al. Leukocyte glucocorticoid receptor expression and
immunoregulation in veterans with and without post-traumatic stress disorder. Mol Psychiatry
2007; 12(5): 443–53.
  35. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain
1995; 118: 279–306.
  36. Dickerson BC. Advances in functional magnetic resonance imaging: technology and clinical
applications. Neurotherapeutics 2007; 4(3): 360–70.
  37. Driessen M, Beblo T, Mertens M et al. Posttraumatic stress disorder and fMRI activation patterns
of traumatic memory in patients with borderline personality disorder. Biol Psychiatry 2004; 55(6):
603–11.
  38. Felmingham K, Kemp AH, Williams L et al. Dissociative responses to conscious and non-conscious
fear impact underlying brain function in post-traumatic stress disorder. Psychol Med 2008; 38(12):
1771–80.
  39. Fujita M, Southwick SM, Denucci CC et al. Central type benzodiazepine receptors in Gulf War
veterans with posttraumatic stress disorder. Biol Psychiatry 2004; 56(2): 95–100.
  40. Geuze E, van Berckel BN, Lammertsma AA et al. Reduced GABAA benzodiazepine receptor binding
in veterans with post-traumatic stress disorder. Mol Psychiatry 2008; 13(1): 74–83, 3.
  41. Geuze E, Vermetten E, Bremner JD. MR-based in vivo hippocampal volumetrics: 1. Review of
methodologies currently employed. Mol Psychiatry 2005a; 10(2): 147–59.
  42. Geuze E, Vermetten E, Bremner JD. MR-based in vivo hippocampal volumetrics: 2. Findings in
neuropsychiatric disorders. Mol Psychiatry 2005b; 10(2): 160–84.
  43. Geuze E, Vermetten E, de Kloet CS, Hijman R, Westenberg HG. Neuropsychological performance is
related to current social and occupational functioning in veterans with posttraumatic stress disorder.
Depress Anxiety 2009; 26(1): 7–15.
  44. Geuze E, Vermetten E, de Kloet CS, Westenberg HG. Precuneal activity during encoding in veterans
with posttraumatic stress disorder. Prog Brain Res 2008b; 167: 293–7.
  45. Geuze E, Vermetten E, Ruf M, de Kloet CS, Westenberg HG. Neural correlates of associative learning
and memory in veterans with posttraumatic stress disorder. J Psychiatr Res 2008c; 42(8): 659–69.
66 Vermetten AND Lanius

  46. Gilbertson MW, Shenton ME, Ciszewski A et al. Smaller hippocampal volume predicts pathologic
vulnerability to psychological trauma. Nat Neurosci 2002; 5(11): 1242–7.
  47. Gilboa A, Shalev AY, Laor L et al. Functional connectivity of the prefrontal cortex and the amygdala
in posttraumatic stress disorder. Biol Psychiatry 2004; 55(3): 263–72.
  48. Goldman-Rakic PS. Topography of cognition: parallel distributed networks in primate association
cortex. Annu Rev Neurosci 1988; 11:137–56.
  49. Golier JA, Yehuda R, Lupien SJ et al. Memory performance in Holocaust survivors with posttraumatic
stress disorder. Am J Psychiatry 2002; 159(10): 1682–8.
  50. Grillon C. Models and mechanisms of anxiety: evidence from startle studies. Psychopharmacology
(Berl) 2008; 199(3): 421–37.
  51. Grillon C, Southwick SM, Charney DS. The psychobiological basis of posttraumatic stress disorder.
Mol Psychiatry 1996; 1(4): 278–97.
  52. Hendler T, Rotshtein P, Yeshurun Y et al. Sensing the invisible: differential sensitivity of visual cortex
and amygdala to traumatic context. Neuroimage 2003; 19(3): 587–600.
  53. Jueptner M, Weiller C. Review: does measurement of regional cerebral blood flow reflect synaptic
activity? Implications for PET and fMRI. Neuroimage 1995; 2(2): 148–56.
  54. Karl A, Schaefer M, Malta LS et al. A meta-analysis of structural brain abnormalities in PTSD.
Neurosci Biobehav Rev 2006; 30(7): 1004–31.
  55. Katz DB, Steinmetz JE. Psychological functions of the cerebellum. Behav Cogn Neurosci Rev 2002;
1(3): 229–41.
  56. Katkin ES, Wiens S, Ohman A. Nonconscious fear conditioning, visceral perception, and the
development of gut feelings. Psychol Sci 2001; 12(5): 366–70.
  57. Lanius RA, Bluhm R, Lanius U, Pain C. A review of neuroimaging studies in PTSD: heterogeneity of
response to symptom provocation. J Psychiatr Res 2006; 40(8): 709–29.
  58. Lanius RA, Frewen PA, Girotti M et al. Neural correlates of trauma script-imagery in posttraumatic
stress disorder with and without comorbid major depression: a functional MRI investigation.
Psychiatry Res 2007; 155(1): 45–56.
  59. Lanius RA, Hopper JW, Menon RS. Individual differences in a husband and wife who developed
PTSD after a motor vehicle accident: a functional MRI case study. Am J Psychiatry 2003a; 160(4):
667–9.
  60. Lanius RA, Hopper JW, Menon RS. Individual differences in a husband and wife who developed
PTSD after a motor vehicle accident: a functional MRI case study. Am J Psychiatry 2003b; 160(4):
667–9.
  61. Lanius RA, Williamson PC, Bluhm RL et al. Functional connectivity of dissociative responses in
posttraumatic stress disorder: a functional magnetic resonance imaging investigation. Biol Psychiatry
2005; 57(8): 873–84.
  62. Lanius RA, Williamson PC, Boksman K et al. Brain activation during script-driven imagery induced
dissociative responses in PTSD: a functional magnetic resonance imaging investigation. Biol
Psychiatry 2002; 52(4): 305–11.
  63. Lanius RA, Williamson PC, Densmore M et al. Neural correlates of traumatic memories in posttraumatic
stress disorder: a functional MRI investigation. Am J Psychiatry 2001; 158(11): 1920–2.
  64. Lanius RA, Williamson PC, Densmore M et al. The nature of traumatic memories: a 4-T FMRI
functional connectivity analysis. Am J Psychiatry 2004; 161(1): 36–44.
  65. Lanius RA, Williamson PC, Hopper J et al. Recall of emotional states in posttraumatic stress disorder:
an fMRI investigation. Biol Psychiatry 2003; 53(3): 204–10.
  66. Lanius RA, Vermetten E, Loewenstein RJ et al. Neural and Endocrine Systems in Dissociation, Am J
Psychiatry, submitted.
  67. LeDoux JE. Emotional memory: in search of systems and synapses. Ann N Y Acad Sci 1993; 702:
149–57.
  68. Liberzon I, Britton JC, Phan KL. Neural correlates of traumatic recall in posttraumatic stress disorder.
Stress 2003a; 6(3): 151–6.
  69. Liberzon I, Britton JC, Phan KL. Neural correlates of traumatic recall in posttraumatic stress disorder.
Stress 2003b; 6(3): 151–6.
  70. Liberzon I, Sripada CS. The functional neuroanatomy of PTSD: a critical review. Prog Brain Res 2008;
167: 151–69.
  71. Liberzon I, Taylor SF, Amdur R et al. Brain activation in PTSD in response to trauma-related stimuli.
Biol Psychiatry 1999; 45(7): 817–26.
  72. Lindauer RJ, Booij J, Habraken JB et al. Cerebral blood flow changes during script-driven imagery in
police officers with posttraumatic stress disorder. Biol Psychiatry 2004; 56(11): 853–61.
  73. Mirzaei S, Knoll P, Keck A et al. Regional cerebral blood flow in patients suffering from post-
traumatic stress disorder. Neuropsychobiology 2001; 43(4): 260–4.
  74. Morgan MA, Romanski LM, LeDoux JE. Extinction of emotional learning: contribution of medial
prefrontal cortex. Neurosci Lett 1993; 163(1): 109–13.
Brain Circuits in Posttraumatic Stress Disorder 67

  75. Murray EA, Bussey TJ. Consolidation and the medial temporal lobe revisited: methodological
considerations. Hippocampus 2001; 11(1): 1–7.
  76. Myers KM, Davis M. Mechanisms of fear extinction. Mol Psychiatry 2007; 12(2): 120–50.
  77. Nakao T, Nakagawa A, Yoshiura T et al. Brain activation of patients with obsessive-compulsive
disorder during neuropsychological and symptom provocation tasks before and after symptom
improvement: a functional magnetic resonance imaging study. Biol Psychiatry 2005; 57(8): 901–10.
  78. Neves G, Cooke SF, Bliss TV. Synaptic plasticity, memory and the hippocampus: a neural network
approach to causality. Nat Rev Neurosci 2008; 9(1): 65–75.
  79. Osuch EA, Willis MW, Bluhm R, Ursano RJ, Drevets WC. Neurophysiological responses to traumatic
reminders in the acute aftermath of serious motor vehicle collisions using. Biol Psychiatry 2008;
64(4): 327–35.
  80. Pavic L, Gregurek R, Petrovic R et al. Alterations in brain activation in posttraumatic stress disorder
patients with severe hyperarousal symptoms and impulsive aggressiveness. Eur Arch Psychiatry
Clin Neurosci 2003; 253(2): 80–3.
  81. Pezze MA, Feldon J. Mesolimbic dopaminergic pathways in fear conditioning. Prog Neurobiol 2004;
74(5): 301–20.
  82. Phan KL, Fitzgerald DA, Nathan PJ, Tancer ME. Association between amygdala hyperactivity to
harsh faces and severity of social anxiety in generalized social phobia. Biol Psychiatry 2006; 59(5):
424–9.
  83. Pissiota A, Frans O, Fernandez M et al. Neurofunctional correlates of posttraumatic stress disorder:
a PET symptom provocation study. Eur Arch Psychiatry Clin Neurosci 2002; 252(2): 68–75.
  84. Protopopescu X, Pan H, Tuescher O et al. Differential time courses and specificity of amygdala
activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry 2005;
57(5): 464–73.
  84. Quirk GJ, Armony JL, LeDoux JE. Fear conditioning enhances different temporal components of
tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron 1997; 19(3): 613–24.
  85. Quirk GJ, Garcia R, Gonzalez-Lima F. Prefrontal mechanisms in extinction of conditioned fear. Biol
Psychiatry 2006; 60(4): 337–43.
  86. Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction:
human neuroimaging research--past, present, and future. Biol Psychiatry 2006; 60(4): 376–82.
  87. Rauch SL, van der Kolk BA, Fisler RE et al. A symptom provocation study of posttraumatic stress
disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry 1996;
53(5): 380–7.
  88. Rauch SL, Whalen PJ, Shin LM et al. Exaggerated amygdala response to masked facial stimuli in
posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 2000; 47(9): 769–76.
  89. Rogan MT, Staubli UV, LeDoux JE. Fear conditioning induces associative long-term potentiation in
the amygdala. Nature 1997; 390(6660): 604–7.
  90. Rohleder N, Joksimovic L, Wolf JM, Kirschbaum C. Hypocortisolism and increased glucocorticoid
sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic
stress disorder. Biol Psychiatry 2004; 55: 745–51.
  91. Reul JM, Nutt DJ. Glutamate and cortisol--a critical confluence in PTSD? J Psychopharmacol 2008;
22(5): 469–72.
  92. Roth RH, Tam SY, Ida Y, Yang JX, Deutch AY. Stress and the mesocorticolimbic dopamine systems.
Ann N Y Acad Sci 1988; 537: 138–47.
  93. Sarter M, Markowitsch HJ. Involvement of the amygdala in learning and memory: a critical review,
with emphasis on anatomical relations. Behav Neurosci 1985; 99(2): 342–80.
  94. Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. 1957.
J Neuropsychiatry Clin Neurosci 2000; 12(1): 103–13.
  95. Seedat S, Warwick J, van Heerden B et al. Single photon emission computed tomography in
posttraumatic stress disorder before and after treatment with a selective serotonin reuptake inhibitor.
J Affect Disord 2004; 80(1): 45–53.
  96. Semple WE, Goyer PF, McCormick R et al. Attention and regional cerebral blood flow in posttraumatic
stress disorder patients with substance abuse histories. Psychiatry Res 1996a; 67(1): 17–28.
  97. Semple WE, Goyer PF, McCormick R et al. Attention and regional cerebral blood flow in posttraumatic
stress disorder patients with substance abuse histories. Psychiatry Res 1996b; 67(1): 17–28.
  98. Semple WE, Goyer PF, McCormick R et al. Higher brain blood flow at amygdala and lower frontal
cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with
normals. Psychiatry 2000a; 63(1): 65–74.
  99. Semple WE, Goyer PF, McCormick R et al. Higher brain blood flow at amygdala and lower frontal
cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with
normals. Psychiatry 2000b; 63(1): 65–74.
100. Shin LM, Kosslyn SM, McNally RJ et al. Visual imagery and perception in posttraumatic stress
disorder. A positron emission tomographic investigation. Arch Gen Psychiatry 1997a; 54(3): 233–41.
68 Vermetten AND Lanius

101. Shin LM, McNally RJ, Kosslyn SM et al. A positron emission tomographic study of symptom
provocation in PTSD. Ann N Y Acad Sci 1997b; 821: 521–3.
102. Shin LM, McNally RJ, Kosslyn SM et al. Regional cerebral blood flow during script-driven imagery
in childhood sexual abuse-related PTSD: a PET investigation. Am J Psychiatry 1999; 156(4): 575–84.
103. Shin LM, Orr SP, Carson MA et al. Regional cerebral blood flow in the amygdala and medial
prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch
Gen Psychiatry 2004; 61(2): 168–76.
104. Shin LM, Whalen PJ, Pitman RK et al. An fMRI study of anterior cingulate function in posttraumatic
stress disorder. Biol Psychiatry 2001a; 50(12): 932–42.
105. Shin LM, Whalen PJ, Pitman RK et al. An fMRI study of anterior cingulate function in posttraumatic
stress disorder. Biol Psychiatry 2001b; 50(12): 932–42.
106. Shin LM, Wright CI, Cannistraro PA et al. A functional magnetic resonance imaging study of
amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic
stress disorder. Arch Gen Psychiatry 2005; 62(3): 273–81.
107. Southwick SM, Bremner JD, Rasmusson A et al. Role of norepinephrine in the pathophysiology and
treatment of posttraumatic stress disorder. Biol Psychiatry 1999; 46(9): 1192–204.
108. Squire LR, Zola-Morgan S. The medial temporal lobe memory system. Science 1991; 253(5026): 1380–6.
109. Stam R. PTSD and stress sensitisation: a tale of brain and body Part 1: human studies. Neurosci
Biobehav Rev 2007a; 31(4): 530–57.
110. Stam R. PTSD and stress sensitisation: a tale of brain and body Part 2: animal models. Neurosci
Biobehav Rev 2007b; 31(4): 558–84.
111. Stam R, Bruijnzeel AW, Wiegant VM. Long-lasting stress sensitisation. Eur J Pharmacol 2000; 405(1–
3): 217–24.
112. Turner BH, Gupta KC, Mishkin M. The locus and cytoarchitecture of the projection areas of the
olfactory bulb in Macaca mulatta. J Comp Neurol 1978; 177(3): 381–96.
113. van den Heuvel OA, Veltman DJ, Groenewegen HJ et al. Disorder-specific neuroanatomical correlates
of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Arch Gen
Psychiatry 2005; 62(8): 922–33.
114. van der Hart O, Bolt H, van der Kolk BA. Memory fragmentation in dissociative identity disorder.
J Trauma Dissociation 2005; 6(1): 55–70.
115. Van Hoesen GW, Pandya DN, Butters N. Cortical afferents to the entorhinal cortex of the Rhesus
monkey. Science 1972; 175(29): 1471–3.
116. Vasterling JJ, Duke LM, Brailey K et al. Attention, learning, and memory performances and
intellectual resources in Vietnam veterans: PTSD and no disorder comparisons. Neuropsychology
2002; 16(1): 5–14.
117. Vermetten E, Bremner JD. Dissociative Amnesia: Re-remembering traumatic memories. In: Memory
disorders in psychiatric practice. Berrios GE, Hodges J, eds. Cambridge University Press: Cambridge,
2000: 400–32.
118. Vermetten E, Bremner JD. Circuits and systems in stress. II. Applications to neurobiology and
treatment in posttraumatic stress disorder. Depress Anxiety 2002; 16(1): 14–38.
119. Vermetten E, Bremner JD. Olfaction as a traumatic reminder in posttraumatic stress disorder: case
reports and review. J Clin Psychiatry 2003; 64(2): 202–7.
120. Vermetten E, Douglas Bremner J. Functional brain imaging and the induction of traumatic recall:
a cross-correlational review between neuroimaging and hypnosis. Int J Clin Exp Hypn 2004; 52(3):
280–312.
121. Vermetten E, Schmahl C, Lindner S, Loewenstein RJ, Bremner JD. Hippocampal and amygdalar
volumes in dissociative identity disorder. Am J Psychiatry 2006; 163(4): 630–6.
122. Vermetten E, Schmahl C, Southwick SM, Bremner JD. Positron tomographic emission study of
olfactory induced emotional recall in veterans with and without combat-related posttraumatic stress
disorder. Psychopharmacol Bull 2007; 40(1): 8–30.
123. Vermetten E, Spiegel D. Perceptual Processing and Traumatic Stress: Contributions from Hypnosis.
In: Traumatic Dissociation: Neurobiology and Treatment, Vermetten, E, Dorahy, Spiegel D, eds.
American Psychiatric Press 2007: 103–20.
124. Vermetten E, Dorahy M, Spiegel D. Traumatic Dissociation; Neurobiology and Treatment.
Washington, American Psychiatric Press; 2007.
125. Vermetten E, Lanius R, Bremner JD. Contributions of traumatic stress studies to the neurobiology of
dissociation and dissociative disorders: Implications for schizophrenia. In: Andrew M, Ingo S, Martin
D, eds. Psychosis, Trauma and Dissociation; Emerging Perspectives on Severe Psychopathology.
Wiley Blackwell: Oxford, 221–38.
126. Vincent JL, Kahn I, Snyder AZ, Raichle ME, Buckner RL. Evidence for a frontoparietal control system
revealed by intrinsic functional connectivity. J Neurophysiol 2008; 100(6): 3328–42.
127. Vogt BA, Miller MW. Cortical connections between rat cingulate cortex and visual, motor, and
postsubicular cortices. J Comp Neurol 1983; 216(2): 192–210.
Brain Circuits in Posttraumatic Stress Disorder 69

128. Walker DL, Toufexis DJ, Davis M. Role of the bed nucleus of the stria terminalis versus the amygdala
in fear, stress, and anxiety. Eur J Pharmacol 2003; 463(1–3): 199–216.
129. Wang JX, Poe G, Zochowski M. From network heterogeneities to familiarity detection and
hippocampal memory management. Phys Rev E Stat Nonlin Soft Matter Phys 2008; 78: 041905.
130. Yamada S, Uenoyama Y, Maeda K, Tsukamura H. Role of noradrenergic receptors in the bed nucleus
of the stria terminalis in regulating pulsatile luteinizing hormone secretion in female rats. J Reprod
Dev 2006; 52(1): 115–21.
131. Yang P, Wu MT, Hsu CC, Ker JH. Evidence of early neurobiological alternations in adolescents with
posttraumatic stress disorder: a functional MRI study. Neurosci Lett 2004a; 370(1): 13–8.
132. Yang P, Wu MT, Hsu CC, Ker JH. Evidence of early neurobiological alternations in adolescents with
posttraumatic stress disorder: a functional MRI study. Neurosci Lett 2004b; 370(1): 13–8.
133. Yehuda R, Golier JA, Yang RK, Tischler L. Enhanced sensitivity to glucocorticoids in peripheral
mononuclear leukocytes in posttraumatic stress disorder. Biol Psychiatry 2004; 55(11): 1110–6.
134. Yehuda R, Lowy MT, Southwick SM, Shaffer D, Giller EL Jr. Lymphocyte glucocorticoid receptor
number in posttraumatic stress disorder. Am J Psychiatry 1991; 148(4): 499–504.
135. Zubieta JK, Chinitz JA, Lombardi U et al. Medial frontal cortex involvement in PTSD symptoms: a
SPECT study. J Psychiatr Res 1999; 33(3): 259–64.
 6 The genetics of posttraumatic stress
disorder
Eduard Maron and Jakov Shlik

The diagnostic definition of posttraumatic stress disorder (PTSD) postulates its onset in response
to external terrifying events. While an exposure to traumatic conditions is likely to cause
serious distress in almost any individual, only a proportion of them develop clinical features
of PTSD (1). Epidemiological studies estimate that 40% to 90% of the general population may
experience traumatic events during their life, but that only 15% to 24% develop PTSD (2-4).
Thus, the exposure to a traumatic event is necessary, but not sufficient factor in the etiology of
PTSD. Among various factors underlying the individual vulnerability to PTSD, the genetics
may have an important role in the onset and course of this disease. The genetics of PTSD
are often overlooked, with only few recent reviews drawing attention to this intriguing topic
(5-8). Relatively scarce genetic research is in contrast with growing need to understand the
predisposition and risks for PTSD. This chapter summarizes available studies and findings,
which contribute to a better recognition of the genetic mechanisms of PTSD, keeping in mind
limitations and problems accompanying this type of research. In addition, we discuss novel
genetic approaches and directions to stimulate further investigations in this area.

Familial aggregation studies

Family studies explore the heritability of disease by estimation of its occurrence among first
degree relatives of affected subjects. Generally these studies provide evidence of an increased
rate of familial psychiatric morbidity among PTSD patients, whereas the stronger association
was revealed for major depression with less consistent support for anxiety or PTSD. One family
interview–based study involving 127 female probands and 639 first-degree relatives reported
that PTSD following rape was associated with familial vulnerability to major depression that
serves as a risk factor for developing PTSD (9). Several other studies demonstrated the two- to
four-fold increased risk of developing PTSD in subjects with a family history of depression,
anxiety disorders, psychosis, or personality disorders (2, 3, 10). Dierker and Merikangas (11)
examined familial psychopathology in 263 probands and 1,206 adult first-degree relatives
showing associations between PTSD in probands and affective disorders among female
relatives or drug abuse among male relatives. However, no specific elevation in PTSD risk was
detected in the relatives of probands with PTSD in their study. The familial relationship between
PTSD and major depression was confirmed in a study by Sautter et al. (12), demonstrating
that relatives of PTSD probands show higher levels of familial depression than the relatives
of healthy comparison subjects. Although they found that the prevalence of both anxiety and
PTSD appeared to be higher in the relatives of probands with PTSD, no statistically significant
differences were shown when compared to controls. Their last finding was conflicting with a
family study of Sack et al. (13), who reported that parental PTSD was associated with a five
fold increased risk of PTSD in offspring of Cambodian refugees living in the Western United
States.
Kozaric-Kovacic et al. (14) have found that familial psychopathology is reasonably
stronger in case of comorbid PTSD. Specifically, the rate of family history of psychiatric illness
was more frequent in Croatian combat veterans with comorbid depression and PTSD than in
those with PTSD alone (35% vs. 6%, respectively). Previously Yehuda et al. (15) demonstrated
a significantly higher prevalence of both current and lifetime PTSD and other psychiatric
disorders in the offspring of Holocaust survivors than in the comparison subjects, even though
these offspring as a group did not have greater exposure to life-threatening events. Several
The genetics of posttraumatic stress disorder 71

studies have shown that family history of affective disorders may predict exposure to traumatic
stressors independently from the risk of developing PTSD (10, 16). The distinct hereditary
aspects of exposure to trauma and PTSD may confound genetic research on traumatic stress.
Furthermore, the PTSD symptoms in probands with familial PTSD could not be fully explained
only by genetic transmission. It was found that children in close contact with traumatized first
responders may develop posttraumatic symptoms through secondary traumatization. For example,
one factor associated with probable emotional disturbance in children throughout New York City 6
months after the September 11, 2001 terrorist attack on the World Trade Center was having a family
member exposed to the attack (17, 18). The examination of mental health problems in New York
City public school children (N = 8,236) 6 months after the World Trade Center attack revealed that
children with emergency medical technician in the family had nearly 19% prevalence of probable
PTSD (19). The role of genetic factors in these findings is not known.

Twin studies

Twin studies compare resemblance for a condition between members of a twin pair, using
the fact that identical (monozygotic, MZ) twins share 100% of their genes while nonidentical
(dizygotic, DZ) twins share on average 50% of their genes. Interpretation of twin studies is
limited by the fact that MZ twins tend to share similar environment more than DZ twins. In
a small Norwegian sample of 81 adult twins with anxiety disorders, PTSD was only found in
cotwins of anxiety probands and was twice as prevalent in MZ (20%) versus DZ (7%) twins (20).
The most compelling evidence for a genetic predisposition to PTSD came from the Vietnam Era
Twin (VET) Registry data, including 4,042 male veteran twin (2,224 MZ and 1,818 DZ) pairs.
True et al. (21) explored in this sample the effects of heredity, shared environment, and unique
environment on the liability for 15 self-reported symptoms of PTSD from symptom clusters
of reexperiencing, avoidance, and hyperarousal. They found that the MZ twin correlations
were higher than the DZ correlations for all of the symptoms and heritability estimates were
in the range of 30% to 35% for most of the individual symptoms after controlling for the
effects of trauma exposure. There was no evidence that environment shared by twin siblings
have contributed to the development of PTSD symptoms. Their parallel VET Registry study
examined the relationship of genetic influences on the extent of trauma exposure by analyzing
specific events, like volunteering for service in Vietnam, time served in Southeast Asia, combat
experiences, and combat decoration awards (22). In this study, the correlation within MZ and
DZ twin pairs for volunteering for service in Vietnam were 0.40 and 0.22, respectively; for
actual service in Southeast Asia, the MZ correlation was 0.41 and the DZ correlation was 0.24.
Analysis of twin pairs in which both siblings served in Southeast Asia (n = 820) demonstrated
a correlation for self-reported combat experiences within MZ and DZ pairs of 0.53 and 0.30,
respectively. Genetic factors accounted for 36% of the variance in service in Southeast Asia,
47% of the variance in combat exposure, and 54% of the variance in the likelihood of receiving
a combat medal. The family environment did not have a significant effect on any of these
variables. Another smaller study by Stein et al. (1) in a sample of 291 female–female, 75 male–
male, and 40 opposite-sex twin pairs from the Vancouver area in Canada showed that for pairs
with both twins exposed to trauma, MZ pairs were more concordant for all clusters of PTSD
than DZ pairs with heritability estimates similar to those in the VET Registry study.

Molecular genetic studies

In the research on the heritability of psychiatric disorders, linkage and association studies
aim to clarify the molecular basis of epidemiological genetic findings. Linkage studies point
to a chromosomal location of the gene or genes associated with a familial transmission of a
phenotype of interest, estimating the likelihood of two gene loci to be inherited together. This
model is difficult to apply to genetic research on PTSD because the essential condition for PTSD
onset, exposure to trauma, is a variable that cannot be influenced (6). No linkage studies in
72 Maron AND Shlik

PTSD have been published. Main research efforts so far focus on candidate genes inferred from
the knowledge on pathophysiology and drug action substrates in PTSD as well as relevant
findings in other psychiatric disorders. This approach aims to link the illness to common
variations in DNA sequence, such as sequence repeats or single nucleotide polymorphisms
(SNPs) and patterns of their proximate occurrence (haplotypes). These studies employ the
association method with case control design and/or family-based analyses. In contrast to other
anxiety disorders, such as panic disorder or obsessive–compulsive disorder, fewer genetic
association studies in PTSD have been published. All of them compared the allelic or genotype
frequencies of candidate genes between cases and controls and only few explored haplotypes.
Overall, these findings reviewed below are still preliminary to confirm the involvement of any
specific genetic loci in the development of PTSD, but several of them deserve closer inspection
(data summarized in Table 6.1).

Dopamine-related genes

Dopamine D2 receptor (DRD2) gene was the first candidate in PTSD association studies.
Comings et al. (23, 24) implicated this gene in PTSD based on the association between this gene
and alcohol abuse, the condition highly prevalent among individuals with PTSD. They reported
significantly increased frequency of DRD2 TaqI “A1” alleles in the veterans who developed PTSD
as compared to those who did not. Interpretation of these findings was limited by small sample
size and comorbid drug or alcohol abuse. In attempt to replicate these findings, Gelernter et al.
(25) studied DRD2 TaqI “A” allele frequencies in their sample of European–American Vietnam
combat veterans with PTSD. Neither allelic nor haplotype frequencies significantly differed
between the patient and control groups, excluding major role of genetic variation at the DRD2
locus in predisposition to PTSD. Their study was also restricted by small sample size and high
comorbidity rates. A study of Young et al. (26) aimed to determine the effect of alcohol use on
the possible association between PTSD and DRD2 A1 allele. In line with previous observations
they found significantly higher frequency of the A1 allele in the Vietnam combat veterans of
the Australian armed forces with PTSD than in the matched control group. However, further
analysis revealed that A1 allelic frequency was about twice higher in PTSD subgroup of harmful
drinkers then in nonharmful drinkers, whereas frequency of A1 allele in the latter subgroup did
not significantly differ from control subjects. Moreover, daily amount and hourly rate of alcohol
consumed were markedly higher in PTSD carriers of A1 allele than in those with A2 allele. In a
subsequent study they extended the role of DRD2 locus on the four psychopathological factors,
including somatic concerns, anxiety/insomnia, social dysfunction, and depression in untreated
veterans with PTSD (27, 28). They found that the carriers of A1 allele were showing significantly
higher anxiety, depression, and social dysfunction scores than A2 allele carriers. Interestingly, they
also demonstrated that A1 allele is associated with greater improvements in social functioning in
PTSD patients following 8-week treatment with paroxetine when compared to those without this
allele. These findings indicate that DRD2 A1 allele may be implicated in expression of general
psychopathological symptoms, such as depression, anxiety, or social dysfunction as well as
alcohol use rather than associated with PTSD diagnosis. Pertinently, postmortem and positron
emission tomography studies have demonstrated that A1 allele is associated with decreased
density of DRD2 in human brain (29, 30). In another study, lower density of brain DRD2 was
correlated with higher level of craving for alcohol (31). In the context of these findings, the nature
of association between DRD2 A1 allele and PTSD remains unclear.
The gene of dopamine transporter (DAT), a key protein regulating synaptic reuptake
of dopamine, is another marker recently associated with PTSD. Investigating a polymorphic
variable number tandem repeats (VNTR) region in the SLC6A3 3’ untranslated region,
Segman et al. (32) found a significant association between nine repeat allele and nine repeat
homozygous genotype, and the susceptibility to chronic PTSD. Notably, the PTSD association
studies may be at risk for false negative results because of including potential unexposed
cases as controls. More important, Segman et al. (32) diminished this risk by limiting their
control group only to subjects who were exposed to similar traumatic events as patients, but
Table 6.1   Association studies in Posttraumatic Stress Disorder.

Genes Polymorphisms Sample (males) Ethnicity Comorbidity Main findings [reference]

DRD2 TaqI “A1” 37 cases non-Hispanic Alcohol or drug Significantly more “A1” allele carriers among PTSD subjects as
Whites dependence compared to non-PTSD (59% versus 5% p=0.0001) [Comings et al.
19 controls 1996]
TaqI “A1” 52 cases European- Alcohol or drug No difference in A1 allele frequencies between PTSD sample (0.15) and
87 controls American dependence controls (0.19) [Gelernter et al. 1999]

TaqI “A1” 57 cases Caucasian Excluded PSYH, BD, Significantly higher scores on GHQ 2 (anxiety/insomnia), GHQ 3 (social
OCD, DEM dysfunction) and GHQ 4 (depression) in A1 allele carriers [Lawford
et al. 2006]
TaqI “A1” 63 cases Caucasian Excluded PSYH, BD, Greater improvement in GHQ 3 (social dysfunction) in A1 allele carriers
OCD, DEM with paroxetine treatment [Lawford et al. 2003]
TaqI “A1” 91 cases Caucasian Alcohol problems Significantly higher frequency of A1 allele in PTSD harmful drinkers
The genetics of posttraumatic stress disorder

51 (18) controls (28%) than in nonharmful drinkers (14%) or in controls (7%) [Young
et al. 2002]
DAT SLC6A3 3´ VNTR 102 (57) cases Jewish Anxiety disorders, Association with 9 repeat allele (p=0.012, OR=1.72) and 9 repeat
104 (49) controls depression homozygous genotype (p=0.047) [Segman et al., 2002]

DBH -1021C/T 133 cases Croatian Excluded Significantly lower plasma DBH activity in PTSD combat veterans
34 controls Caucasian with CC genotype as compared to veterans without PTSD (p<0.001)
[Mustapic et al., 2007]
5-HTT 5-HTTLPR 100 (43) cases Korean Mostly excluded Higher frequency of S-allele in PTSD patients than in controls (0.87
197 (76) controls versus 0.81; p=0.044, OR=1.65) [Lee et al. 2005]
5-HTTLPR 19 (6) cases American, Depression Significant association between low-expression variant and PTSD in
mostly White adults with low social support and exposed to hurricane [Kilpatrick
570 (211) controls et al. 2007]
MAO-B G/A substitution in 106 cases Croatian Depression, GAD, No significant difference in either the allelic (p=0.25-0.89) or genotype
intron 13 242 controls Caucasian alcoholism (p=0.24-1.00) frequencies [Pivac et al. 2007]
73
 74

Table 6.1   (Continued)

Investigated
genes polymorphisms Sample (males) Ethnicity Comorbidity Main findings [reference]

APOE €2, €3 and € 4 54 cases Caucasian Depression, PD, Significantly higher CAPS reexperiencing scores and poorer memory on
isoforms Alcohol problems the WMS-III in €2 allele carriers [Freeman et al. 2005]

BDNF G-712A, C270T, 96 (73) cases European- Unspecified No significant difference in either the allelic, genotype or haplotype
Val66Met 250 (103) controls American frequencies (p=0.23-0.84) [Zhang et al. 2006]
Val66Met 107 (45) cases Korean Mostly excluded No significant difference in either the allelic (p=0.57) or genotype
161 (52) controls (p=0.81) frequencies [Lee et al. 2006]

GABRB3 CA repeat alleles 86 cases Caucasian Not excluded Higher total scores on GHQ in the G1 non-G1 hetero-zygotes than in
(G1-G11) homozygotes (p=0.002) [Feusner et al. 2001]

GCR N363S, BclI 118 cases Unspecified Excluded active No significant difference in either N363S allelic (p=0.46) or BclI
42 controls comorbidity genotype (p=0.40) frequencies [Bachmann et al. 2005]

FKBP5 rs3800373 rs992105 900 (384) > 95% Black- Significant interaction of 4 SNPs (rs9296158, rs3800373, rs1360780,
nonpsychiatric clinic American and rs9470080; minimum p=0.0004) with the severity of child abuse to
rs9296158 patients predict level of adult PTSD symptoms [Binder et al. 2008]
rs737054
rs1360780
rs1334894
rs9470080
rs4713916
NPY Leu7Pro 77 cases European- Alcohol dependence No difference in Pro 7 allele frequencies between PTSD sample (3.9)
202 controls American and controls (2.0) [Lappalainen et al. 2002]

ApoE – apolipoprotein E, BDNF – brain-derived neurotrophic factor, DAT – dopamine transporter, DBN – dopamine beta-hydroxylase, DRD – dopamine receptor, FKBP5 – FK506 binding protein 5, GABA –
gamma-amino-butyric acid, GABRB3 – gamma-amino-butyric acid type A receptor ß3 subunit, GCR – glucocorticoid receptor, MAO-B – monoamine oxidases B, NPY – neuropeptide Y, 5-HTT – serotonin
transporter, VNTR – variable number tandem repeat, CAPS – Clinician Administered PTSD Scale, GHQ – General Health Questionnaire-28 (comprises the somatic symptoms, depression, anxiety/insomnia and
social dysfunction subscales), WMS-III – Weschler Memory Scale-Third Edition, BD – bipolar disorder, GAD – generalized anxiety disorder, DEM – dementia, OCD – obsessive-compulsive disorder, PD – panic
disorder, PSYH – psychosis.
Maron AND Shlik
The genetics of posttraumatic stress disorder 75

did not develop PTSD. Neuroimaging studies in various samples showed lack of a functional
effect of SLC6A3 polymorphism on the availability of DAT in human brain (33-36). However,
a recent study examining the effect of SLC6A3 genotype on brain DAT availability in a large
sample of healthy subjects has revealed significantly higher striatal DAT density with mean
increase about 9% in nine repeat allele carriers as compared to 10 repeat allele homozygotes
(37). Whether increased removal of dopamine from synaptic cleft, as determined by nine repeat
allele, is one of the pathogenetic factors in PTSD needs confirmation. Other disturbances in
genetic regulation of catecholamine metabolism could be also related to PTSD. Similarly to
patients with paranoid schizophrenia and psychotic depression (38), the war veterans with
current and chronic PTSD have significantly lower plasma dopamine beta-hydroxylase (DBH)
activity, in contrast to normal level of DBH activity in combat-exposed war veterans without
PTSD (39). Furthermore, plasma DBH activity was significantly lower in veterans with PTSD
carrying CC genotype of 1021C/T SNP in the five flanking region of DBH as compared to
veterans without PTSD. However, neither genotypes nor allelic frequencies significantly
differed between the two groups of war veterans. Notably, this polymorphism accounts for 35–
52% of the interindividual variations in plasma DBH activity (40), whereas association between
plasma DBH activity and CC genotype has been also reported in alcoholic subjects (41).

Serotonin transporter gene

Serotonin transporter (5-HTT), a key protein regulating serotonin neurotransmission, contains

a functional polymorphism in the 5’ regulatory promoter region (5-HTTLPR), involving two
alleles, corresponding to a 44-bp insertion (long or L-allele) or deletion (short or S-allele). This
polymorphism became the usual suspect in genetic studies of psychiatric disorders after Lesch
et al. (42) reported a decreased 5-HTT transcriptional activity and diminished serotonin uptake
of S variant in comparison to LL genotype and a positive association of S allele with anxiety
traits in humans. On the other hand, 5-HTT is the target for selective serotonin reuptake
inhibitors—antidepressants commonly used in treatment of PTSD. There is only one published
study reporting possible association between 5-HTTLPR and PTSD phenotype (43). This study
was conducted in a Korean sample of PTSD patients, most of them with non–combat-related
stressors, including serious accidents, fire, injury, or physical assault. The modest, but significant
association was demonstrated in their sample with S allele been more frequent among patients.
The interpretation of these results is limited by small sample size and a possibility that some of
the control subjects may still develop PTSD upon exposure to a traumatic event. Moreover, the
higher frequency of S allele in Korean and other Asian populations in comparison to Western
populations may indicate the distinct role of 5-HTTLPR polymorphism in different ethnic
groups. The finding of Lee et al. (43) is still of interest considering the findings in depression
(44-47), where S allele of 5-HTTLPR contributed to development of depression via interaction
with stressful life events. These data suggest that 5-HTTLPR may modify the risk of PTSD
and other stress-related disorders. Supporting this view, a recent study of adults exposed to
the 2004 Florida hurricanes conferred that 5-HTTLPR polymorphism may mediate risks of
postdisaster PTSD and major depression, particularly in those with low social support (48).
These relationships, are, however, not straightforward as other investigations, including
a meta-analysis of 14 studies, found no clear influence of 5-HTTPLR polymorphism, or its
interaction with life stressors, on the onset of affective disorders (49, 50).

Monoamine oxidase gene

Monoamine oxidase (MAO), existing in two isoforms (MAO-A and MAO-B), catalyzes the
oxidative deamination of several biogenic amines, including serotonin. Decreased platelet
MAO-B activity was demonstrated in patients with PTSD in some studies, indicating possible
involvement of this enzyme in PTSD (51-53). However, no difference in MAO-B enzymatic
levels was found between patients and control subjects by Pivac et al. (54), who also evaluated
the relationship between platelet MAO-B activity and G/A substitution polymorphism in
76 Maron AND Shlik

intron 13 of MAO-B gene in combatrelated PTSD veterans with or without psychotic features,
combat-exposed veterans without PTSD and healthy control male subjects. Higher platelet
MAO-B activity was found only in PTSD patients with psychotic symptoms, whereas G/A
polymorphism was unrelated to platelet MAO-B activity and was not associated with PTSD (55).
The transcriptionally more active longer alleles or genotypes of the functional polymorphism
of the MAO-A gene, uVNTR, were significantly associated with panic phenotypes in female
but not male patients (56-58). Considering the high comorbidity rate between panic disorder
and PTSD, this polymorphism deserves more attention in further association studies.

Apolipoprotein E gene

Apolipoprotein E (APOE) is a mediator of lipoprotein binding to the low-density lipoprotein

receptor, E4 isoform, which has been associated with memory impairment (59), smaller
hippocampal volumes (60), and increased rates of hippocampal volume loss (61). The
individuals with chronic PTSD exhibited more impaired memory, attentional, and executive
function deficits (62) and smaller hippocampal volumes than comparison subjects (63). Based
on these observations, Freeman et al. (64) have examined the possible effect of APOE4 allele
on the specific cognitive symptoms in male veterans with combat-related PTSD. Their initial
analysis did not reveal any associations with PTSD symptoms or memory functioning in APOE4
allele carriers as compared to those without this allele. However, they found that subjects
with APOE2 allele had significantly worse symptoms of reexperiencing, but not avoidance or
arousal clusters, and more impaired memory function than the remainder of the study sample.
Despite the novelty of these findings, the study did not confirm the proposed hypothesis and
do not allow to draw clear conclusions due to small sample size.

Brain-derived neurotrophic factor gene

The possible involvement of brain-derived neurotrophic factor (BDNF) gene in the regulation
of stress-related behaviors seems very intriguing due to its important role in the maintenance
of neuronal plasticity (65). Rasmusson et al. (66) observed downregulated BDNF mRNA levels
in the hippocampal dentate gyrus of rats exposed to footshock or reexposed to cues previously
paired with footshock. Based on this finding, Zhang et al. (67) suggested that stress condition
may inhibit hippocampal BDNF expression, which could be relevant to the pathogenesis of
stress-related disorders, including PTSD. They screened a newly identified SNP, G-712A,
and two previously reported SNPs—C270T and Val66Met—in the patients with Alzheimer’s
disease, affective disorders, schizophrenia, substance dependence, and PTSD. No significant
differences in allele, genotype, or haplotype frequencies of the three BDNF SNPs were found
between the patients with PTSD and normal controls. In addition, neither genotype nor allele
frequencies of Val66Met polymorphism significantly differed between the patients with PTSD
and unrelated healthy controls in Korean population (68). These studies have excluded a
major role of BDNF gene in predisposition to PTSD what is in line with the findings on lack of
associations between BDNF gene and panic disorder (69, 70).

Gamma-aminobutyric acid gene

The involvement of gamma-aminobutyric acid (GABA) system in the pathogenesis of PTSD

is supported by peripheral measurements, animal models, and neuroimaging. The reduced
benzodiazepine–GABA-A receptor binding was demonstrated in various brain regions in
PTSD veterans in some but not all studies (71-73). To date, the role of GABA-related genes
in PTSD has not been specifically examined in case-control association studies. Feusner et al.
(74) had demonstrated an association between GABAA receptor c´3 subunit gene locus and
higher levels of General Health Questionnaire-28 (GHQ) cluster symptoms among Caucasian
male PTSD veterans. In particular, total score of the GHQ subscale scores on the somatic
The genetics of posttraumatic stress disorder 77

symptoms, anxiety/insomnia, depression and social dysfunction were higher in PTSD subjects
heterozygous for the G1 microsatellite polymorphism than in homozygous groups.Although
the nature of this effect is not clear, these findings, similar to their above-mentioned consequent
studies (27, 28) implicated the candidate genes in the expression of general psychopathology
rather than in PTSD. The studies in other disorders frequently comorbid with PTSD have found
that 485 G>A polymorphism in peripheral benzodiazepine receptor gene was significantly
associated with panic disorder in Japanese sample (75); however, exonic sequence variants
of the GABA-B receptor 1 gene were not implicated in susceptibility to panic disorder (76).
Additionally, no associations were detected between depressive symptomatology and GABA-A
receptor alpha-1 subunit gene in patients with mood disorders (77) or between two missense
variations in peripheral benzodiazepine receptor gene and mood disturbances (78).

Glucocorticoid receptor gene

The possible involvement of glucocorticoid-related genes in predisposition to PTSD is

suggested based on the apparent alterations in the hypothalamic–pituitary–adrenal (HPA)
axis, resulting in neuroendocrine abnormalities, such as lowered cortisol levels, and increased
sensitivity to glucocorticoids (79-82). A polymorphism in exon 2 of glucocorticoid receptor (GR)
gene, N363S, which is known to alter the N terminal transactivation domain, was found to be
associated with glucocorticoid hypersensitivity (83) and increased salivary cortisol response to
psychosocial stress (84). The other polymorphism located in intron 2 of the same gene, defined
as BclI, was associated with increased glucocorticoid sensitivity and greater cortisol suppression
after lowdose dexamethasone (85, 86), but also with diminished cortisol response to stress (84).
Bachmann et al. (87) examined the association between these polymorphisms and PTSD and
their role in GR sensitivity in Vietnam veterans with PTSD and matched for combat exposure
non-PTSD controls. In this study, the allelic and genotype frequencies of both polymorphisms
did not differ between PTSD patients and controls or previously reported population. There was
no clear relationship between the studied genotypes and glucocorticoid sensitivity as assessed
by low-dose dexamethasone suppression test and the dermal vessel vasoconstrictor assay.
Notably, in contrast to previous findings, the basal plasma cortisol levels did not significantly
differ between PTSD veterans and combatexposed controls and the low-dose dexamethasone
suppression test resulted in similar cortisol suppression in both groups. Only some trends were
found in the subgroup of PTSD patients with BclI GG genotype, which were more responsive to
dermal vessel vasoconstrictor assay and had higher clinician-administered PTSD scale scores
that were significantly and negatively correlated with basal plasma cortisol levels.

FK506 binding protein 5 (FKBP5) gene

FKBP5 is a cochaperone regulating GR signaling (88, 89). Several studies had served FKBP5
gene as an intriguing candidate gene for psychiatric disorders. The polymorphisms in FKBP5
were associated with recurrence or disease status of major depression and treatment response
to antidepressants (90, 91). In addition, the positive association between FKBP5 variations and
peritraumatic dissociation, which is considered to be a risk factor for PTSD, was demonstrated
by Koenen et al. (92) in medically injured children. Binder et al. (93) have explored the
interaction between genetic and environmental risk factors in the development of PTSD,
including exposure to child abuse, non–child-abuse trauma, and genetic polymorphisms of the
FKBP5 gene. In their cross-sectional study consisting of 762 genotyped, nonpsychiatric, mainly
Black (>95%) male and female patients, several FKBP5 SNPs did not directly predict PTSD
symptom outcome or interact with level of non–child-abuse trauma to predict PTSD symptom
severity. However, four SNPs of the FKBP5 gene interacted with severity of child abuse as a
predictor of adult PTSD symptoms, suggesting an interaction between this gene and childhood
environment in the development of PTSD. They also observed significant interactions between
FKBP5 risk allele carrier status, PTSD, and cortisol response to dexamethasone suppression test
in a subgroup of this sample, demonstrating that the majority of patients with risk alleles and
78 Maron AND Shlik

PTSD showed enhanced cortisol suppression or enhanced GR sensitivity, which is a possible

endocrine signature of PTSD. Notably, same SNPs were associated with higher FKBP5 protein
levels or a stronger induction of FKBP5 mRNA by cortisol in healthy probands (90) and also
as implicated by Koenen et al. (92) in psychological response to medical trauma in children.
Interestingly, Segman et al. (94) detected upregualtion of FKBP5 mRNA expression in peripheral
blood mononuclear cells immediately following trauma exposure in those subjects, who later
developed chronic PTSD. These evidences strongly implicate FKBP5 gene in susceptibility to
PTSD and its pathogenesis.

Neuropeptide Y gene

Previously described functional Leu7Pro polymorphism in the neuropeptide Y (NPY) gene

has been recently shown to affect intracellular processing and secretion of preproNPY peptide.
Kallio et al. (95) demonstrated that healthy subjects with Pro7/Leu7 genotype have an average
of 42% higher maximal increases in the plasma concentration of NPY during exercise-induced
sympathetic activation as compared with Leu7/Leu7 carriers. This study has linked Leu7Pro
polymorphism to magnitude of NPY release in response to physiological stressor. On the other
hand, the lower baseline plasma NPY and blunted yohimbine-stimulated increases in plasma
NPY were demonstrated in PTSD patients in comparison to healthy controls (96). In this
study, baseline plasma NPY levels in patients correlated negatively with combat exposure scale
scores, baseline PTSD, and panic symptoms. In a parallel study by the same group, a signifi-
cant increase of plasma NPY was demonstrated in response to high-intensity military training
in healthy soldiers and significant depletion of plasma NPY occurred when stress was extended
(97). Consequently, Lappalainen et al. (98) had tested whether the Leu7Pro polymorphism of
NPY gene is associated with a greater risk of alcohol dependence, secondarily investigating an
independent sample of patients with PTSD. A significantly higher frequency of the Pro7 allele
was observed in alcohol-dependent sample as compared to controls, but not in PTSD patients.

Gene expression studies

Investigation of gene expression patterns has a potential to expand the knowledge about genetic
substrates of psychiatric disorders on transcriptional levels. Microarray studies of peripheral
gene transcription signatures have suggested a shared expression of the majority of genes
in brain and peripheral blood (99) and showed promising results in somatic and psychiatric
disorders (100-104). To date, two studies exploring peripheral gene expression in PTSD have
been published.
Segman et al. (94) were first to hypothesize that transcriptional response of peripheral
blood mononuclear cell may correlate with the development of PTSD among trauma survivors.
To examine this, the gene expression patterns of subjects exposed to traumatic event, mostly
to motor vehicle accident, were screened using oligonucleotide microarrays, immediately
following trauma at the emergency and four months later. This study provided initial evidence
that peripheral transcriptional signatures at both time points distinguished survivors who had
developed acute or chronic PTSD from those who were well at follow-up and correlated with
the severity of PTSD symptom clusters. From the 4,512 active transcripts identified in their
set, they found 656 transcripts that were differentially expressed between PTSD-affected and
nonaffected subjects. A general reduction in expression of transcription activators in PTSD
affected survivors was detected, whereas several differentiating genes were encoding for
proteins that are known to be involved in stress response, transcriptional activation, cell cycle
and proliferation, immune activation, signal transduction, and apoptosis. On the other hand,
the subjects with PTSD demonstrated significantly increased representations of genes involved
in RNA or nucleotide metabolism and processing as well as significantly enriched signatures for
genes that encode for neural and endocrine proteins. More important, 533 from 656 differentially
expressed transcripts were known to be expressed in pertinent brain and neuroendocrine
The genetics of posttraumatic stress disorder 79

regions. For example, gene transcripts expressed in the amygdala, hippocampus, and HPA axis
were particularly abundant among the genes distinguishing the subjects with PTSD.
Another data set on peripheral gene expression signatures in PTSD was recently presented
by Zieker et al. (105). Their study assessed the transcriptional activity of gene expression in
whole blood of eight patients who developed PTSD after Ramstein air show catastrophe (1989)
and eight control subjects. The authors hypothesized that PTSD results from a failure of the
body to reverse the acute stress response; therefore, genes involved in stress and immune
responses could be differentially transcribed in PTSD patients. Using customized “stress/
immune chips” for selected genes related to inflammation, apoptosis, stress response, and
related pathways, they found that four upregulated and 14 downregulated genes, with 5% of
total valid transcripts compared, differentiated the patients from controls. Most downregulated
transcripts were associated with immune functions or with reactive oxygen species. The
additional polymerase chain reaction confirmed downregulation of the following genes:
coding endothelial differentiation sphingolipid, interleukin-18 and 16, superoxide dismutase
1, and thioredoxin reductase 1. Notably, the assessment of peripheral gene expression profiles
was conducted in patients 16 years after the traumatic event. Despite this long interval,
authors argued that patients maintained the specific features of PTSD. However, patients did
not differ from controls on metabolic level, where comparable levels of cortisol, adrenaline,
noradrenaline, vanillylmandelic acid, homovanillic acid, and cytokines were detected in both
groups. Taken together, the transcripts identified in this investigation indicate that a number of
genes related to oxidative pathway and immune system could be good candidates for further
genetic association studies and treatment targets in PTSD.
The studies above warrant replications in larger controlled and more homogenous
samples. The indications of altered gene expression in PTSD challenge whole-genome
association studies to explore novel polymorphisms in the genes demonstrating different
transcriptional activity.

Comorbidity and genetics

High comorbidity between PTSD and other psychiatric disorders indicate that PTSD and comorbid
conditions may share genetic components. This is not surprising considering the universal pathogenic
role of stress in mental illness. As mentioned above, the S allele of 5-HTTLPR polymorphism is
probably one of the important genetic modifiers, which contributes to development of both
major depression and PTSD via interaction with adverse life events or traumas. Unfortunately, no
consistent confirmation from molecular studies exploring this aspect exists today; however, twin
studies lend indirect support for shared or common genetic vulnerability.
Several recent studies have estimated the degree to which a common genetic vulnerability
can explain the nature of associations between PTSD and various psychiatric conditions
based on the data from 6,744 male veterans of VET Registry. Koenen et al. (106) found that
common genetic liability explained 62.5% of PTSD and major depression comorbidity, whereas
genetic influences common to major depression explained 15% of the total variance in risk
for PTSD and 58% of the genetic variance in PTSD. In addition, they showed that individual-
specific environmental influences common to major depression explained only 11% of the
individual-specific environmental variance in PTSD, indicating that environmental influences
on both disorders appear to be largely disorder specific. Subsequent analysis demonstrated
that the magnitude of covariance (genetic plus individual-specific environmental) between
major depression and PTSD was about twice as large as that of the covariance (shared plus
individual-specific environmental) between conduct disorder and PTSD (107). This suggests
that the etiology of PTSD is more closely related to major depression than to conduct disorder.
In contrast, the shared genetic effects explained 63% of the association between PTSD and
nicotine dependence, whereas the remaining covariance was explained by individual-specific
environmental effects (108). These studies underscore a substantial genetic overlap between
PTSD and major depression and nicotine dependence, making the genes implicated in the
etiology of comorbid disorders strong candidates for PTSD and vice versa.
80 Maron AND Shlik

Earlier, Chantarujikapong et al. (109) estimated the magnitude of genetic and

environmental contributions to the lifetime co-occurrence of generalized anxiety disorder,
panic disorder, and PTSD using smaller sample from VET Registry consisting of 3,327 MZ and
DZ male–male twin pair members. The liability for symptoms of generalized anxiety disorder
was due to a 37.9% additive genetic contribution common to symptoms of panic disorder
and PTSD. Liability for symptoms of panic disorder was due to a 20.7% additive genetic
contribution common to symptoms of generalized anxiety disorder and PTSD, and a 20.1%
additive genetic influence specific to panic symptoms. Additive genetic influences common
to symptoms of generalized anxiety disorder and panic disorder accounted for 21.3% of the
genetic variance in PTSD. Additive genetic influences specific to PTSD accounted for 13.6%
of the genetic variance in PTSD. Remaining variance for all three disorders was due to unique
environmental factors both common and specific to each phenotype. These results suggest that
each of these disorders has etiologically distinct components as well as common genetic and
unique environmental contributions.
Taken together, the high comorbidity between PTSD and other psychiatric disorders may
represent the evidence of pleiotropy, where the same genes contribute to the development of
several different disorders or endophenotypes.

Animal genetic studies

The animal studies applying stress models are largely used in exploring various PTSD- related
aspects, including neuroendocrine status or reactivity of autonomic nervous system and
behavioral changes in response to stress (reviewed in next chapter). These models are also
useful in the genetic research. Two strategies are used to establish the nature of interactions
between stress and genes. One direction is to study the effects of gene knockout or transgenic
overexpression on stress-related behavior. Another approach investigates the effect of exposure
to stress on changes in gene expression profiles or their transcriptional activity.
Despite the advantages of knockout models in research on anxiety, the relevance of these
studies to PTSD remains uncertain. For example, several animal studies demonstrated that
knockout mice lacking 5-HTT or 5-HT1A receptor exhibit increased anxiety-related behaviors
in conflict tests, including the open-field, elevated-plus maze, elevated-zero maze, and novelty-
suppressed feeding paradigms (110-116). The 5-HT1A receptor knockout mice also showed
increased behavioral inhibition when faced with complex and ambiguous threatening cues (117).
Although the generalization of fearful behavior to contextual fear conditioning may serve as a
model of PTSD and thus implicate 5-HT1A receptor in this anxiety disorder, it should be noted that
5-HT1A density was not altered in the brain of patients with PTSD (118). Other knockout studies
found a decrease in anxiety-like behavior associated with elevated baseline and poststress exposure
levels of corticosterone in mice lacking the beta3 nicotinic receptor subunit (119) and less anxiety-
related responses and less freezing to a tone after auditory fear conditioning and stress sensitization
in transient receptor potential vanilloid type 1 channel knock-out mice (120). Moreover, significantly
decreased anxiety response was observed after acute stress in mice with knockout of cellular prion
protein (121), whereas anxiety- and stress-related responses were lowered in mice lacking melanin-
concentrating hormone 1 receptor (122) or interleukin 6 (123). On the other hand, anxiety-like
behaviors and/or sensitivity to stress responses increased in mice deficient in corticotropin-releasing
hormone receptor type 1 and 2 (124-126) and in galanin GAL-R1 receptor subtype (127). However,
anxious behavior and stress hormone levels remained unaffected during stress exposure in the
mice deficient in both the GABAB(1) receptor isoforms (128) and neuromedin U central receptor
(129) or were not clearly related to stress exposure in 5-HT3A receptor knockout mice (130).
The stress paradigms are also used in exploring the effect of behavioral and hormonal
responses to stress exposure on the transcriptional levels of relevant genes. In particular,
expression of mRNA for GR was significantly reduced across all hippocampal subfields
in the animals after single prolonged stress, whereas mRNA level of mineralocorticoid
receptor (MR), but not GR, remained persistently downregulated during following 2 weeks.
Furthermore, the animals exhibited hypersensitive glucocorticoid fast feedback induced by
The genetics of posttraumatic stress disorder 81

the stress exposure, demonstrating a decreased MR/GR ratio; by contrast, chronically stressed
animals with normal fast feedback demonstrated normalization in their glucocorticoid
receptor mRNA levels (131). These findings may confirm that hypersensitive glucocorticoid
fast feedback induced by specific stress paradigm may serve as an animal model of PTSD-
specific neuroendocrine abnormality. Interestingly, the mice with transgenic overexpression of
forebrain MR demonstrated diminished anxiety-like behavior accompanying by decrease in
the hippocampal GR and increase in 5HT1A expressions, whereas female mice also exhibited
moderate suppression of the corticosterone response to restraint stress (132). The rats exposed
to restraint stress in the water demonstrated initial downregulation of mRNA for growth
hormone receptor (GHR) in the dentate gyms, which level rapidly enhanced up to 4 hours
after stress. This biphasic enhancement of GHR mRNA expression followed the elevation of
plasma glucocorticoid levels and paralleled with biphasic expressions of mRNAs for MR and
GR in the same region, suggesting that glucocorticoids may interact with GHR in modulation
of hippocampal reactions to stress (134). The other recent study demonstrated that animals
subjected to single prolonged stress exhibited increase in hippocampal levels of both glycine
transporter 1 and vesicle-associated membrane protein 2 mRNA in response to contextual fear
(135). In addition, animals with stronger changes of both behavior and corticosterone levels
in response to predator-scent stress displayed a lack of upregulation in hippocampal mRNA
expression for activity-regulated, cytoskeletal-associated protein (Arc), in contrast to those
with the partial and minimal stress responses (136). On the other hand, the animals showing
extreme behavioral response selectively displayed persistent downregulation of mRNA for
BDNF and upregulation of mRNA for its intracellular kinaseactivating receptor, TrkB, in the CA1
subregion of the hippocampus, compared to animals with partial or minimal responses or to
unexposed controls (137). Since both BDNF and Arc seem to be involved in the longer phases of
long-term potentiation and consequently memory formation (138, 139), their persistently reduced
expression in animals with extreme behavioral response might reflect or mediate changes in
neural plasticity and synaptic functioning underlying chronic stress-induced psychopathologic
processes (136). Earlier findings revealed that exposure to stress has lead to increased expression
of messenger RNA encoding the early immediate transcription factor c-Fos (140), and those
for acetylcholinesterase, but to decreased levels for the acetylcholine-synthesizing enzyme
choline acetyltransferase and the vesicular acetylcholine transporter (141). These data may
indicate that stress-induced changes in cholinergic gene expression could result in a reduction
of available acetylcholine and decline in cholinergic neurotransmission. Preliminary microarray
tests showed that the gene expression profiles in the hippocampus region in clusters of cell
signaling, metabolism, cytoskeleton, and apoptosis, differentiated the stressed maladapted rats
from stressed, well-adapted rats. In addition, the two pathways (mainly with immunoactivity),
cell growth and cycle, and proliferation and apoptosis functionality, were upregulated, while
one, namely, calcium-signaling pathway was downregulated in the amygdala of stressed rats
(142). These findings are of particular interest considering above-mentioned human microarray
findings in PTSD; however, direct parallels can not yet be drown.
Recently, the concept of epigenetic regulatory mechanisms, and specifically, modifications
of chromatin remodelling has been applied in animal models investigating stress-related
behaviors. Most attention has been given to the effects of stress on histone H3 phosphorylation,
which modifies transcriptional activation of silent genes in distinct neuronal populations (143).
Chandramohan et al. (144) have found that exposure to novelty enhanced phosphorylation and
phosphoacetylation of histone H3 in the dentate gyrus throughout the rostrocaudal axis of the
hippocampus, suggesting that selected population of mature dentate neurons is recruited to
allow transcriptional induction of genes necessary for the cellular adaptation to stress. These
studies indicate a high potential of epigenetic approach in advancing genetic research on PTSD.

Conclusions

Similar to other multifactorial and complex diseases, the genetic studies in PTSD face critical
scrutiny and methodological challenges. To date, the genetic research on PTSD has made
82 Maron AND Shlik

modest progress, whereas interpretation of available findings is often complicated and cannot
clearly explain the vulnerability to PTSD. Most of the data are obtained from small samples
and ethnically heterogeneous comorbid populations mainly consisting of males with combat
PTSD, suggesting that the findings may not apply to females, children, or individuals exposed
to other types of trauma. Possible impact of personality traits or individual characteristics on
the vulnerability to traumatic experience has not been well delineated, and only few genetic
studies recognized the necessity to compare PTSD patients to non-PTSD subjects exposed
to the same or similar stressor. PTSD offers a unique opportunity to study interactions
between the genes and the environment. The hypothesis-driven approach to association
studies in PTSD, based on findings in other psychiatric disorders or animal studies, may
be significantly augmented by genomewide association and gene expression studies using
advanced biotechnology and informatics. The emerging research on imaging genomics (145)
may further broaden the understanding of interplay between genetic and neurobiological
bases of anxiety regulation, including PTSD. More transaltional research is warranted to link
the findings on genetic basis of anxiety and stress response in animal and human subjects.
The recognition of genetic factors influencing vulnerability to stressors and PTSD may help
to develop more effective prevention and remediation efforts in this increasingly important
area of public health.

References

   1. Stein MB, Jang KL, Taylor S, Vernon PA, Livesley WJ. Genetic and environmental influences on
trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry 2002;
159(10): 1675–81.
   2. Breslau N, Davis GC, Andreski P, Peterson E. Traumatic events and posttraumatic stress disorder in
an urban population of young adults. Arch Gen Psychiatry 1991 48(3): 216–22.
   3. Breslau N, Kessler RC, Chilcoat HD et al. Trauma and posttraumatic stress disorder in the community:
the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry 1998; 55(7): 626–32.
   4. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the
National Comorbidity Survey. Arch Gen Psychiatry 1995; 52(12): 1048–60.
   5. Segman RH, Shalev AY. Genetics of posttraumatic stress disorder. CNS Spectr 2003; 8(9): 693–8.
   6. Broekman BF, Olff M, Boer F. The genetic background to PTSD. Neurosci Biobehav Rev 2007 31(3):
348–62.
   7. Koenen KC. Genetics of posttraumatic stress disorder: Review and recommendations for future
studies. J Trauma Stress 2007; 20(5): 737–50.
   8. Maron E, Hettema JH, Shlik J. The genetics of human anxiety disorders. In: Huston JP, Robert J,
Blanchard D. Caroline Blanchard, Guy Griebel, David Nutt, eds. Handbook of Anxiety and Fear
2008; 17: 475–510.
   9. Davidson JR, Tupler LA, Wilson WH, Connor KM. A family study of chronic post-traumatic stress
disorder following rape trauma. J Psychiatr Res 1998; 32(5): 301–9.
  10. Reich J, Lyons M, Cai B. Familial vulnerability factors to post-traumatic stress disorder in male
military veterans. Acta Psychiatr Scand 1996; 93(2): 105–12.
  11. Dierker LC, Merikangas KR. Familial psychiatric illness and posttraumatic stress disorder: findings
from a family study of substance abuse and anxiety disorders. J Clin Psychiatry 2001; 62(9):
715–20.
  12. Sautter FJ, Cornwell J, Johnson JJ, Wiley J, Faraone SV. Family history study of posttraumatic stress
disorder with secondary psychotic symptoms. Am J Psychiatry 2002; 159(10): 1775–7.
  13. Sack WH, Clarke GN, Seeley J. Posttraumatic stress disorder across two generations of Cambodian
refugees. J Am Acad Child Adolesc Psychiatry 1995; 34(9): 1160–6.
  14. Kozaric´-Kovacic´ D, Hercigonja DK, Grubisic´-Ilic´ M. Posttraumatic stress disorder and depression
in soldiers with combat experiences. Croat Med J 2001; 42(2): 165–70.
  15. Yehuda R, Schmeidler J, Wainberg M, Binder-Brynes K, Duvdevani T. Vulnerability to posttraumatic
stress disorder in adult offspring of Holocaust survivors. Am J Psychiatry 1998; 155(9): 1163–71.
  16. Bromet E, Sonnega A, Kessler RC. Risk factors for DSM-III-R posttraumatic stress disorder: findings
from the National Comorbidity Survey. Am J Epidemiol 1998; 147(4): 353–61.
  17. Hoven CW, Duarte CS, Lucas CP et al. Psychopathology among New York city public school children
6 months after September 11. Arch Gen Psychiatry 2005 62(5): 545–52.
  18. Hoven CW, Duarte CS, Mandell DJ. Children’s mental health after disasters: the impact of the World
Trade Center attack. Curr Psychiatry Rep 2003; 5(2): 101–7.
The genetics of posttraumatic stress disorder 83

  19. Duarte CS, Hoven CW, Wu P et al. Posttraumatic stress in children with first responders in their
families. J Trauma Stress 2006; 19(2): 301–6.
  20. Skre I, Onstad S, Torgersen S, Lygren S, Kringlen E. A twin study of DSM-III-R anxiety disorders.
Acta Psychiatr Scand 1993; 88(2): 85–92.
  21. True WR, Rice J, Eisen SA et al. A twin study of genetic and environmental contributions to liability
for posttraumatic stress symptoms. Arch Gen Psychiatry 1993 50(4): 257–64.
  22. Lyons MJ, Goldberg J, Eisen SA et al. Do genes influence exposure to trauma? A twin study of combat.
Am J Med Genet 1993; 48(1): 22–7.
  23. Comings DE, Comings BG, Muhleman D et al. The dopamine D2 receptor locus as a modifying gene
in neuropsychiatric disorders. JAMA 1991; 266(13): 1793–800.
  24. Comings DE, Muhleman D, Gysin R. Dopamine D2 receptor (DRD2) gene and susceptibility to
posttraumatic stress disorder: a study and replication. Biol Psychiatry 1996; 40(5): 368–72.
  25. Gelernter J, Southwick S, Goodson S et al. No association between D2 dopamine receptor (DRD2)
“A” system alleles, or DRD2 haplotypes, and posttraumatic stress disorder. Biol Psychiatry 1999;
45(5): 620–5.
  26. Young RM, Lawford BR, Noble EP et al. Harmful drinking in military veterans with post-traumatic stress
disorder: association with the D2 dopamine receptor A1 allele. Alcohol Alcohol 2002; 37(5): 451–6.
  27. Lawford BR, McD Young R, Noble EP et al. D2 dopamine receptor gene polymorphism: paroxetine
and social functioning in posttraumatic stress disorder. Eur Neuropsychopharmacol 2003; 13(5):
313–20.
  28. Lawford BR, Young R, Noble EP, Kann B, Ritchie T. The D2 dopamine receptor (DRD2) gene is
associated with co-morbid depression, anxiety and social dysfunction in untreated veterans with
post-traumatic stress disorder. Eur Psychiatry 2006; 21(3): 180–5.
  29. Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ. Allelic association of the D2 dopamine
receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry 1991; 48(7):
648–54.
  30. Pohjalainen T, Rinne JO, Någren K et al. The A1 allele of the human D2 dopamine receptor gene
predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 1998; 3(3): 256–60.
  31. Heinz A, Siessmeier T, Wrase J et al. Correlation between dopamine D(2) receptors in the ventral
striatum and central processing of alcohol cues and craving. Am J Psychiatry 2004; 161(10): 1783–9.
  32. Segman RH, Cooper-Kazaz R, Macciardi F et al. Association between the dopamine transporter gene
and posttraumatic stress disorder. Mol Psychiatry 2002; 7(8): 903–7.
  33. Heinz A, Goldman D, Jones DW et al. Genotype influences in vivo dopamine transporter availability
in human striatum. Neuropsychopharmacology 2000; 22(2): 133–9.
  34. Jacobsen LK, Staley JK, Zoghbi SS et al. Prediction of dopamine transporter binding availability by
genotype: a preliminary report. Am J Psychiatry 2000; 157(10): 1700–3.
  35. Martinez D, Gelernter J, Abi-Dargham A et al. The variable number of tandem repeats polymorphism
of the dopamine transporter gene is not associated with significant change in dopamine transporter
phenotype in humans. Neuropsychopharmacology 2001; 24(5): 553–60.
  36. Lynch DR, Mozley PD, Sokol S et al. Lack of effect of polymorphisms in dopamine metabolism
related genes on imaging of TRODAT-1 in striatum of asymptomatic volunteers and patients with
Parkinson’s disease. Mov Disord 2003; 18(7): 804–12.
  37. van Dyck CH, Malison RT, Jacobsen LK et al. Increased dopamine transporter availability associated
with the 9-repeat allele of the SLC6A3 gene. J Nucl Med 2005; 46(5): 745–51.
  38. Cubells JF, Zabetian CP. Human genetics of plasma dopamine beta-hydroxylase activity: applications
to research in psychiatry and neurology. Psychopharmacology (Berl) 2004; 174(4): 463–76.
  39. Mustapic´ M, Pivac N, Kozaric´-Kovacic´ D et al. Dopamine beta-hydroxylase (DBH) activity and
-1021C/T polymorphism of DBH gene in combat-related post-traumatic stress disorder. Am J Med
Genet B Neuropsychiatr Genet 2007; 144(8): 1087–9.
  40. Zabetian CP, Anderson GM, Buxbaum SG et al. A quantitative-trait analysis of human plasmadopamine
beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am J
Hum Genet 2001; 68(2): 515–22.
  41. Köhnke MD, Zabetian CP, Anderson GM et al. A genotype-controlled analysis of plasma dopamine
beta-hydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in
noradrenergic function. Biol Psychiatry 2002; 52(12): 1151–8.
  42. Lesch KP, Bengel D, Heils A et al. Association of anxiety-related traits with a polymorphism in the
serotonin transporter gene regulatory region. Science 1996; 274(5292): 1527–31.
  43. Lee HJ, Lee MS, Kang RH et al. Influence of the serotonin transporter promoter gene polymorphism
on susceptibility to posttraumatic stress disorder. Depress Anxiety 2005; 21(3): 135–9.
  44. Caspi A, Sugden K, Moffitt TE et al. Influence of life stress on depression: moderation by a
polymorphism in the 5-HTT gene. Science 2003; 301(5631): 386–9.
  45. Eley TC, Sugden K, Corsico A et al. Gene-environment interaction analysis of serotonin system
markers with adolescent depression. Mol Psychiatry 2004; 9(10): 908–15.
84 Maron AND Shlik

  46. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a
serotonin transporter polymorphism in the prediction of episodes of major depression: a replication.
Arch Gen Psychiatry 2005; 62(5): 529–35.
  47. Kim JM, Stewart R, Kim SW et al. Interactions between life stressors and susceptibility genes
(5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry 2007; 62(5): 423–8.
  48. Kilpatrick DG, Koenen KC, Ruggiero KJ et al. The serotonin transporter genotype and social support
and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am J
Psychiatry 2007; 164(11): 1693–9.
  49. Gillespie NA, Whitfield JB, Williams B, Heath AC, Martin NG. The relationship between stressful life
events, the serotonin transporter (5-HTTLPR) genotype and major depression. Psychol Med 2005;
35(1): 101–11.
  50. Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT. Meta-analysis of the association between two
polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B
Neuropsychiatr Genet 2005; 133(1): 110–5.
  51. Davidson J, Lipper S, Kilts CD, Mahorney S, Hammett E. Platelet MAO activity in posttraumatic
stress disorder. Am J Psychiatry 1985; 142(11): 1341–3.
  52. Cicin-Sain L, Mimica N, Hranilovic D et al. Posttraumatic stress disorder and platelet serotonin
measures. J Psychiatr Res 2000; 34(2): 155–61.
  53. Kozaric´-Kovacic´ D, Ljubin T, Rutic´-Puz L et al. Platelet monoamine oxidase activity, ego strength,
and neuroticism in soldiers with combat-related current posttraumatic stress disorder. Croat Med J
2000; 41(1): 76–80.
  54. Pivac N, Mück-Seler D, Sagud M, Jakovljevic´ M. Platelet serotonergic markers in posttraumatic
stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26(6): 1193–8.
  55. Pivac N, Knezevic J, Kozaric-Kovacic D et al. Monoamine oxidase (MAO) intron 13 polymorphism
and platelet MAO-B activity in combat-related posttraumatic stress disorder. J Affect Disord 2007;
103(1–3): 131–8.
  56. Deckert J, Catalano M, Syagailo YV et al. Excess of high activity monoamine oxidase A gene promoter
alleles in female patients with panic disorder. Hum Mol Genet 1999; 8(4): 621–4.
  57. Maron E, Lang A, Tasa G et al. Associations between serotonin-related gene polymorphisms and
panic disorder. Int J Neuropsychopharmacol 2005; 8(2): 261–6.
  58. Samochowiec J, Hajduk A, Samochowiec A et al. Association studies of MAO-A, COMT, and 5-HTT
genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Res
2004; 128(1): 21–6.
  59. Flory JD, Manuck SB, Ferrell RE, Ryan CM, Muldoon MF. Memory performance and the apolipoprotein
E polymorphism in a community sample of middle-aged adults. Am J Med Genet 2000; 96(6):
707–11.
  60. Kuller LH, Shemanski L, Manolio T et al. Relationship between ApoE, MRI findings, and cognitive
function in the Cardiovascular Health Study. Stroke 1998; 29(2): 388–98.
  61. Cohen RM, Small C, Lalonde F, Friz J, Sunderland T. Effect of apolipoprotein E genotype on
hippocampal volume loss in aging healthy women. Neurology 2001; 57(12): 2223–8.
  62. Golier J, Yehuda R. Neuropsychological processes in post-traumatic stress disorder. Psychiatr Clin
North Am 2002; 25(2): 295–315.
  63. Bremner JD, Randall P, Scott TM et al. MRI-based measurement of hippocampal volume in patients
with combat-related posttraumatic stress disorder. Am J Psychiatry 1995; 152(7): 973–81.
  64. Freeman T, Roca V, Guggenheim F, Kimbrell T, Griffin WS. Neuropsychiatric associations
of apolipoprotein E alleles in subjects with combat-related posttraumatic stress disorder. J
Neuropsychiatry Clin Neurosci 2005; 17(4): 541–3.
  65. McAllister AK, Katz LC, Lo DC. Neurotrophins and synaptic plasticity. Annu Rev Neurosci 1999; 22:
295–318.
  66. Rasmusson AM, Shi L, Duman R. Downregulation of BDNF mRNA in the hippocampal dentate
gyrus after re-exposure to cues previously associated with footshock. Neuropsychopharmacology
2002; 27(2): 133–42.
  67. Zhang H, Ozbay F, Lappalainen J et al. Brain derived neurotrophic factor (BDNF) gene variants and
Alzheimer’s disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance
dependence. Am J Med Genet B Neuropsychiatr Genet 2006; 141(4): 387–93.
  68. Lee HJ, Kang RH, Lim SW et al. Short Communication: No association between the brain-derived
neurotrophic factor gene Val66Met polymorphism and posttraumatic stress disorder. Stress and
Health 2006; 22: 115–9.
  69. Lam P, Cheng CY, Hong CJ, Tsai SJ. Association study of a brain-derived neurotrophic factor
(Val66Met) genetic polymorphism and panic disorder. Neuropsychobiology 2004; 49(4): 178–81.
  70. Shimizu E, Hashimoto K, Koizumi H et al. No association of the brain-derived neurotrophic factor
(BDNF) gene polymorphisms with panic disorder. Prog Neuropsychopharmacol Biol Psychiatry
2005; 29(5): 708–12.
The genetics of posttraumatic stress disorder 85

  71. Bremner JD, Innis RB, Southwick SM et al. Decreased benzodiazepine receptor binding in prefrontal
cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 2000; 157(7): 1120–6.
  72. Fujita M, Southwick SM, Denucci CC et al. Central type benzodiazepine receptors in Gulf War
veterans with posttraumatic stress disorder. Biol Psychiatry 2004; 56(2): 95–100.
  73. Geuze E, van Berckel BN, Lammertsma AA et al. Reduced GABAA benzodiazepine receptor binding
in veterans with post-traumatic stress disorder. Mol Psychiatry 2008; 13(1): 74–83.
  74. Feusner J, Ritchie T, Lawford B et al. GABA(A) receptor beta 3 subunit gene and psychiatric morbidity
in a post-traumatic stress disorder population. Psychiatry Res 2001; 104(2): 109–17.
  75. Nakamura K, Yamada K, Iwayama Y et al. Evidence that variation in the peripheral benzodiazepine
receptor (PBR) gene influences susceptibility to panic disorder. Am J Med Genet B Neuropsychiatr
Genet 2006; 141(3): 222–6.
  76. Sand PG, Godau C, Riederer P et al. Exonic variants of the GABA(B) receptor gene and panic disorder.
Psychiatr Genet 2000; 10(4): 191–4.
  77. Serretti A, Macciardi F, Cusin C et al. GABAA alpha-1 subunit gene not associated with depressive
symptomatology in mood disorders. Psychiatr Genet 1998; 8(4): 251–4.
  78. Kurumaji A, Nomoto H, Yamada K, Yoshikawa T, Toru M. No association of two missense variations
of the benzodiazepine receptor (peripheral) gene and mood disorders in a Japanese sample. Am J
Med Genet 2001; 105(2): 172–5.
  79. Smith MA, Davidson J, Ritchie JC et al. The corticotropin-releasing hormone test in patients with
posttraumatic stress disorder. Biol Psychiatry 1989; 26(4): 349–55.
  80. Yehuda R, Kahana B, Binder-Brynes K et al. Low urinary cortisol excretion in Holocaust survivors
with posttraumatic stress disorder. Am J Psychiatry 1995; 152(7): 982–6.
  81. Yehuda R, Levengood RA, Schmeidler J et al. Increased pituitary activation following metyrapone
administration in post-traumatic stress disorder. Psychoneuroendocrinology 1996; 21(1): 1–16.
  82. Stein MB, Yehuda R, Koverola C, Hanna C. Enhanced dexamethasone suppression of plasma cortisol
in adult women traumatized by childhood sexual abuse. Biol Psychiatry 1997; 42(8): 680–6.
  83. Huizenga NA, Koper JW, De Lange P et al. A polymorphism in the glucocorticoid receptor gene may
be associated with and increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 1998;
83(1): 144–51.
  84. Wüst S, Van Rossum EF, Federenko IS et al. Common polymorphisms in the glucocorticoid receptor
gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metab
2004; 89(2): 565–73.
  85. Panarelli M, Holloway CD, Fraser R et al. Glucocorticoid receptor polymorphism, skin
vasoconstriction, and other metabolic intermediate phenotypes in normal human subjects. J Clin
Endocrinol Metab 1998; 83(6): 1846–52.
  86. van Rossum EF, Roks PH, de Jong FH et al. Characterization of a promoter polymorphism in the
glucocorticoid receptor gene and its relationship to three other polymorphisms. Clin Endocrinol
(Oxf) 2004; 61(5): 573–81.
  87. Bachmann AW, Sedgley TL, Jackson RV et al. Glucocorticoid receptor polymorphisms and
posttraumatic stress disorder. Psychoneuroendocrinology 2005; 30(3): 297–306.
  88. Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG. Squirrel monkey immunophilin
FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology 2000; 141(11): 4107–13.
  89. Schiene-Fischer C, Yu C. Receptor accessory folding helper enzymes: the functional role of peptidyl
prolyl cis/trans isomerases. FEBS Lett 2001; 495(1–2): 1–6.
  90. Binder EB, Salyakina D, Lichtner P et al. Polymorphisms in FKBP5 are associated with increased
recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004;
36(12): 1319–25.
  91. Lekman M, Laje G, Charney D et al. The FKBP5-Gene in depression and treatment response-an
association study in the sequenced treatment alternatives to relieve depression (STAR*D) cohort.
Biol Psychiatry 2008; 63(12):1103-10.
  92. Koenen KC, Saxe G, Purcell S et al. Polymorphisms in FKBP5 are associated with peritraumatic
dissociation in medically injured children. Mol Psychiatry 2005; 10(12): 1058–9.
  93. Binder EB, Bradley RG, Liu W et al. Association of FKBP5 polymorphisms and childhood abuse with
risk of posttraumatic stress disorder symptoms in adults. JAMA 2008; 299(11): 1291–305.
  94. Segman RH, Shefi N, Goltser-Dubner T et al. Peripheral blood mononuclear cell gene expression
profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol Psychiatry
2005; 10(5): 500–13.
  95. Kallio J, Pesonen U, Karvonen MK et al. Enhanced exercise-induced GH secretion in subjects with
Pro7 substitution in the prepro-NPY. J Clin Endocrinol Metab 2001; 86(11): 5348–52.
  96. Rasmusson AM, Hauger RL, Morgan CA et al. Low baseline and yohimbine-stimulated plasma
neuropeptide Y (NPY) levels in combat-related PTSD. Biol Psychiatry 2000; 47(6): 526–39.
  97. Morgan CA 3rd, Wang S, Southwick SM et al. Plasma neuropeptide-Y concentrations in humans
exposed to military survival training. Biol Psychiatry 2000 47(10): 902–9.
86 Maron AND Shlik

  98. Lappalainen J, Kranzler HR, Malison R et al. A functional neuropeptide Y Leu7Pro polymorphism
associated with alcohol dependence in a large population sample from the United States. Arch Gen
Psychiatry 2002; 59(9): 825–31.
  99. Liew CC, Ma J, Tang HC, Zheng R, Dempsey AA. The peripheral blood transcriptome dynamically
reflects system wide biology: a potential diagnostic tool. J Lab Clin Med 2006; 147: 126–32.
100. Barnes MG, Aronow BJ, Luyrink LK et al. Gene expression in juvenile arthritis and spondyloarthropathy:
pro-angiogenic ELR+ chemokine genes relate to course of arthritis. Rheumatology (Oxford) 2004;
43(8): 973–9.
101. Morello F, de Bruin TW, Rotter JI et al. Differential gene expression of blood-derived cell lines in
familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 2004; 24(11): 2149–54.
102. Bull TM, Coldren CD, Moore M et al. Gene microarray analysis of peripheral blood cells in pulmonary
arterial hypertension. Am J Respir Crit Care Med 2004 170(8): 911–9.
103. Philibert RA, Crowe R, Ryu GY et al. Transcriptional profiling of lymphoblast lines from subjects
with panic disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144(5): 674–82.
104. Maron E, Kallassalu K, Tammiste A, et al. Peripheral gene expression profiling of CCK-4-induced panic
in healthy subjects. Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 2. [Epub ahead of print]
105. Zieker J, Zieker D, Jatzko A et al. Differential gene expression in peripheral blood of patients suffering
from post-traumatic stress disorder. Mol Psychiatry 2007; 12(2): 116–8.
106. Koenen KC, Fu QJ, Ertel K et al. Common genetic liability to major depression and posttraumatic
stress disorder in men. J Affect Disord 2008; 105(1–3): 109–15.
107. Fu Q, Koenen KC, Miller MW et al. Differential etiology of posttraumatic stress disorder with conduct
disorder and major depression in male veterans. Biol Psychiatry 2007; 62(10): 1088–94.
108. Koenen KC, Hitsman B, Lyons MJ et al. A twin registry study of the relationship between posttraumatic
stress disorder and nicotine dependence in men. Arch Gen Psychiatry 2005; 62(11): 1258–65.
109. Chantarujikapong SI, Scherrer JF, Xian H et al. A twin study of generalized anxiety disorder
symptoms, panic disorder symptoms and post-traumatic stress disorder in men. Psychiatry Res
2001; 103(2–3): 133–45.
110. Gross C, Zhuang X, Stark K et al. Serotonin1A receptor acts during development to establish normal
anxiety-like behaviour in the adult. Nature 2002; 416(6879): 396–400.
111. Heisler LK, Chu HM, Brennan TJ et al. Elevated anxiety and antidepressant-like responses in
serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci U S A 1998; 95(25): 15049–54.
112. Holmes A, Lit Q, Murphy DL, Gold E, Crawley JN. Abnormal anxiety-related behavior in serotonin
transporter null mutant mice: the influence of genetic background. Genes Brain Behav 2003; 2(6): 365–80.
113. Parks CL, Robinson PS, Sibille E, Shenk T, Toth M. Increased anxiety of mice lacking the serotonin1A
receptor. Proc Natl Acad Sci U S A 1998; 95(18): 10734–9.
114. Pattij T, Groenink L, Hijzen TH et al. Autonomic changes associated with enhanced anxiety in
5-HT(1A) receptor knockout mice. Neuropsychopharmacology 2002; 27(3): 380–90.
115. Ramboz S, Oosting R, Amara DA et al. Serotonin receptor 1A knockout: an animal model of
anxietyrelated disorder. Proc Natl Acad Sci U S A 1998; 95(24): 14476–81.
116. Sibille E, Pavlides C, Benke D, Toth M. Genetic inactivation of the Serotonin(1A) receptor in mice
results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A)
receptor binding, and benzodiazepine-resistant anxiety. J Neurosci 2000; 20(8): 2758–65.
117. Klemenhagen KC, Gordon JA, David DJ, Hen R, Gross CT. Increased fear response to contextual cues
in mice lacking the 5-HT1A receptor. Neuropsychopharmacology 2006; 31(1): 101–11.
118. Bonne O, Bain E, Neumeister A et al. No change in serotonin type 1A receptor binding in patients
with posttraumatic stress disorder. Am J Psychiatry 2005; 162(2): 383–5.
119. Booker TK, Butt CM, Wehner JM, Heinemann SF, Collins AC. Decreased anxiety-like behavior in
beta3 nicotinic receptor subunit knockout mice. Pharmacol Biochem Behav 2007; 87(1): 146–57.
120. Marsch R, Foeller E, Rammes G et al. Reduced anxiety, conditioned fear, and hippocampal long-term
potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci 2007;
27(4): 832–9.
121. Nico PB, de-Paris F, Vinadé ER et al. Altered behavioural response to acute stress in mice lacking
cellular prion protein. Behav Brain Res 2005; 162(2): 173–81.
122. Smith DG, Davis RJ, Rorick-Kehn L et al. Melanin-concentrating hormone-1 receptor modulates
neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice
Neuropsychopharmacology 2006; 31(6): 1135–45.
123. Chourbaji S, Urani A, Inta I et al. IL-6 knockout mice exhibit resistance to stress-induced development
of depression-like behaviors. Neurobiol Dis 2006; 23(3): 587–94.
124. Bale TL, Contarino A, Smith GW et al. Mice deficient for corticotropin-releasing hormone receptor-2
display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 2000; 24(4): 410–4.
125. Gammie SC, Hasen NS, Stevenson SA, Bale TL, D’Anna KL. Elevated stress sensitivity in
corticotropinreleasing factor receptor 2 deficient mice decreases maternal, but not intermale
aggression. Behav Brain Res 2005; 160(1): 169–77.
The genetics of posttraumatic stress disorder 87

126. Müller MB, Zimmermann S, Sillaber I et al. Limbic corticotropin-releasing hormone receptor 1
mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 2003; 6(10):
1100–7.
127. Holmes A, Kinney JW, Wrenn CC et al. Galanin GAL-R1 receptor null mutant mice display increased
anxiety-like behavior specific to the elevated plus-maze. Neuropsychopharmacology 2003;
28(6):1031–44.
128. Jacobson LH, Bettler B, Kaupmann K, Cryan JF. Behavioral evaluation of mice deficient in GABA(B(1))
receptor isoforms in tests of unconditioned anxiety. Psychopharmacology (Berl) 2007; 190(4):541–53.
129. Zeng H, Gragerov A, Hohmann JG et al. Neuromedin U receptor 2-deficient mice display differential
responses in sensory perception, stress, and feeding. Mol Cell Biol 2006; 26(24): 9352–63.
130. Bhatnagar S, Sun LM, Raber J et al. Changes in anxiety-related behaviors and hypothalamicpituitary-
adrenal activity in mice lacking the 5-HT-3A receptor. Physiol Behav 2004; 81(4): 545–55.
131. Liberzon I, López JF, Flagel SB, Vázquez DM, Young EA. Differential regulation of hippocampal
glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder.
J Neuroendocrinol 1999; 11(1): 11–7.
132. Rozeboom AM, Akil H, Seasholtz AF. Mineralocorticoid receptor overexpression in forebrain
decreases anxiety-like behavior and alters the stress response in mice. Proc Natl Acad Sci U S A
2007;104(11): 4688–93.
134. Fujikawa T, Soya H, Fukuoka H et al. A biphasic regulation of receptor mRNA expressions for growth
hormone, glucocorticoid and mineralocorticoid in the rat dentate gyrus during acute stress. Brain
Res 2000; 874(2): 186–93.
135. Iwamoto Y, Morinobu S, Takahashi T, Yamawaki S. Single prolonged stress increases contextual
freezing and the expression of glycine transporter 1 and vesicle-associated membrane protein 2
mRNA in the hippocampus of rats. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31(3): 642–51.
136. Kozlovsky N, Matar MA, Kaplan Z et al. The immediate early gene Arc is associated with
behavioral resilience to stress exposure in an animal model of posttraumatic stress disorder. Eur
Neuropsychopharmacol 2008; 18(2): 107–16.
137. Kozlovsky N, Matar MA, Kaplan Z et al. Long-term down-regulation of BDNF mRNA in
rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. Int J
Neuropsychopharmacol 2007; 10(6): 741–58.
138. Guzowski JF, Lyford GL, Stevenson GD et al. Inhibition of activity-dependent arc protein expression
in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of
long-term memory. J Neurosci 2000; 20(11): 3993–4001.
139. Plath N, Ohana O, Dammermann B et al. Arc/Arg3.1 is essential for the consolidation of synaptic
plasticity and memories. Neuron 2006; 52(3): 437–44.
140. Friedman A, Kaufer D, Shemer J et al. Pyridostigmine brain penetration under stress enhances
neuronal excitability and induces early immediate transcriptional response. Nat Med 1996;
2(12):1382–5.
141. Kaufer D, Friedman A, Seidman S, Soreq H. Acute stress facilitates long-lasting changes in cholinergic
gene expression. Nature 1998; 393(6683): 373–7.
142. Zhang L, Zhou R, Xing G, et al. Identification of gene markers based on well validated and
subcategorized stressed animals for potential clinical applications in PTSD. Med Hypotheses.
2006;66(2):309-14.
143. Bilang-Bleuel A, Ulbricht S, Chandramohan Y et al. Psychological stress increases histone H3
phosphorylation in adult dentate gyrus granule neurons: involvement in a glucocorticoid
receptordependent behavioural response. Eur J Neurosci 2005 22(7): 1691–700.
144. Chandramohan Y, Droste SK, Reul JM. Novelty stress induces phospho-acetylation of histone H3 in rat
dentate gyrus granule neurons through coincident signalling via the N-methyl-D-aspartate receptor
and the glucocorticoid receptor: relevance for c-fos induction. J Neurochem 2007; 101(3):815–28.
145. Hariri AR, Weinberger DR. Functional neuroimaging of genetic variation in serotonergic
neurotransmission. Genes Brain Behav 2003; 2(6): 341–9.
 7 Setting apart the affected—a novel animal
model for posttraumatic stress disorder and its
translational perspective
Joseph Zohar, Michael Matar, and Hagit Cohen

INTRODUCTION

Although animal models of psychiatric disorders are limited to the assessment of measurable
and observable behavioral parameters and cannot assess complex psychological symptoms
such as thought, meaning, and dreams, they are still useful. Valid and reliable animal models
may provide a means for researching biomolecular, pathophysiological, and pharmacological
features of the disorder in ways which are not feasible in human studies. They are not only
relatively cheap but also enable an intervention with compounds and methods that would not
be allowed in humans. Animal models also enable a prospective follow-up design, in which
the disorder is triggered at a specified time and in a uniform manner, in controllable and sta-
tistically sound population samples (in terms of size and composition, including genetically
manipulated and inbred strains), and enable the assessment of behavioral and gross physi-
ological parameters. Moreover, and unlike studies in human subjects, they enable the assess-
ment of concomitant biomolecular changes in dissected brain areas.
Certain criteria must be fulfilled in order to achieve a satisfactory degree of reliability
and validity in modeling the complexities of psychiatric disorders. For example, the behavioral
responses must be clearly observable and measurable, must reliably reflect clinical symptoma-
tology, and pharmacological agents known to affect symptoms in human subjects should cor-
rect the parameters that model symptoms with equal efficacy.
However, many animal models for psychiatric disorders are from their onset subject to a
hypothetical paradigm, for example, bulbectomy or inescapable shock for an animal model of
depression, and so on. In posttraumatic stress disorder (PTSD) the situation is entirely different; the
trigger is well-known and universal—exposure to a traumatic event, and hence the center of grav-
ity shifts from how to induce it to how to “diagnose” those animals who develop PTSD vs. those
who do not. The behavioral cutoff criteria were introduced, based on this concept—setting apart
the affected—isolates and studies those animals who developed “PTSD-like behavior,” comparing
them to those who did not develop PTSD (although they were exposed to trauma) and to those
who were not exposed.
Researchers who work with animals have long been aware that individual study subjects tend
to display a varying range of responses to stimuli, certainly where stress paradigms are concerned.
This heterogeneity in responses was accepted for many years, regarded as unavoidable, and mostly
swept under the carpet. The hallmark of PTSD is the differential response to trauma, and the main
issue is why the majority of those exposed to trauma do not develop PTSD (the resilience issue),
and only a minority do. Hence, in an animal model of PTSD, the heterogeneity in animal responses
might be regarded the heart of the model as it presents face validity rather than a problem. It stands
to reason that an animal model that includes “diagnostic criteria” may augment the validity of the
disorder studied. However, the criteria for classification should be clearly defined, reliably repro-
ducible, and yield results that conform to findings in human subjects.
This chapter will present findings from a series of studies in an animal model of PTSD
employing individual behavioral response classification. A brief introduction to the standard
stress paradigm, the standard behavioral methods, and the definition of the cutoff behavioral
criteria (CBC) employed for classification will precede this.

The Predator-Scent Stress Paradigm

Stress paradigms in animals studies aim to model criterion A of the DSM-IV-TR diagnostic
criteria (1) They have thus consisted of extremely stressful experiences that create a sense of
threat and helplessness in the study subjects. Many of the paradigms emphasize the ethological
validity of the threatening or painful experience.
Setting Apart the Affected 89

The standard stressor in the following studies consists of exposure of rodents to the scent
of the urine of their prime predator—the cat. Blanchard et al. (2–7), Adamec et al. (8–13), and oth-
ers (14–16) have established the validity of this paradigm, in which adult rodents are inescapably
exposed to urine-soiled substrate (cat litter) for 5–10 minutes in a closed environment, where both
“fight” and “flight” options are ineffective. Predator stress has ecological validity in that it mimics
brief, intense threatening experiences inducing the expected range of behavioral and physiological
responses. The potency of predator scent stress (PSS) is comparable to that of paradigms in which
the threat is more tangible and immediate, as compared to paradigms based on induction of other
stressors such as inescapable pain, electric shock, or direct (protected) proximity to a kitten or a
cat. Exposure to unsoiled cat litter serves as the standard trauma-cue paradigm, and immediate
response to the cue is assessed by freezing behavior recorded on an overhead camera.

Behavioral Assessments
A variety of mazes and open environments have been employed to assess changes in exploratory
behavior resulting from stress exposure and to reflect the response amplitude. These test envi-
ronments assess behaviors that indicate anxiety-like fearful behaviors and behaviors reflecting
avoidance. Various learning and memory tasks are employed in which both exploration and
learned task performance can be assessed. Some studies have investigated social behavior in
home cages and in challenge situations. The startle response that characterizes many PTSD
patients has also been employed as one of the more definitively measurable parameters for the
hypervigilant/hyperalert component of the behavioral responses.(8, 15) In the following stud-
ies, exploratory behavior on the elevated plus maze (EPM) serves as the main platform for the
assessment of overall behavior, and the acoustic startle response (ASR) paradigm provides a
precise quantification of hyperalertness, in terms of magnitude of response and habituation to
the stimulus. For details regarding these tests, see Cohen et al.(17–23)
As to the timing of behavioral assessments, a large number of studies performed in a
range of research centers indicate quite clearly that behavioral changes that are observed in
rodents at Day 7 after stress exposure are unlikely to change significantly over the next 30
days.(23) The average life expectancy for the domestic rat is between 2.5 and 3 years. Hence,
behavioral patterns observed at Day 7 can reliably be taken to represent PTSD-like responses
(i.e., “translating” a week for a rat to a month for a human).

Classification according to Cutoff Behavioral Criteria

Data from a series of studies had previously shown that 7 days after a single 10-minute pred-
ator-scent exposure, the overall exposed population displayed significantly decreased time
spent in the open arms and increased time in the closed arms of the EPM (which is translated
to “avoidant” and “anxiety-like behavior”), and higher mean startle responses as compared
to control rats (Figure 7.1). It is important to note that the rats’ behavior was not uniformly
disturbed but rather demonstrated a broad range of variation in response severity. The pooled
data were reexamined for definable behavioral criteria and revealed a group of animals whose
behavioral response patterns clearly demonstrated no significant difference from unexposed
control animals, and a second group whose responses to both test paradigms were equally
significantly at the extreme end on all measures. Each of these groups was significantly distinct
from animals whose behavior lay between the extremes.
The behavioral measures for each of these groups on the EPM and ASR tests were
employed to define the basic cutoff behavioral criteria (CBC). As clinical diagnostic criteria
require a sufficient number of symptoms from three symptom clusters in order to achieve sat-
isfactory diagnostic specificity, the CBC response classification process would require that a
given rat fulfill all criteria on both tests to be performed in series. The standard algorithm for
the CBC classification model also requires that prior to classification, a significant overall effect
be demonstrated. (Figure 7.2).
The CBCs enable us to clearly define a given rat as displaying extreme behavioral response
(EBR) or minimal behavioral response (MBR; that is, extreme responses on both EPM and ASR
tests led to classification as EBR, whereas minimal responses were defined as MBR)—both
of which have been validated in a large series of studies. The remaining rats display clearly
disrupted behavior patterns compared to controls, but the extent of the disruption does not
90 Zohar, Matar, and Cohen

2000

Star Amplitude
1500

1000

500 100
75

n
atio
50
25

bitu
0 0

Ha
1 –2 5
2

rtle
Time sp 3 –5 0
ent in th 4

Sta
e open a 5
rms (min
)

Figure 7.1  The effect of single PSS-exposure vs. unexposed control on rat anxiety-like behavior and acoustic
startle response & habituation. The graphic representation of the data from both paradigms (EPM and ASR)
reveals two obvious and rather distinct features. Firstly, it is clear that PSS-exposure alters the response of the
majority of individuals to at least some degree. Secondly the cluster of individuals that forms in the upper left hand
corner of the graph (i.e. more extreme responses to exposure) is quite distinct from the majority of individuals and
could therefore be interpreted as representing “PTSD-like” behavior.

A No

Verification of overall effect if EPM & ASR parameters:

of PSS exposure: Exposed groups > Unexposed controls

Yes

EPM: Five munites (entire session) spent in closed arms with Extreme
B no oper-arm entries Behavioral
& Yes Response
ASR: Mean startle amplitude > 800 units (at 110 Db) with no
Application of the CBC’s to if habituation over time. ((EBR)
the data:
No

EPM: 0–1 minute spent in closed arms and ≥ open arm Minimal
entries Behavioral
if & Yes Response
ASR: Mean amplitudes ≤ 700 units (at 110Db) and
habituation is demonstrated. ((MBR)
No

Partial
Behavioral
Neither EBR nor MBR Neither EBR nor MBR Yes
Response
((PBR)

Figure 7.2  The Cut-off Behavioral Criteria (CBC) algorithm.

Setting Apart the Affected 91

80.01% 50%

MBR PBR

MBR
PBR EBR EBR
24.7%
1.33%

18.66%
25.3%

A: Unexposed populations B: PSS-exposed animals

Figure 7.3  Re-analysis of data applying Cut-off Behavioral Criteria A) Unexposed populations B) PSS-exposed
animals.

cross the threshold for EBR. These are labeled partial behavioral responders (PBR) and have as
yet not been further subclassified.(19, 22, 23)
The pooled behavioral data for entire exposed populations were reexamined according
to the CBCs, revealing that the overall prevalence rate for EBR rats was approximately 25%
(Figure 7.3A), as compared to 1.3% in unexposed control populations (Figure 7.3B). The preva-
lence of MBR rats in the PSS-exposed groups was 24.7% (Figure 7.3A) as compared to 80.0% in
the control groups (Figure 7.2B).
The implication of this initial finding was that all prior study analyses must have included
a significant proportion of animals whose behavior had not been affected by the stressor (MBR)
and many animals whose response was of uncertain significance (PBR), alongside those whose
response was unequivocally one of severely disrupted behavioral patterns (EBR). Hence, the
method offered a feasible means for classifying animal response patterns to trauma, thereby
increasing the conceptual accuracy of the data.
It is interesting to note that the proportion of the entire exposed population fulfilling
criteria for extreme responses (EBR) was also compatible with epidemiological data for PTSD
among trauma-exposed human populations (24), which report that between 15% and 35% ful-
fill criteria for PTSD and that approximately 20% to 30% display partial or subsymptomatic
clinical pictures.(24–26) This compatibility further supported the concept of criterion-based
classification in terms of face validity.

SELECTED CBC-BASED STUDIES

Behavioral response patterns vs. time

Time is an integral factor in traumatic stress–induced disorders. The prevalence rates of EBR
rats were assessed among PSS-exposed rats on Days 1, 3, 5, 7, 30, and 90 after exposure (Figure
7.4). Initially (Day 1) almost all animals displayed extreme disruptions of behavior (EBR =
90%). The proportion of EBR animals dropped rapidly over Days 3 and 5 to about 25% at Day
7. This proportion remained stable till Day 30, dropping to about 15% by Day 90. The resulting
time curve of EBR prevalence rates parallels the rates of stress-related symptoms in humans,
culminating in acute and chronic traumatic stress disorders.(23)

Physiological correlates
Physiological data were correlated with behavioral classification in a series of studies, includ-
ing the HPA axis (circulating corticosterone, dehydroepiandrosterone (DHEA), and its sulphate
derivative DHEA-S levels), autonomic nervous system (heart rate and heart rate variability) (19,
27), and immune system.(28) Although the gross population data had shown that the parameters
92 Zohar, Matar, and Cohen

100
90

Prevalence of EBR rats

80
70
60
50
40
30
20
10
0
1 3 5 7 14 30 90
Days after PSS-exposure

Figure 7.4  Prevalence of EBR rats after single PSS-exposure as a function of time.

in each study displayed significant responses to the stressor, CBC classification revealed that
animals whose behavior conformed to EBR criteria were characterized by significantly more dis-
turbances on all measures, whereas MBR rats displayed almost none.

Strain/genetic studies
The CBC classification model was applied to genetically manipulated rodent strains in order to
examine two aspects of PTSD. One study assessed the HPA-axis response in rat strains inbred
to have either deficient or excessive HPA-axis responsiveness, compared to outbred rats.
The other examined the heritability of vulnerability vs. resilience factors using inbred (near-
isogenic) mouse strains exposed to PSS and classified according to the CBC method.
a) HPA-axis response Lewis and Fischer rats: PTSD has been associated with disordered
levels of circulating cortisol, an integral component of the stress response (increased levels
according to some studies, and decreased in others).(29–45) Naturalistic clinical observations
in intensive care units (46) and treatment of septic shock (47, 48) show that administration of
cortisol reduces the incidence of cases of PTSD.(46–48)
The animal model provides an opportunity to address questions such as whether low
basal cortisol levels represent a consequence of traumatic exposure (i.e., possible neurotoxic
effects of trauma) or a predisposing trait for pathological stress reactions, by looking at popula-
tions of inbred Lewis and Fischer rats compared to outbred Sprague–Dawley rats. Lewis rats
exhibit a reduced synthesis and secretion of corticotrophin-releasing factor (CRF), leading to
reduced plasma ACTH and reduced CORT release from the adrenal cortex, whereas Fischer
rats possess a hyperresponsive HPA axis. Prevalence rates of EBR individuals were significantly
higher in Lewis (50%) than in Fischer rats (10%), or controls (25%) (49). Moreover, exogenous
administration of cortisol to Lewis rats, before applying the stressor, decreased the prevalence
of EBR significantly (8%).(49) These results suggest that a blunted HPA-axis response to stress
may play a role in the susceptibility to experimentally induced PTSD-like behavioral changes,
especially as these effects were reversed by preexposure administration of corticosterone.
b) Stress-induced behavioral responses in inbred mouse strains: Twin and family studies of
PTSD patients raise questions as to a possible genetic predisposition to PTSD, although the
relative contributions of the genotype and environment to endophenotypic expression are
unclear.
Six inbred strains of mice frequently employed in transgenic research were assessed at
baseline and 7 days after PSS exposure.(50) Inbred strains are expected to demonstrate ∼97.5%
homozygosity of loci as the result of at least 20 generations of sibling matings. The results,
however, revealed an unexpectedly high degree of within-strain individual heterogeneity at
baseline and in the degree of response to stress. This within-strain phenotypic heterogene-
ity might imply that environmental factors play a significant role in characterizing individual
responses, in spite of the significant strain-related, that is, genetic, underpinnings.(51, 52)
Setting Apart the Affected 93

Molecular Neurobiological Correlates

Selected brain areas, especially hippocampal substructures and frontal cortex, of rats classified
according to the CBC procedure have been studied in correlation to both their behavioral and
physiological response patterns. The studies have examined the expression of genes and gene
products for key intracellular and intercellular biomolecules associated with neuromodulation,
synaptic plasticity, and receptor systems. In some studies, these data have also been correlated
to individual performance on memory-related tasks.
The development of an EBR response has been shown to be associated with a distinct
pattern of long-term and persistent downregulation of mRNA for brain-derived neurotrophic
factor (BDNF) and synaptophysin, and an upregulation of glucocorticoid receptor (GR) protein
levels and tyrosine kinase receptor (TrkB) mRNA in the CA1 subregion of the hippocampus,
compared to PBR and MBR animals and to unexposed controls.(53) The persistently higher lev-
els of glucocorticoids are associated with the attenuation of BDNF, synaptophysin, and imme-
diately early genes such as activity-regulated, cytoskeletal-associated protein (Arc) and zif/268
expression in the EBR rats, suggesting that they reflect or mediate the characteristic changes
in neural plasticity and synaptic functioning underlying chronic stress-induced behavioral
disruption. Neurotrophins, and particularly BDNF, are known to modulate many aspects of
neuronal plasticity (54, 55) and the selection of functional neuronal connections in the CNS.
(56–58) The decreased expression of BDNF (mRNA and protein) levels in EBR individuals may
be associated with a decrease in synaptic plasticity and impairment of the stabilization of syn-
aptic connectivity, which may be linked to vulnerability to psychopathology. Decreased hip-
pocampal expression of synaptophysin, a major integral protein on synaptic vesicles, might
also be associated with hippocampal damage that may occur during stress exposure.(59) Taken
together, decreased hippocampal expression of these genes may have physiological conse-
quences, for example, inducing damage to hippocampal neurons.
SSRIs and other antidepressant drugs were found to reinforce synaptic strength in mood-
related brain regions in a manner akin to that achieved in experimental models of synaptic plas-
ticity.(60, 61) Pei et al. (62) reported that repeated administration of the monoamine reuptake
inhibitors— paroxetine, venlafaxine, or desipramine—induced region-specific increases in Arc
mRNA (in the frontal and parietal cortex and hippocampal CA1 area). Thus, whereas downreg-
ulation of Arc mRNA has been shown to promote stress-induced psychopathology in synaptic
networks, long-term administration of SSRIs and so on might either prevent or reverse this
effect. Taken together, SSRIs might, therefore, be able to protect and/or to rescue the functional
integrity of neuronal circuitry from the effects of stress.(53)

Drug studies
Acute-phase pharmacotherapeutic interventions that effectively alleviate symptoms and
possess potential preventive effects on the development of PTSD founded on large-scale, dou-
ble-blind, controlled, and prospective clinical trails are lacking. The CBC classification model
affords distinct advantages in the prospective study of the therapeutic and preventive potential
of medications. The model enables the prospective study of associations between the behav-
ioral efficacy of the drug in question in a quantifiable manner over specific periods of time, and
the biomolecular and physiological correlates of these behavioral effects. The CBC model was
applied to the study of number of drugs—a selective serotonin reuptake inhibitor (sertraline),
corticosteroids, and a benzodiazepine (alprazolam).
a) Early intervention with an SSRI (Sertraline): Based on the rationale that the acute phase
in rodents is represented by the first 7 days following stress exposure (discussed in “Behavioral
Assessments” in this chapter), rats were randomly allocated to 7 days of treatment either
immediately following exposure or as of day 7, compared to saline treatment. Behavioral and
biomolecular assessments performed at Day 7 (or Day 14) demonstrated the following: Brief,
immediate postexposure intervention with sertraline had an observable short-term effect on
stress-induced behavioral changes that was comparable to the later treatment regimen and
compared to the saline-treated control group.(63) Seven days of treatment with sertraline
immediately after PSS-exposure elicited a statistically significant reduction (14%) in prevalence
rates of EBR and an increase of 5% in prevalence rates of minimal response (MBR) compared
to the placebo-control group. The early treatment group displayed a reduced prevalence of
extreme anxiety-like and avoidant behaviors on the EPM and an attenuation of the exaggerated
94 Zohar, Matar, and Cohen

30 p < 0 .0 0 0 1

CA1 BDNF mRNA levels/β actin

p < 0 .0 0 1 p < 0 .0 0 0 1
25

20

15

10

0
U n e x p o se d S a lin e S e r tr a lin e
E x p o se d

BDNF
β actin
CON Saline Sertraline
Figure 7.5  Quantitative analysis of BDNF mRNA expression. BDNF mRNA expression levels in the CA1 hip-
pocampal subregion following saline or sertraline treatment.

hyperarousal responses, equivalent to the patterns of behavior of unexposed animals, and a sig-
nificant degree of reversal of the deficit in habituation of the acoustic startle response observed
in controls.(63) These finding suggest that SSRI drugs represent potential agents for secondary
intervention in the acute aftermath of traumatic stress exposure and are thus worthy of further
investigation. Moreover, 7 days of treatment with sertraline immediately after PSS-exposure
normalized long-term changes of BDNF mRNA in PTSD-like animals in parallel with the
improvement in their behavioral responses (Unpublished data - Figure 7.5).
b) Early intervention with corticosterone: As corticosteroid treatment is clinically indi-
cated only in cases in which there is significant physical illness or polytrauma, recurrent
clinical reports of a significant preventive effect in terms of the incidence of concomitant
PTSD are difficult to interpret, despite their relative frequency and impressive results.(46–48,
64–66) The CBC model was employed to examine the effect of a single high-dose interven-
tion with the adrenocorticoid stress hormone CORT given immediately after exposure. This
regimen was compared to lower doses, later treatment, and saline. Stress-induced behavioral
responses were assessed at Day 30 and trauma-cue triggered freezing-response was assessed
on Day 31.
The results clearly showed that a single 25 mg/kg dose of CORT administered immedi-
ately after exposure to the scent of predator urine resulted in a statistically significant reduction
of 13.2% in the prevalence rates of EBR individuals at 30 days, with a concomitant increase of
12.4% in the prevalence of MBR individuals, as compared to saline , that is, a significant shift
toward less extreme behavioral disruption ensuing from traumatic stress.(67) Rats in the high-
dose CORT group responded markedly less extremely to exposure to the trauma cue (24% of
time freezing) than the saline-control group (80% of time freezing). This pattern of response
suggests that the single high-dose CORT treatment had conferred some degree of resilience to
future trauma-related stress exposure.(67) Lower doses of CORT (0.1–5.0 mg/kg) were ineffec-
tive in attenuating behavioral disruptions and significantly increased the prevalence of EBR (at
Day 30) and the vulnerability to the trauma cue as compared to placebo.
The marked attenuation of the response of treated individuals to the trauma cue 31 days
after exposure is of significance. The time frame in which CORT was administered (1 hour after
stress exposure) conforms to the time frame within which the memory consolidation process
takes place at the cellular level (3–6 hours after initiation of data acquisition). The time at which
the effect was assessed was sufficiently distant from the initial exposure, which goes to show
that the effect was mediated by memory-related processes. Furthermore, the same pattern was
Setting Apart the Affected 95

observed in another study, where the protein synthesis inhibitor Anisomycin was effective
when administrated within an hour after exposure, but not when administered later on (after
reactivation of the trauma by a trauma cue).(68) This may suggest that the single high-dose
CORT treatment interfered similarly, by disrupting consolidation of the short-term memory to
long-term memory.(67)
c) Early intervention with benzodiazepine (Alprazolam): Benzodiazepines are commonly
used to relieve distress. Because it has been claimed that early administration of BNZ may be
associated with a less favorable outcome (69) and because there is a possibility that BNZ may
impede adequate processing of acute grief (70), their effects vis-à-vis exposure to stress were
examined in the CBC model.
In this placebo-controlled study, the short-term efficacy and the long-term sequelae of brief
early postexposure administration of a commonly prescribed benzodiazepine (Alprazolam) for the
prevention of subsequent PTSD-like behavioral changes were examined. The results demonstrated
that rats treated immediately after the initial exposure were rendered significantly more vulnerable
to the trauma cue and by far more vulnerable to reexposure to PSS than the placebo control groups.
However, when the treatment was initiated after 1 week, it did not affect vulnerability.(71) It will
be important to establish whether this finding is replicable and whether it is related to specific ben-
zodiazepines and/or a certain time frame, both in animal and in clinical studies. How could this
finding be explained? What might be the mechanism? One possible mechanism might be related
to the effect of Alprazolam on cortisol secretion. The marked suppression of corticosterone activity
during alprazolam treatment and the sharp rebound after its cessation may well be key factors in
the pathogenesis of some behavioral responses observed in this study when BNZ treatment was
initiated. As was mentioned above, the protective effect of cortisol secretion being entirely abol-
ished by early administration of BNZ coupled with polarity of plasma corticosterone levels may be
of great pathogenetic significance, especially in the consolidation phase.(71)

Conclusions

Animal models might complement clinical research and enable modalities that are difficult
to attain in clinical studies. However, it is difficult to come up with an adequate animal
model for psychiatric disorders. Because it is possible, in PTSD, to accurately mimic the main
etiological factor, that is, exposure to trauma, an animal model of PTSD may be easier to
defend. The animal model presented, which is a combination of an exposure to predator
and a focus on setting apart the affected based on behavioral cutoff criteria, demonstrated
high face validity, construct validity, and predictive validity. The cumulative results of our
studies indicate that the validity of this contribution can be further enhanced by classifying
individual animal study subjects according to their response patterns. This approach enables
researchers to test interventions that might be impossible (i.e., Anisomycin) or difficult (e.g.,
BNZ, SSRI, Cortisol) to carry out in a clinical setting without any proper preclinical basis. The
animal model also enables the researcher to go one step further and correlate specific ana-
tomic biomolecular and physiological parameters with the degree and pattern of individual
behavioral response.

REFERENCES

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4 ed.
Washington, DC. American Psychiatric Association; 2005.
  2. Blanchard DC, Griebel G, Blanchard RJ. Conditioning and residual emotionality effects of predator
stimuli: some reflections on stress and emotion. Prog Neuropsychopharmacol Biol Psychiatry 2003;
27(8): 1177–85.
  3. Blanchard RJ, Blanchard DC. Anti-predator defense as models of fear and anxiety. In: Blanchard RJ
and S. Parmigiani, ed. Brain. London: Harwood Academic Publishers, 1990.
  4. Blanchard RJ, Blanchard DC, Rodgers J, Weiss SM. The characterization and modelling of antipredator
defensive behavior. Neurosci Biobehav Rev 1990; 14(4): 463–72.
  5. Blanchard RJ, Griebel G, Henrie JA, Blanchard DC. Differentiation of anxiolytic and panicolytic drugs
by effects on rat and mouse defense test batteries. Neurosci Biobehav Rev 1997; 21(6): 783–9.
96 Zohar, Matar, and Cohen

  6. Blanchard RJ, Nikulina JN, Sakai RR et al. Behavioral and endocrine change following chronic
predatory stress. Physiol Behav 1998; 63(4): 561–9.
  7. Blanchard RJ, Yang M, Li CI, Gervacio A, Blanchard DC. Cue and context conditioning of defensive
behaviors to cat odor stimuli. Neurosci Biobehav Rev 2001; 25(7–8): 587–95.
  8. Adamec R. Transmitter systems involved in neural plasticity underlying increased anxiety and
defense--implications for understanding anxiety following traumatic stress. Neurosci Biobehav Rev
1997; 21(6): 755–65.
  9. Adamec R, Head D, Blundell J, Burton P, Berton O. Lasting anxiogenic effects of feline predator stress
in mice: sex differences in vulnerability to stress and predicting severity of anxiogenic response from
the stress experience. Physiol Behav 2006; 88(1–2): 12–29.
10. Adamec R, Muir C, Grimes M, Pearcey K. Involvement of noradrenergic and corticoid receptors in
the consolidation of the lasting anxiogenic effects of predator stress. Behav Brain Res 2007; 179(2):
192–207.
11. Adamec R, Strasser K, Blundell J, Burton P, McKay DW. Protein synthesis and the mechanisms of
lasting change in anxiety induced by severe stress. Behav Brain Res 2006; 167(2): 270–86.
12. Adamec RE, Blundell J, Burton P. Relationship of the predatory attack experience to neural plasticity,
pCREB expression and neuroendocrine response. Neurosci Biobehav Rev 2006; 30(3): 356–75.
13. Adamec RE, Shallow T. Lasting effects on rodent anxiety of a single exposure to a cat. Physiol Behav
1993; 54(1): 101–9.
14. Diamond DM, Campbell AM, Park CR et al. Influence of predator stress on the consolidation vs. retrieval
of long-term spatial memory and hippocampal spinogenesis. Hippocampus 2006; 16(7): 571–6.
15. File SE, Zangrossi Jr H, Sanders FL, Mabbutt PS. Dissociation between behavioral and corticosterone
responses on repeated exposures to cat odor. Physiol Behav 1993; 54: 1109–11.
16. Griebel G, Blanchard DC, Jung A et al. Further evidence that the mouse defense test battery is useful
for screening anxiolytic and panicolytic drugs: effects of acute and chronic treatment with alprazolam.
Neuropharmacology 1995; 34(12): 1625–33.
17. Cohen H, Benjamin J, Kaplan Z, Kotler M. Administration of high-dose ketoconazole, an inhibitor of
steroid synthesis, prevents posttraumatic anxiety in an animal model. Eur Neuropsychopharmacol
2000; 10: 429–35.
18. Cohen H, Friedberg S, Michael M, Kotler M, Zeev K. Interaction of CCK-4 induced anxiety and post-
cat exposure anxiety in rats. Depress Anxiety 1996; 4(3): 144–5.
19. Cohen H, Zohar J, Matar M. The relevance of differential response to trauma in an animal model of
post-traumatic stress disorder. Biol Psychiatry 2003; 53(6): 463–73.
20. Cohen H, Kaplan Z, Kotler M. CCK-antagonists in a rat exposed to acute stress: implication for
anxiety associated with post-traumatic stress disorder. Depress Anxiety 1999; 10(1): 8–17.
21. Cohen H, Matar MA, Richter-Levin G, Zohar J. The contribution of an animal model toward
uncovering biological risk factors for PTSD. Ann N Y Acad Sci 2006; 1071: 335–50.
22. Cohen H, Zohar J. Animal models of post traumatic stress disorder: the use of cut off behavioral
criteria. Ann N Y Acad Sci 2004; 1032: 167–78.
23. Cohen H, Zohar J, Matar MA et al. Setting apart the affected: the use of behavioral criteria in animal
models of post traumatic stress disorder. Neuropsychopharmacology 2004; 29(11): 1962–70.
24. Breslau N, Davis GC, Andreski P, Peterson E. Traumatic events and posttraumatic stress disorder in
an urban population of young adults. Arch Gen Psychiatry 1991; 48(3): 216–22.
25. Breslau N, Kessler RC, Chilcoat HD et al. Trauma and posttraumatic stress disorder in the community:
the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry 1998; 55(7): 626–32.
26. Resnick HS, Kilpatrick DG, Dansky BS, Saunders BE, Best CL. Prevalence of civilian trauma and
posttraumatic stress disorder in a representative national sample of women. J Consult Clin Psychol
1993; 61(6): 984–91.
27. Cohen H, Maayan R, Touati-Werner D et al. Decreased circulatory levels of neuroactive steroids
in behaviorally more extremely affected rats subsequent to exposure to a potentially traumatic
experience. Int J Neuropsychopharmacol 2007; 10(2): 203–9.
28. Cohen H, Ziv Y, Cardon M et al. Maladaptation to mental stress mitigated by the adaptive immune system
via depletion of naturally occurring regulatory CD4+CD25+ cells. J Neurobiol 2006; 66(6): 552–63.
29. Mason JW, Giller EL, Kosten TR, Ostroff RB, Podd L. Urinary free-cortisol levels in posttraumatic
stress disorder patients. J Nerv Ment Dis 1986; 174(3): 145–9.
30. Mason JW, Giller EL, Kosten TR, Harkness L. Elevation of urinary norepinephrine/cortisol ratio in
posttraumatic stress disorder. J Nerv Ment Dis 1988; 176(8): 498–502.
31. Pitman RK, Orr SP. Twenty-four hour urinary cortisol and catecholamine excretion in combat-related
posttraumatic stress disorder. Biol Psychiatry 1990; 27(2): 245–7.
32. Yehuda R, Lowy MT, Southwick SM, Shaffer D, Giller EL Jr. Lymphocyte glucocorticoid receptor
number in posttraumatic stress disorder. Am J Psychiatry 1991a; 148(4): 499–504.
33. Yehuda R, Giller EL, Southwick SM, Lowy MT, Mason JW. Hypothalamic-pituitary-adrenal
dysfunction in posttraumatic stress disorder. Biol Psychiatry 1991b; 30(10): 1031–48.
Setting Apart the Affected 97

34. Yehuda R, Southwick S, Giller EL, Ma X, Mason JW. Urinary catecholamine excretion and severity of
PTSD symptoms in Vietnam combat veterans. J Nerv Ment Dis 1992; 180(5): 321–5.
35. Resnick HS, Yehuda R, Pitman RK, Foy DW. Effect of previous trauma on acute plasma cortisol level
following rape. Am J Psychiatry 1995; 152(11): 1675–7.
36. Yehuda R. Risk and resilience in posttraumatic stress disorder. J Clin Psychiatry 2004; 65(1): 29–36.
37. Bremner JD, Innis RB, Ng CK et al. Positron emission tomography measurement of cerebral metabolic
correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen
Psychiatry 1997; 54(3): 246–54.
38. Foa EB, Stein DJ, McFarlane AC. Symptomatology and psychopathology of mental health problems
after disaster. J Clin Psychiatry 2006; 67(2): 15–25.
39. Delahanty DL, Raimonde AJ, Spoonster E. Initial posttraumatic urinary cortisol levels predict
subsequent PTSD symptoms in motor vehicle accident victims. Biol Psychiatry 2000; 48(9): 940–7.
40. Rasmusson AM, Lipschitz DS, Wang S et al. Increased pituitary and adrenal reactivity in premenopausal
women with posttraumatic stress disorder. Biol Psychiatry 2001; 50(12): 965–77.
41. Elzinga BM, Schmahl CG, Vermetten E, van Dyck R, Bremner JD. Higher cortisol levels following exposure
to traumatic reminders in abuse-related PTSD. Neuropsychopharmacology 2003; 28(9): 1656–65.
42. Yehuda R, McEwen BS. Protective and damaging effects of the biobehavioral stress response: cognitive,
systemic and clinical aspects: ISPNE XXXIV meeting summary. Psychoneuroendocrinology 2004;
29(9): 1212–22.
43. Spivak B, Shohat B, Mester R et al. Elevated levels of serum interleukin-1 beta in combat-related
posttraumatic stress disorder. Biol Psychiatry 1997; 42(5): 345–8.
44. Maes M, Lin AH, Delmeire L et al. Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations
in posttraumatic stress disorder following accidental man-made traumatic events. Biol Psychiatry
1999; 45(7): 833–9.
45. Baker DG, Ekhator NN, Kasckow JW et al. Plasma and cerebrospinal fluid interleukin-6 concentrations
in posttraumatic stress disorder. Neuroimmunomodulation 2001; 9(4): 209–17.
46. Schelling G, Richter M, Roozendaal B et al. Exposure to high stress in the intensive care unit may have
negative effects on health-related quality-of-life outcomes after cardiac surgery. Crit Care Med 2003;
31(7): 1971–80.
47. Schelling G, Stoll C, Kapfhammer HP et al. The effect of stress doses of hydrocortisone during septic
shock on posttraumatic stress disorder and health-related quality of life in survivors. Crit Care Med
1999; 27(12): 2678–83.
48. Schelling G, Briegel J, Roozendaal B et al. The effect of stress doses of hydrocortisone during septic
shock on posttraumatic stress disorder in survivors. Biol Psychiatry 2001; 50(12): 978–85.
49. Cohen H, Zohar J, Gidron Y et al. Blunted HPA axis response to stress influences susceptibility to
posttraumatic stress response in rats. Biol Psychiatry 2006; 59(12): 1208–18.
50. Cohen H, Zohar J, Matar M, Loewenthal U, Kaplan Z. The impact of environment factors in
determining post-exposure responses in isogenic strains of mice: can genetic predisposition explain
phenotypic vulnerability? Int J Neuropsychopharmacol 2007; in press.
51. Caspi A, Moffitt T. Gene–environment interactions in psychiatry: joining forces with neuroscience.
Nat Rev Neurosci 2006; 7: 583–90.
52. Moffitt T, Caspi A, Rutter M. Measured gene–environment interactions in psychopathology. Perspect
Psychol Sci 2006; 1: 5–27.
53. Kozlovsky N, Matar MA, Kaplan Z et al. The immediate early gene Arc is associated with
behavioral resilience to stress exposure in an animal model of posttraumatic stress disorder. Eur
Neuropsychopharmacol 2007; 2: 2.
54. Shieh PB, Ghosh A. Molecular mechanisms underlying activity-dependent regulation of BDNF
expression. J Neurobiol 1999; 41(1): 127–34.
55. Thoenen H. Neurotrophins and neuronal plasticity. Science 1995; 270(5236): 593–8.
56. Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci 2001; 2(1): 24–32.
57. Wang MJ, Huang HM, Chen HL, Kuo JS, Jeng KC. Dehydroepiandrosterone inhibits lipopolysaccharide-
induced nitric oxide production in BV-2 microglia. J Neurochem 2001; 77(3): 830–8.
58. Mamounas LA, Altar CA, Blue ME et al. BDNF promotes the regenerative sprouting, but not survival,
of injured serotonergic axons in the adult rat brain. J Neurosci 2000; 20(2): 771–82.
59. Thome J, Pesold B, Baader M et al. Stress differentially regulates synaptophysin and synaptotagmin
expression in hippocampus. Biol Psychiatry 2001; 50(10): 809–12.
60. Duman RS. Synaptic plasticity and mood disorders. Mol Psychiatry 2002; 7: 29–34.
61. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med 2001; 7: 541–7.
62. Pei Q, Zetterstrom TS, Sprakes M, Tordera R, Sharp T. Antidepressant drug treatment induces Arc
gene expression in the rat brain. Neuroscience 2003; 121(4): 975–82.
63. Matar MA, Cohen H, Kaplan Z, Zohar J. The effect of early poststressor intervention with sertraline on
behavioral responses in an animal model of post-traumatic stress disorder. Neuropsychopharmacology
2006; 31(12): 2610–8.
98 Zohar, Matar, and Cohen

64. Schelling G. Effects of stress hormones on traumatic memory formation and the development of
posttraumatic stress disorder in critically ill patients. Neurobiol Learn Mem 2002; 78(3): 596–609.
65. Schelling G, Kilger E, Roozendaal B et al. Stress doses of hydrocortisone, traumatic memories, and
symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol
Psychiatry 2004; 55(6): 627–33.
66. Weis F, Kilger E, Roozendaal B et al. Stress doses of hydrocortisone reduce chronic stress symptoms
and improve health-related quality of life in high-risk patients after cardiac surgery: a randomized
study. J Thorac Cardiovasc Surg 2006; 131(2): 277–82.
67. Cohen H, Matar MA, Buskila D, Kaplan Z, Zohar J. Early post-stressor intervention with high dose
corticosterone attenuates post traumatic stress response in an animal model of PTSD. Biol Psychiatry
2008; 64(8):708–717.
68. Cohen H, Kaplan Z, Matar M et al. Anisomycin, a protein synthesis inhibitor, disrupts traumatic
memory consolidation and attenuates post traumatic stress response in rats. Biol Psychiatry 2006;
60(7): 767–76.
69. Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY. Treatment of recent trauma survivors with
benzodiazepines: a prospective study. J Clin Psychiatry 1996; 57(9): 390–4.
70. British Medical Association & Royal Pharmaceutical Society of Great Britain. British National
Formulary, London & Wallingford: BMJ Books and Pharmaceutical Press; 2000.
71. Matar M, Zohar J, Kaplan Z, Cohen H. Alprazolam treatment immediately after stress exposure
interferes with the normal HPA-stress response and increases vulnerability to subsequent stress in an
animal model of PTSD. Eur Neuropsychopharmacology 2009; 19(4):283–295.
 8 Psychosocial treatments of posttraumatic
stress disorder
Kerry J Ressler and Barbara O Rothbaum

Introduction

Impressive advances in treating posttraumatic stress disorder (PTSD) have been made in the
past decade with respect to group psychotherapy, individual psychodynamically oriented
therapy, and cognitive–behavioral therapy. Notably the Institute of Medicine (1) has recently
confirmed the efficacy for exposure-based psychotherapy treatment for PTSD while finding
that the current data are inadequate to determine the efficacy of medication treatment for
PTSD.(1)
During this same period of time, the neuroscience that underlies the psychotherapy for
treating fear-based disorders is rapidly progressing and is being translated to the clinic in the
form of pharmacological augmentation of emotional learning.
This chapter summarizes the literature on psychosocial interventions for PTSD, begin-
ning with a brief review of traditional therapies. We then examine the larger literature on the
efficacy of cognitive–behavioral procedures with PTSD, along with exciting experimental
approaches such as virtual reality–based treatment for PTSD and pharmacological augmenta-
tion of emotional learning combined with psychotherapy.

Traditional interventions

Hypnotherapy
Hypnosis has been advocated in the treatment of trauma since it was introduced by Freud to attain
the abreaction and catharsis he deemed necessary to resolve a psychic conflict (see (2) for a review)
and continues to be used to treat trauma survivors. Spiegel noted that hypnosis may be useful
in treating PTSD because hypnotic phenomena such as dissociation are common in coping with
trauma as it occurs and in its sequelae, and hypnosis may facilitate the recall of traumatic events that
were encoded in a dissociative state and that, therefore, are not available to conscious recollection.
A number of case studies have reported that hypnosis was useful in treating posttrauma
disturbances following a variety of traumas, but most of these lack methodological rigor and
thus cannot allow strong conclusions to be drawn. In the one controlled study (3) of 112 trauma
victims, the relative efficacies of hypnosis, desensitization, and psychodynamic psychotherapy
were compared against a waiting list control group. The participants were victims of a variety
of traumas who all met symptom criteria for PTSD; the majority did not directly experience the
trauma but had lost a loved one. The results indicated that participants in all three treatment
conditions were more improved than those in the waiting list condition, but no differences
across the three treatments were observed. Inspection of the pre- and post-treatment means
indicated 29% improvement on the Impact of Event Scale (IES) (4) for those in psychodynamic
therapy, 34% for hypnotherapy, and 41% for desensitization, compared to about 10% improve-
ment in the waiting list condition. The results suggest that hypnotherapy, as well as desensiti-
zation and psychodynamic therapy, may offer some help for posttrauma suffering.
Since these earlier studies, few other sufficiently powered comparative studies of hyp-
notherapy have been performed. The most recent large review of psychosocial therapy for
PTSD from the Institute of Medicine (IOM) (1) and Cochrane Database review (5) found that
hypnosis remains understudied, and that, therefore, based on this extremely limited body
of evidence (little empirical support, as there are few randomized clinical trials [RCTs]), the
IOM committee stated that it would be inappropriate to reach a conclusion regarding the
efficacy of hypnotherapy.(1)
100 Ressler and Rothbaum

Psychodynamic treatments
Treatment by dynamic psychotherapy has often been advocated as a final component of crisis
intervention.(6–8) However, empirical investigations of their efficacy are scarce, and those that
do exist are not usually well controlled. In an attempt to account for posttrauma reactions,
psychodynamic theorists, for example, (9) emphasize concepts such as denial, abreaction,
catharsis, and stages of recovery from trauma. The target of Horowitz’s brief psychodynamic
therapy is the resolution of intrapsychic conflict arising from a traumatic experience rather
than specific symptom reduction. Other psychodynamic theorists focus largely on group pro-
cess.(10) Several studies have suggested that psychodynamic treatments may be useful in the
treatment of PTSD, while others have not found them effective. Psychodynamic psychotherapy
was not found useful in the treatment of a traumatized Vietnam veteran.(11) After 19 months
of no progress with psychodynamic psychotherapy, therapy by imagery was introduced. The
therapist presented a trauma-related scene and allowed the client to develop it spontaneously
through associations rather than by plan. The use of the imagery technique was not planned
in advance, but rather it was introduced at appropriate times in the context of a session. The
client moved onto other trauma-related scenes when he was ready. Avoidance was addressed
through psychodynamic techniques of dealing with transference and resistance. Ten sessions
of this imagery therapy were effective in ameliorating the client’s PTSD as observed by the
therapist and reported by the client. Although constrained by the limitations of a single case
report and unsystematic measures, this report suggests that traditional “talking” therapy was
not helpful for PTSD, whereas behaviorally oriented techniques appeared to be effective.
Using psychoanalytic-oriented therapy, Bart (12) reported that trauma victims worsened
following treatment. On the other hand, short-term dynamic group therapy for nine rape vic-
tims was determined to be somewhat helpful. Fear and hostility decreased significantly from
pre- to post-treatment, but three of the seven victims who completed the study reported only
slight change in their overall level of distress. Unfortunately, no control group was included
and the content of the therapy sessions was not specified.
Twenty-eight victims of the Beverly Hills Supper Club fire were treated with individual
short-term (6–12 sessions) psychodynamic psychotherapy.(13) Diagnoses included PTSD, com-
plicated bereavement, major depressive disorder, and adjustment disorder. Patients who com-
pleted treatment showed more improvement than patients with interrupted treatment. Lindy
et al. (13) subsequently observed that all treated patients “improved to a subclinical level two
years after the fire” (p. 602).
As mentioned above in the section on hypnotherapy, Brom et al. (3) conducted a con-
trolled study of Horowitz’s brief psychodynamic therapy, comparing this treatment with
hypnosis, desensitization, and a waiting list control group. Although the authors found no
differences among the three active treatment conditions, inspection of the means on the IES
suggested that psychodynamic therapy in this study yielded inferior outcome compared to
desensitization (29% vs. 41% mean pre–post reduction).
The efficacy of a brief psychodynamic treatment based upon Horowitz’s (9) model for
bereavement was investigated in 61 women who had lost their husbands.(14) Patients were ran-
domly assigned either to 12 weekly sessions of brief dynamic therapy or to a mutual help group
led by a nonclinician. Although many of the participants in this study reported symptoms of PTSD,
death of a husband does not necessarily qualify as a DSM criterion A trauma. Results indicated that
patients in both conditions improved slightly on both interview and self-report ratings of PTSD
symptoms, but there were no group differences. Using a quasiexperimental design, interpersonal
process group therapy (IPGT) was compared with a naturally occurring waiting list control in 43
female childhood sexual abuse survivors.(15) The IPGT treatment was based on the treatment
guidelines established by Courtois (16) and Yalom.(10) History of abuse was the only specified
inclusion criterion. Results indicated that IPGT patients improved on several measures including
PTSD diagnostic status. At pretreatment, 91% of the IPGT group and 85% of the control group met
DSM criteria for PTSD; at posttreatment, only 39% of the IPGT group vs. 83% of the control group
met criteria for PTSD. The IPGT group showed greater symptom reduction than did the control
group on some measures (e.g., self-report measure of intrusion), whereas both groups evidenced
similar symptom reduction on other measures (e.g., depression, dissociation).
In summary, most studies of psychodynamic psychotherapy were plagued by method-
ological flaws, including lack of controls, lack of adequate assessment of outcome, and vaguely
Psychosocial treatments of posttraumatic stress disorder 101

described treatments. Similar to the data with hypnotherapy, The Institute of Medicine (1) and
Cochrane Database review (5) found that psychodynamic psychotherapy approaches to PTSD
remains understudied, and therefore, that based on this extremely limited body of evidence (little
empirical support; there are few randomized clinical trials [RCTs]), the IOM committee stated that
it would be inappropriate to reach a conclusion regarding the efficacy of psychodynamic psycho-
therapy.(1) Thus, the information about the efficacy of traditional interventions with PTSD from
these studies is quite limited and is open to various interpretations. Clearly controlled studies
need to be performed for these approaches to become more broadly validated.

Cognitive–behavioral therapy

Cognitive–behavior therapy (CBT) includes a variety of treatment programs, including expo-

sure procedures, cognitive restructuring procedures, anxiety management programs, and their
combinations. Reviews of the extant literature on the treatment of PTSD are quite positive
regarding CBT.(1, 5, 17–20) A recent meta-analysis found the largest treatment effects for cogni-
tive–behavioral techniques and selective serotonin reuptake inhibitor (SSRI) medications.(20)
One form of CBT employed with PTSD sufferers is exposure treatment, which assists patients
in confronting their feared memories and situations. Another recent comprehensive review of
CBT studies for PTSD found the strongest evidence for exposure therapy.(21) Both exposure in
imagination and exposure in real life to trauma-related events appear to be therapeutic.
The exposure treatment that has been developed by Foa and Rothbaum (22, 23) and their col-
leagues typically incorporates imaginal exposure that has the patient recall the traumatic memories
in the therapist’s office. The patient is asked to go back in his or her mind to the time of the trauma
and to relive it in his or her imagination. He or she is asked to close his or her eyes and to describe it
out loud in the present tense, as if it were happening now. Very often, this narrative is tape-recorded
(audiotaped) and that tape is sent home with the patient so that he or she may practice imaginal
exposure daily at home between therapy sessions. Although this reliving is often painful for the
patient initially, it quickly becomes less painful as exposure is repeated. The idea behind this type
of treatment is that the trauma needs to be emotionally processed, or digested, so that it can become
less painful.(24, 25) Also, many victims with PTSD mistakenly view the process of remembering
their trauma as dangerous and, therefore, devote much effort to avoiding thinking about or pro-
cessing the trauma. Imaginal reliving serves to disconfirm this mistaken belief.
Other forms of exposure involve repeatedly confronting realistically safe situations,
places, or objects that are reminders of the trauma (called in vivo, or in real life, exposure) until
they no longer elicit such strong emotions. Some therapists have patients write repeatedly
about the trauma as a form of exposure.(26) In systematic desensitization (SD), the patient
is taught how to relax, then presented with reminders of the trauma gradually, working up
a hierarchy from the least disturbing to the most disturbing. If they become very anxious or
upset, they stop the trauma imagery, relax themselves, then go back to the material for expo-
sure, until they can encounter all memories or situations without becoming upset.
Another CBT approach, anxiety management training (AMT), involves teaching patients
skills to control their anxiety and has also been helpful with PTSD. Stress inoculation training
(SIT), the AMT program that has received the most attention, was developed for victims who
remained highly fearful 3 months after being raped.(27) SIT typically consists of education and
training of coping skills. These skills include deep muscle relaxation training, breathing con-
trol, role playing, covert modeling, thought stopping, and guided self-dialogue following SIT.
The idea is that sufferers of PTSD experience a great deal of anxiety in their lives because they
are frequently reminded of the trauma. Very often, when they become anxious, this is a cue for
them to feel they are in danger and thus to become even more scared. SIT aims to teach skills to
help decrease this anxiety in many different situations, to help “take the edge off.”

Exposure therapy
The efficacy of exposure treatment for PTSD was first demonstrated with several case reports
on war veterans.(28–30) Both flooding in imagination (31) and flooding in vivo to trauma-
related events (29) appeared to be therapeutic. Most of these treatments also included addi-
tional techniques, such as anger control or relaxation training.
102 Ressler and Rothbaum

Prolonged exposure (PE) has been found to be highly effective in the treatment of women with
PTSD following physical and sexual assault compared to waiting list or minimal attention-control
conditions in five studies.(32–36) The percentage of treatment completers who no longer met criteria
for PTSD ranged between 40% and 95% for PE, compared to 0% and 12% in the control conditions.
The first controlled study of the treatment of PTSD in rape survivors randomly assigned PTSD rape
survivors to one of four conditions: stress inoculation training (SIT), prolonged exposure (PE), sup-
portive counseling (SC), or waiting list control (WL). Exposure treatment consisted of nine biweekly
individual sessions. The first two sessions were devoted to information gathering, explaining the treat-
ment rationale, and treatment planning including the construction of a hierarchy of feared situations
for in vivo exposure. During the remaining sessions, survivors were instructed to relive in imagination
their traumatic experiences and describe it aloud “as if it were happening now.” Exposure continued
for about 60 minutes and was tape-recorded so that survivors could practice imaginal exposure as
homework by listening to the tape. Also for homework, survivors were instructed to approach feared
situations or objects that were realistically safe. Detailed instructions for conducting exposure therapy
with PTSD patients can be found in Foa and Rothbaum.(23)
SIT began with information regarding the assault and the survivor’s history gathered in
Session 1, followed by brief breathing retraining to alleviate anxiety aroused by the discussion
of the assault. The rationale for treatment was explained in Session 2, and coping skills were
taught in Sessions 3 to 9. Skills were applied first to a non-assault–related example, and then
to an assault-related example. Supportive counseling focused on assisting patients in solving
daily problems that may or may not be assault related. Discussion of the assault itself was
largely avoided because such discussions were viewed as a form of exposure. Patients were
redirected to “here and now” issues when they began discussing the assault. Patients were
taught problem solving, and therapists engaged in active listening and support. Survivors in
the waiting list condition were assessed at the same 5-week intervals as the treated survivors
and were contacted by phone in between to maintain contact. Treatments were delivered in
nine biweekly 90-minute individual sessions. All conditions produced improvement on all
measures immediately posttreatment and at follow-up.
SIT produced significantly more improvement on PTSD symptoms than WL immedi-
ately following treatment. At follow-up, PE produced superior outcome on PTSD symptoms.
Patients who received PE continued to improve after treatment termination, whereas patients
in the SIT and SC conditions evidenced no change between posttreatment and follow-up.(37)
The exposure technique studied has proven successful even in cases complicated by other
diagnoses such as conversion mutism.(38)
A second study compared PE, SIT, the combination of SIT and PE, and a waiting list
control group.(33) All three active treatments showed significant improvement in PTSD symp-
toms and depressive symptoms at posttest, and the waiting list group did not improve. These
treatment effects were maintained at 6-month follow-up. On most outcome measures, PE was
more effective than the other two treatments, although this difference did not always reach
significance. An examination of patients who achieved good end-state functioning showed
that 21% of patients in SIT, 46% of patients in PE, and 32% of patients in SIT/PE achieved this
goal at posttreatment. At 6-month follow-up, 75% of patients in PE, 68% of patients in SIT, and
50% of patients in SIT/PE lost the PTSD diagnosis, whereas all waiting list patients retained the
diagnosis. The hypothesis that the combined treatment would be superior was not supported.
The authors suggested that these results may be due to the fact the patients in that condition
actually received less prolonged imaginal exposure and SIT training than participants in the
individual treatments, as treatment sessions were all equal in length. Versions of the PE pro-
gram have been helpful in preventing the development of chronic PTSD following rape (39)
and in treating PTSD in abused children.(40)
Additional studies also provide support for the efficacy of exposure treatment for PTSD
in samples heterogeneous with regard to their traumas. Richards et al. (41) treated 14 partici-
pants with PTSD with either four sessions of imaginal exposure followed by four sessions of
in vivo exposure, or in vivo followed by imaginal exposure. Patients in both treatment condi-
tions improved considerably. The authors noted that the percentage of symptom reduction of
65% to 80% seen in this study is much higher than those of most treatment studies for other
anxiety disorders. Also, at posttreatment and at 1-year follow-up, no patients met criteria for
PTSD. The only notable difference between the two exposure types was in the area of phobic
Psychosocial treatments of posttraumatic stress disorder 103

avoidance, on which in vivo exposure appeared to be more effective regardless of the order in
which it was presented. In another study of outpatients with PTSD resulting from a variety of
traumas, (42) exposure, cognitive therapy, and exposure plus cognitive therapy combination
were all equally successful in reducing PTSD at posttreatment and 6-month follow-up. All
three treatments were more effective than relaxation.
Exposure treatment was efficacious in an open trial of eight weekly sessions of imaginal
and in vivo exposure with 23 traumatized individuals with PTSD.(43) Participants improved
significantly on a variety of measures at posttreatment, with reductions of 42% on the IES, 61%
on a measure of general health (General Health Questionnaire), 38% on a general symptom
checklist (the Symptom Checklist-90, or SCL-90), and 35% on the Clinician-Administered PTSD
Scale (CAPS).
Exposure therapy was compared to cognitive therapy in a mixed sample of trauma sur-
vivors.(44) Type of trauma included crime (52%), accident (34%), and other (15%). There was a
significant improvement on all measures at posttreatment, which was maintained at follow-up
for both treatments, with no significant differences between the two treatments.
Similar exposure therapy programs have been successful with different trauma popula-
tions.(45–50) In all these studies, exposure therapy programs included both imaginal and in
vivo exposure. However, three studies have demonstrated that imaginal exposure to the trau-
matic memory in the absence of in vivo exposure produce quite good outcome. Bryant and col-
leagues (51) found imaginal exposure to be more effective than supportive therapy and Tarrier
et. al (52) found this program to be as effective as cognitive therapy.
There are several published reports of successful treatment of PTSD in veterans with expo-
sure therapy. In the largest and best controlled study to date of exposure therapy with veterans
(53), 277 female veterans and active-duty personnel (n = 7) with PTSD were randomly assigned
to receive 10 weekly sessions of PE or present-centered therapy (PCT). Women who received PE
experienced greater reduction in PTSD symptoms and were more likely to no longer meet PTSD
criteria and to achieve total remission than those who received PCT. It is also notable that PE was
delivered by VA therapists, not CBT experts. In a controlled study, Keane, Fairbank, Caddell,
and Zimering (54) compared the progress of 11 male veterans in an exposure therapy with 13
waiting list controls. Participants demonstrated significantly greater improvement in reexperi-
encing symptoms as well as trauma-related depression and anxiety than waiting list controls by
the end of treatment and these gains were maintained at 6-month follow-up. In another study,
Cooper and Clum (55) compared two groups of seven veterans treated for PTSD. Both groups
received individual and group treatment ordinarily offered by VA psychologists at their veterans
facilities. The experimental group also received nine sessions of imaginal exposure, along with
several more sessions to build rapport and prepare for the exposure sessions. At 3-month follow-
up, scores on measures of trait anxiety and depression were similar in both groups, but symp-
toms of reexperiencing, hyperarousal, and avoidance were significantly better in the exposure
group. In a similar vein, Boudewyns and colleagues (56) treated 19 members of an inpatient unit
with direct therapeutic exposure while 19 other patients on the same unit served as controls. At
8-month follow-up, the researchers found that there were no differences between the two groups
on psychophysiological measures, but improvement in overall functioning was better in patients
who had received exposure therapy. Glynn et al. (57) found that veterans who received exposure
treatment, whether followed with 16 sessions of behavioral family therapy or alone, showed a
significant reduction in PTSD symptoms over waiting list controls. Pitman et al. (58) found sig-
nificant reductions in levels of chronic PTSD in a sample of 20 Vietnam veterans participating in
6 to 12 sessions of exposure therapy. However, no control group was available for comparison.
Likewise, Frueh, Turner, Beidel, Mirabella, and Jones (59) studied the effectiveness of a 29-session
treatment, held over 17 weeks, which included imaginal exposure. Overall, the study provided
evidence of significant reduction in anxiety in 11 veterans who completed treatment but again the
findings were limited by the absence of a control group. Finally, Bisson and Jones (60) report that
18 Gulf War veterans with PTSD showed significant reductions symptoms of PTSD, depression,
and general psychiatric distress. Reductions in symptoms were maintained at 3-month follow-
up, but again no comparison to a control group was made.
Exposure therapy has not been as consistently effective when delivered in a group format
in a VA setting. In a large VA cooperative study of male Vietnam veterans (n = 360), trauma-
focused group psychotherapy was not significantly more effective than a present-centered
104 Ressler and Rothbaum

comparison group treatment that avoided trauma focus.(61) However, recent uncontrolled pilot
trials at Atlanta, VA, of exposure therapy delivered in a combination of group and individual
sessions have been more effective. An open trial of 102 veterans treated with Group-Based
Exposure Therapy (GBET) found clinically significant and lasting reductions in the symptoms
of war-related PTSD with large effect sizes on treating clinicians’ assessments and moderate
to large effect sizes on self-report PTSD scales.(62) Another pilot study with 37 participants
using a hybrid treatment model combining individually recorded audiotapes of three trau-
matic memories and daily exposure practice nested in a 10-week behavioral group therapy
format has been effective in treating OEF/OIF and Persian Gulf combat veterans. There were
no significant differences between those with (30%) and without traumatic brain injury (TBI)
on pretreatment measures nor was TBI status a predictor of significantly different treatment
response.(63)
Note that the most recent large meta-analytic reviews have concluded that among all
types of psychosocial therapies, the best and largest RCTs exist for exposure-based models. The
recent Cochrane Database review concluded that both individual and group trauma-focused
CBT/Exposure therapy were effective in the treatment of PTSD.(5) In addition, the Institute of
Medicine concluded that “The committee finds that the evidence is sufficient to conclude the
efficacy of exposure therapies in the treatment of PTSD.”(1)

Virtual reality exposure therapy

A new medium for conducting exposure therapy has been introduced recently. Virtual real-
ity exposure (VRE) presents the user with a computer-generated view of a virtual world that
changes in a natural way with head motion. During VRE sessions patients wear the head-
mounted display with stereo earphones that provide visual and audio cues consistent with
being in the virtual environment that is used to reactivate their traumatic cues.
Studies have been done across a variety of anxiety disorders, with treatment for PTSD being
one of the most exciting forefronts of this technology. In one investigation, Vietnam veterans with
PTSD are exposed to two virtual environments, a virtual Huey helicopter flying over a “Virtual
Vietnam” and a clearing surrounded by jungle. In this way, patients are repeatedly exposed to
their most traumatic memories but immersed in Vietnam stimuli. The results of the first patient
to complete the virtual Vietnam treatment indicate preliminary success.(64) The subject was an
unemployed 50-year-old Caucasian male on 100% Veterans Administration (VA) compensation
who served in Vietnam 26 years prior to the onset of this study as a helicopter pilot. He met
criteria for current PTSD, current major depressive disorder, and past alcohol abuse. Treatment
was delivered in fourteen 90-minute individual sessions conducted twice weekly over 7 weeks.
Scores on all measures decreased from pre- to post-treatment. No statistical analyses were incor-
porated because this was a single subject. The following symptom measures decreased at least
30%: CAPS total (34%), CAPS reexperiencing (61%), CAPS arousal (36%), IES total (45%), IES
intrusion (42%), IES avoidance (50%), and Spielberger-state anger (63%).
Following this pilot study, Rothbaum and colleagues examined 10 male patients exposed
to two virtual Vietnam environments. They found that there were significant decreases in all
three symptom clusters and that the patient’s reported symptoms on the Impact of Events Scale
were significantly decreased.(65)
Positive findings in the study of Vietnam veterans has led other groups to propose
VR environments to facilitate PTSD treatment in civilians. For example, subsequent to the
September 11, 2001, terrorist attacks on the World Trade Centers (WTC) in New York, Difede
and Hoffman (66) constructed a scenario in which persons associated with these events could
be exposed to the events again in VR. In their first report, a case study was presented using
VR to provide exposure to the trauma memory with a patient who had failed to improve with
traditional exposure therapy. The authors reported significant reduction of PTSD symptoms
after repeatedly exposing the patient to explosions, sound effects, virtual people jumping from
the burning buildings, towers collapsing, and dust clouds and attributed this success partly
due to the increased realism of the VR images as compared to the mental images the patient
could generate without VR. Positive treatment outcomes from a waiting list–controlled VR
study with patients who were not successful in previous imaginal therapy are currently in
press by this group.(67, 68) A very recent study by Difede and colleagues examined VRE for
Psychosocial treatments of posttraumatic stress disorder 105

the treatment of PTSD following September 11, 2001.(69) This pilot study examined thirteen VR
treatment subjects compared to eight waiting list control subjects, and determined that the VR
group showed a significant decline on Clinician-Administered PTSD Scale (CAPS) scores com-
pared to waiting list. A case study of the first Iraq veteran with PTSD treated with the Virtual
Iraq indicated a 56% decrease in CAPS scores with four sessions of VRE.(70)
The results from the studies discussed above consistently support the efficacy of imagi-
nal and in vivo exposure for the treatment of PTSD resulting from a variety of traumas. These
results are even more impressive, given the methodological precision that was applied to
many of these studies. Notably, there are now very good VR environments for the Iraq war,
the Vietnam War, the World Trade Center bombings, Terrorist attacks in Israel, and a variety
of other non–trauma-based environments. However, despite the fact that almost 100 papers
discussing virtual reality exposure therapy for anxiety-related disorders are now in the lit-
erature, many are not optimally designed.(71) Additional randomized clinical controlled trials
and trials of increased size will likely lead to exciting new uses and validation for virtual reality
approaches in the future.

Anxiety management techniques (AMT)

Of the various AMT programs, stress inoculation training (SIT), (72) developed for rape survi-
vors with chronic fear and anxiety, has received the most attention. The efficacy of SIT has been
supported by several reports from Veronen, Kilpatrick, and their colleagues and others.(37, 73)
In an uncontrolled investigation, a clear treatment effect emerged on rape-related fear, anxiety,
phobic anxiety, tension, and depression in female rape survivors who showed elevated fear and
avoidance to phobic stimuli 3 months postrape.(27) A later study was designed to compare 10
sessions each of SIT, peer counseling, and systematic desensitization (SD).(27) Survivors were
permitted to select their treatment and the vast majority opted for SIT, few chose peer counsel-
ing, and none chose SD, which precluded statistical analyses. The authors reported noticeable
improvement from pre- to post-treatment on most measures for the SIT completers. Case stud-
ies of rape survivors treated with SIT or its variant also indicated positive results.(74)
In a controlled study, the efficacy of six 2-hour sessions of three types of group therapy
for rape-related fear and anxiety were compared to a naturally occurring waiting list control
group, including SIT, assertion training, or supportive psychotherapy plus information.(73)
SIT was similar to that described by Kilpatrick et al. (72) with two exceptions: (1) cognitive
restructuring, assertiveness training, and role play were excluded because they were used
in the comparative treatment, and (b) exposure in vivo was added to the application phase.
Results indicated that all three treatments were highly effective in reducing rape-related fears,
intrusion, and avoidance symptoms, with no group differences evident, whereas no improve-
ments were found in the waiting list control group. Improvement was maintained at 6-month
follow-up on rape-related fear measures, but not on depression, self-esteem, and social fears.
A controlled study compared three different forms of relaxation for 90 Vietnam veterans.
(75) Relaxation, relaxation plus deep breathing exercises, and relaxation plus deep breathing
plus biofeedback were equally, but only mildly, effective in leading to improvement. The effects
of cognitive therapy and SD were studied in rape survivors, some of whom entered treatment
an average of 2 weeks after their assault.(76, 77) Ratings of fear, anxiety, depression, and social
adjustment, all showed significant gains for both cognitive therapy and SD.
In summary, among anxiety management approaches, SIT has received the most support
for PTSD. Other AMTs such as relaxation or cognitive therapy are best viewed as treatment
components of a comprehensive treatment package.

Systematic desensitization
Some of the earliest studies of behavioral treatments for PTSD adopted the SD technique
pioneered by Wolpe.(78) Although participants in these studies showed improvement in post-
trauma symptoms, methodological problems plagued each of these studies, rendering the
results inconclusive. An exception was the Brom et al. (3) study described in detail in the section
on hypnotherapy and psychodynamic therapy. In this study, patients in the desensitization
condition showed a mean improvement of 41% on the IES, which was higher than the other
treatments examined, although the difference did not reach statistical significance. In light of the
106 Ressler and Rothbaum

methodological problems with the resulting lack of strong conclusions to be drawn, SD will be
reviewed very briefly below.
The successful outcome of SD compared to a no-treatment control group was demon-
strated in two studies with war veterans using psychophysiological measures (electromyo-
graphy and heart rate), (79, 80) but the treatment required a large number of sessions over
an extended period of time and PTSD was not assessed. Thirteen to eighteen sessions of SD
with the last two sessions spent in in vivo exposure were used successfully with three automo-
bile accident survivors.(81) Several uncontrolled studies demonstrated that SD was effective
with rape survivors in reducing fear, anxiety, depression, and social maladjustment.(76, 82, 83)
However, SD alone was not successful in one case study of a rape survivor.(84)
In summary, several studies examined the effects of SD with a variety of trauma survivors,
most showing some beneficial results. However, the lack of adequate control conditions and/or
the absence of PTSD diagnoses and measures in some of the studies limit the conclusions that can
be drawn from them. With the empirical finding that relaxation during confrontation with feared
material was not necessary, and with evidence for the inferiority of SD to flooding in most anxiety
disorders, the use of SD for anxiety disorders, including PTSD, was largely abandoned. In its place,
researchers and clinicians have used a variety of imaginal and in vivo exposure techniques.

Eye movement desensitization and reprocessing

Eye movement desensitization and reprocessing (EMDR) (85) is a form of exposure (desensiti-
zation) accompanied by saccadic eye movements. Briefly, the technique involves the patient’s
imagining a scene from the trauma, focusing on the accompanying cognition and arousal, while
the therapist waves two fingers across the patient’s visual field and instructs the patient to
track the fingers. The sequence is repeated until anxiety decreases, at which point the patient is
instructed to generate a more adaptive thought and to associate it with the scene while moving
his or her eyes. After each session patients indicate their subjective units of discomfort (SUDS)
level and their degree of belief in a positive cognition (validity of positive cognition; VoPC).
A number of case studies have reported positive findings with EMDR; for a compre-
hensive review, see.(86) In the first study of EMDR, Shapiro (87) randomly assigned trauma
survivors to either one session of EMDR or an exposure control condition (EMDR without the
eye movements). The results showed that patients who received EMDR reported lower SUDS
ratings after the one session of EMDR than did patients in the exposure control condition, but
lack of methodological rigor makes this finding difficult to interpret. Combat veterans were
randomly assigned to two 90-minute EMDR sessions, an exposure control (EC; EMDR without
the eye movements), both as an adjunct to standard milieu treatment for veterans with PTSD,
or standard milieu treatment alone.(88) SUDS ratings to traumatic stimuli were lower in the
EMDR group, and therapists rated more patients as responders in the EMDR vs. EC group.
However, the three groups did not differ in their lack of response as seen on standardized self-
report measures, interviews of PTSD, or on physiological responses.
Jensen (89) randomly assigned 74 veterans with PTSD to either three sessions of EMDR con-
ducted over 10 days or to a control condition of standard VA services. Neither group improved
on the PTSD severity measure. SUDS ratings decreased in the EMDR group but not in controls.
Silver et al. (90) compared standard milieu treatment with milieu treatment plus EMDR, bio-
feedback, or group relaxation training in a sample of 100 veterans with PTSD. Results indicated
that EMDR led to greater reduction of symptoms relative to the control and the biofeedback
groups, but as the study was uncontrolled, the strength of the findings is limited.
In a study addressing the role of eye movement, Pitman et al. (91) compared EMDR with
and without the eye movement component in a crossover design with 17 male veterans diag-
nosed with PTSD. Patients were randomly assigned to the two conditions. The results of this
methodologically vigorous study indicated that both treatments produced modest improve-
ment in symptoms as measured by the IES, but not on the independent assessment. In contrast
to expectations, on the IES, there was slightly more improvement in the eyes-fixed condition
than from EMDR. Twenty-three trauma survivors received either standard EMDR or one of
two variations: an EMDR analog in which eye movements were induced by a flashing light
rather than a waving finger and an analog in which a light blinked only in the center of the
visual field.(92) The groups did not differ on physiological measures, SUDS, or the VoPC. No
analyses on PTSD severity were reported, but following treatment, only 5 of the 23 participants
Psychosocial treatments of posttraumatic stress disorder 107

met criteria for PTSD. Using a sample of 36 survivors of heterogeneous traumas, Vaughan
et al. (93) compared EMDR with imagery habituation training (IHT), a procedure that involved
repeated presentation of traumatic stimuli in the form of an oral scenario, and applied muscle
relaxation training. The authors concluded that all three groups were equally improved on
the independent assessors’ rating of PTSD. Wilson et al. (94) compared EMDR to a delayed-
treatment condition in a mixed sample of traumatized individuals about half of whom had
PTSD. Overall, patients in the EMDR group reported decreases in presenting complaints and
in anxiety, and increases in positive cognitions at posttreatment, whereas the waiting list group
reported no improvement.
A well-controlled study on the efficacy of EMDR was conducted by Rothbaum (95), who
randomized 21 female survivors of rape to either EMDR or a waiting list control group. Measures
consisted of standardized self-report and interview instruments, with the interviews conducted
by a blind evaluator. Treatment consisted of four weekly sessions conducted by a well-trained
clinician, and treatment adherence was monitored and deemed acceptable by an independent
evaluator designated by EMDR’s originator. EMDR led to improvement on PTSD symptoms on
both interview (57% reduction in symptom severity) and IES (74% reduction), and gains were
maintained at a 3-month follow-up. These reductions were significantly different from the con-
trol group, who evidenced no change in symptoms. In a comparison study, participants were ran-
domly assigned to either routine clinical care, 12 sessions of biofeedback-assisted relaxation, or 12
sessions of EMDR.(96) At posttreatment and at a 3-month follow-up, the EMDR-treated partici-
pants were more improved on self-report, psychometric, and standardized measures. However,
there were no differences on psychophysiological measures. EMDR was compared to general
outpatient treatment in a managed care organization (HMO).(97) On measures of PTSD, depres-
sion, and anxiety, EMDR was superior. In a well-controlled study involving EMDR, a course of
nine sessions of EMDR was compared to nine sessions of a CBT treatment consisting of prolonged
imaginal exposure, stress inoculation training, and cognitive therapy.(98) The results indicated
that CBT was superior to EMDR at posttreatment and 1-year follow-up. Another well-controlled
study evaluated the relative efficacy of Prolonged Exposure (PE) and EMDR compared to a no-
treatment waiting list control (WAIT) in the treatment of PTSD in adult female rape victims (n
= 74). Improvement in PTSD, as assessed by blind independent assessors, and depression, dis-
sociation, and state anxiety was significantly greater in both PE and EMDR group than the WAIT
group (20 completers per group). PE and EMDR did not differ significantly for change from base-
line to either posttreatment or 6-month follow-up measurement for any quantitative scale (36),
but on a measure of good end-state functioning at 6 months posttreatment, participants who had
received PE were doing better than participants who had received EMDR.
In summary, several studies report beneficial effects of EMDR, although other studies
report equivocal findings with EMDR not resulting in significant improvements over control
conditions or comparison treatments, especially on blind, standardized PTSD measures. The
recent Cochrane Database review concluded that EMDR was more effective than traditional
therapies or no therapy but not different from CBT and stress management.(5) The Institute of
Medicine, however, found that “the overall body of evidence for EMDR to be low quality to
inform conclusion regarding treatment efficacy. Four studies, three of medium and one of small
sample size, had no major limitations, but only two showed positive effect for EMDR.” The
committee judged that the overall evidence is inadequate to determine efficacy and that future
well-designed studies are critical.(1)

Combined Treatment Approaches

Combined Psychosocial Treatment Programs

A modified version of Foa et al’s SIT/PE combination program was adopted to treat 10 motor
vehicle accident (MVA) survivors.(99) The modification consisted of the addition of pleasur-
able activity scheduling and discussion of existential issues. Results of this study suggest that
the 9 to 12 sessions of combined treatment reduced PTSD symptoms by 68% on the CAPS.
A comprehensive treatment package was studied in an uncontrolled investigation.
(100) The treatment, trauma management therapy, consisted of education, individual expo-
sure therapy, including the “core fear,” programmed practice of the exposure, and social and
108 Ressler and Rothbaum

emotional rehabilitation (SER). SER was conducted in a group format and consisted of social
skills training, anger management, and veterans’ issues management. Fifteen male Vietnam
combat veterans with PTSD were entered, and 11 completed 29 treatment sessions over 17
weeks. Results indicated significant improvements from pre- to post-treatment on the Clinical
Global Impressions (CGI), Hamilton Rating Scale for Anxiety, heart rate reactivity to trau-
matic cues, total hours of sleep, number of social activities, frequency of nightmares, and
trends toward significant improvement on the CAPS and flashbacks. There was no significant
improvement noted on self-report measures, including the Beck Depression Inventory, Social
Phobia, and Anxiety Inventory, or the Spielberger Anger Expression Inventory.
A quasiexperimental design tested a combination therapy for rape survivors with PTSD.
(101) Nineteen female sexual assault survivors received cognitive processing therapy (CPT)
over 12 weekly sessions in a group format. CPT includes education, exposure via writing about
the assault and sharing it in a group, and cognitive restructuring components. Treated partici-
pants were not randomly assigned but rather were compared to a naturally occurring waiting
list control group. Results were very encouraging for the efficacy of CPT in this population.
CPT subjects improved significantly from pre- to post-treatment on PTSD and depression rat-
ings and maintained their improvement throughout the 6-month follow-up period. The wait-
ing list subjects evidenced no change during a comparable 12-week period.
In a later report with a larger sample, Resick (102) reported that of the 66 women who
completed CPT, 97% met full criteria for PTSD at pretreatment, and of these only 12% met cri-
teria for PTSD at posttreatment. Fifty-three women completed a 6-month follow-up and only
11% met criteria for PTSD. At pretreatment, 52% met criteria for major depression. At post-
treatment, only 12.5% were still depressed. At the 6-month follow-up, 8% were depressed. In a
controlled trial comparing CPT, PE, and waiting list control groups, Resick et al. (103) reported
that female sexual assault survivors who received CPT or PE were significantly more improved
than the waiting list control group from pre- to post-treatment on PTSD and depressive symp-
tomatology. CPT and PE were equally effective in reducing PTSD. CPT has been found effec-
tive in a group and individual format for adult survivors of child sexual abuse compared to a
waiting list control (104), in a randomized trial with military veterans (105), with incarcerated
adolescents (106) and refugees, even when delivered through an interpreter.(107)
Another study testing a combination treatment approach compared self-exposure plus
cognitive restructuring to progressive relaxation training in 20 female sexual assault survivors.
(108) Results indicated superiority at posttreatment and follow-up for the participants treated
with exposure plus cognitive restructuring.
In two randomized, controlled dismantling studies, a writing-only component for PTSD
patients has fared well. In a dismantling study of CPT, the full protocol was compared to its com-
ponents, cognitive therapy and written accounts, in 150 adult women with PTSD. Each treatment
was delivered for 6 weeks, with 2 hours of therapy per week. Results indicated that patients in all
three conditions improved substantially and equivalently on PTSD and related measures.(109) A
randomized controlled trial (n = 125) was conducted at a Dutch outpatient clinic to evaluate the
efficacy of a structured writing therapy or CBT as compared to a waiting list control condition.
Treatment consisted of five 1.5-hour sessions of CBT or writing for participants with ASD or acute
PTSD and ten 1.5-hour sessions for participants with chronic PTSD. Results indicated improve-
ments with both active treatments with no differences between the two treatments.(110)
An recent meta-analytic review by Bradley and colleagues (17) examined all studies
between 1980 and 2003 examining psychotherapy for PTSD. They found that across CBT,
exposure therapy, EMDR, and combined treatment studies from this period, “The majority of
patients treated with psychotherapy for PTSD in randomized trials recover or improve, render-
ing these approaches some of the most effective psychosocial treatments to date.” One of the
main caveats they note, however, was that polysymptomatic presentations render generaliz-
ability to the population indeterminate.

Pharmacological Augmentation of Psychotherapy

Although combining treatments with apparently different modes of action, such as SSRI anti-
depressant therapy, which, with psychotherapy for anxiety would seem straightforward,
numerous large trials and reviews have been disappointing. These studies have suggested that
standard treatment for anxiety or depression with combined chronic pharmacotherapy and
psychotherapy provide little benefit over either treatment alone.(111–114)
Psychosocial treatments of posttraumatic stress disorder 109

In one of the only studies to combine antidepressant medication with CBT for PTSD, out-
patient men and women with chronic PTSD completed 10 weeks of open-label sertraline and
then were randomly assigned to five additional weeks of sertraline alone (n = 31) or sertraline
plus 10 sessions of twice-weekly PE (n = 34). Results indicated that sertraline led to a signifi-
cant reduction in PTSD severity after 10 weeks but was associated with no further reductions
after 5 more weeks. Participants who received PE showed further reduction in PTSD severity.
This augmentation effect was observed only for participants who showed a partial response to
medication. Thus, the addition of PE to sertraline for PTSD improves outcome for individuals
experiencing a less than full response to the medication.(115)
An alternative approach to both standard chronic pharmacological treatments that tend
to target symptom clusters but not necessarily the root cause of the disorder, is the possibility
of enhancing the specific new learning that occurs with psychotherapy. The pathways medi-
ating this learning are on the one hand very complex, but on the other hand, specific learn-
ing processes that utilize brain regions such as the amygdala and PFC that are involved with
extinction of fear are well understood. The sections below will discuss evidence that those with
disorders of aversive emotion respond to behavioral therapy and utilize new emotional learn-
ing to compete with or inhibit the aversive memories, a process known as extinction that may
be enhanced with specific pharmacotherapy. Together these approaches offer tantalizing future
ways in which fear, aversive, and traumatic memories may be modulated to alleviate suffering
due to negative memories.
The inhibition of fear acquired by associative learning has been studied in both animals
and humans. Following the pairing of an aversive unconditioned stimulus (UCS) to a neutral
conditioned stimulus (CS), a conditioned fear response is established. If the neutral CS is then
repeatedly presented in the absence of the UCS, a procedure known as extinction training, the
result is an inhibition of the conditioned fear response to the neutral CS. From an operational
perspective, extinction may thus be defined as “a reduction in the strength or probability of a
conditioned fear response as a consequence of repeated presentation of the CS in the absence
of the UCS.”(116)
A variety of behavioral observations support the hypothesis that extinction is a form of
learning and not “unlearning” or the forgetting of a conditioned association reviewed in.(117)
Thus, Davis and colleagues tested the hypothesis that enhancing neurotransmission at NMDA
receptors would facilitate extinction.(118) D-cycloserine (DCS) is a partial NMDA agonist, act-
ing at the strychnine-insensitive glycine recognition site of the NMDA receptor complex to
enhance NMDA receptor activity.(119, 120) The central findings of this study were that both
systemic and amygdala-specific administration of DCS dose-dependently enhanced extinction
of previously conditioned fear but did not influence fear in rats that had not received extinc-
tion training. The general findings of this study have been replicated by numerous groups
with extinction of fear with startle and freezing and with extinction of appetitive cues, such as
cocaine-conditioned place preference.(121–128) Collectively, data from rodent studies suggest
that DCS, a drug already shown to be safe for use in humans for treating tuberculosis, may have
potential use in the facilitation of extinction-based therapies for human anxiety disorders.
From a therapeutic standpoint, the behavior therapies for different anxiety disorders gen-
erally involve some form of extinction training.(116) This involves graded exposure to the feared
object or event in the absence of actual harm. This exposure may be imaginal or in vivo where
the feared stimulus is directly encountered by the patient, or in virtual reality. Considering the
similarity between extinction training in rodents and exposure therapy for anxiety disorders
in humans, novel ways to integrate pharmacotherapy with psychotherapy seemed plausible.
Historically, there has been hope to combine these two approaches into a treatment more effec-
tive than either alone, but unfortunately this has not generally been achieved.(112, 129) In fact,
sometimes, combining pharmacotherapy with psychotherapy can make a bad situation worse.
(111, 130) However, extinction-based therapies for anxiety may be an exception to this trend.
To determine whether DCS would also improve extinction of fear in human patients
with fear-related disorders, a double-blind, placebo-controlled trial in a controlled exposure
paradigm was performed.(131) Twenty-eight subjects with fear of heights (acrophobia) were
treated with two sessions of behavioral exposure therapy using virtual reality exposure to
heights within a virtual glass elevator. Single doses of placebo or DCS were taken prior to
each of the two sessions of virtual reality exposure therapy. Exposure therapy combined with
DCS resulted in significantly larger reductions of acrophobia symptoms on all main outcome
110 Ressler and Rothbaum

measures, including fear within the virtual environment, acrophobia symptoms outside of
the environment, and acrophobia-related anxiety. In addition, subjects receiving DCS showed
significantly greater decreases in a physiological measure of anxiety during the Behavioral
Avoidance Test (BAT). These preliminary data provided initial support for the use of acute
dosing of DCS as an adjunct to exposure-based psychotherapy to accelerate the associative
learning processes that contribute to correcting psychopathology.
Since that experiment, DCS has also been used in a double-blind, placebo-controlled trial
for the treatment of social anxiety disorder, utilizing exposure therapy as well. In this study, 27
subjects received 4 exposure therapy sessions combined with DCS or placebo. Those receiving
DCS in addition to exposure therapy reported significantly less social anxiety compared with
patients receiving exposure therapy plus placebo. Controlled effect sizes were in the medium
to large range.(132, 133) An additional recent study has also examined using DCS to acceler-
ate obsession-related distress reduction in patients with obsessive–compulsive disorder (OCD)
undergoing extinction-based exposure therapy. DCS given prior to the therapy was found to
decrease both the number of exposure sessions required to achieve clinical milestones and the
rate of therapy dropout. After four exposure sessions, patients in the DCS group reported sig-
nificantly greater decreases in obsession-related distress compared to the placebo group.(134)
There are currently two negative findings of DCS use in the augmentation of extinction in
humans. However, in both studies, one utilizing exposure therapy for the treatment of spider
phobia (135) and the second utilizing extinction for a conditioned cue in healthy human subjects
(136), the placebo-controlled groups had good recovery as well. This suggests, as has been found
in the animal studies, that if a “floor effect” of complete extinction is accomplished, then DCS may
not augment extinction any further. Rather it appears that DCS may be most useful in disorders
in which either a large number of therapy sessions is normally needed for a response or in which
the nature of the disorder is quite refractory to normal exposure-based therapy approaches.
At least four randomized clinical trials of DCS augmentation of treatment for PTSD are
currently ongoing but none yet published. There is a great deal of excitement as to whether
these new approaches will lead to advances in psychosocial treatment methodologies. It is
hoped that, with progress in the neurobiology and neuropharmacology of extinction of fear,
previously undiscovered approaches to pharmacotherapy will significantly enhance treatment
for refractory mood and anxiety disorders, including PTSD.

Summary and conclusions

Overall, the most controlled studies of psychosocial treatments for PTSD have been conducted
on cognitive–behavioral treatments. These studies demonstrate that techniques such as pro-
longed exposure procedures, stress inoculation training, and cognitive processing therapy are
effective in reducing symptoms of PTSD. Systematic desensitization has largely been aban-
doned in favor of pure exposure techniques. Relaxation and cognitive therapy are best viewed
as treatment components rather than standalone treatments. Contrary to clinical intuition,
there is no evidence indicating the superiority of programs that combine different cognitive–
behavioral techniques.
Many of the studies examining EMDR have methodological flaws and the results are
mixed. Reports on the efficacy of psychodynamic interventions on posttrauma problems are
equivocal: some report negative results, and others are more optimistic, but the majority of the
reports are not well controlled. Because these interventions are widely employed with trauma
survivors, it is imperative that their efficacy be examined in well-controlled studies.
New approaches combining the neuroscience of exposure/extinction therapy with phar-
macotherapy aimed at specifically enhancing the emotional learning process that occurs with
psychotherapy are also quite promising and very exciting.
In summary, results suggest that psychotherapy for PTSD leads to large improvements
from baseline and that these are among the most powerful types of approaches for treating
psychiatric disorders. Notably, the Institute of Medicine (1) report states that “evidence is suf-
ficient to conclude the efficacy of exposure therapy in the treatment of PTSD” in contrast to
current medication approaches for PTSD where “the committee found the evidence for all
classes of drugs reviewed inadequate to determine efficacy for patients with PTSD.” (1) Thus,
Psychosocial treatments of posttraumatic stress disorder 111

psychosocial treatment approaches, particularly exposure therapy, is the most validated form
of treatment for PTSD. The importance of future randomized clinical trials for different types of
treatment and combinations of pharmacotherapy and psychotherapy are of utmost importance
going forward.

References

   1. Institutes of Medicine. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence.

Washington, DC: National Academies Press; 2008.
   2. Spiegel D. Hypnosis in the treatment of victims of sexual abuse. Psychiatr Clin North Am 1989;
12(2): 295–305.
   3. Brom D, Kleber RJ, Defares PB. Brief psychotherapy for posttraumatic stress disorders. J Consult
Clin Psychol 1989; 57(5): 607–12.
   4. Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress. Psychosom
Med 1979; 41(3): 209–18.
   5. Bisson J, Andrew M. Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane
Database Syst Rev 2007(3): CD003388.
   6. Burgess AW, Holmstrom LL. Rape trauma syndrome. Am J Psychiatry. 1974; 131(9): 981–6.
   7. Evans HI. Psychotherapy for the rape victim: some treatment models. Hosp Community Psychiatry
1978; 29(5): 309–12.
   8. Fox S, Scherl D. Crisis intervention with victims of rape. Social Work 1972; 17: 37–42.
   9. Horowitz MJ. Stress-Response Syndromes. Northvale, NJ: Jason Aronson; 1976.
  10. Yalom I. The Theory and Practice of Group Psychotherapy. 4th ed. New York: Basic; 1995.
  11. Grigsby JP. The use of imagery in the treatment of posttraumatic stress disorder. J Nerv Ment Dis
1987; 175(1): 55–59.
  12. Bart P. Unalienating Abortion, Demystifying Depression, and Restoring Rape Victims. Paper
Presented at: 128th Annual Meeting of the American Psychiatric Association. Anaheim, CA; 1975.
  13. Lindy JD, Green BL, Grace M, Titchener J. Psychotherapy with survivors of the Beverly Hills Supper
Club fire. Am J Psychother 1983; 37(4): 593–610.
  14. Marmar CR, Horowitz MJ, Weiss DS, Wilner NR, Kaltreider NB. A controlled trial of brief psychotherapy
and mutual-help group treatment of conjugal bereavement. Am J Psychiatry 1988; 145(2): 203–9.
  15. Scarvalone P, Cloitre M, Difede J. Interpersonal Process Therapy for Incest Survivors: Preliminary
Outcome Data. Paper Presented at: Society for Psychotherapy Research. Vancouver, British Columbia;
1995.
  16. Courtois C. Healing the incest wound: adult survivors in therapy. New York: W.W. Norton; 1988.
  17. Bradley R, Greene J, Russ E, Dutra L, Westen D. A multidimensional meta-analysis of psychotherapy
for PTSD. Am J Psychiatry 2005; 162(2): 214–27.
  18. Rothbaum BO, Meadows EA, Resick P, Foy DW. Cognitive-behavioral Treatment Position Paper for
the ISTSS Treatment Guidelines Committee.
  19. Solomon SD, Gerrity ET, Muff AM. Efficacy of treatments for posttraumatic stress disorder. An
empirical review. JAMA 1992; 268(5): 633–8.
  20. Van Etten ML, Taylor S. Comparative efficacy of treatments for posttraumatic stress disorder: a
meta-analysis. Clin Psychol Psychotherapy 1998; 5: 126–45.
  21. Rothbaum BO, Meadows EA, Resick PA, Foy DW. Cognitive-behavioral therapy. In: Foa EB, Keane
TM, Friedman MJ, eds. Effective Treatments for PTSD: Practice Guidelines from the International
Society for Traumatic Stress Studies. New York: Guilford, 2000: 60–83.
  22. Foa EB, Rothbaum BO. Treating the Trauma of Rape: Cognitive-Behavioral Therapy for PTSD. New
York: The Guilford Press; 1998.
  23. Foa EB, Hembree E, Rothbaum BO. Prolonged Exposure Therapy for PTSD: Emotional Processing of
Traumatic Experiences, Therapist Guide. New York: Oxford University Press; 2007.
  24. Foa E, Sketetee G, Rothbaum BO. Behavioral/cognitive conceptualizations of post-traumatic stress
disorder. Behav Ther 1989; 20: 155–76.
  25. Foa EB, Kozak MJ. Emotional processing of fear: exposure to corrective information. Psychol Bull
1986; 99(1): 20–35.
  26. Resick P, Schnicke MK. Cognitive Processing Therapy for Rape Victims: A Treatment Manual.
Newbury Park: Sage; 1993.
  27. Veronen LJ, Kilpatrick DG. Stress management for rape victims. In: Meichenbaum D, Jaremko ME,
eds. Stress Reduction and Prevention. New York: Plenum; 1983.
  28. Fairbank JA, Gross RT, Keane TM. Treatment of posttraumatic stress disorder. Evaluating outcome
with a behavioral code. Behav Modif 1983; 7(4): 557–68.
  29. Johnson CH, Gilmore JD, Shenoy RS. Use of a feeding procedure in the treatment of a stress-related
anxiety disorder. J Behav Ther Exp Psychiatry 1982; 13(3): 235–7.
112 Ressler and Rothbaum

  30. Keane TM, Kaloupek DG. Imaginal flooding in the treatment of a posttraumatic stress disorder.
J Consult Clin Psychol 1982; 50(1): 138–40.
  31. Keane TM, Fairbank JA, Caddell JM, Zimering RT. Implosive (flooding) therapy reduces symptoms
of PTSD in Vietnam combat veterans. Behav Ther 1989; 20: 245–60.
  32. Foa EB, Rothbaum BO, Riggs D, Murdock T. Treatment of posttraumatic stress disorder in rape
victims: a comparison between cognitive-behavioral procedures and counseling. J Consult Clin
Psychol 1991; 59: 715–23.
  33. Foa EB, Dancu CV, Hembree EA. A comparison of exposure therapy, stress inoculation training, and
their combination for reducing posttraumatic stress disorder in female assault victims. J Consult
Clin Psychol 1999; 67(2): 194–200.
  34. Foa EB, Hembree EA, Cahill SP et al. Randomized trial of prolonged exposure for posttraumatic
stress disorder with and without cognitive restructuring: outcome at academic and community
clinics. J Consult Clin Psychol 2005; 73(5): 953–64.
  35. Resick PA, Nishith P, Weaver TL, Astin MC, Feurer CA. A comparison of cognitive-processing
therapy with prolonged exposure and a waiting condition for the treatment of chronic posttraumatic
stress disorder in female rape victims. J Consult Clin Psychol 2002; 70: 867–79.
  36. Rothbaum BO, Astin MC, Marsteller F. Prolonged exposure vs. eye movement desensitization and
reprocessing (EMDR) for PTSD rape victims. J Trauma Stress 2005; 18: 607–16.
  37. Foa EB, Rothbaum BO, Riggs DS, Murdock TB. Treatment of posttraumatic stress disorder in rape
victims: a comparison between cognitive-behavioral procedures and counseling. J Consult Clin
Psychol 1991; 59(5): 715–23.
  38. Rothbaum BO, Foa E. Exposure treatment of PTSD concomitant with conversion mutism: a case
study. Behav Ther 1991; 22: 449–56.
  39. Foa EB, Hearst-Ikeda D, Perry KJ. Evaluation of a brief cognitive-behavioral program for the
prevention of chronic PTSD in recent assault victims. J Consult Clin Psychol 1995; 63(6): 948–55.
  40. Deblinger E, McLeer SV, Henry D. Cognitive behavioral treatment for sexually abused children
suffering post-traumatic stress: preliminary findings. J Am Acad Child Adolesc Psychiatry 1990;
29(5): 747–52.
  41. Richards DA, Lovell K, Marks IM. Post-traumatic stress disorder: evaluation of a behavioral
treatment program. J Trauma Stress 1994; 7(4): 669–80.
  42. Marks I, Lovell K, Noshirvani H, Livanou M, Thrasher S. Treatment of posttraumatic stress disorder
by exposure and/or cognitive restructuring: a controlled study. Arch Gen Psychiatry 1998; 55(4):
317–25.
  43. Thompson JA, Charlton PF, Kerry R, Lee D, Turner SW. An open trial of exposure therapy based on
deconditioning for post-traumatic stress disorder. Br J Clin Psychol 1995; 34: 407–16.
  44. Tarrier N, Pilgrim H, Sommerfield C et al. A randomized trial of cognitive therapy and imaginal
exposure in the treatment of chronic posttraumatic stress disorder. J Consult Clin Psychol 1999;
67(1): 13–8.
  45. Gillespie K, Duffy M, Hackman A, Clark DM. Community based cognitive therapy in the treatment
of posttraumatic stress disorder following the Omagh bomb. Behavior Research and Therapy 2002;
40(4): 345–57.
  46. Difede J, Eskra D. Adaptation of Cognitive Processing Therapy for the treatment of PTSD following
terrorism: A case study of a World Trade Center (1993) survivor. J Trauma Practice 2002; 1(3/4):
155–65.
  47. Marks I, Lovell K, Noshirvani H, Livanou M, Thrasher S. Treatment of posttraumatic stress disorder
by exposure and/or cognitive restructuring. Arch Gen Psychiatry 1998; 55: 317–25.
  48. Taylor S, Thordarson DS, Maxfield L et al. Efficacy, speed, and adverse effects of three PTSD treatments:
exposure therapy, relaxation training, and EMDR. J Consult Clin Psychol 2003; 71: 330–8.
  49. Thompson JA, Charlton PF, Kerry R, Lee D, Turner SW. An open trial of exposure therapy based on
deconditioning for post-traumatic stress disorder. Br J Clin Psychol 1995; 34: 407–16.
  50. Paunovic N, Ost LG. Cognitive-behavior therapy vs exposure in the treatment of PTSD in refugees.
Behav Res and Ther 2001; 39: 1183–97.
  51. McNally RJ, Bryant RA, Ehlers A. Does early psychological intervention promote recovery from
posttraumatic stress? Psychological Science in the Public Interest 2003; 4: 45–79.
  52. Tarrier N, Pilgrim H, Sommerfield C et al. A randomized trial of cognitive therapy and imaginal exposure
in the treatment of chronic posttraumatic stress disorder. J Consult Clin Psychol 1999; 67: 13–8.
  53. Schnurr PP, Friedman MJ, Engel CC et al. Cognitive behavioral therapy for posttraumatic stress
disorder in women. J Am Med Assoc 2007; 297: 820–30.
  54. Keane TM, Fairbank JA, Caddell JM, Zimering RT. Implosive (flooding) therapy reduces symptoms
of PTSD in Vietnam combat veterans. Behav Ther 1989; 20: 245–60.
  55. Cooper NA, Clum GA. Imaginal flooding as a supplementary treatment for PTSD in combat
veterans: A controlled study. Behav Ther 1989; 3: 381–91.
Psychosocial treatments of posttraumatic stress disorder 113

  56. Boudewyns PA, Hyer LA, Woods MG, Harrison W, McCannie EW. PTSD among Vietnam veterans:
An early look at treatment outcome using direct therapeutic exposure. J Trauma Stress 1990; 3:
359–68.
  57. Glynn SM, Eth S, Randolph ET et al. A test of behavioral family therapy to augment exposure for
combat-related posttraumatic stress disorder. J Consult Clin Psychol 1999; 67(2): 243–51.
  58. Pitman RK, Orr SP, Altman B et al. Emotional processing and outcome of imaginal flooding therapy
in Vietnam veterans with chronic posttraumatic stress disorder. Compr Psychiatry 1996; 37: 409–18.
  59. Frueh BC, Turner SM, Beidel DCC, Mirabella RF, Jones WJ. Trauma management therapy: A
preliminary evaluation of a multi-component behavioral treatment for chronic combat-related
PTSD. Behav Res and Ther 1996; 34: 533–43.
  60. Bisson JI, Jones N. Taped imaginal exposure as a treatment for post-traumatic stress reactions. J R
Army Med Corps 1995; 141(1): 20–4.
  61. Schnurr PP, Friedman MJ, Foy DW et al. Randomized trial of trauma-focused group therapy for
posttraumatic stress disorder: Results from a department of veterans affairs cooperative study. Arch
Gen Psychiatry 2003; 60: 481–9.
  62. Ready DJ, Brown-Thomas KB, Worley V et al. A Field Test of Group Based Exposure Therapy with
102 Veterans with War-Related Posttraumatic Stress Disorder. J Traumatic Stress; in press.
  63. Crowe CM, Price M, Bradley R. Preliminary findings from an uncontrolled pilot of a novel delivery model
for exposure therapy in OEF/OIF and Persian Gulf combat veterans. Unpublished manuscript; 2007.
  64. Rothbaum BO, Hodges L, Alarcon R et al. Virtual Vietnam: a Virtual Environment for the Treatment
of Vietnam War Veterans with Posttraumatic Stress Disorder. Paper Presented at: Lake George
Research Conference on Posttraumatic Stress Disorder, Lake George, NY; 1998.
  65. Rothbaum BO, Hodges LF, Ready D, Graap K, Alarcon RD. Virtual reality exposure therapy for
Vietnam veterans with posttraumatic stress disorder. J Clin Psychiatry 2001; 62(8): 617–22.
  66. Difede J, Hoffman HG. Virtual reality exposure therapy for World Trade Center posttraumatic stress
disorder: a case report. Cyberpsychol Behav 2002; 5: 529–35.
  67. Difede J, Cukor J, Jayasinghe N et al. Virtual reality exposure therapy for the treatment of
posttraumatic stress disorder following September 11, 2001. J Clin Psychiatry 2007; in press.
  68. Difede J, Hoffman H, Jaysinghe N. Innovative use of virtual reality technology in the treatment of
PTSD in the aftermath of September 11. Psychiatr Serv 2002; 53(9): 1083–5.
  69. Difede J, Cukor J, Jayasinghe N et al. Virtual reality exposure therapy for the treatment of
posttraumatic stress disorder following September 11, 2001. J Clin Psychiatry 2007; 68(11): 1639–47.
  70. Gerardi M, Rothbaum BO, Ressler K, Heekin M, Rizzo A. Virtual reality exposure therapy Using a
virtual Iraq: Case report. J Traumatic Stress; in press.
  71. Parsons TD, Rizzo AA. Affective outcomes of virtual reality exposure therapy for anxiety and
specific phobias: a meta-analysis. J Behav Ther Exp Psychiatry; 2007.
  72. Kilpatrick DG, Veronen LJ, Resick PA. Psychological sequelae to rape: assessment and treatment
strategies. In: Dolays DM, Meredith RL, eds. Behavioral Medicine: Assessment and Treatment
Strategies. New York: Plenum; 1982: 473–97.
  73. Resick PA, Jordan CG, Girelli SA et al. A comparative victim study of behavioral group therapy for
sexual assault victims. Behav Ther 1988; 19: 385–401.
  74. Pearson MA, Poquette BM, Wasden RE. Stress inoculation and the treatment of post-rape trauma: a
case report. Behav Ther 1983; 6: 58–9.
  75. Watson CG, Tuorila JR, Vickers KS, Gearhart LP, Mendez CM. The efficacies of three relaxation
regimens in the treatment of PTSD in Vietnam War veterans. J Clin Psychol 1997; 53(8): 917–23.
  76. Frank E, Anderson B, Stewart BD et al. Efficacy of cognitive behavior therapy and systematic
desensitization in the treatment of rape trauma. Behav Ther 1988; 19: 403–20.
  77. Frank E, Stewart BD. Depressive symptoms in rape victims. A revisit. J Affect Disord 1984; 7(1): 77–85.
  78. Wolpe J. Psychotherapy by reciprocal inhibition. Stanford, CA: Stanford University Press; 1988.
  79. Bowen GR, Lambert JA. Systematic desensitization therapy with post-traumatic stress disorder
cases. In: Figley CR, ed. Trauma and its Wake. New York: Brunner/Mazel; 1986; 2: 280–91.
  80. Peniston EG. EMG biofeedback-assisted desensitization treatment for Vietnam combat veteran’s
post-traumatic stress disorder. Clinical Biofeedback Health 1986; 9: 35–41.
  81. Muse M. Stress-related, posttraumatic chronic pain syndrome: behavioral treatment approach. Pain
1986; 25: 389–94.
  82. Frank E, Stewart BD. Treating depression in victims of rape. Clin Psychol 1983; 8: 65–74.
  83. Turner SM. Systematic Desensitization of Fears and Anxiety in Rape Victims. Paper Presented at:
Advancement of Behavior Therapy. San Francisco, CA; 1979.
  84. Becker JV, Abel GG. Behavioral treatment of victims of sexual assault. In: Turner SM, Calhoun KS,
Adams HE, eds. Handbook of Clinical Behavior Therapy. New York: Wiley; 1981: 347–79.
  85. Shapiro F. Eye Movement Desensitization and Reprocessing: Basic Protocols, Principles, and
Procedures. New York: Guilford; 1996.
114 Ressler and Rothbaum

  86. Lohr JM, Tolin DF, Lilienfeld SO. Efficacy of eye movement desensitization and reprocessing:
implications for behavior therapy. Behav Ther 1998; 29: 123–56.
  87. Shapiro F. Efficacy of the eye movement desensitization procedure in the treatment of traumatic
memories. J Trauma Stress 1989; 2: 199–223.
  88. Boudewyns PA, Stwertka SA, Hyer LA. Eye movement desensitization for PTSD of combat: a
treatment outcome pilot study. Behav Ther 1993; 16: 29–33.
  89. Jensen JA. An investigation of eye movement desensitization and reprocessing (EMDR) as a
treatment for posttraumatic stress disorder (PTSD) symptoms of Vietnam combat veterans. Behav
Ther 1994; 25: 311–25.
  90. Silver SM, Brooks A, Obenchain J. Treatment of Vietnam war veterans with PTSD: a comparison
of eye movement desensitization and reprocessing, biofeedback, and relaxation training. J Trauma
Stress 1995; 8(337–42).
  91. Pitman RK, Orr SP, Altman B et al. Emotional processing during eye movement desensitization
and reprocessing therapy of Vietnam veterans with chronic posttraumatic stress disorder. Compr
Psychiatry 1996; 37(6): 419–29.
  92. Renfrey G, Spates CR. Eye movement desensitization: a partial dismantling study. J Behav Ther Exp
Psychiatry 1994; 25(3): 231–9.
  93. Vaughan K, Armstrong MS, Gold R et al. A trial of eye movement desensitization compared to image
habituation training and applied muscle relaxation in post-traumatic stress disorder. J Behav Ther
Exp Psychiatry 1994; 25(4): 283–91.
  94. Wilson SA, Becker LA, Tinker RH. Eye movement desensitization and reprocessing (EMDR)
treatment for psychologically traumatized individuals. J Consult Clin Psychol 1995; 63(6): 928–37.
  95. Rothbaum BO. A controlled study of eye movement desensitization and reprocessing in the treatment
of posttraumatic stress disordered sexual assault victims. Bull Menninger Clin 1997; 61(3): 317–34.
  96. Carlson JG, Chemtob CM, Rusnak K, Hedlund NL, Muraoka MY. Eye movement desensitization
and reprocessing (EDMR) treatment for combat-related posttraumatic stress disorder. J Trauma
Stress 1998; 11(1): 3–24.
  97. Marcus SV, Marquis P, Sakai C. Controlled study of treatment of PTSD using EMDR in an HMO
setting. Psychotherapy 1997; 34: 307–15.
  98. Devilly GJ, Spence SH. The relative efficacy and treatment distress of EMDR and a cognitive-
behavior trauma treatment protocol in the amelioration of posttraumatic stress disorder. J Anxiety
Disord 1999; 13(1–2): 131–57.
  99. Hickling EJ, Blanchard EB. The private practice psychologist and manual-based treatments: post-
traumatic stress disorder secondary to motor vehicle accidents. Behav Res Ther 1997; 35(3): 191–203.
100. Frueh BC, Turner SM, Beidel DC, Mirabella RF, Jones WJ. Trauma management therapy: a preliminary
evaluation of a multicomponent behavioral treatment for chronic combat-related PTSD. Behav Res
Ther 1996; 34(7): 533–43.
101. Resick PA, Schnicke MK. Cognitive processing therapy for sexual assault victims. J Consult Clin
Psychol 1992; 60(5): 748–56.
102. Resick P. Does Prior History of Victimization Affect Rape Therapy Outcome? Paper Presented at:
Research Workshop on Violence in the Lives of Women: Impact and Treatment. NIMH, Washington,
DC; 1994.
103. Resick PA, Nishith P, Astin M. A Controlled Trial Comparing Cognitive Processing Therapy and
Prolonged Exposure: Preliminary Findings. Paper Presented at: Lake George Research Conference
On Posttraumatic Stress Disorder. Lake George, NY; 1998.
104. Chard KM. An evaluation of cognitive processing therapy for the treatment of posttraumatic stress
disorder related to childhood sexual abuse. J Consult Clin Psychol 2005; 73: 965–71.
105. Monson CM, Schnurr PP, Resick PA et al. Cognitive processing therapy for veterans with military-
related posttraumatic stress disorder. J Consult Clin Psychol 2006; 74(5): 898–907.
106. Ahrens J, Rexford L. Cognitive processing therapy for incarcerated adolescents with PTSD.
J aggression, maltreatment and trauma 2002; 6(1): 201–16.
107. Schulza PM, Hubera CL, Resick PA. Practical adaptations of cognitive processing therapy with
Bosnian refugees: Implications for adapting practice to a multicultural clientele. Cogn Behav Pract
2006; 13(4): 310–21.
108. Echeburua E, de Corral P, Zubizarreta I, Sarasua B. Psychological treatment of chronic posttraumatic
stress disorder in victims of sexual aggression. Behav Modif 1997; 21(4): 433–56.
109. Resick PA, Galovski TE, Uhlmansiek MO et al. A randomized clinical trial to dismantle components
of cognitive processing therapy for posttraumatic stress disorder in female victims of interpersonal
violence. J Consult Clin Psychol, in press.
110. van Emmerik AAP, Kamphuis JK, Emmelkamp PMG. Treating acute stress disorder and posttraumatic
stress disorder with cognitive behavioral therapy or structured writing therapy: a randomized
controlled trial. Psychother Psychosom 2008; 77: 93–100.
Psychosocial treatments of posttraumatic stress disorder 115

111. Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine, or their
combination for panic disorder: A randomized controlled trial. JAMA 2000; 283(19): 2529–36.
112. Foa E, Franklin ME, Moser J. Context in the clinic: How well do cognitive-behavioral therapies and
medications work in combination? Biol Psych 2002; 52: 987–97.
113. Foa EB, Liebowitz MR, Kozak MJ et al. Randomized, placebo-controlled trial of exposure and ritual
prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder.
Am J Psychiatry 2005; 162(1): 151–61.
114. Otto MW, Basden SL, Leyro TM, McHugh RK, Hofmann SG. Clinical perspectives on the combination
of D-cycloserine and cognitive-behavioral therapy for the treatment of anxiety disorders. CNS Spectr
2007; 12(1): 51–6, 59–61.
115. Rothbaum BO, Cahill S, Foa EB et al. Augmentation of sertraline with prolonged exposure in the
treatment of PTSD. J Traumatic Stress 2006; 19: 625–38.
116. Rothbaum BO, Davis M. Applying learning principles to the treatment of post-trauma reactions.
Ann N Y Acad Sci 2003; 1008: 112–21.
117. Myers KM, Davis M. Behavioral and neural analysis of extinction. Neuron 2002; 36(4): 567–84.
118. Walker DL, Ressler KJ, Lu KT, Davis M. Facilitation of conditioned fear extinction by systemic
administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle
in rats. J Neurosci 2002; 22(6): 2343–51.
119. Monahan JB, Handelmann GE, Hood WF, Cordi AA. D-cycloserine, a positive modulator of the
N-methyl-D-aspartate receptor, enhances performance of learning tasks in rats. Pharmacol Biochem
Behav 1989; 34(3): 649–53.
120. Hood W, Compton R, Monahan J. D-cycloserine: a ligand for the N-methyl-D-aspartate coupled
glycine receptor has partial agonist characteristics. Neurosci Lett 1989; 98(1): 91–5.
121. Lee JL, Milton AL, Everitt BJ. Reconsolidation and extinction of conditioned fear: inhibition and
potentiation. J Neurosci 2006; 26(39): 10051–6.
122. Botreau F, Paolone G, Stewart J. d-Cycloserine facilitates extinction of a cocaine-induced conditioned
place preference. Behav Brain Res 2006; 172(1): 173–8.
123. Ledgerwood L, Richardson R, Cranney J. D-cycloserine facilitates extinction of learned fear: effects
on reacquisition and generalized extinction. Biol Psychiatry 2005; 57(8): 841–7.
124. Richardson R, Ledgerwood L, Cranney J. Facilitation of fear extinction by D-cycloserine: theoretical
and clinical implications. Learn Mem 2004; 11(5): 510–6.
125. Ledgerwood L, Richardson R, Cranney J. D-cycloserine and the facilitation of extinction of
conditioned fear: consequences for reinstatement. Behav Neurosci 2004; 118(3): 505–13.
126. Ledgerwood L, Richardson R, Cranney J. Effects of D-cycloserine on extinction of conditioned
freezing. Behav Neurosci 2003; 117(2): 341–9.
127. Yang YL, Chao PK, Ro LS, Wo YY, Lu KT. Glutamate NMDA receptors within the amygdala
participate in the modulatory effect of glucocorticoids on extinction of conditioned fear in rats.
Neuropsychopharmacology 2007; 32(5): 1042–51.
128. Yang YL, Lu KT. Facilitation of conditioned fear extinction by d-cycloserine is mediated by mitogen-
activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein
synthesis in basolateral nucleus of amygdala. Neuroscience. 2005; 134(1): 247–60.
129. Otto M. Learning and “Unlearning” Fears: Preparedness, Neural Pathways, and Patients. Biol Psych
2002; 52: 917–20.
130. Marks I, Swinson R, Basoglu M et al. Alprazolam and exposure alone and combined in panic disorder
with agoraphobia. A controlled study in London and Toronto. Br J Psychiatry 1993; 162: 776–87.
131. Ressler KJ, Rothbaum BO, Tannenbaum L et al. Cognitive enhancers as adjuncts to psychotherapy:
use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 2004;
61(11): 1136–44.
132. Hofmann SG, Pollack MH, Otto MW. Augmentation treatment of psychotherapy for anxiety
disorders with D-cycloserine. CNS Drug Rev. Fall-Winter 2006; 12(3–4): 208–17.
133. Hofmann SG, Meuret AE, Smits JA et al. Augmentation of exposure therapy with D-cycloserine for
social anxiety disorder. Arch Gen Psychiatry 2006; 63(3): 298–304.
134. Kushner MG, Kim SW, Donahue C et al. D-Cycloserine augmented exposure therapy for obsessive
compulsive disorder. Biol Psychiatry 2007; in press.
135. Guastella AJ, Dadds MR, Lovibond PF, Mitchell P, Richardson R. A randomized controlled trial of
the effect of d-cycloserine on exposure therapy for spider fear. J Psychiatr Res 2007; 41(6): 466–71.
136. Guastella AJ, Lovibond PF, Dadds MR, Mitchell P, Richardson R. A randomized controlled trial of
the effect of d-cycloserine on extinction and fear conditioning in humans. Behav Res Ther 2007;
45(4): 663–72.
 9 Pharmacotherapy of posttraumatic stress
disorder
Lakshmi N Ravindran and Murray B Stein

Introduction

With vivid descriptions dating back to ancient Greece, the battlefield phenomenon, known in
its various incarnations as “soldier’s heart,” “shell shock,” and “combat fatigue,” is not just
limited to military populations. Studies on the more recent construct of “posttraumatic stress
disorder” (PTSD), initially accepted by the psychiatric community in 1980, (1) now suggest a
lifetime prevalence of 6.8% in the general U.S. population.(2) With recent world events and
media coverage bringing increased awareness to this disabling disorder, the drive to find effec-
tive treatments for this condition is even greater.
This goal of this chapter is to review the evidence base of pharmacological interven-
tions for PTSD. Wherever possible, the review is reliant on randomized, double-blind, placebo-
controlled trials to provide the most meaningful information. However, in cases where this is
not feasible, other evidence (e.g., open-label or active-control trials) may be mentioned. The
use of pharmacotherapy to prevent development of PTSD following trauma is discussed in a
subsequent chapter (see the chapter by Bisson and Zohar, this volume). Effective psychothera-
peutic interventions for PTSD also exist and are commonly used either as monotherapy or in
conjunction with pharmacological agents. Details substantiating these management strategies
are also discussed in another chapter (see chapter by Ressler and Rothbaum, this volume)

Antidepressants

Selective Serotonin Reuptake Inhibitors

The class of medications known as the selective serotonin reuptake inhibitors (SSRIs) has
largely replaced all other classes of antidepressants as first-line agents for the acute treatment
of PTSD. At this time, only paroxetine and sertraline have official FDA approval for treatment
of this disorder; however, clinically all SSRIs are generally used for this purpose. Although
each SSRI is structurally distinct with varying effects on the different neurotransmitters, as
a class they serve to enhance serotonin function in the brain. The exact mechanism by which
they accomplish this remains uncertain, but it is thought to involve effects on 2nd messenger
systems and/or neuropeptides, such as brain-derived neurotrophic factor (BDNF).(3)
One of the earliest reports of SSRI efficacy in chronic PTSD came from van der Kolk
and colleagues (4) who reported results of a 5-week placebo-controlled trial of fluoxetine in
both civilian and combat populations. They found fluoxetine resulted in significant decreases
in overall PTSD symptomatology following the treatment period, particularly in the symp-
tom clusters of hyperarousal and numbing. The other notable finding from this trial was the
marked difference in symptom severity change between civilians (40%) and combat veterans
(15%), although it should be noted that the severity of PTSD symptoms at baseline was signifi-
cantly worse in the veteran population. Nevertheless, this discrepancy may have been respon-
sible in part for the contention that combat-related PTSD is less responsive to pharmacological
intervention. Since then, two other placebo-controlled studies have confirmed the utility of
fluoxetine in PTSD, with one study finding it effective even for combat-related symptoms.(5,
6) In contrast, two placebo-controlled trials failed to find positive effects for treatment with
fluoxetine. The authors of the first study (7) suggested that the lack of effect may have been due
to the severe, chronic nature of the combat-related trauma in their subjects, while the authors
of the second study (8) wondered whether the use of lower doses and a predominantly female
population may have played a role in the decreased response rates found in their results.
Pharmacotherapy of Posttraumatic Stress Disorder 117

Following the early reports of successful use of SSRIs for this disorder, several other large
placebo-controlled trials have since been conducted with a number serving as the basis for
regulatory approval of two particular SSRIs, sertraline and paroxetine. Two large multicenter
trials comparing placebo and sertraline treatment over 12 weeks found moderate effects for
active drug (effect sizes ≈0.5) (9, 10), with the former study also noting particular effects for
sertraline on the hyperarousal and numbing/avoidance clusters of symptoms. Similarly, two
large trials found that paroxetine significantly decreased PTSD symptoms in all three symp-
toms clusters, following 12 weeks of treatment compared to placebo.(11, 12) More recently,
Marshall et al. (13) provided additional support for the efficacy of paroxetine when they stud-
ied an urban population with a high minority quotient. They noted that paroxetine appeared to
be helpful for treatment of core PTSD symptoms along with associated features of PTSD, which
included significant dissociative symptoms and interpersonal issues.
Currently, there is only one double-blind study involving the use of citalopram that com-
pares it to sertraline and placebo; (14) however, although citalopram was able to demonstrate
an overall improvement in the PTSD symptoms by the end of this study, the results failed to
demonstrate significant differences in efficacy between the three treatment arms. Nevertheless,
open-label trials have suggested a role for citalopram in the treatment of PTSD, in adults as
well as children and adolescents.(15–18) Similarly, open-label trials have also demonstrated
moderate success using escitalopram (19) and fluvoxamine.(20–23).
While the findings from the above trials support specific PTSD symptom reduction with
SSRIs, evidence in the literature also suggests that SSRIs may be useful in improving and sus-
taining amelioration in quality of life for this population, with the majority of the recovery
occurring during the acute treatment phase.(24)
At this time, SSRIs represent the most extensively investigated class of medications in
PTSD research. A recent report from the Institute of Medicine (IOM) concluded that evidence
for SSRI efficacy in PTSD was inconclusive, citing the less-than-robust effect overall effect sizes.
(25) Nonetheless, many studies, as cited above, suggest a beneficial role for SSRIs in the treat-
ment of PTSD—though the magnitude of benefits varies widely among individuals and, gen-
erally, is less than would be desired of a first-line treatment. Among the SSRIs, there is every
reason to believe that efficacy is shared by the entire class. As such, the use of a particular SSRI
for PTSD should take into consideration factors such as side effects, prior response, and per-
haps family history of response. Dosages of SSRIs for the treatment of PTSD are in the same
range as those recommended for major depressive disorder. Because many patients with PTSD
suffer from comorbid MDD, (26) the use of SSRIs is expected to benefit both conditions.

Duration of treatment with SSRIs

There is evidence from several studies that extended treatment with SSRIs may provide addi-
tional benefit in PTSD. Londberg and colleagues (27) studied a cohort of patients who had pre-
viously completed one of two double-blind, placebo-controlled trials using sertraline as an
acute-phase treatment for PTSD. Of these, 252 subjects were enrolled into a 24-week, open-
label, continuation-phase study, again using sertraline. The investigators observed that not only
did 54% of nonresponders during the original 12-week acute-phase trials convert to responders,
but 92% of the original acute-phase responders maintained their recovery. Subsequent analyses of
investigational measures also showed that 20% to 25% of the overall improvement in PTSD symp-
toms occurred during this extended continuation phase and similarly that 41% of the improvement
in depressive symptoms and 31% of the improvement in quality of life also occurred during this
period. Finally, when a subsample (N = 96) of the responders from this continuation-phase study
were rerandomized to double-blind maintenance treatment with either sertraline or placebo for an
additional 28 weeks, both relapse (sertraline 5.3% vs. placebo 26.1%) and discontinuation (sertraline
15.8% vs. placebo 45.7%) rates were significantly higher in the placebo group.(28) A similar study
was conducted by Martenyi and colleagues (29) using fluoxetine. Following an initial 12 week, acute-
phase, placebo-controlled trial, fluoxetine responders were subsequently rerandomized for con-
tinuation treatment of a further 24 weeks. At endpoint, SSRI treatment was found to be superior to
placebo with respect to time to relapse (p = 0.027), and once again patients receiving active treatment
had significantly greater improvement in their PTSD symptoms compared to those on placebo (p =
0.011). Overall, there were also fewer dropouts from the fluoxetine group (5.8%) compared to those
receiving placebo (16.1%)
118 Ravindran and Stein

This collection of studies highlights the importance of providing extended treatment for PTSD
in order to elicit maximal improvement of symptoms, maintain recovery, and prevent relapse. The
noteworthy finding from Londberg et al. (27) regarding conversion of nonresponders to responders
only after the acute-phase treatment also serves to underline the necessity for patience when treat-
ing this population (although this may be clinically feasible only when there is at least some initial
response to SSRI treatment). At present, guidelines for duration of pharmacotherapy treatment rec-
ommend continuing medications for 6 to 12 months in cases of acute PTSD or 12 to 24 months for
chronic PTSD; under certain circumstances, such as persistent residual symptoms or poor psycho-
social functioning, an even longer treatment period may be of benefit.(30, 31)

Dual Reuptake Inhibitors

There are two serotonin/norepinephrine reuptake inhibitors currently available on the mar-
ket. There are currently only two placebo-controlled trials assessing the use of Venlafaxine
extended-release (XR) in PTSD. In the first, Davidson and colleagues (32) conducted an acute-
phase, three-arm treatment study comparing venlafaxine XR to sertraline and placebo. At
endpoint, venlafaxine XR was found to be significantly more efficacious than placebo on the
primary outcome measure of PTSD symptom reduction, specifically on the subscales meas-
uring symptoms of avoidance-numbing and hyperarousal; these differences in improvement
were seen as early as Week 2. Furthermore, the results of an analysis to control for depression
severity and severity by treatment suggested that the improvement in PTSD symptoms was
not mediated by improvement in depressive symptoms, which was an important finding as
the two conditions are so often comorbid. There were no significant differences in efficacy on
primary or secondary outcome measures between venlafaxine XR and sertraline.
In one of the few longer-term pharmacotherapy studies investigating medications other
than SSRIs, Davidson et al. (33) carried out a 6-month placebo-controlled trial using venlafax-
ine. Once again, venlafaxine was found to be superior to placebo with respect to improvement
in overall PTSD symptoms (p = 0.006), in particular for symptom clusters of reexperiencing (p
= 0.008) and avoidance-numbing (p = 0.006), with a trend toward significance for symptoms of
hyperarousal (p = 0.06). The authors also noted that the superior efficacy of the drug was sus-
tained from Week 12 (the typical end of an acute-phase trial) to endpoint. Finally, Venlafaxine
XR-treated patients also showed greater improvement on measures of resilience, stress-vul-
nerability, and quality of life relative to their placebo-treated counterparts. Although there are
relatively few randomized clinical trials to support its use in PTSD, it probably represents a
very reasonable 1st or 2nd line pharmacotherapy option.
The other dual reuptake inhibitor, duloxetine, has only recently been approved for use in
the United States, Canada, and parts of Europe. At present, there are no published, randomized
clinical trials investigating its efficacy in the treatment of PTSD. However, based on its putative
mechanism of action and some preliminary evidence from trials investigating its use in depres-
sion and other anxiety disorders (34–37), there is reason to believe duloxetine may be useful
and that it merits investigating for treatment of PTSD.

Tricyclic Antidepressants
The tricyclic antidepressants (TCAs) represent one of the earliest classes of antidepressant to
be used in a widespread fashion. They are still commonly used and quite effective (for depres-
sion), although they have largely been relegated to second- or third-line agents as a result of
their adverse-effect profile, which includes a number of anticholinergic effects.
In one of the earliest controlled trials investigating antidepressant efficacy in PTSD, 18
hospitalized male veterans completed a double-blind, crossover trial consisting of two 4-week
treatment periods with an intervening 4-day switchover period.(38) The trial, which employed
desipramine (up to 200 mg daily) did not find significant differences in PTSD symptom change
between the two treatments, although there did seem to be an improvement in observer-rated
depression symptoms with desipramine. Of note is that the period of active treatment was quite
short (only 4 weeks) and the investigators did not utilize observer-rated scales for PTSD but
rather employed substitute items chosen post hoc from more general depression and anxiety
scales. A larger trial, comparing amitriptyline and placebo in 46 veterans with chronic PTSD,
was conducted by Davidson and colleagues in 1990.(39) In this case, amitriptyline showed
Pharmacotherapy of Posttraumatic Stress Disorder 119

some benefit over placebo on certain measures but not on the structured interview for PTSD.
One notable result from this trial was the overall relative lack of response in both treatment
groups, even after 12 weeks of treatment, with 64% of the amitriptyline-treated group and 72%
of the placebo group still meeting criteria for PTSD. This finding highlights the common situ-
ation of persistent residual symptoms, with significant clinical impact, even in patients who
may have had a degree of response to treatment. Two other placebo-controlled trials using
TCAs have also been conducted. These are discussed below in the section of the chapter enti-
tled “Monoamine Oxidase Inhibitors.”

Monoamine Oxidase Inhibitors

The monoamine oxidase inhibitors (MAOIs) represent an older class of antidepressants that
works to increase monoamine availability by irreversibly inhibiting the enzyme, monoamine oxi-
dase, responsible for their breakdown. Although MAOIs are effective antidepressants, their use
is mainly limited by the need to maintain a strict low-tyramine diet to decrease the risk of hyper-
tensive crises. Consequently, MAOIs are rarely first-line agents for treatment of psychiatric dis-
orders. Nevertheless, there have been placebo-controlled trials using these medications. Frank et
al. (40) compared phenelzine, imipramine, and placebo in 34 Vietnam veterans with PTSD. Both
active treatment groups displayed significantly improved PTSD symptoms compared to placebo,
with the phenelzine-treated group showing particular improvement in intrusive or reexperienc-
ing symptoms. A subsequent study by Kosten et al. (41) examining the same medications, but in a
slightly larger sample of 60 veterans, found similar results in terms of active treatment vs. placebo.
This time, however, there seemed to be a more pronounced advantage for the subjects receiving
phenelzine. In contrast to these two trials, findings from a smaller, double-blind, crossover study
(N = 13) in which patients were randomized to treatment with either phenelzine or placebo did
not reveal differences between treatment groups.(42) There are no other placebo-controlled tri-
als of irreversible MAOIs in PTSD. We are unaware of more recent trials with MAOIs or of trials
that compare MAOIs to SSRIs. It is, therefore, difficult to specify where in the PTSD therapeutic
armamentarium MAOIs should be used. Would MAOIs be useful for SSRI- or SNRI-refractory
patients? There are no data to support such a contention at this time.
A subtype of MAOIs, called reversible inhibitors of monoamine oxidase A (RIMAs) have
also been available. The selectivity and reversibility of the RIMAs are thought to render them
safer to use. An initial trial of the RIMA, brofaromine, found it to be effective over placebo in
individuals suffering from PTSD for ≥ 1 year.(43) However, outcomes from a subsequent, large,
placebo-controlled trial failed to differentiate active treatment from placebo, although both groups
did demonstrate significant symptom reduction. Moclobemide, another RIMA, was compared to
fluoxetine and tianeptine (a drug thought to work by selectively accelerating serotonin reuptake)
in a study comparing different classes of antidepressants in PTSD.(44) All three treatment groups
showed significant improvement in severity of PTSD symptoms with no between-group differ-
ences. However, this was a head-to-head trial with no placebo-control group.
At this time, neither brofaromine nor moclobemide is commercially available in the
United States, although the latter is available in Canada, Europe, and other parts of the world.

Bupropion
The proposed mechanism of action for the antidepressant bupropion involves dual reuptake
inhibition of both norepinephrine and dopamine, although with negligible serotonergic activity.
(45) Due to its nicotinic antagonist activity, it is also commonly used as a smoking cessation aid.
In the only placebo-controlled trial investigating change in PTSD symptoms as a primary out-
come measure, subjects treated with bupropion sustained release (SR) could not be distinguished
from the placebo group.(46) An earlier study that compared bupropion SR to placebo for smok-
ing cessation in veterans with chronic PTSD found the active drug helpful for this purpose, but
no differences were found between groups on the secondary measures of PTSD outcome.(47)

Mirtazapine
In 1994, mirtazapine was introduced to the psychiatric pharmacopoeia. It is thought to enhance
both serotonin and norepinephrine release via blockade of presynaptic α2-adrenergic receptors.
At the same time, mirtazapine also exerts a significant blocking effect at the both the 5-HT2 and
120 Ravindran and Stein

5-HT3 serotonergic receptors and notably at the H1 histaminic receptor.(48) At this time, only a
single 8-week, placebo-controlled pilot trial exists to study the use of mirtazapine in PTSD.(49)
In the sample of 29 patients, the authors claimed mirtazapine (up to 45 mg daily) produced a
significant treatment effect on the global improvement item of their primary outcome measure,
as well as amelioration on a number of secondary measures. For patients on mirtazapine, sta-
tistical analyses showed moderate (0.42) to strong (1.06) effect sizes with respect to change in
PTSD symptoms. However, the conclusions of the study were limited by the small sample size,
and unfortunately, there have been no subsequent larger trials to substantiate the findings.

Nefazodone
Nefazodone is an antidepressant that works via antagonist activity at the postsynaptic 5-HT2A
receptor and inhibition of presynaptic serotonin and norepinephrine reuptake, as well as dis-
playing relatively potent antagonism of the alpha-1-adrenergic receptor.(50)
Although a number of open trials have suggested a utility for nefazodone in PTSD,
there is a dearth of randomized clinical trials to support this. In the only published placebo-con-
trolled trial (51), there was a significant decline in PTSD symptom scores in nefazodone-treated
subjects compared to those receiving placebo, but the population studied was relatively small.
Another double-blind, head-to-head comparison of nefazodone to sertraline demonstrated effi-
cacious reduction of PTSD symptoms over time in both treatment arms, with no differences
between groups.(52) The lack of larger published trials is most likely due to the recent with-
drawal of nefazodone from the market in Europe, Canada, Australia, and New Zealand, follow-
ing reports of its association with hepatotoxicity in a number of patients. Given these concerns,
the use of nefazodone is effectively a more academic consideration rather than a practical one.

Anticonvulsants

Numerous anticonvulsant medications are known to have mood-stabilizing properties and

have thus found a role in the treatment of various psychiatric disorders. While their value has
been most pronounced in treating bipolar disorder, there is also evidence to support some
utility in the depressive disorders and certain anxiety disorders.(53) The hypothesis then that
a kindling and sensitization mechanism may figure in the development of PTSD (54) has natu-
rally led researchers to question their possible effectiveness for treatment of this particular
anxiety disorder. Within this class, the medications that have been of most interest include car-
bamazepine, valproic acid, lamotrigine, gabapentin, topiramate, tiagabine, and levetiracetam.
Although literature from case reports and open trials suggest they may be helpful, controlled
studies investigating the usefulness of these medications has only been conducted in a limited
way for PTSD, and with mixed results.
A preliminary 12-week placebo-controlled trial of 15 subjects suggested that lamotrigine
may be helpful for the reexperiencing and avoidance/numbing symptoms clusters of PTSD.
(55) However, the limited sample size precluded more definitive conclusions. In 2006, Connor
and colleagues conducted a 12-week, open-label trial of tiagabine, thought to function as a
selective GABA reuptake inhibitor.(56) Responders following the open-label treatment period
(N = 18) were then randomized to continuation treatment or placebo for a further 12 weeks.
Although there was no difference in relapse rates between treatment groups, there did appear
a trend of increased remission in the tiagabine group (p=0.08). However, in a subsequent
double-blind, placebo-controlled trial with much more substantial numbers (N = 232), no dif-
ferences were found between groups in any of the primary or secondary outcome measures.
(57) Likewise, Davis et al. (58) were unable to find any differences in PTSD outcomes between
85 veterans randomized to 8 weeks of placebo or divalproex monotherapy. However, it is pos-
sible that the relatively briefer duration of the trial and the chronicity of illness in these subjects
(M = 24.4 years) may have played a role in the lack of response seen. Finally, a randomized, pla-
cebo-controlled trial of topiramate augmentation therapy of 40 male veterans failed to find any
treatment effect for active medication after 7 weeks (59), although it should be acknowledged
that the dropout rate, mainly due to adverse events (topiramate N = 8, placebo N = 2), for this
trial was quite high. In contrast, the only double-blind, placebo-controlled topiramate mono-
therapy trial found that topiramate was actually helpful in reducing reexperiencing symptoms
Pharmacotherapy of Posttraumatic Stress Disorder 121

of PTSD (p = 0.038), although there was no statistically significant difference between treatment
groups in overall PTSD scores.(60) Nevertheless, the authors suggested that the results war-
ranted further investigation in larger trials.
At best the results of these limited numbers of trials are mixed and no definitive conclu-
sions on the utility of anticonvulsants for PTSD can be drawn. As such, the role of anticonvul-
sants for the treatment of PTSD remains uncertain, and only future controlled trials with larger
and more diverse study populations will help in illuminating their function for this disorder.

Benzodiazepines and Other Hypnotics

Benzodiazepines and sedative–hypnotic medications are among the commonest adjunctive

therapies for antidepressants in the treatment of PTSD.(61) Their use is mainly directed toward
symptomatic treatment of the chronic sleep difficulties and other hyperarousal symptoms,
such as irritability, so common in PTSD. Surprisingly, despite their widespread clinical use for
this disorder, there are few controlled trials in the literature to support these practices.
A randomized, single-blind, crossover study of clonazepam (up to 2 mg daily) failed to find
significant differences in outcome compared to placebo, although the study population was lim-
ited to only six subjects.(62) Braun et al. (63) chose to study a relatively larger sample of 16 sub-
jects with chronic PTSD, who were randomized to either alprazolam or placebo for 5 weeks with
subsequent crossover following an intervening 2-week washout period. In this case, the investi-
gators found that alprazolam conferred benefit in terms of improvement in PTSD symptoms.
The paucity of clinical trials investigating benzodiazepines is of concern given the preva-
lent use of these medications in the PTSD population. Further, the “mixed” results even from
this limited sample, serve to underline the need for more definitive investigations to support
and reinforce effective clinical decision making.

Antipsychotics

The use of adjunctive antipsychotic use, particularly atypical antipsychotics, for PTSD is becom-
ing increasingly common in clinical practice. Multiple rationales for this practice can be found
in the literature. Among individuals suffering from PTSD, it has been estimated that up to 40%
may experience psychotic symptoms, typically positive symptoms such as hallucinations and
delusions (64), and the presence of these symptoms is not entirely explained by the presence of
comorbid psychotic disorders or medical problems. (65) In addition, it has been hypothesized
that dopamine dysfunction may not only trigger the production of these psychotic symptoms
but may also play a role in mediation of hyperarousal symptoms, such as hypervigilance, exag-
gerated startle, and irritability.(66, 67) Together these lines of thought suggest an initial rational
neurochemical basis for the use of atypical antipsychotics in PTSD. These medications have
also been shown to have anxiolytic properties themselves, thought to be based in part in the
enhanced noradrenergic transmission that results from antagonism of the 5-HT2A receptors.
Additional anxiolytic activity has been attributed to antagonism of the α2-adrenergic recep-
tor and partial agonism at the 5-HT1A receptor.(68) Finally, the sedating effects of the atypical
antipsychotics, mainly ascribed to histaminic H1 receptor blockade, are often used to target the
sleep difficulties so characteristic of PTSD. Given the multitude of effects, it is not surprising
that atypical use is so widespread for this disorder. Although not reviewed here, there certainly
appears to be both theoretical and substantial evidentiary bases to support the use of atypicals
as adjunctive therapy in certain subpopulations suffering from PTSD (69–71); however, the
question remains as to whether there is evidence to substantiate their use as a monotherapy
treatment in this disorder.
Despite the availability of 6 different atypical antipsychotics (olanzapine, risperidone,
quetiapine, ziprasidone, clozapine, and aripiprazole) currently available on the market,
there are only two published double-blind, placebo-controlled trials of atypical antipsychotic
monotherapy for PTSD. In the first, Butterfield et al. (72) conducted a 10-week, placebo-con-
trolled trial of olanzapine (up to 20 mg daily) and found that although both treatment groups
improved over time, there were no notable differences in outcome between groups. Potential
122 Ravindran and Stein

shortcomings suggested to explain this included the small sample size (N = 15) with unusually
elevated placebo response rate, shorter than customary treatment duration that may have missed
delayed responders, a primarily female population (gender may affect treatment response),
diverse trauma types included, and the presence of comorbidity in all but one subject. A more
recent 12-week pilot study (73) compared flexibly dosed risperidone monotherapy (mean daily
dose = 2.62 mg) to placebo. In this case, low-dose risperidone appeared to confer a significant
therapeutic benefit in treatment of PTSD symptoms relative to placebo, as well as being reason-
ably well tolerated. Once again, however, limited conclusions can be drawn because of the small
sample size (N = 20).
These trials notwithstanding, there does seem to be a role for atypical antipsychotics in
the treatment of PTSD and their use in clinical practice is likely to continue. However, that does
not mitigate the need for larger research trials exploring the use of olanzapine, risperidone,
and the other atypicals to validate these practices. The main limitations to their current use
include the presence of significant metabolic effects, such as glucose and lipid dysregulation.
As such, these side effects should be carefully and routinely monitored, even when these drugs
are administered in low doses.

Adrenergic Agents

A number of brief reports in the literature have suggested a utility for adrenergic agents in the
treatment of PTSD (74–77), particularly for the symptoms of hyperarousal. One of these, cloni-
dine, works as an agonist at the postsynaptic α2-adrenergic receptor, most commonly used as
an antihypertensive, but it has also been reported, when used in conjunction with impramine,
to have a role in decreasing nightmares.(78) However, at this time there are no placebo-
controlled trials to substantiate this. Guanfacine is another centrally acting alpha adrenergic
agent that works in much the same way as clonidine. In the case of guanfacine, there is a single
placebo-controlled trial for its use in veterans with chronic PTSD, but the results of the trial did
not support a positive effect on posttraumatic symptoms, sleep disturbance, or general mood
disturbance.(79) In contrast, the antihypertensive agent, prazosin, a centrally acting selective
α1-antagonist, has shown more promise. Raskind et al. (80) carried out a 20-week, placebo-
controlled, crossover trial with prazosin in 10 veterans with chronic PTSD and severe night-
mares. The superiority of prazosin was seen on all primary outcome measures that included
change in levels of distressing dreams and overall PTSD severity. These findings were subse-
quently replicated using a larger sample of veterans (N = 40) and a parallel group design over 8
weeks.(81) Most recently, Taylor et al. (82) noted similar results in a smaller outpatient sample
(N = 13) of civilians with chronic PTSD, nightmares, and sleep disturbance who underwent a
7-week crossover trial (each treatment period was 3 weeks). Noteworthy findings during pra-
zosin treatment included a substantial increase in total sleep time (94 minutes), shorter REM
latency with increased REM sleep time, and a change toward normal dream content. Hopefully,
additional studies of longer duration will continue to substantiate these results.

Novel Agents

The quest to discover and develop novel pharmacological agents to treat PTSD is an ongoing
pursuit. Although several agents are under investigation, two agents that may be promising
include d-cycloserine and hydrocortisone.
D-cycloserine, a partial agonist of the n-methyl-d-aspartate (NMDA) receptor, has been
of interest in certain anxiety disorders, including social anxiety disorder (83, 84) and obsessive–
compulsive disorder (85). A single pilot study (86) of 11 outpatients with chronic PTSD compared
d-cycloserine to placebo in a 12-week, double-blind, crossover design (each treatment period
was 4 weeks). The active treatment did appear to cause improvement of numbing/avoidance
symptoms of PTSD, although placebo patients also registered improvement of these symptoms.
D-cycloserine also appeared to improve certain neurocognitive measures compared to placebo.
Larger, parallel group design studies may help to further elucidate the utility of this medication
for PTSD.
Pharmacotherapy of Posttraumatic Stress Disorder 123

Interest in glucocorticoid dysregulation mechanisms in PTSD has prompted the investi-

gation of hydrocortisone as a possible early intervention to prevent PTSD and more recently
as a potential treatment for PTSD. A preliminary, placebo-controlled, crossover trial (3-month
duration) of low-dose hydrocortisone (10 mg daily) appeared to show some benefit in reduc-
ing PTSD symptoms, particularly of the reexperiencing and avoidance type.(87) However, the
results of this study should be interpreted with extreme caution as the sample consisted of
only three subjects, with two subjects on concurrent sleep medication and one also receiving
concurrent psychotherapy. Nevertheless, if a larger trial were able to replicate these findings,
the results would certainly be intriguing.

Conclusions

Pharmacological agents represent an important and effective tool in the clinician’s armamen-
tarium for treatment of PTSD. Although the evidence base to support the success of different
medication classes to treat this illness continues to expand and develop, there are always addi-
tional areas of research that remain to be explored. In particular, there is a need to develop better
predictors of response to specific drug classes or psychotherapy, as well as a better understand-
ing of situations in which combination treatment with medication and psychotherapy might
be most appropriate. Also helpful would be improved strategies to enhance compliance and
tolerability of pharmacological interventions, as well as developing more definitive guidelines
around the necessity for continuation and maintenance treatment over more extended periods.
Although there is certainly a preliminary evidence base to support the use of many medica-
tions for PTSD, it is equally evident that there is a relative dearth of well-powered, definitive,
randomized controlled trials and consequent need to conduct such trials, of both acute and
long-term outcomes and in a variety of populations (e.g., recent combat veterans and persons
exposed to childhood trauma) to substantiate and validate many of the findings, including
their generalizability. And finally there is a pressing need to develop well-tolerated pharmaco-
logical treatments that work better, that is, those that have a more profound impact on symp-
tom reduction and restoration of functioning.
Establishing successful treatment strategies for PTSD remains a crucial and active area
of research with psychotherapy and pharmacotherapy representing the twin cornerstones of
intervention for this disorder. Deciding on which technique is the most appropriate for a given
patient depends on many factors, including but not limited to illness severity, comorbidity, pre-
vious response to treatment, and preference of both patient and clinician. Regardless of what
type of treatment is eventually chosen, the ultimate goals of intervention should be symptom
reduction, and ideally, resolution, as well as a full return of optimal psychosocial functioning.

Acknowledgments

Several authoritative reviews (88, 89) provided invaluable assistance during the compilation
and synthesis of the literature for this chapter. We are grateful to the authors of those reviews
for making their work available as extremely useful sources of reference.

REFERENCES

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-III).
3rd ed. Washington DC: American Psychiatric Association; 2008.
  2. Kessler RC, Berglund P, Demler O et al. Lifetime prevalence and age-of-onset distributions of DSM-IV
disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62(6): 593–602.
  3. Duman RS. Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 1998; 44(5):
324–35.
  4. van der Kolk BA, Dreyfuss D, Michaels M et al. Fluoxetine in posttraumatic stress disorder. J Clin
Psychiatry 1994; 55(12): 517–22.
  5. Connor KM, Sutherland SM, Tupler LA, Malik ML, Davidson JR. Fluoxetine in post-traumatic stress
disorder. Randomised, double-blind study. Br J Psychiatry 1999; 175: 17–22.
124 Ravindran and Stein

  6. Martenyi F, Brown EB, Zhang H, Prakash A, Koke SC. Fluoxetine vs. placebo in posttraumatic stress
disorder. J Clin Psychiatry 2002; 63(3): 199–206.
  7. Hertzberg MA, Feldman ME, Beckham JC, Kudler HS, Davidson JR. Lack of efficacy for fluoxetine in
PTSD: a placebo controlled trial in combat veterans. Ann Clin Psychiatry 2000; 12(2): 101–5.
  8. Martenyi F, Brown EB, Caldwell CD. Failed efficacy of fluoxetine in the treatment of posttraumatic
stress disorder: results of a fixed-dose, placebo-controlled study. J Clin Psychopharmacol 2007; 27(2):
166–70.
  9. Brady K, Pearlstein T, Asnis GM et al. Efficacy and safety of sertraline treatment of posttraumatic
stress disorder: a randomized controlled trial. JAMA 2000; 283(14): 1837–44.
10. Davidson JR, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM. Multicenter, double-blind
comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen
Psychiatry 2001; 58(5): 485–92.
11. Marshall RD, Beebe KL, Oldham M, Zaninelli R. Efficacy and safety of paroxetine treatment for
chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 2001; 158(12): 1982–8.
12. Tucker P, Zaninelli R, Yehuda R et al. Paroxetine in the treatment of chronic posttraumatic stress
disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 2001; 62(11): 860–8.
13. Marshall RD, Lewis-Fernandez R, Blanco C et al. A controlled trial of paroxetine for chronic PTSD,
dissociation, and interpersonal problems in mostly minority adults. Depress Anxiety 2007; 24(2):
77–84.
14. Tucker P, Potter-Kimball R, Wyatt DB et al. Can physiologic assessment and side effects tease out
differences in PTSD trials? A double-blind comparison of citalopram, sertraline, and placebo.
Psychopharmacol Bull 2003; 37(3): 135–49.
15. Seedat S, Stein DJ, Emsley RA. Open trial of citalopram in adults with post-traumatic stress disorder.
Int J Neuropsychopharmacol 2000; 3(2):135–40.
16. Seedat S, Lockhat R, Kaminer D, Zungu-Dirwayi N, Stein DJ. An open trial of citalopram in adolescents
with post-traumatic stress disorder. Int Clin Psychopharmacol 2001; 16(1): 21–5.
17. Seedat S, Stein DJ, Ziervogel C et al. Comparison of response to a selective serotonin reuptake
inhibitor in children, adolescents, and adults with posttraumatic stress disorder. J Child Adolesc
Psychopharmacol 2002; 12(1): 37–46.
18. English BA, Jewell M, Jewell G, Ambrose S, Davis LL. Treatment of chronic posttraumatic stress disorder
in combat veterans with citalopram: an open trial. J Clin Psychopharmacol 2006; 26(1): 84–8.
19. Robert S, Hamner MB, Ulmer HG, Lorberbaum JP, Durkalski VL. Open-label trial of escitalopram in
the treatment of posttraumatic stress disorder. J Clin Psychiatry 2006; 67(10): 1522–6.
20. De Boer M, Op den Velde W, Falger PJ et al. Fluvoxamine treatment for chronic PTSD: a pilot study.
Psychother Psychosom 1992; 57(4): 158–163.
21. Marmar CR, Schoenfeld F, Weiss DS et al. Open trial of fluvoxamine treatment for combat-related
posttraumatic stress disorder. J Clin Psychiatry 1996; 57(8): 66–70.
22. Davidson JR, Weisler RH, Malik M, Tupler LA. Fluvoxamine in civilians with posttraumatic stress
disorder. J Clin Psychopharmacol 1998; 18(1): 93–5.
23. Escalona R, Canive JM, Calais LA, Davidson JR. Fluvoxamine treatment in veterans with combat-
related post-traumatic stress disorder. Depress Anxiety 2002; 15(1): 29–33.
24. Rapaport MH, Endicott J, Clary CM. Posttraumatic stress disorder and quality of life: results across
64 weeks of sertraline treatment. J Clin Psychiatry 2002; 63(1): 59–65.
25. Committee on Treatment of Posttraumatic Stress Disorder (Institute of Medicine). Treatment of
Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National
Academies Press; 2007.
26. Shalev AY, Freedman S, Peri T et al. Prospective study of posttraumatic stress disorder and depression
following trauma. Am J Psychiatry 1998; 155(5): 630–7.
27. Londborg PD, Hegel MT, Goldstein S et al. Sertraline treatment of posttraumatic stress disorder:
results of 24 weeks of open-label continuation treatment. J Clin Psychiatry 2001; 62(5): 325–31.
28. Davidson J, Pearlstein T, Londborg P et al. Efficacy of sertraline in preventing relapse of posttraumatic
stress disorder: results of a 28-week double-blind, placebo-controlled study. Am J Psychiatry 2001;
158(12): 1974–81.
29. Martenyi F, Brown EB, Zhang H, Koke SC, Prakash A. Fluoxetine v. placebo in prevention of relapse
in post-traumatic stress disorder. Br J Psychiatry 2002; 181: 315–20.
30. Foa EB, Davidson JR, Frances A. The expert consensus guidelines series: treatment of posttraumatic
stress disorder. J Clin Psychiatry 1999; 60 (Suppl 16): 3–76.
31. Stein DJ, Bandelow B, Hollander E et al. WCA Recommendations for the long-term treatment of
posttraumatic stress disorder. CNS Spectr 2003; 8(8 Suppl 1): 31–9.
32. Davidson J, Rothbaum BO, Tucker P et al. Venlafaxine extended release in posttraumatic stress
disorder: a sertraline- and placebo-controlled study. J Clin Psychopharmacol 2006; 26(3): 259–67.
33. Davidson J, Baldwin D, Stein DJ et al. Treatment of posttraumatic stress disorder with venlafaxine
extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry 2006; 63(10): 1158–65.
Pharmacotherapy of Posttraumatic Stress Disorder 125

34. Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. Duloxetine in the treatment of major depressive
disorder: a double-blind clinical trial. J Clin Psychiatry 2002; 63(3): 225–31.
35. Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. Duloxetine in the long-term treatment of
major depressive disorder. J Clin Psychiatry 2003; 64(10): 1237–44.
36. Hartford J, Kornstein S, Liebowitz M et al. Duloxetine as an SNRI treatment for generalized anxiety
disorder: results from a placebo and active-controlled trial. Int Clin Psychopharmacol 2007; 22(3): 167–74.
37. Endicott J, Russell JM, Raskin J et al. Duloxetine treatment for role functioning improvement in
generalized anxiety disorder: three independent studies. J Clin Psychiatry 2007; 68(4): 518–24.
38. Reist C, Kauffmann CD, Haier RJ et al. A controlled trial of desipramine in 18 men with posttraumatic
stress disorder. Am J Psychiatry 1989; 146(4): 513–6.
39. Davidson J, Kudler H, Smith R et al. Treatment of posttraumatic stress disorder with amitriptyline
and placebo. Arch Gen Psychiatry 1990; 47(3): 259–66.
40. Frank JB, Kosten TR, Giller EL Jr, Dan E. A randomized clinical trial of phenelzine and imipramine for
posttraumatic stress disorder. Am J Psychiatry 1988; 145(10): 1289–91.
41. Kosten TR, Frank JB, Dan E, McDougle CJ, Giller EL Jr. Pharmacotherapy for posttraumatic stress
disorder using phenelzine or imipramine. J Nerv Ment Dis 1991; 179(6): 366–70.
42. Shestatzky M, Greenberg D, Lerer B. A controlled trial of phenelzine in posttraumatic stress disorder.
Psychiatry Res 1988; 24(2): 149–55.
43. Katz RJ, Lott MH, Arbus P et al. Pharmacotherapy of post-traumatic stress disorder with a novel
psychotropic. Anxiety 1994; 1(4): 169–74.
44. Onder E, Tural U, Aker T. A comparative study of fluoxetine, moclobemide, and tianeptine in the
treatment of posttraumatic stress disorder following an earthquake. Eur Psychiatry 2006; 21(3): 174–9.
45. Davidson JR, Connor KM. Bupropion sustained release: a therapeutic overview. J Clin Psychiatry
1998; 59(4): 25–31.
46. Becker ME, Hertzberg MA, Moore SD et al. A placebo-controlled trial of bupropion SR in the treatment
of chronic posttraumatic stress disorder. J Clin Psychopharmacol 2007; 27(2): 193–7.
47. Hertzberg MA, Moore SD, Feldman ME, Beckham JC. A preliminary study of bupropion sustained-
release for smoking cessation in patients with chronic posttraumatic stress disorder. J Clin
Psychopharmacol 2001; 21(1): 94–8.
48. Stimmel GL, Dopheide JA, Stahl SM. Mirtazapine: an antidepressant with noradrenergic and specific
serotonergic effects. Pharmacotherapy 1997; 17(1): 10–21.
49. Davidson JR, Weisler RH, Butterfield MI et al. Mirtazapine vs. placebo in posttraumatic stress
disorder: a pilot trial. Biol Psychiatry 2003; 53(2): 188–91.
50. Davis R, Whittington R, Bryson HM. Nefazodone. A review of its pharmacology and clinical efficacy
in the management of major depression. Drugs 1997; 53(4): 608–36.
51. Davis LL, Jewell ME, Ambrose S et al. A placebo-controlled study of nefazodone for the treatment of
chronic posttraumatic stress disorder: a preliminary study. J Clin Psychopharmacol 2004; 24(3): 291–7.
52. McRae AL, Brady KT, Mellman TA et al. Comparison of nefazodone and sertraline for the treatment
of posttraumatic stress disorder. Depress Anxiety 2004; 19(3): 190–6.
53. Mula M, Pini S, Cassano GB. The role of anticonvulsant drugs in anxiety disorders: a critical review
of the evidence. J Clin Psychopharmacol 2007; 27(3): 263–72.
54. Post RM, Weiss SR, Smith M, Li H, McCann U. Kindling vs. quenching. Implications for the evolution
and treatment of posttraumatic stress disorder. Ann N Y Acad Sci 1997; 821: 285–95.
55. Hertzberg MA, Butterfield MI, Feldman ME et al. A preliminary study of lamotrigine for the treatment
of posttraumatic stress disorder. Biol Psychiatry 1999; 45(9): 1226–9.
56. Connor KM, Davidson JR, Weisler RH, Zhang W, Abraham K. Tiagabine for posttraumatic stress
disorder: effects of open-label and double-blind discontinuation treatment. Psychopharmacology
(Berl) 2006; 184(1): 21–5.
57. Davidson JR, Brady K, Mellman TA, Stein MB, Pollack MH. The efficacy and tolerability of tiagabine
in adult patients with post-traumatic stress disorder. J Clin Psychopharmacol 2007; 27(1): 85–8.
58. Davis LL, Davidson JR, Ward LC et al. Divalproex in the treatment of posttraumatic stress disorder: a
randomized, double-blind, placebo-controlled trial in a veteran population. J Clin Psychopharmacol
2008; 28(1): 84–8.
59. Lindley SE, Carlson EB, Hill K. A randomized, double-blind, placebo-controlled trial of augmentation
topiramate for chronic combat-related posttraumatic stress disorder. J Clin Psychopharmacol 2007;
27(6): 677–81.
60. Tucker P, Trautman RP, Wyatt DB et al. Efficacy and safety of topiramate monotherapy in civilian
posttraumatic stress disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry
2007; 68(2): 201–6.
61. Mellman TA, Clark RE, Peacock WJ. Prescribing patterns for patients with posttraumatic stress
disorder. Psychiatr Serv 2003; 54(12): 1618–21.
62. Cates ME, Bishop MH, Davis LL, Lowe JS, Woolley TW. Clonazepam for treatment of sleep disturbances
associated with combat-related posttraumatic stress disorder. Ann Pharmacother 2004; 38(9): 1395–9.
126 Ravindran and Stein

63. Braun P, Greenberg D, Dasberg H, Lerer B. Core symptoms of posttraumatic stress disorder
unimproved by alprazolam treatment. J Clin Psychiatry 1990; 51(6): 236–8.
64. Hamner MB, Frueh BC, Ulmer HG, Arana GW. Psychotic features and illness severity in combat
veterans with chronic posttraumatic stress disorder. Biol Psychiatry 1999; 45(7): 846–52.
65. Sareen J, Cox BJ, Goodwin RD, Asmundson JG. Co-occurrence of posttraumatic stress disorder with
positive psychotic symptoms in a nationally representative sample. J Trauma Stress 2005; 18(4): 313–22.
66. Charney DS, Deutch AY, Krystal JH, Southwick SM, Davis M. Psychobiologic mechanisms of
posttraumatic stress disorder. Arch Gen Psychiatry 1993; 50(4): 295–305.
67. Seedat S, Stein MB, Oosthuizen PP, Emsley RA, Stein DJ. Linking posttraumatic stress disorder and
psychosis: a look at epidemiology, phenomenology, and treatment. J Nerv Ment Dis 2003; 191(10):
675–81.
68. Philip NS, Carpenter LL, Tyrka AR, Price LH. Augmentation of antidepressants with atypical
antipsychotics: a review of the current literature. J Psychiatr Pract 2008; 14(1): 34–44.
69. Hamner MB, Robert S. Emerging roles for atypical antipsychotics in chronic post-traumatic stress
disorder. Expert Rev Neurother 2005; 5(2): 267–75.
70. Gao K, Muzina D, Gajwani P, Calabrese JR. Efficacy of typical and atypical antipsychotics for primary
and comorbid anxiety symptoms or disorders: a review. J Clin Psychiatry 2006; 67(9): 1327–40.
71. Pae CU, Lim HK, Peindl K et al. The atypical antipsychotics olanzapine and risperidone in the
treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-
controlled clinical trials. Int Clin Psychopharmacol 2008; 23(1): 1–8.
72. Butterfield MI, Becker ME, Connor KM et al. Olanzapine in the treatment of post-traumatic stress
disorder: a pilot study. Int Clin Psychopharmacol 2001; 16(4): 197–203.
73. Padala PR, Madison J, Monnahan M et al. Risperidone monotherapy for post-traumatic stress
disorder related to sexual assault and domestic abuse in women. Int Clin Psychopharmacol 2006;
21(5): 275–80.
74. Horrigan JP. Guanfacine for PTSD nightmares. J Am Acad Child Adolesc Psychiatry 1996; 35(8):
975–6.
75. Horrigan JP, Barnhill LJ. The suppression of nightmares with guanfacine. J Clin Psychiatry 1996;
57(8): 371.
76. Porter DM, Bell CC. The use of clonidine in post-traumatic stress disorder. J Natl Med Assoc 1999;
91(8): 475–7.
77. Raskind MA, Dobie DJ, Kanter ED et al. The alpha1-adrenergic antagonist prazosin ameliorates
combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases. J Clin
Psychiatry 2000; 61(2): 129–33.
78. Kinzie JD, Leung P. Clonidine in cambodian patients with posttraumatic stress disorder. J Nerv Ment
Dis 1989; 177(9): 546–50.
79. Neylan TC, Lenoci M, Samuelson KW et al. No improvement of posttraumatic stress disorder
symptoms with guanfacine treatment. Am J Psychiatry 2006; 163(12): 2186–8.
80. Raskind MA, Peskind ER, Kanter ED et al. Reduction of nightmares and other PTSD symptoms in
combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry 2003; 160(2): 371–3.
81. Raskind MA, Peskind ER, Hoff DJ et al. A parallel group placebo controlled study of prazosin for
trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder.
Biol Psychiatry 2007; 61(8): 928–34.
82. Taylor FB, Martin P, Thompson C et al. Prazosin effects on objective sleep measures and clinical
symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study. Biol Psychiatry
2008; 63(6): 629–32.
83. Hofmann SG, Meuret AE, Smits JA et al. Augmentation of exposure therapy with D-cycloserine for
social anxiety disorder. Arch Gen Psychiatry 2006; 63(3): 298–304.
84. Guastella AJ, Richardson R, Lovibond PF et al. A randomized controlled trial of D-cycloserine
enhancement of exposure therapy for social anxiety disorder. Biol Psychiatry 2008; 63(6): 544–9.
85. Kushner MG, Kim SW, Donahue C et al. D-cycloserine augmented exposure therapy for obsessive-
compulsive disorder. Biol Psychiatry 2007; 62(8): 835–8.
86. Heresco-Levy U, Kremer I, Javitt DC et al. Pilot-controlled trial of D-cycloserine for the treatment of
post-traumatic stress disorder. Int J Neuropsychopharmacol 2002; 5(4): 301–7.
87. Aerni A, Traber R, Hock C et al. Low-dose cortisol for symptoms of posttraumatic stress disorder. Am
J Psychiatry 2004; 161(8): 1488–90.
88. Zhang W, Davidson JR. Post-traumatic stress disorder: an evaluation of existing pharmacotherapies
and new strategies. Expert Opin Pharmacother 2007; 8(12): 1861–70.
89. Ipser J, Seedat S, Stein DJ. Pharmacotherapy for post-traumatic stress disorder - a systematic review
and meta-analysis. S Afr Med J 2006; 96(10): 1088–109.
10 Early interventions following traumatic
events
Jonathan I Bisson, Arieh Y Shalev, and Joseph Zohar

It is well recognized that traumatic events can cause significant psychological reactions.
However, research published in recent years has suggested that individual responses vary
greatly and range from a very limited or absent psychological reaction through to marked dis-
tress.(1, 2) Such work has convincingly challenged the notion that most individuals involved
in traumatic events experience significant distress initially that gradually reduces over time.
This trajectory appears to be one of several that can occur. Four distinct types of response
have been described (2, 3): a resilient response in which no psychological symptoms are present
shortly after the event or subsequently, a delayed response in which psychological symptoms
gradually develop over time, a prolonged response in which psychological symptoms manifest
immediately and do not reduce over time, and a recovery response in which individuals experi-
ence psychological symptoms initially that then gradually reduce over time.
Creamer et al. (2) found that around a third of individuals admitted to hospital in
Australia as a result of traumatic injury described a resilient response, a third a prolonged response,
with a sixth reporting a delayed response, and a sixth a recovery response. Creamer et al’s. results
are not entirely consistent with other studies that have found a trend for reduction of psycho-
logical symptoms over time if mean symptom levels are tracked.(4, 5) However, the Galea et
al. study concerned an entire cohort of survivors and would still accommodate Creamer’s four
subgroups, and Foa and Rothbaum (5) mainly reported on survivors with a significant initial
response, essentially limiting the possible responses to prolonged or recovery types.
There appears to be no indication to intervene with individuals who have a resilient
response but a strong indication to intervene effectively with those with prolonged responses. The
decision as to whether and when to intervene with those with a delayed or recovery response is
more challenging. If effective preventative interventions exist, these would be ideal for those
with delayed responses, if effective interventions are available that speed up recovery in the
recovery group these would be indicated. Sadly these decisions are further complicated by our
current inability to accurately predict who will follow which trajectory (6, 7, 8) and everyone
would have to be monitored longitudinally to determine this.
The development of an intervention effective at preventing the development of post-
traumatic stress disorder (PTSD) and other psychological difficulties following traumatic
events has become something of a holy grail for researchers and clinicians. Sadly the task is
proving to be difficult. Multiple attempts to develop effective interventions have now proved
unsuccessful, despite many having had excellent face validity and several being grounded in
a sound theoretical base.(9) One of the problems in many early intervention studies has been
lack of initial diagnosis and measurement of severity of symptoms, resulting in the treatment
of a mixed bag of subjects with both high and low risk of developing PTSD. Thankfully there
remains considerable energy to develop effective early interventions and more recent attempts
appear to have been helpfully informed by previous work.
Early interventions following traumatic events now represent a heterogeneous group of
approaches, delivered at a variety of different time points to various populations. They include
pharmacological interventions commenced within a few hours of the traumatic event (10),
single session psychological interventions for everybody involved within one month of a trau-
matic events (11, 12), responses directed at whole communities (13), brief psychological inter-
ventions for those with marked symptoms within one month of the traumatic event (14), and
longer psychological interventions for individuals suffering from acute PTSD between 1 and 3
months after a traumatic event.(15)
There is no single widely accepted definition of early intervention, a limited number
of identifiable candidate interventions, and an absence of information regarding the optimal
128 Bisson, Shalev, and Zohar

timing of early intervention. We have, therefore, considered the term early intervention to
include any intervention delivered within three months of a traumatic event and limited our focus
to early interventions that primarily aim to prevent or treat symptoms of acute stress disorder or post-
traumatic stress disorder.

Theoretical Models

Social, psychological, and biological models have been developed to explain the responses of
individuals following traumatic events. Early interventions address factors considered impor-
tant in all three models although, to date, the best researched interventions have primarily
focused on the psychological and biological models. The three models described below are
helpful, although when considered in isolation they may inhibit the development of more
holistic approaches to early intervention. It seems likely to us that an optimal response would
encompass social, psychological, and biological factors. Social factors such as lack of social
support and subsequent stressors may have a role as markers of those with little early response
who require follow-up or targeted social interventions.(7)

Social Models

The social model of emotional response to a traumatic event considers mental distress to repre-
sent the best coping strategy available to an individual at that time. It does not view responses
as pathological but rather as a reflection of an individual’s own coping in the context of their
situation. Social models regard the wider influence of social forces as more important than
other influences as causes or precipitants of mental illness (16) and assert that the abilities of
individuals with distress are constrained by barriers set up by others, for example, responses
to disability. The social model would consider important factors to include self-management,
advocacy, human rights, self-defined needs, community development, nonmedicalization,
education, employment, and employment support.
Treating emerging mental disorders, including PTSD, is not an inherent goal of social
models of responses to traumatic events. However, social models do address putative media-
tors of PTSD symptom trajectories following traumatic exposure. Their main thrust is to provide
individuals who were exposed to a potentially traumatic event with the kind of interpersonal
and social responses that might increase the likelihood of better adaptation, better use of social
resources, and thereby sustain the recovery in those with initial symptoms and reduce the like-
lihood of delayed responses.

Psychological Models

Unfortunately most of the current psychological models are concerned within individual fac-
tors (as opposed to between individual factors) and among those mainly ones that explain
the occurrence of PTSD, but not the occurrence of recovery. Consequently, most of the inter-
ventions that have been derived from these models address individuals (rather than groups,
families, confidants, or attachment networks), who already have symptoms, and follow the
general therapeutic model of an encounter between a professional (usually highly skilled) and
a “patient” or a “client.” Within that kind of “psychology” the following knowledge has been
gained.
The earliest psychological models were based on PTSD being a fear-based condition,
characterized by excessive response elements such as avoidance, physiological reactivity,
and a resistance to modification, for example (17). Foa and Kozak (18) built on this work to
develop a respected theory that argued for a breakdown in emotional processing following
traumatic events. Cognitive-based theories consider the importance of preexisting beliefs and
models of the world and the difficulty assimilating the information provided by a traumatic
experience into them. For example, Janoff Bullman (19) described PTSD sufferers as having
their assumptions shattered about the world being a meaningful and benevolent place.
Early Interventions Following Traumatic Events 129

Brewin et al. (20) developed the dual representation theory of PTSD, proposing that
various factors affect the outcome of emotional processing, including severity and length of
trauma, its meaning to the person, accompanying emotions such as shame and guilt, and the
availability of appropriate emotional support. The theory distinguishes between memories
that are easily verbally recalled and give rise to emotions related to the trauma and memories
that cannot be deliberately accessed and give rise to symptoms such as dreams and flashbacks.
It has received some support from recent replicated findings of reduced verbal declarative
memory in PTSD sufferers.(21) Ehlers and Clark (22) subsequently proposed a cognitive model
of PTSD in which the trauma memory has not been integrated into the context of preceding
and subsequent experience. Problematic appraisals of the trauma and/or its aftermath have
occurred with the development of dysfunctional behavior and cognitive strategies, prevent-
ing memory elaboration, exacerbating symptoms, and hindering reassessment of problematic
appraisals. They argue that PTSD develops when the traumatic memory induces a sense of
current threat promoted by excessive negative reappraisals of what happened.
Psychological models addressing interaction between individuals are badly missing, as
are those that combine the effect of traumatic fear responses with those of the often experienced
traumatic loss or grief.

Biological Models

Our understanding of the neurobiology of PTSD has undoubtedly advanced in recent years,
although many findings require further replication to confirm them. The amygdala is believed
to play a key role in the development and maintenance of PTSD. It receives information about
external stimuli and determines their emotional relevance.(23) The amygdala triggers emo-
tional responses, including the fight, flight, or freezing response, and alterations in stress hor-
mones and catacholemines. The hippocampus and medial prefrontal cortex are believed to
influence the response of the amygdala by exerting an inhibitory control over the initial alarm
responses (e.g., (24)). Hippocampal lesions have been associated with a stronger fear response,
and smaller hippocampal volumes have been associated with PTSD (25), possibly as a vulner-
ability factor for developing the disorder.(26) Decreased activity in medial prefrontal and ante-
rior cingulate areas has been found to be correlated with increased activity in the amygdala,
leading to the suggestion that PTSD represents a failure of these areas to regulate the activity of
the amygdala, which results in hyperreactivity to threat.(27) Several studies have found altera-
tion of the cortisol responses in people with posttraumatic stress disorder and an enhanced
response to the dexamethasone suppression test.(28) Increased adrenergic response to the trau-
matic event has arguably been associated with PTSD, for example (29, 30), with the suggestion
that an initial adrenergic surge may be associated with the consolidation of traumatic memo-
ries.(31) Altered cortisol levels may promote the development and symptomatology of PTSD
by disinhibiting traumatic memory retrieval and also failing to contain a sympathetic stress
response.(32) Pitman (33) suggested that a positive feedback cycle is formed with overconsoli-
dation of memories as a result of this (see Figure 10.1).
Another biological model focuses on memory and speculates about what would have
happened had we interfered with either the consolidation of traumatic emotional memory or
with the maintenance of those memories. An elegant work by Cohen, Zohar et al. (34) look-
ing at Lewis rats and comparing them to Fischer rats, looked at this more closely, providing
support for this notion (see chapter 7). They used an animal model looking at anisomycin, the
protein inhibiting consolidation, and found that, if given right after the exposure, it is associ-
ated with a reduction in the rates of PTSD-like symptoms.(34) Moreover, other interventions
that also interfere with memory consolidation were found to be effective, including galanin
administration and exploring the effect of increased cortisol secretion (intact HPA axis plastic-
ity) as an effective way to decrease the impact of memory consolidation. The potential role of
PKMzeta is being explored in a preliminary study as well.
All of the data converge to probably support the potential role in regard to early inter-
vention or manipulation of memory consolidation process (i.e., trying to prevent the consoli-
dation) as a potential tool for future early intervention in the first few hours or weeks after
trauma, assuming that it might have a potential preventive effect.
130 Bisson, Shalev, and Zohar

Positive Feedback Cycle

(after Pitman, 1989)

XS initial (UCR) or
Trauma (UCS)/
later (CR) stress
Reminders (CS)
hormone release

Overconsolidation
of memories Figure 10.1  Positive Feed­
back Cycle (after Pitman,
Too much significance leads to too much remembrance 1989).

Types of Early Intervention

Various early interventions have been developed as described above. The exact nature of the
intervention depends on several factors, not least the nature of the traumatic event. If the event
is a disaster then interventions at an organizational and community level are required, with a
focus on immediate practical and pragmatic support, the reinstatement of normal roles within
communities, and the move toward restoration of a normal social structure. Hobfoll et al. (13)
have recently published an authoritative paper in this area reviewing the limited evidence
for specific approaches but concluding that there are five empirically supported intervention
principles. These are promoting sense of safety, sense of self- and community-efficacy, con-
nectedness, calming, and hope. Other important work in this area has been produced by the
Inter-Agency Standing Committee.(35)
Early interventions that have focused on individuals or small groups of people affected by
traumatic events have been subjected to better designed trials to determine their efficacy. During
the 1980s there was a growth in attempts to offer everybody involved in traumatic events a group
or individual intervention to reduce the risk of later psychological sequelae. The most widely
quoted intervention has been that of psychological debriefing, although this term has been used to
cover such a wide range of different interventions that, without description of the actual nature of
the intervention being described, it is impossible to determine from the term psychological debrief-
ing alone what is actually meant. Since the early 1980s such interventions have been used with
groups and individuals, the majority being based either loosely or more strictly on a process origi-
nally described for use in groups of ambulance personnel called Critical Incident Stress Debriefing
(CISD).(36) This involved a seven-stage approach in which individuals were guided through a
vivid description of what actually happened; their emotional reactions at the time; and then edu-
cated about the possible consequences, how to deal with them, and where to seek further support
if necessary. It was later argued that CISD should be given as one component of a more complex
package of interventions, known as critical incident stress management (CISM).(37)
In the last decade the focus has moved from single-session interventions to more com-
plex approaches designed for all individuals involved, including CISM, trauma risk man-
agement (38), and psychological first aid.(39) These interventions have potential but have
not yet been subjected to randomized controlled trials to determine their true efficacy. More
efficacy research has been done with multiple-session psychological treatments ranging
from supportive counseling and education approaches to more formal cognitive behavioral
Early Interventions Following Traumatic Events 131

therapy (CBT) interventions increasingly targeting symptomatic individuals. (14, 15)

The CBT approaches have been trauma focused and contain various well recognized tech-
niques from effective trauma-focused cognitive behavioural therapy (TFCBT) interventions
for chronic PTSD. Most of them contain some form of prolonged imaginal exposure to the
traumatic event, in vivo exposure to feared situations, and a variable amount of cognitive
therapy techniques. The pharmacological agents tested have largely adhered to the biological
theories of the development of PTSD. For example propranolol has been used in an attempt
to reduce the adrenergic surge (10), and hydrocortisone has been used to address the lowered
cortisol hypothesis.(40)

The Efficacy of Early Interventions

Given the limited space available in a single chapter, we have restricted our assessment of the efficacy
of early interventions to randomized controlled trial research. That is not to say that some interven-
tions not described may be shown to be effective in the future or to claim that the evidence available
from randomized controlled trials is beyond criticism. Indeed much of it can be criticized when
scrutinized closely, and it is important to be cautious when scrutinizing the results, particularly with
regard to the generalizability of them across different populations than those considered.
Given the differences between the interventions and populations included in randomized
controlled trials, we have separated them into seven groups based on the categories adopted by the
United Kingdom’s National Institute of Health and Clinical Excellence Guidelines on PTSD (9):
1. Single session interventions provided to any individual exposed to a traumatic event with
the aim of preventing PTSD
Systematic reviews and meta-analyses of this data have been conducted by various groups
(41, 12) and have consistently shown that there is no convincing evidence to suggest that pro-
viding a single-session individual psychological intervention, following traumatic events, is
useful for most people. Indeed some studies have found that individual psychological debrief-
ing may exacerbate traumatic stress symptoms in some people (42), particularly those who are
most distressed.(43) Randomized controlled trials (RCTs) of group psychological debriefing
have not produced convincing evidence of its effectiveness (44, 45) but have not suggested the
possibility of a harmful effect. Indeed, a post hoc analysis found that soldiers exposed to a large
number of traumatic events may experience some benefit from group debriefing.(45) Table 10.1
summarizes the trials included in a recent systematic review.(46) A subsequent RCT that con-
sidered the distribution of an educational pamphlet shortly after attendance at an emergency
unit (47) failed to demonstrate superiority over no intervention.
2. Multiple session interventions provided to any individual exposed to a traumatic event
with the aim of preventing PTSD
Tables 10.2 and 10.3 summarize the RCTs included in the recent Cochrane Systematic
Review.(48) The only statistically significant differences found were in favor of the wait list
control group over adapted critical incident stress debriefing for self-reported PTSD symptoms
immediately postintervention, and for preventive counseling over monitoring/usual care for
self-reported PTSD symptoms immediately postintervention.
3. Multiple-session interventions begun in the first month with the aim of preventing PTSD or
ongoing distress in individuals with acute stress disorder
Tables 10.2 and 10.3 summarize the RCTs included in a recent Systematic Review. (49)
Statistically significant differences were found in favor of TFCBT over wait list and supportive
counseling, TFCBT plus anxiety management over supportive counseling, TFCBT plus hypno-
sis over supportive counseling, and TFCBT over cognitive restructuring.
4. Multiple-session interventions begun in the first month with the aim of preventing PTSD or
ongoing distress based on other risk factors
Tables 10.2 and 10.3 summarize the RCTS included in a recent Systematic Review. (49) No
statistically significant differences were found between the interventions and controls.
Table 10.1  Summary of randomized controlled trials of one-off early psychological interventions (need permission to reproduce from Guildford).
132

Main
Target Comparison Time post- Duration Outcome Effect Size Follow-up
Authors (Year) Treatment Tested Population Group Sample (n) trauma (mins) Measure Outcome (Hedges’s unbiased g) Period

Bordow & Immediate Review MVA victims Standard    70 < 1 week 60 Traumatic Social Worker Unable to 3–4 months
Porritt (1979) 3 month Social Care neurosis input fared calculate
(53) Worker input symptoms best followed
by immediate
review
Bunn & Clarke Individual Relatives of Standard    30 <12 hours 20 Composite Intervention Unable to 5 minutes
(1979) (54) Counselling seriously ill/ Care of anxiety group fared calculate
injured scores better
Hobbs et al Debriefing MVA victims Standard   106 24–48 hours 60 IES Intervention 0.21 4 months
(1996) (55) / Care group fared
Mayou et al worse
(2000) (56)
Lee et al Debriefing Miscarriage Standard    39 14 days 60 IES No significant -0.12 4 months
(1996) (57) Care difference
Stevens & Individual MVA, Assault Standard    42 <24 hours 60 IES No significant Unable to 3 months
Adshead Counselling or Dog Bite Care difference calculate
(1996) (58)
Bisson et al Debriefing Acute Burn   103 2–19 days 30–120 IES Intervention 0.22 3 months
(1997) (42) Trauma Victims group fared
worse
Conlon et al Debriefing MVA victims Advice and    40 < 14 days 30 IES No significant -0.02 3 months
(unpublished) Leaflet difference
(59)
Dolan et al Debriefing Accident and Standard    69 < 14 days 45–120 IES No significant 0.04 1 month
(unpublished) Emergency Care difference
(60) Attenders
Rose et al Debriefing Victims of Standard   105 < 1 month 60 PSS No significant Psychological 6 months
(1999) (61) Education violence Care difference debriefing vs.
standard care - 0.06.
Psychological
debriefing vs.
education – 0.24

(Continued) 
Bisson, Shalev, and Zohar
Table 10.1  (Continued)

Main
Target Comparison Time Duration Outcome Effect Size Follow-up
Authors (Year) Treatment Tested Population Group Sample (n) post-trauma (mins) Measure Outcome (Hedges’s unbiased g) Period
Campfield & Individual or small Victims of Delayed    77 < 10 hours or 60–120 PDS < 10 hours -2.56 2 weeks
Hills (2001) group debriefing robbery debriefing > 48 hours group fared
(62) better
Litz et al Group CISD Soldiers No 1,050 In Kosovopre 48–148 mins PCL No significant Unable to 9 months
(unpublished) Stress Education deployed on a Intervention redeployment Mean = 88.1 difference calculate
(44) class peacekeeping (sd 25.2)
Early Interventions Following Traumatic Events

mission mins
Sijbrandij et al Emotional Civilian No   236 11–19 days 45–60 SI-PTSD No significant Emotional 6 weeks
(in press) (63) debriefing survivors intervention (median = 15) differences. Debriefing – 0.18
Psychoeducational of various Some Educational
debriefing traumatic evidence debriefing - 0.03
events worse outcome
in emotional
debriefing
Marchand et al Ind’l debriefing Victims of an No    75 First session ? duration IES No significant Completers - 0.5 Post Rx
(2006) (64) over two sessions armed robbery intervention 2 – 22 days difference Intention to 3 months
a week apart (mean 11.21, Treat (ITT) - 0.48
sd = 6.75)
133
Table 10.2  Summary of randomized controlled trials of multiple session early psychological interventions (need permission to reproduce from Journal).
134

Time since
Intervention and trauma at start Severity T Stress Randomized (n) : Follow-up Significant
Source control conditions Population of intervention Criterion outcomes completers (n) period differences

Andre (1997) (65) Up to 6 sessions of Assaulted bus drivers At least 14 days None IES 132 : 6 months Insufficient data
CBT vs. usual care
Bisson (2003) (66) Four 60 min. sessions Physical injury from 5–10 weeks Acute psychol’l CAPS, IES 152 : 124 3 and 13 TFCBT better than
of exposure based civilian trauma distress completed to 3 months standard care at
CBT vs. standard care months 13 months only
Brom (1993) (67) Up to six sessions of Outpatient victims of Not reported None IES, TSI 738 randomized, 3 months Neutral
individual preventative MVA 151 agreed to
counselling vs. enter study : 121
monitoring group completed
Bryant (1998) (14) Five 90 min. weekly Outpatients following Mean 9.9 days Acute Stress IES, CIDI 24: 24 completed 6 months TFCBT better than
sessions of exposure MVA or industrial (CBT); 10.3 Disorder PTSD and 4 years SC
based CBT vs accident days SC module
supportive counselling
Bryant (1999) (68) Five 90 min. weekly Outpatients following Mean 10.3 days Acute Stress CAPS, IES 56: 45 completed 6 months TFCBT and TFCBT
sessions of prolonged MVA or non- sexual (exposure plus Disorder and 4 years plus AM better than
exposure or prlonged assault anx mgmt), 10.0 SC
exposure plus anxiety days (PE), 10.6
management vs. days (SC)
supportive counselling
Bryant (2003) (69) Five 90 min. weekly Outpatients with mild 2 weeks Acute Stress CAPS, IES 24: 24 completed 6 months TFCBT better than
sessions of eposure trauamatic brain injury Disorder SC
based CBT vs. om MVA or non-sexual
supportive counselling assault
Bryant (2005) (70) Six 90 min. sessions of Outpatients following Mean 15.8 days Acute Stress CAPS, IES 87: 69 completed 6 months TFCBT and TFCBT
exposure based CBT MVA or non-sexual (CBT); 13.5 Disorder and 3 years plus hypnosis better
or CBT plus hypnosis assault days (CBT- than SC.
vs. supportive hypnosis); 14.0
counselling days (SC)
Bryant (2008) (71) Five 90 min sessions Outpatient victims of Mean 22.8 days Acute Stress CAPS, IES 69 completed 6 months Exposure therapy
of exposure therapy or civilian trauma Disorder and Cognitive
cognitive restructuring restructuring better
vs. waiting list than WL. ET better
than CR
Bisson, Shalev, and Zohar

(Continued) 
Table 10.2  (Continued)

Time since
Intervention and trauma at start Severity T Stress Randomized (n) : Follow-up Significant
Source control conditions Population of intervention Criterion outcomes completers (n) period differences

Bugg (submitted)(72) One face to face Outpatient victims of 5–6 weeks Acute Stress PDS 148 randomized: 3 and 6 Neutral
and two telephone MVA, occupational Disorder 67 available to months post
sessions with a writing injury or assault initial follow-up trauma
task and information
intervention vs
information only
Echeburua (1996) (73) Five 60 min. session Female victims of 1.4 months Acute PTSD Scale of 20: 20 completed 3, 6 and 12 TFCBT better than
of exposure based rape or sexual Severity months relaxation at 12
CBT vs. relaxation assault of PTSD month f’up only
Symptoms
Ehlers (2003) (74) Twelve plus three Outpatient victims 4 months Acute and CAPS, PDS 85: 80 completed 3 and 9 TFCBT better than
90 min. sessions of of MVA chronic 12 participants months self help booklet
trauma focused CBT PTSD met criteria for and WL
or self help booklet acute PTSD and
Early Interventions Following Traumatic Events

vs. wating list were included in

this review. All
12 completed
Foa (2006) (75) Four 2 hour sessions Female victims of 20.5 days to PTSD SCID- 90: 66 completed 3 and 9 Neutral
of exposure based sexual and non- assessment symptom PTSD, months
CBT or supportive sexual assault criteria PSSI
counselling
vs. continuous
assessment.
Gamble (2005) (76) 1 session of face to Mothers following Within 72 hours None MINI-PTSD 103: 102 3 months Intervention better
face counselling and traumatic birth. completed initial than treatment as
1 session of telephone follow-up, 103 usual at 3 months
counselling lasting completed 3 only
up to 60 mins vs month follow-up
treatment as usual
Gidron (2001) (77) Two sessions of Outpatient victims of 24 hours Heart rate PDS Number 3–4 months Neutral
Memory structuring an MVA. greater than randomized
intervention vs. 95 beats per unclear: 17
supportive listening minute in completed
emergency
room.
135

(Continued) 
 136

Table 10.2  (Continued)

Time since
Intervention and trauma at start Severity T Stress Randomized (n) : Follow-up Significant
Source control conditions Population of intervention Criterion outcomes completers (n) period differences

Gidron (2007) (78) Two sessions of Outpatient victims of Within 48 hours Heart rate PDS Number 3 months Neutral
Memory structuring an MVA. greater than randomized
intervention vs. 95 beats per unclear: 34
supportive listening minute in completed
emergency
room.
Kazak (2005) (79) Three 45min sessions 38 caregivers and Median 6 days, None IES-R 38: 31 completed 2 months Neutral
of adapted CBT parents of children range 0–10 available to
and family therapy newly diagnosed days follow-up
intervention vs with cancer.
treatment as usual
Marchand (2006) (80) Two 1 hour sessions Outpatient victims 11.21 days Meet criterion SCID, IES 75: 61 available 3 months No intervention
of adapted critical of armed robbery. A1 and A2 for at 1 month better than adapted
incident stress PTSD follow-up CISD initially only
debriefing vs a no
intervention control
group
Öst unpublished (81) Sixteen 60 min. Outpatient victims of 6.8 weeks Acute PTSD CAPS, 43: 41 completed Follow-up TFCBT better
sessions of exposure violent crime. IES-R data not yet than wait list
based CBT vs. waiting available
list
Ryding (1998) (82) Two group sessions Women following Not clearly None IES 106: 100 6 months Neutral
of counselling and emergency stated, a few completed post partum
education vs caesarean section. days after
treatment as usual. giving birth
Ryding (2004) (83) Two group sessions Women following 2 months None IES 162: 147 available 6 months Neutral
of counselling and emergency at initial follow-up post partum
education vs caesarean section.
treatment as usual.

(Continued) 
Bisson, Shalev, and Zohar
Table 10.2  (Continued)

Time since
Intervention and trauma at start Severity T Stress Randomized (n) : Follow-up Significant
Source control conditions Population of intervention Criterion outcomes completers (n) period differences

Sijbrandij (2007) (43) Four 2 hour weekly Outpatient victims 40 days Acute PTSD, SI-PTSD 143: 117 4 months Neutral
sessions of exposure of civilian traumatic (some completed
based CBT vs. waiting events. participants did
list not meet the
onset criterion)
Setting Apart the Affected

Shalev et al. Twelve weekly 1.5 Adult survivors of 29.5±5.5 days Full or partial CAPS, PSS- Randomized Five (early PE and CT better
(in press) (49) hour sessions of traumatic events ASD (partial = SR PE: 72 interventions) than other groups
prolonged exposure, admitted to a ASD without CT: 52 Eight (Early
cognitive therapy, general hospital ER dissociation or WL: 120 and delayed
SSRI, Placebo, and (83% motor vehicle ASD without SSRI/PBO: 52 interventions)
waitlist accidents; 11% avoidance Completers: and fourteen
terrorist attacks; 6% criterion) PE: 53 months.
work accidents and CT: 46
other events) WL: 103
SSRI/PBO: 44
Van Emmerick Five 90 minute Outpatients following Mean of 119.40 ASD, acute IES 125: 85 No consistent TFCBT and writing
(2008) (84) sessions of exposure civilian trauma days PTSD completed point of long intervention better
based CBT, or a 66 eligible for term follow- than wait list
writing intervention vs. Or chronic this review: 47 up
waiting list condition. PTSD completed
Wagner (2007) (85) Up to six 90 Inpatients following > 4 weeks Acute PTSD PCL 8: 8 completed 3 months Neutral
min. sessions of civilian trauma post-trauma
behavioural activation
and treatment as usual
vs. treatment as usual.
Zatzick (2001) (86) Collaborative care Physically injured Within 1 month All hospitalized PCL 34: 26 completed 3 months Neutral
intervention, including hospitalized MVA & individuals
assignment to trauma assault victims.
support specialist vs
usual care
Zatzick (2004) (87) Multifaceted Physically injured Not clearly Significant PCL 121: 106 retained 1, 3, 6 and 12 Neutral
collaborative care for hospitalized MVA & stated but soon symptoms of at 1 month, 99 months
PTSD and alcohol assault victims. after admission PTSD and/or retained at 12
abuse depression months
137
138 Bisson, Shalev, and Zohar

Table 10.3  Summary of outcomes for randomized controlled trials of multiple session early psychological interventions (need
permission to reproduce from Journal).

Comparison Follow-up Trials (n) Sample (n) RR, SMD or WMD (95% CI)

Interventions within one month for all exposed to the trauma

Adapted Critical Incident Stress Post Rx 1   75 7.34 (0.04, 14.64)*
Debriefing vs Usual Care (PTSD 3 months post 1   75 5.77 (-1.03, 12.57)
symptoms self-report) trauma
Adapted Critical Incident Stress Post Rx 1   75 3.82 (0.42, 35.04)
Debriefing vs Usual Care (PTSD 3 months post 1   75 2.55 (0.24, 26.87)
diagnosis) trauma
Preventive Counselling vs Monitoring/ Post Rx 1 103 -0.64 (-1.94, 0.66)
usual care (PTSD symptoms Clinician 3 months post 1 103 -1.29 (-2.47, -0.11)*
administered) trauma
Preventive Counselling vs Monitoring/ Post Rx 2 202 1.24 (0.72, 2.13)
usual care (PTSD diagnosis) 3 months post 1 103 0.35 (0.10, 1.23)
trauma
Group counselling vs control group 6 months post 1 147 0.53 (0.25, 1.10)
(PTSD diagnosis) trauma
Group counselling vs control group 6 months post 1 147 -1.30 (-6.11, 3.51).
(PTSD symptoms self-report) trauma
Brief family intervention vs treatment as ? follow-up 1   16 -3.63 (-18.22, 10.96)
usual (PTSD symptoms self-report for
primary caregivers)
Brief family intervention vs treatment as ? follow-up 1   13 -11.20 (-33.75, 11.35)
usual (PTSD symptoms self-report for
secondary caregivers)
Collaborative Care vs Usual Care for an 1 month post 1   29 0.36 (0.09, 1.48)
inpatient service (PTSD diagnosis) trauma
4 months post 1   26 0.39 (0.10, 1.48)
trauma
Collaborative Care vs Usual Care for 1 month post 1   29 -6.60 (-15.93, 2.73) 6.40
an inpatient service (PTSD symptoms trauma 1   26 (-5.58, 18.38)
self-report) 4 months post
trauma
Interventions within one month for individuals with specific risk factors other than acute stress disorder
Memory structuring intervention vs 3 months post 1   17 0.28 (0.04, 2.02)
supportive listening (PTSD diagnosis) trauma
Interventions for individuals with acute
stress disorder
Therapist Guided Self Help plus Post treatment 1 104 1.83 (-2.57, 6.23)
Psycho-education vs Psycho-education 3 months post 1 104 1.10 (-3.80, 6.00)
only (PTSD symptoms self-report) trauma
Trauma focused CBT vs waitlist (PTSD Post treatment 1   60 -24.40 (-37.20, -11.60)*
symptoms clinician rated)
Trauma focused CBT vs waitlist (PTSD Post treatment 1   60 0.43 (0.25, 0.75)
diagnosis)
Trauma Focused CBT vs Supportive Post treatment 3 100 -21.51 (-30.24, -12.77)*
Counselling (PTSD symptoms clinician 3 months post 3   98 -21.42 (-31.42, -11.42)*
rated) - completers trauma
2–4 year post 3   76 -13.66 (-20.56, -6.77)*
trauma
Trauma Focused CBT vs Supportive Post treatment 4 142 0.41 (0.28, 0.90)
Counselling (PTSD diagnosis) - ITT 6 months post 4 142 0.40 (0.19, 0.82)
trauma
2–4 years 3 137 0.72 (0.48, 1.07)

(Continued)
Setting Apart the Affected 139

Table 10.3  (Continued)

Comparison Follow-up Trials (n) Sample (n) RR, SMD or WMD (95% CI)

Trauma Focused CBT vs Trauma Post treatment 1   29 -4.46 (-19.28, 10.36)

Focused CBT plus Anxiety 6 months post 1   26 -4.77 (-24.40, 14.86)
Management (PTSD symptoms clinician trauma
rated) – completers
Trauma Focused CBT vs Trauma Post treatment 1   29 1.40 (0.27, 4.18)
Focused CBT plus Anxiety Management 6 months post 1   26 0.67 (0.13, 3.35).
((PTSD diagnosis) – ITT trauma
Trauma Focused CBT plus Anxiety Post treatment 1   31 -17.44 (-13.12, -1.76)*
Management vs Supportive Counselling 6 months post 1   28 -25.85 (-42.61, -9.09)*
(PTSD symptoms clinician rated) – trauma
completers
Trauma Focused CBT plus Anxiety Post treatment 1   31 0.36 (0.12, 1.07)
Management vs Supportive Counselling 6 months post 1   28 0.35 (0.12, 0.99)*
(PTSD diagnosis) – ITT trauma
Trauma Focused CBT vs Trauma Post treatment 1   47 -0.22 (-11.84, 11.40)
Focused CBT plus Hypnosis (PTSD 6 months post 1   47 -0.42 (-15.65, 14.81)
symptoms clinician rated) – completers trauma
Longer ? post 1   37  -0.68 (-16.40, 15.04)
trauma
Trauma Focused CBT vs Trauma Post treatment 1   63 1.21 (0.60, 2.46)
Focused CBT plus Hypnosis (PTSD 6 months post 1   63 0.91 (0.52, 1.58)
diagnosis) – ITT trauma
Longer ? post 1   63 0.84 (0.48, 1.49)
trauma
Trauma Focused CBT plus Hypnosis Post treatment 1   45 -21.77 (-35.71, -7.83)*
vs Supportive Counselling (PTSD 6 months post 1   45 -15.49 (-31.62, 0.64)
symptoms clinician rated) – completers trauma
Longer ? post 1   34 -18.05 (-35.58, -0.52)*
trauma
Trauma Focused CBT plus Hypnosis Post treatment 1   54 0.60 (0.30, 1.18)
vs Supportive Counselling (PTSD 6 months post 1   54 0.69 (0.39, 1.19)
diagnosis) – ITT trauma 1   54 0.70 (0.43, 1.13)
Longer ? post
trauma
Trauma focused CBT vs cognitive Post treatment 1   60 -11.50 (-25.39, 2.39)
restructuring (without exposure) 6 months post 1   60 -17.70 (-32.50, -2.90)*
(PTSD symptoms clinician rated) – ITT trauma
Trauma focused CBT vs cognitive Post treatment 1   60 0.53 (0.30, 0.94)*
restructuring (without exposure) (PTSD 6 months post 1   60 0.58 (0.34, 1.00)
diagnosis) – ITT trauma
Cognitive restructuring (without Post treatment 1   60 -12.90 (-25.78, -0.02)
exposure) vs waitlist (PTSD symptoms
clinician rated) – ITT
Cognitive restructuring (without Post treatment 1   60 0.83 (0.59, 1.16)
exposure) vs waitlist (PTSD
diagnosis) – ITT
Interventions beginning within three months for individuals with traumatic stress symptoms other than acute
stress disorder
Trauma Focused CBT vs Waitlist (PTSD Post treatment 4 268 -0.54 (-1.12, 0.03)
symptoms clinician rated) – ITT 3–5 months 1   61 -1.22 (-8.05, 5.61)
post trauma
9–11 months 2   73 -0.85 (-2.49, 0.79)
post trauma
13 months 1 152 -6.01 (-12.44, 0.42)
post trauma

(Continued)
140 Bisson, Shalev, and Zohar

Table 10.3  (Continued)

Comparison Follow-up Trials (n) Sample (n) RR, SMD or WMD (95% CI)

Trauma Focused CBT vs Waitlist (PTSD Post treatment 6 455 0.81 (0.56, 1.18)
diagnosis) – ITT 3-5 months 2 141 0.64 (0.42, 0.99)*
post trauma
9–11 months 2   54 0.42 (0.03, 5.23)
post trauma
13 months 1 115 0.74 (0.36, 1.51)
post trauma
Trauma Focused CBT vs Supportive Post treatment 1   60 -1.65 (-8.36, 5.06)
Counselling (PTSD symptoms clinician 3–5 months 1   60 -2.01 (-9.17, 5.15)
rated) – ITT post trauma
9–11 months 1   60 2.51 (-4.79, 9.81)
post trauma
Trauma Focused CBT vs Supportive Post treatment 1   60 1.16 (0.78, 1.71)
Counselling (PTSD diagnosis) – ITT
Supportive Counselling vs Waitlist Post treatment 1   59 1.17 (-5.70, 8.04)
(PTSD symptoms clinician rated) – ITT 3–5 months 1   59 0.79 (-6.27, 7.85)
post trauma
9–11 months 1   59 -4.67 (-11.93, 2.59)
post trauma
Supportive Counselling vs Waitlist Post treatment 1   59 0.93 (0.61, 1.39)
(PTSD diagnosis) – ITT
Stepped collaborative care vs usual 1 month post 1 101 0.85 (0.42, 1.69)
care for an inpatient service (PTSD trauma
diagnosis) 3 months post 1 101 0.90 (0.44, 1.85)
trauma
6 months post 1 102 0.64 (0.33, 1.23)
trauma
12 months 1   95 0.73 (0.34, 1.60)
post trauma
Interventions for individuals with acute post traumatic stress disorder
Behavioural activation vs treatment as Post treatment 1    8 -18.70 (-43.41, 6.01)
usual (PTSD symptoms self-report) – ITT
Trauma Focused CBT vs Waitlist (PTSD Post treatment 3 150 -0.86 (-1.60, -0.12)*
symptoms clinician rated) – ITT 3–5 months 1   95 -0.88 (-6.52, 4.76)
post trauma
9–11 months 1   12 -33.67 (-52.77, -14.57)*
post trauma
Trauma Focused CBT vs Waitlist (PTSD Post treatment 4 193 0.56 (0.27, 1.18)
diagnosis) – ITT 3–5 months 1   95 0.85 (0.50, 1.44)
post trauma
9–11 months 1   12 0.09 (0.01, 1.35)
post trauma
Structured writing therapy vs waitlist Post treatment 1   42 -14.22 (-25.48, -2.96)*
(PTSD symptoms self-report) – ITT
Structured writing therapy vs waitlist Post treatment 1   42 0.61 (0.25, 1.47)
(PTSD diagnosis) – ITT
Trauma Focused CBT vs Relaxation Post treatment 1   20 -6.70 (-13.84, 0.44)
(PTSD symptoms clinician 6 months post 1   20 -4.30 (-9.02, 0.42)
administered) – ITT trauma
12 months 1   20 -5.50 (-10.20, -0.80)*
post trauma
Trauma Focused CBT vs Relaxation Post treatment 1   20 0.40 (0.10, 1.60)
(PTSD diagnosis) – ITT 6 months post 1   20 0.33 (0.02, 7.32)
trauma
12 months 1   20 0.20 (0.01, 3.70)
post trauma
Setting Apart the Affected 141

5. Studies beginning within 3 months, offering intervention to individuals with traumatic

stress symptoms (other than acute stress disorder (ASD))
Tables 10.2 and 10.3 summarize the RCTs included in a recent Systematic Review. (49)
The only statistically significant difference found was in favor of TFCBT over the wait list con-
trol group for PTSD diagnosis 3 to 5 months postintervention.
6. Studies offering intervention to individuals with a diagnosis of acute PTSD
Tables 10.2 and 10.3 summarize the RCTs included in the recent Systematic Review. (49)
Statistically significant differences were found in favor of TFCBT over a wait list control group
and TFCBT over relaxation but only at 12 months posttrauma. A recent RCT (49) randomized
289 individuals with acute PTSD to 12 sessions of trauma-focused prolonged exposure (PE),
trauma-focused cognitive therapy (CT), escitalopram (a selective serotonin reuptake inhibitor),
a placebo medication, or a wait list control group. Participants of the wait list started 12 sessions
of “delayed” PE, 5 months from the traumatic event. At 5 months, the PE and CT groups fared
statistically significantly better than the other three groups. The early and delayed PE groups
did not differ, 8 months after the traumatic event. The results were maintained 14 months after
the traumatic event.
7. Pharmacological interventions provided within 3 months of a traumatic event with the aim
of preventing or treating PTSD
Table 10.4 summarizes the pharmacological trials. There is no good evidence that a phar-
macological intervention can prevent the development of PTSD even in those perceived to be at
higher risk, that is, individuals with raised heart rate (10) or significant symptoms shortly after a
traumatic event.(50, 51) The limited evidence of greater reduction in symptoms and physiologi-
cal response to a trigger in the Pitman study is compromised by the higher rate of dropouts in
the propranolol group and the absence of an intention to treat analysis. A promising result was
of hydrocortisone in the Schelling et al. (40) study, but again the sample size was very small and
the extreme nature of the study group severely limits generalizability. The one RCT of medication
for acute PTSD (49) described above found no positive effect over placebo or wait list and a sta-
tistically significant inferior performance than the two trauma-focused psychological treatments
used. However, it was not sufficiently powered to examine the efficacy of escitalopram per se.
Currently, Zohar, Shalev et al. are finalizing a large study that will include 200 patients,
randomized to receive escitalopram (120mg/day for 24 weeks) or placebo, beginning within
1 month of trauma. This study is carried out in hospital emergency rooms and related to civil-
ians (mostly car accidents). This type of study will be able to give us a better indication of what
might or might not be effective.
Despite the disappointing results to date, efforts to discover pharmacological interven-
tions for PTSD should be energetically pursued, as pharmacotherapy can be dispensed to large
numbers of survivors at risk without the inherent limitations of delivering psychological thera-
pies in mass casualty disasters.(52)

Suggested Model of Care

With the information available at present, there is no good evidence to suggest that any for-
mal intervention should be recommended or made available on a routine basis to everybody
involved in a traumatic event. This has led to the majority of guidelines to be cautious in their
recommendations. They largely advise against individual psychological debriefing (9, 13), but
caution against doing nothing, and argue for the delivery of supportive practical and prag-
matic input. This will often involve basic needs such as housing, finances, food, and nutrition
in the first instance and follow a hierarchy of needs. The only good evidence for the effective-
ness for early interventions at present concerns multiple-session cognitive–behavioral therapy
interventions for acute stress disorder and acute PTSD. However, methodological issues, such
as comparing to waiting list vs. placebo and being single-blind, hamper the interpretation and
generalizability of those studies.
A pragmatic approach to early intervention grounded in the research evidence avail-
able would develop social care systems that provide basic pragmatic, practical support in a
 142

Table 10.4  Summary of randomized controlled trials of early pharmacological interventions.

Main Outcome
Authors (Year) Treatment Tested Population Sample (n) Time post-trauma Duration Measure Outcome

Schelling et al (2001) (40) Intravenous hydrocortisone Septic shock victims on 20 < 24 hours 12 days PTSS-10 HC group better than placebo
vs. placebo ITU at 31 months
Pitman et al (2002) (10) Propranolol 40mg qds vs. Emergency Unit trauma 31 <6 hours 19 days CAPS No significant dfifference at 1
placebo victims and 3 months
Mellman et al (2002) (88) Temazepam 30 mg 5 days, MVA, Assault, Industrial 22 14 days 7 days PTSD No significant difference at
15mg 2 days vs. placebo accident 6 weeks, trend in favour of
placebo
Shalev et al., in press (49) Twelve weeks of Adult survivors of traumatic SSRI: 26 29.5+/-5.5 days 12 weeks CAPS No significant differences
escitalopram (SSRI; up to events admitted to a PBO: 26 between any group at 5
20mg) placebo (PBO) and general hospital ER with WL: 120 months
waitlist (WL) control full or partial ASD
Stein et al (2007) (89) Propranolol 40mg tds vs. Physically injured 48 < 48 hours 14 days PCL-C No significant differences at 8
Gabapentin 400mg tds vs. months
placebo
Bisson, Shalev, and Zohar
Early Interventions Following Traumatic Events 143

sympathetic and empathic manner and allows follow-up and identification of trauma survivors
who need further care. Despite the absence of conclusive research, easily accessible, accurate infor-
mation that identifies normal reactions seems likely to be reassuring, encourages self-support and
social support, and attempts to identify individuals who are developing difficulties. Individuals
who are developing difficulties should be monitored and, if their symptoms do not resolve within
1 month of the traumatic event, should be offered trauma-focused cognitive-behavioral therapy.
This would usually comprise up to 12 sessions, with some sessions at 90 minutes. If individuals
do not respond to this, they should be reassessed and alternative interventions planned. By this
time an individual will probably be suffering from chronic PTSD. There is no evidence for the use
of medication as an early intervention to prevent or treat traumatic stress symptoms. However, in
cases of marked depressive responses, antidepressants can be justified.(9)

Service/Organization Implications

There is a clear need to develop services with a focus on ensuring all first responders have an
understanding of normal reactions to traumatic events; how to deal with distressed people in
a sympathetic, empathic manner; and to acknowledge the importance of practical, pragmatic
support and the lack of need for formal interventions for everybody. This means that mental
health professionals’ key role in the immediate aftermath of disaster is to prepare and provide
ongoing support and supervision to those individuals providing the immediate support. As
time goes on services need staff who are able to fully assess traumatized individuals to deter-
mine their needs and then deliver evidence-based interventions (trauma-focused cognitive-
behavioral therapy interventions with the current evidence).

Future Research Directions

There is an urgent need for further research into this area. Of particular importance is research
into early biological changes and the development of pharmacological approaches based on
these. Likewise, other trauma-focused interventions that have been shown to be effective in
chronic PTSD, in particular eye movement desensitization and reprocessing, should be sub-
jected to formal evaluation as an early intervention, particularly for symptomatic individuals.
There is also a need to develop better systems and community responses, as it appears that a
comprehensive community response and public health approach offers the best hope of reduc-
ing the overall impact of traumatic events on society.

References

  1. Bonano G, Galea S, Bucciarelli A et al. Psychological resilience after disaster: New York City in the
aftermath of the September 11th terrorist attacks. Psychol Sci 2006; 17: 181–6.
  2. Creamer M, O’Donnell ML, Parslow R. Predicting healthy adjustment resistance and resilience fol-
lowing traumatic injury. Presented at ISTSS annual conference, Baltimore; 2007.
  3. Bonanno GA. Loss, trauma and human resilience: Have we underestimated the human capacity to
thrive after extremely aversive events? Am Psychol 2004; 59(1): 20–8.
  4. Galea S, Vlahov D, Resnick H et al. Trends of probable post-traumatic stress disorder in New York
City after the September 11 terrorist attacks. Am J Epidemiol 2003; 158: 514–24.
  5. Foa E, Rothbaum B. Treating the trauma of rape: Cognitive-behavioral therapy for PTSD. New York:
Guilford Press; 1998.
  6. Bryant R. Early predictors of posttraumatic stress disorder. Biol Psychiatry 2003; 53(9): 789–95.
  7. Brewin CR, Andrew B, Valentine JD. Meta-analysis of risk factors for posttraumatic stress disorder in
trauma-exposed adults. J Consult Clin Psychol 2000; 68: 748–66.
  8. Shalev A, Freedman S, Peri T et al. Predicting PTSD in trauma survivors: prospective evaluation of self-
report and clinician-administered instruments. Br J Psych 1997; 170: 558–64.
  9. [NCCMH] National Collaborating Centre for Mental Health. Post-traumatic stress disorder: The
management of PTSD in adults and children in primary and secondary care. London and Leicester:
Gaskell and BPS; 2005.
10. Pitman RK, Sanders KM, Zusman RM et al. Pilot study of secondary prevention of posttraumatic
stress disorder with propranolol. Biol Psychiatry 2002; 51: 189–92.
144 Bisson, Shalev, and Zohar

11. Rose S, Bisson J, Churchill R et al. Psychological debriefing for preventing post traumatic stress dis-
order (PTSD). Cochrane Database Syst Rev 2005; 2: CD002946.
12. Van Emmerik A, Kamphuis J, Hulsbosch A et al. Single session debriefing after psychological trauma:
a meta analysis. Lancet 2002; 360(9335): 766–71.
13. Hobfoll SE, Watson P, Bell CC et al Five Essential Elements of Immediate and Mid–Term Mass Trauma
Intervention: Empirical Evidence. Psychiatry 2007; 70: 283–315.
14. Bryant R, Harvey A, Basten C et al. Treatment of acute stress disorder: a comparison of cognitive-
behavioural therapy and supportive counselling. J Consult Clin Psychol 1998; 66(5): 862–6.
15. Ehlers A, Clark D, Hackmann A et al. A randomized controlled trial of cognitive therapy, a self-help
booklet, and repeated assessments as early interventions for posttraumatic stress disorder. Arch Gen
Psychiatry 2003; 60: 1024−31.
16. Tyrer P, Steinberg, D. Models for Mental Disorders: Conceptual models in Psychiatry. Chichester:
John Wiley and Sons; 2003.
17. Keane T, Zimering R, Caddell J. A behavioural formulation of post-traumatic stress disorder in
Vietnam veterans. Behav Ther 1985; 8: 9–12.
18. Foa E, Kozak M. Emotional processing of fear: exposure to corrective information. Psychol Bull 1986;
99: 20–35.
19. Bullman J. Shattered Assumptions: Towards a New Psychology of Trauma. New York: Free Press; 1992.
20. Brewin C, Dalgleish T, Joseph S. A dual representation theory of posttraumatic stress disorder. Psychol
Rev 1996; 103: 670–86.
21. Brewin CR, Kleiner JS, Vasterling JJ et al. Memory for emotionally neutral information in posttrau-
matic stress disorder: A meta-analytic investigation. J Abnorm Psychol 2007; 116(3): 448–63.
22. Ehlers A, Clark DM. A cognitive model of posttraumatic stress disorder. Behav Res Ther 2000; 38: 319–45.
23. Davis M. Neural systems involved in fear and anxiety measured with fear-potentiated startle. Am
Psychol 2006; 61(8): 741–56.
24. Armony JL, LeDoux JE. How the brain processes emotional information. Ann N Y Acad Sci 1997; 821:
259–70.
25. Bremner JD, Staib LH, Kaloupek D et al. Neural correlates of exposure to traumatic pictures and
sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emis-
sion tomography study. Biol Psychiatry 1999; 45: 806–16.
26. Gilbertson MW, Shenton ME, Ciszewski A, Kasai et al. Smaller hippocampal volume predicts patho-
logic vulnerability to psychological trauma. Nat Neurosci 2002; 5(11): 1242–7.
27. Shin L, Rauch S, Pitman R. Amygdala, medial prefrontal cortex and hippocampal function in PTSD.
Ann N Y Acad Sci 2006; 1071: 67–79.
29. Yehuda R, Golier JA, Halligan SL et al. The ACTH response to dexamethasone in PTSD. Am J
Psychiatry 2004; 161(8): 1397–403.
29. Delahanty DL, Nugent NR, Christopher NC et al. Initial urinary epinephrine and cortisol levels pre-
dict acute PTSD symptoms in child trauma victims. Psychoneuroendocrinology 2005; 30(2): 121–8.
30. Videlock EJ, Peleg T, Segman R et al. Stress hormones and post-traumatic stress disorder in civilian
trauma victims: a longitudinal study. Part II: The adrenergic response. Int J Neuropsychopharmacol
2007; 11(3): 373–80.
31. Pitman RK, Delahanty DL. Conceptually driven pharmacologic approaches to acute trauma. CNS
Spectr 2005; 10(2): 99–106.
32. Pitman RK, Altman B, Greenwald E et al. Psychiatric complications during flooding therapy for post-
traumatic stress disorder. J Clin Psychiatry 1991; 52: 17–20.
33. Pitman RK. Post-traumatic stress disorder, hormones, and memory. Biol Psychiatry 1989; 26: 221–3.
34. Cohen H, Zohar J, Gidron Y et al. Blunted HPA axis response to stress influences susceptibility to
posttraumatic stress response in rats. Biol Psychiatry 2006; 59(12): 1208–18.
35. Inter-agency standing committee (IASC). IASC guidelines on mental health and psychosocial input sup-
port in emergency situations. Geneva: IASC; 2007.
36. Mitchell J. When disaster strikes…the critical incident stress debriefing process. J Emerg Med Serv
1983; 8: 36–39.
37. Mitchell J, Everly G. The scientific evidence for critical incident stress management. J Emerg Med Serv
1997; 22: 86–93.
38. Jones N, Roberts P, Greenberg N. Peer-group risk assessment: a post-traumatic management strategy
for hierarchical organizations. Occup Med 2003; 53: 469–475.
39. National child traumatic stress network and national center for PTSD. 2nd ed. Psychological First
Aid: Field operations guide; 2006.
40. Schelling G, Briegel J, Roozendaal B et al. The effect of stress doses of hydrocortisone during septic
shock on posttraumatic stress disorder in survivors. Biol Psychiatry 2001; 50(12): 978–85.
41. Rose S, Bisson J, Wessely S et al. A systematic review of brief psychological interventions (“debrief-
ing”) for the treatment of immediate trauma related symptoms and the prevention of post traumatic
stress disorder. Cochrane Library. (major revision), 2005.
Early Interventions Following Traumatic Events 145

42. Bisson J, Jenkins P, Alexander J et al. Randomised controlled trial of psychological debriefing for vic-
tims of acute burn trauma. Br J Psychiatry 2005; 171(1): 78–81.
43. Sijbrandij M, Olff M, Reitsma J et al. Treatment of acute posttraumatic stress disorder with brief cogni-
tive behavioural therapy: a randomized controlled trial. Am J Psychiatry 2007; 164: 82–90.
44. Litz B, Gray M, Bryant R et al. Early intervention for trauma: current status and future directions.
Clinical Psychology – Science & Practice 2002; 9: 112–34.
45. Adler A, Litz B, Castro C et al. A group randomized trial of critical incident stress debriefing provided
to U.S. peacekeepers. J Trauma Stress 2008; 21: 253–63.
46. Bisson JI, McFarlane AC, Rose S et al. Psychological debriefing for adults. Effective Treatments for
PTSD. In Foa E, Keane T, Friedman M et al, eds. Effective Treatments for PTSD. New York: Guilford;
2009, pages 83-105.
47. Turpin G, Downs M, Mason S. Effectiveness of providing self-help information following acute trau-
matic injury: randomised controlled trial. Br J Psychiatry 2005; 187: 76–82.
48. Roberts NP, Kitchiner N, Kenardy J, Bisson JI. Systematic review and meta-analysis of multiple ses-
sion early interventions following traumatic events. Cochrane Library; 2009, Issue 3.
49. Roberts NP, Kitchiner N, Kenardy J, Bisson JI. Systematic review and meta-analysis of multiple ses-
sion early interventions following traumatic events. Am J Psych 2009; 166: 293-301.
50. Mellman T, Clark R, Peacock W. Prescribing patterns for patients with posttraumatic stress disorder.
Psychiatr Serv 2003; 54: 1618–21.
51. Gelpin E, Bonne O, Peri T et al. Treatment of recent trauma survivors with benzodiazepines: a pro-
spective study. J Clin Psychiatry 1996; 57(9): 390–4.
52. Norris FH, Friedman MJ, Watson PJ et al. 60,000 disaster victims speak: part 1. An empirical review
of the empirical literature, 1981–2001. Psychiatry 2002; 65(3): 207–39.
53. Bordow S, Porritt D. An experimental evaluation of crisis intervention. Soc Sci Med [A] 1979; 13: 251–6.
54. Bunn B, Clarke A. Crisis intervention: an experimental study of the effects of a brief period of coun-
selling on the anxiety of relatives of seriously injured or ill hospital patients. Br J Med Psychol 1979;
52(2): 191–5.
55. Hobbs M, Mayou R, Harrison B et al. A randomised controlled trial of psychological debriefing for
victims of road traffic accidents. Br Med J 1996; 313(7070): 1438–9.
56. Mayou R, Ehlers A, Hobbs M. Psychological debriefing for road traffic accident victims: three year
follow-up of a randomised controlled trial. Br J Psychiatry 2000; 176(6): 589–93.
57. Lee C, Slade P, Lygo V. The influence of psychological debriefing on emotional adaptation in women
following early miscarriage: a preliminary study. Br J Med Psychol 1996; 69(1): 47–58.
58. Stevens and Adshead 1996 in Hobbs M, & Adshead G. Preventive psychological intervention for road
crash survivors. In: Mitchell M, ed. The Aftermath of Road Accidents: Psychological, Social and Legal
Perspectives. London: Routledge, 1996: 159–71.
59. Conlon L, Fahy T, Conroy R. PTSD in ambulant RTA victims: prevalence, predictors and a randomised
controlled trial of psychological debriefing in prophylaxis; unpublished.
60. Dolan L, Bowyer D, Freeman C et al. Critical incident stress debriefing after trauma: is it effective?;
unpublished.
61. Rose S, Brewin C, Andrews B et al. A randomized controlled trial of individual psychological debrief-
ing for victims of violent crime. Psychol Med 1999; 29: 793–9.
62. Campfield K, Hills A. Effect of timing of critical incident stress debriefing (CISD) on post-traumatic
symptoms. J Trauma Stress 2001; 14(2): 327–40.
63. Sijbrandij M, Olff M, Reitsma J et al. Emotional or educational debriefing after psychological trauma.
Randomised controlled trial. Br J Psychiatry 2006; 189: 150–5.
64. Marchand A, Guay S, Boyer R et al. A Randomized controlled trial of an adapted form of individual
critical incident stress debriefing for victims of an armed robbery. Brief Treat Crisis Interven 2006;
6(2): 122–9.
65. Andre C, Lelord F, Legeron P et al. Etude controlee sur l’efficacite a 6 mois d’une prise en charge
precoce de 132 conducteurs d’autobus victims d’agression [Effectiveness of early intervention on 132
bus drivers victims of aggressions: a controlled trial]. L’Encephale 1997; 23: 65–71.
66. Bisson JI, Shepherd JP, Joy D et al. Early cognitive-behavioural therapy for post-traumatic stress
symptoms after physical injury. Br J Psychiatry 2004; 184: 63–9.
67. Brom D, Kleber RJ, Hofman MC. Victims of traffic accidents incidence and prevention of post-trau-
matic stress disorder. J Clin Psychol 1993; 49: 131–9.
68. Bryant RA, Sackville T, Dang ST, Moulds M, Guthrie R. Treating acute stress disorder: an evaluation
of cognitive behavior therapy and supportive counseling techniques. Am J Psychiatry 1999; 156(11):
1780–6.
69. Bryant R, Moulds M, Guthrie R et al. Imaginal exposure alone and imaginal exposure with cognitive
restructuring in treatment of posttraumatic stress disorder. J Consult Clin Psychol 2003; 71(4): 706–12.
70. Bryant R, Moulds M, Guthrie R et al. The additive benefit of hypnosis and cognitive-behavioural
therapy in treating acute stress disorder. J Consult Clin Psychol 2005; 73(2): 334–40.
146 Bisson, Shalev, and Zohar

71. Bryant RA, Mastrodomenico J, Felmingham KL et al. Treatment of acute stress disorder: a random-
ized controlled trial. Arch Gen Psychiatry 2008; 65: 659–67.
72. Bugg A, Turpin G, Mason S et al. A randomised controlled trial of the effectiveness of writing as a self-
help intervention for traumatic injury patients at risk of developing post-traumatic stress disorder;
unpublished.
73. Echeburua E, de Corral P, Sarasua B et al. Treatment of acute posttraumatic stress disorder in rape
victims: an experimental study. J Anxiety Disord 1996; 10(3): 185–99.
74. Ehlers A, Clark D, Hackmann A et al. A randomized controlled trial of cognitive therapy, a self-help
booklet and repeated assessments as early interventions for posttraumatic stress disorder. Arch Gen
Psychiatry 2003; 60(10): 1024–32.
75. Foa EB, Zoellner LA, Feeny NC. An evaluation of three brief programs for facilitating recovery after
assault. J Trauma Stress 2006; 19(1): 29–43.
76. Gamble J, Creedy D, Moyle W et al. Effectiveness of a counselling intervention after a traumatic child-
birth: a randomized controlled trial. Birth 2005; 32(1): 11–9.
77. Gidron Y, Gal R, Freedman S et al. Translating research findings to PTSD prevention: results of a
randomized-controlled pilot study. J Trauma Stress 2001; 14(4): 773–80.
78. Gidron Y, Gal R, Givati G et al. Interactive effects of memory structuring and gender in preventing
posttraumatic stress symptoms. J Nerv Ment Dis 2007; 195(2): 1–4.
79. Kazak AE, Simms S, Alderfer MA et al. Feasibility and preliminary outcomes from a pilot study of
a brief psychological intervention for families of children newly diagnosed with cancer. J Pediatr
Psychol 2005; 30(8): 644–55.
80. Marchand A, Guay S, Boyer R et al. A randomized controlled trial of an adapted form of individual
critical incident stress debriefing for victims of an armed robbery. Brief Treat Crisis Interv 2006; 6(2):
122–9.
81. Ost L, Paunovic N, Gillow A. Cognitive-behavior therapy in the prevention of chronic PTSD in crime
victims; unpublished.
82. Ryding E, Wijma K, Wijma B. Postpartum counselling after an emergency caesarean. Clin Psychol
Psychother 1998; 5: 231–7.
83. Ryding El, Wiren E, Johansson G et al. Group counselling for mothers after emergency cesarean sec-
tion: a randomized controlled trial of intervention. Birth 2004; 31(4): 247–53.
84. van Emmerik AAP, Kamphuis JH, Emmelkamp PMG. Treating acute stress disorder and posttrau-
matic stress disorder with cognitive behavioural therapy or structured writing therapy: a random-
ized controlled trial. Psychother Psychosom 2008; 77(2): 93–100.
85. Wagner AW, Zatzick DF, Ghesquiere A et al. Behavioural activation as an early intervention for post-
traumatic stress disorder and depression. Cogn Behav Pract 2007; 4: 341–9.
86. Zatzick D, Roy-Byrne P, Russo JE et al. Collaborative interventions for physically injured trauma
survivors: a pilot randomized effectiveness trial. Gen Hosp Psychiatry 2001; 23(3): 114–23.
87. Zatzick D, Roy-Byrne P, Russo J et al. A randomized effectiveness trial of stepped collaborative care
for acutely injured trauma survivors. Arch Gen Psychiatry 2004; 61(5): 498–506.
88. Mellman TA, Bustamante V, David D et al. Hypnotic medication in the aftermath of trauma. J Clin
Psychiatry 2002; 63: 1183–4.
89. Stein MB, Kerridge C, Dimsdale JE et al. Pharmacotherapy to prevent PTSD: results from a ran-
domized controlled proof-of-concept trial in physically injured patients. J Trauma Stress 2007; 20(6):
923–32.
11 Traumatic stress disorders in children
Soraya Seedat

Introduction

Pediatric posttraumatic stress disorder (PTSD) is unique among disorders of childhood and
adolescence in its requirement of an etiopathogenic agent with enduring sequelae.(1) As in
adults it is characterized by a cluster of symptoms that develop in the aftermath of traumatic
events that involve actual or threatened death or injury or threat to the physical integrity of
one’s self or others. Traumatic events include physical or sexual abuse or maltreatment, road
traffic injuries, violence, war-related trauma, severe burns, and natural disasters, among oth-
ers.(1) These events are considered trauma-tic because they overwhelm a child or adolescent’s
perceived ability to cope. During the traumatic event, there is recruitment of adaptive, stress-
mediating neural systems (e.g., hypothalamic–pituitary–adrenal axis and sympathetic nervous
system) that, in turn, produces adaptive physiological, behavioral, emotional, and cognitive
responses necessary for survival.(2) By definition and according to the DSM-IV-TR, traumatic
events should evoke acute subjective reactions of intense fear, horror, or helplessness.(1, 3)
However, the DSM-IV-TR includes a qualifier for children and adolescents who may
instead show responses of disorganized or agitated behavior.(3) The DSM-IV-TR requirement
of a subjective response acknowledges that individual traumatic reactions play a crucial role in
determining the development of PTSD.
At the time that the diagnosis was first formulated more than 25 years ago(4), the ques-
tion of whether PTSD could manifest in children and adolescents was hotly debated. Since then
the multitude of studies that have emerged in parallel with subsequent iterations of the DSM
have consistently have found that the disorder can be reliably detected in preschool and school-
going children and adolescents, and that youth with chronic PTSD may have a more unremit-
ting course than adults with the disorder.(5–10) While the DSM-IV-TR has made progress in
recognizing that children and adolescents with PTSD may have different symptom patterns
compared with adults,(3) more recent studies using alternative PTSD criteria have suggested
the need for optimal diagnostic algorithms that are more developmentally sensitive, valid, and
stable for making the diagnosis in preschool children.(10, 11) This chapter provides a concep-
tual overview of PTSD in childhood—its diagnosis, epidemiology, phenomenology, psychobi-
ology, as well as current psychotherapeutic and psychopharmacologic treatment approaches.

Epidemiology

In community surveys of PTSD, prevalence rates using DSM-III-R criteria range from 0.1%
among preschool children (age range: 2–5 years)(12) to 3%–6% in older adolescents (age range:
16–22 years).(6, 13) Estimates of PTSD prevalence in children and adolescents who have expe-
rienced trauma are considerably higher with most reported rates in the order of 30% to 40%.
(1, 14–16) Consistent with this, a meta-analysis by Fletcher (16) (2003) of 34 studies of 2,697
children and adolescents found that, overall, across a wide range of trauma, 36% of children
met criteria for PTSD. Of note, the rate of PTSD did not differ markedly across age and devel-
opmental level (<7 years: 39%, 6–12 years: 33%, >12 years: 27%).
The majority of studies of PTSD have been conducted following motor accidents, sexual
abuse, natural disasters, criminal violence, burns, and war. Rates of PTSD in children and young
people (based on studies that have used DSM-III and DSM-III-R criteria) show a similar pat-
tern to those in adults. They are high following sexual abuse (48%–90%), (17, 18) violent crime
(27%–33%),(19, 20) and war (27%–33%).(21, 22) In contrast, natural disasters give rise to consid-
erably lower rates of PTSD (0%–5%).(23–26) In addition to the type of trauma, prevalence rates
148 Seedat

by a variety of other factors are to be considered, including the severity and chronicity of the
trauma; the child’s proximity to the trauma; the personal impact on the child; time lapsed since
the event; and the presence of parental psychopathology, especially parental PTSD.(1, 16)
An important and challenging issue in the trauma field involves early identification of
individuals who will later develop PTSD. Although it was initially thought that a diagnosis of
acute stress disorder (ASD) would address this challenge, studies in adults have found that
approximately three quarters of trauma survivors who meet diagnostic criteria for ASD go on
to develop PTSD; it is also true that only a minority of individuals who develop PTSD after
trauma meet criteria initially for ASD (for review).(27) Several studies have now investigated
the relationship between acute stress disorder (ASD) and longer-term PTSD in children and
adolescents. Similarly, a number of prospective studies of the predictive validity of ASD in chil-
dren and adolescents suggest that current ASD diagnostic criteria are not optimal for identifying
younger children at high risk for the development of PTSD. (10, 28–30) Bryant et al. (31) indexed
the relationship between ASD and subsequent PTSD in injured children aged 7–13 years. At
6 months posttrauma, PTSD was diagnosed in 25% of children who were diagnosed with ASD.
In terms of those children with full ASD, 33% met criteria for PTSD and 50% met criteria for
subsyndromal PTSD, while 11% of those without ASD developed PTSD. Acute stress reactions
that did not include dissociation provided better prediction of PTSD than full ASD criteria.
Similarly, a study in preschool children in the age group of 2 to 6 years and 7 to 10 years
(N = 60) exposed to motor vehicle accidents where assessments for ASD and PTSD, respec-
tively, were conducted at 2 to 4 weeks and again at 6 months using both DSM-IV criteria and
alternative criteria (i.e., reduction in the requisite number of endorsed avoidance symptoms
from 3 to 1 and removal of the DSM-IV criterion A2 concerning emotional responsiveness to
the event), found that the rate of PTSD was 10% using the alternative criteria compared with
1.7% using standard DSM-IV criteria.(10) The alternative criteria also showed better predic-
tive validity and stability over time with 69% of children diagnosed with ASD after trauma
retaining a diagnosis of PTSD at 6 months. Dalgeish et al.,(30) in a large sample of child and
adolescent road-accident survivors who were homogeneous for trauma type, found that the
acute stress disorder dissociation criterion did not have a unique role in predicting later PTSD,
indicating that the significant association between acute stress disorder and later PTSD “may
therefore simply reflect persistence or chronicity in the symptom clusters that acute stress dis-
order and PTSD have in common.” Of note, subacute stress disorder (acute stress disorder
minus dissociation) was approximately three times more sensitive in predicting PTSD than the
full acute stress disorder syndrome in the study, while the full syndrome did not incrementally
increase the ability to predict PTSD in children and adolescents.

Phenomenology of Pediatric PTSD and Acute Stress Disorder

The core symptoms of PTSD span three clusters: intrusion/reexperiencing, avoidance and
numbing, and hyperarousal (3). For each of these clusters, the DSM-IV-TR includes qualifiers
for children and adolescents although the overall number of qualifiers are few. It is noteworthy
that 8 of the 17 criteria require verbal descriptions of symptoms and feeling states.(8) Moreover,
evidence suggests that children with subthreshold symptoms who do not meet full criteria
for PTSD may experience significant levels of disability.(7) Debate, therefore, continues about
whether more distinct criteria should be applied considering that youth’s understanding and
recall of their traumatic experiences may differ substantially from adults and be colored by
developmental aspects. For example, reexperiencing symptoms (recurrent, intrusive recollec-
tions, memories, nightmares, or other senses of reliving the traumatic experience) in young
children, for which at least one symptom must be present, may comprise distressing dreams in
young children that may progress to nightmares of monsters, of rescuing others, or of threats
to the self or others, or there may be frightening dreams without recognizable content. Young
children, rather than reliving the trauma through repeated intrusive memories may reexperi-
ence the trauma through repetitive play (e.g., a child who was involved in a shooting may
repeatedly reenact shootings with a toy gun).(3) Reminders of the trauma (people, places,
activities, or situations that remind the child of the original traumatic event) may also lead to
intense psychological or physiological distress that a child may struggle to verbalize.
Traumatic Stress Disorders in Children 149

To make the diagnosis, at least three symptoms are required from the avoidance clus-
ter (efforts to avoid trauma reminders, including talking about the traumatic event or other
trauma reminders; inability to recall an important aspect of the trauma; decreased inter-
est or participation in previously enjoyed activities; detachment or estrangement from oth-
ers; restricted affect; and sense of a foreshortened future). While there is a recognition in
the DSM-IV-TR that young children may have difficulty verbalizing their internal thoughts
and feelings, the Task Force on Research Diagnostic Criteria has recommended lowering the
requirement in this cluster from three symptoms to one.(32) In addition, there may be omen
formation (i.e., a belief in the ability to foresee future untoward events) and a diminished
ability to report on psychosocial impairment (especially in younger children), and this needs
to be borne in mind during evaluation.(3)
The last cluster, hyperarousal, requires at least two symptoms (difficulty falling or staying
asleep, irritability or angry outbursts, difficulty concentrating, hypervigilance, and increased
startle reactions). Hyperarousal may present with a variety of physical symptoms in young
children, including headaches and stomachaches.(3)
All of the aforementioned symptoms cause marked distress and impairment (in at least one
important life domain) and persist for at least 1 month following trauma. In the initial month after
trauma, a diagnosis of acute stress disorder (ASD) should be considered. The major distinction
between PTSD and ASD is the latter’s emphasis on dissociative symptoms, with the DSM-IV-TR
requiring the presence of at least three of five dissociative symptoms (reduced awareness of the
surroundings, derealization, depersonalization, dissociative amnesia, and emotional numbing).
(3) Several authors have proposed the concept of subthreshold or partial PTSD, which consid-
ers that a child/adolescent may present a number of symptoms below threshold for avoidance
or hyperarousal criteria (subthreshold syndrome), or may even present without any symptom
for one or more of the reexperiencing, avoidance, or hyperarousal criteria (partial syndrome).
(33) In an investigation of children aged 7 to 19, with severe burns, who were compared with 30
nonburned subjects matched for age, sex, SES (socioeconomic status), and parents’ marital status
according to DSM-III criteria, Stoddard et al. (1989) documented that 6.7% of youth met criteria
for PTSD,(34) with children almost three times that number meeting criteria for partial PTSD;(34)
found that 50% of children exposed to community violence in an inner-city community met cri-
teria for PTSD and another 21% met criteria for partial PTSD.
In addition to PTSD and ASD, studies among traumatized children and adolescents
describe associations with a broad range of other psychopathological outcomes, in particular
mood disorders, other anxiety disorders (e.g., generalized anxiety disorder, separation anxiety
disorder), behavioral disorders (e.g., attention-deficit hyperactivity disorder, conduct disorder),
and substance use disorders.(35) For example, in a 10–year longitudinal study using a represen-
tative population sample of children aged 9, 11, and 13 years, exposure to at least one traumatic
event by age 16 was reported by 68% of youth, with 13.4% developing some posttraumatic
stress symptoms.(36) Lifetime occurrence of other mood (12.1%), anxiety (9.8%), and disruptive
behavior disorders (19.2% of youth who were exposed to trauma) was also high.(36)

Comorbidity

Adolescents with PTSD have a substantially higher risk of co-occurring disorders, both in their
lifetime and during the past year.(36, 37) Giaconia and colleagues in a community study of older
adolescents reported that four of five adolescents with PTSD met criteria for at least one addi-
tional disorder and more than two-fifths had two or more other lifetime disorders. Also, more
than 40% of adolescents with PTSD, compared with fewer than 8% of their peers, met criteria for
major depression by age 18, with PTSD usually preceding or occurring at the same age as depres-
sion for those adolescents with both disorders. In contrast, onset of alcohol dependence preceded
onset of PTSD in about a half of cases.
Developmental mental health histories of adults with PTSD were documented across the
first three decades of life in the longitudinal Dunedin Multidisciplinary Health and Development
Study: 100% of those diagnosed with past-year PTSD and 93.5% of those with lifetime PTSD
at age 26 had met criteria for another mental disorder between ages 11 and 21,(38) suggesting
that as PTSD almost always develops in the context of other mental disorders, it is crucial that
150 Seedat

research examining the etiology of the disorder take into account lifetime developmental patterns
of comorbidity. Adolescents with PTSD also face social, academic, cognitive, and emotional dif-
ficulties and are at an increased risk of suicidal thoughts and attempts.(36, 37)

Neurobiology

Developmental differences in the neurobiological underpinnings of PTSD across the life cycle have
also raised questions about whether PTSD is the same or different disorder in children compared
with adults. The disorder is thought to be associated with a range of complex psychobiological
disturbances, involving multiple neurotransmitter and neuroendocrine systems(see other chap-
ters in this volume). Both the hypothalamic–pituitary–adrenal (HPA) axis and locus ceruleus/
norepinephrine/ sympathetic nervous system are critical in the physiological response to trauma.
Neuroendocrine investigations in adults have yielded findings of low-, normal-, and even high-
circulating plasma levels of cortisol and both high and low urinary cortisol levels.(39) A recent sys-
tematic review and meta-analysis of basal cortisol levels in adults with PTSD found no systematic
difference in basal cortisol levels between people with PTSD and controls.(40) However, in sub-
group analyses assessing plasma or serum, significantly lower levels were observed in people with
PTSD than in controls not exposed to trauma. Lower levels were also found in people with PTSD
when females were included, in studies on physical or sexual abuse, and in afternoon samples. The
results of this meta-analysis suggest that low cortisol levels do not relate to PTSD in general but
rather seem to mirror trauma exposure and PTSD subgroups. Similar to the findings in adults, stud-
ies of the psychobiological profile of PTSD in youth have produced mixed results. Methodological
differences across studies, including differences in assessment of PTSD, differences in the age range
and gender ratio, the length of time lapsed since the trauma, and timing and source (plasma versus
urine) of cortisol measurement, may be contributory to these discrepancies.(39)
One of the best replicated neuroanatomical abnormalities in adults with PTSD is hip-
pocampal volume reduction. The hippocampus, a structural component of the limbic system,
has a key role in memory processing, and a growing body of work suggests that the secretion
of glucocorticoids during traumatic stress can have neurotoxic effects on the hippocampus.(41,
42) Increased level of glucocorticoids have also been documented in children with histories of
maltreatment and PTSD.(43, 44) Further, it has been hypothesized that the putative neurotoxic
effects of glucocorticoids may vary according to a number of factors, namely, (i) the develop-
mental stage of the hippocampus, (ii) the amount and sustainability of cortisol released, and
(iii) the severity and/or the chronicity of the trauma/s.(45) However, pediatric studies have
failed to document hippocampal volume reductions in children and adolescents (46–48) and
have instead found either no differences in hippocampal volume between PTSD and controls
or larger hippocampal volumes. This suggests that smaller hippocampal volumes may be the
result of longstanding neuro­developmental experiences of traumatic stress, such that chronic
and/or cumulative exposure of stress during childhood may be necessary for hippocampal
damage. This is in keeping with the developmental model of PTSD that De Bellis has pro-
posed, namely, that childhood trauma may result in perturbations of biological stress response
systems resulting initially in elevated corticotrophin-releasing hormone (CRH) release and
increased secretion of cortisol. Over time, elevated levels of cortisol in the central nervous sys-
tem can exert neurotoxic effects on the developing brain and possibly explain the hippocampal
and other brain structural and functional abnormalities that occur in PTSD.(43) With enhanced
negative feedback inhibition of the HPA axis, there is eventually a lowering of basal cortisol.
Thus, the clinical features characteristic of PTSD may be attributed to cortisol dysregulation
that, in turn, fails to shut down the catecholaminergic response in limbic structures. Resulting
prolonged increases in noradrenergic activity could, in turn, lead to an overconsolidation of
traumatic memories that underlie the intrusive and avoidance symptoms seen in PTSD.(49)
Consistent with the theory that volumetric abnormalities of the hippocampus may rep-
resent a biological marker of chronic stress, a small pilot longitudinal study of children with
a history of maltreatment (N = 15) found that PTSD symptoms and cortisol levels at baseline
were associated with changes in hippocampal volume over a 12–18-month period.(45) Several
studies in children have also noted reductions in cerebellar (50) and corpus callosal (46, 47)
volumes. Consistent with this finding, Jackowski et al. (51), using diffusion tensor imaging
Traumatic Stress Disorders in Children 151

(DTI; a relatively new technique that provides information on white matter coherence and
myelination) in maltreated children with PTSD, found reduced fractional anisotropy (a mea-
sure of water diffusion) in medial and posterior corpus callosal regions. However, whether
the corpus callosal disturbances are a function of the disorder (PTSD) or of the trauma per se
(maltreatment) is questionable, as the study did not include matched trauma-exposed chil-
dren without PTSD. Further investigation of the effects of trauma on corpus callosal and corti-
colimbic circuit abnormalities appears to be a promising avenue for better understanding the
etiopathophysiology of pediatric PTSD.(51)
Relatively few studies in children have examined posttraumatic catecholamine secretion.
In one prospective study of children and adolescents hospitalized for motor vehicle accidents,
significantly elevated plasma noradrenaline concentrations were demonstrated in children with
PTSD at 1 and 6 months after the accident compared to non-PTSD and control groups. In contrast,
evening salivary cortisol concentrations normalized at 6 months, although these concentrations
were elevated at the 1-month time point.(52) Moreover, the higher noradrenaline concentrations
at 6 months were independent of severity in the PTSD group. The authors hypothesized that
elevations in nordadrenaline at 6 months may reflect a persistence of PTSD rather than be a
marker of severity. De Bellis et al. (43) in an investigation of catecholamine and cortisol levels in
prepubertal children with PTSD secondary to past child maltreatment experiences found that
children with PTSD had higher levels of urinary norepinephrine and dopamine levels than both
children with overanxious disorder and controls, higher urinary epinephrine levels than children
with overanxious disorder and higher cortisol levels than normal controls.
Of note, the majority of children with PTSD had comorbid psychopathology, including
mood, anxiety, behavioral, and dissociative symptoms. The confounding biological effects
of comorbidity in PTSD have, to date, received little attention and warrants further study.
Preliminary investigations in adults have reported higher evening salivary cortisol levels in
adults with PTSD comorbid with depression compared with those with only PTSD and only
depression,(53) and higher norepinephrine levels in patients with PTSD and depression than
in patients with only PTSD or normal controls.(54)

Risk and Resilience

As not all children who are trauma-exposed develop PTSD, there has been considerable empha-
sis in recent years on identifying mediating and moderating variables that interact in the onset
and persistence of the disorder. Major questions in the field are, “What characteristics determine
which children/adolescents will thrive in the face of trauma?” “What are the inherent charac-
teristics that underpin the ability to cope with trauma?” The term resilience is widely used as an
“umbrella” term in the trauma context and, in general, typifies those children and adolescents
who experience trauma but who do not go on to develop PTSD. It is not possible to talk about
resilience without talking about vulnerability or risk. Resilience is multidimensional and modifi-
able and is determined by a variety of neurobiologic, genetic, temperamental, and environmen-
tal factors that confer protection in the face of risk.(55) The first community-based prospective
study to follow up children into adulthood and to examine the extent to which potentially mal-
leable individual-level factors measured in childhood could account for the risk of exposure to
traumatic events and the risk of PTSD development after exposure (56) found that youth with
high levels of depressive and anxious feelings in first grade were 1.5 times more likely to expe-
rience PTSD once exposed to trauma, while those with high teacher ratings of aggressive/dis-
ruptive problems soon after entry into the first grade were more likely to experience traumatic
events involving assaultive violence but not after other types of traumatic events.
A number of risk factors for childhood PTSD following trauma exposure have been iden-
tified. These include female gender, previous trauma exposure, the presence of a preexisting
psychiatric disorder (particularly an anxiety disorder), parental psychopathology, and the lack
of social support.(35) Girls have consistently been found to report more PTSD symptoms than
boys following exposure to a wide variety of traumas and may, in fact, be up to six times
more likely to meet criteria for PTSD than boys after major trauma.(6, 37, 57) It has been sug-
gested that girls’ higher risk of trauma exposure may, in part, be explained by the age at which
trauma occurs, in that females have higher rates of PTSD after trauma exposure in childhood
152 Seedat

compared with exposure after the age of 15 years.(58) Other factors that may be contributory
to females’ higher risk for PTSD are the type of trauma (particularly sexual violence), differ-
ences in neuroendocrine responses to stress, and heightened peritrauma perceptions of threat
or uncontrollability.(58) In terms of the traumatic event itself, level of exposure to dangerous
events predicts risk for later PTSD, with this association found for almost all types of trauma.
However, the nature and severity of injury have most often been found to be unrelated to
both acute and persistent PTSD.(59) Heightened arousal (and increased noradrenergic activity)
in the immediate aftermath of trauma, in the form of elevated heart rate, also appears to be
related to later PTSD outcome in injured children.(58) In a study that investigated the extent to
which heart rate levels soon after a traumatic event (as measured during emergency medical
services transport) predicted PTSD symptom severity assessed at 6 weeks and 6 months later
in child trauma victims, Nugent et al. (60) found that heart rate had the strongest relationship,
among other factors, to subsequent PTSD symptoms.
Children who live in social situations characterized by a high degree of social disruption
are at higher risk of developing PTSD. In contrast, “protective” factors such as social sup-
port, low levels of parental PTSD, and low levels of parental trauma-related distress have been
shown to predict lower levels of PTSD symptoms in children. There is mounting evidence that
parental PTSD is a risk factor for childhood PTSD. Children of Holocaust survivors with PTSD
have a higher prevalence of PTSD and lower cortisol excretion than demographically matched
control subjects.(61) A study that examined how parental responses following pediatric injury
might influence children’s posttraumatic stress responses found that parental posttraumatic
stress symptoms (PTSS) significantly predicted symptomatology in the child.(60) Furthermore,
there was an interaction between the child’s initial physiological reactivity and parental symp-
toms of posttraumatic stress. High levels of parental PTSS were especially deleterious for
children who excreted low levels of cortisol soon after their accident, whereas parental PTSS
were less relevant for children with high levels of initial cortisol. Similarly, high parental PTSS
were associated with greater child PTSS in children with low in-hospital heart rate (HR). Thus,
these results suggest that children who are not identified on the basis of their initial biological
responses as being at increased risk for developing PTSS may still develop PTSS, on the basis
of their parents’ response to the traumatic event. There is some indication that the effects of
parental PTSD may stem from early in utero effects and fetal programming of the HPA axis in
that data from a group of mothers and babies exposed to the September 11 attacks showed that
both mothers and babies of mothers who developed PTSD in response to September 11 had
lower cortisol levels compared with mothers and their babies who did not develop PTSD.(62)
Converging evidence from mainly twin and family studies supports the role of genetic influ-
ences in the vulnerability to PTSD. Molecular studies in adults, namely, candidate gene association
studies, have now identified associations with genes involved in various neurotransmitter pathways,
including dopamine (dopamine receptor -2 gene [DRD2], dopamine transporter gene [DAT]) and
serotonin (serotonin transporter gene [SLC6A4]). However, these studies are limited by their cross-
sectional nature and the relative paucity of information they yield regarding the underlying biologi-
cal dysregulations in PTSD.(63) Of interest is a study in medically injured children that examined
genetic polymorphisms in the FKBP5 gene, an HPA axis gene that regulates glucocorticoid receptor
gene activity. The authors noted a significant association between two polymorphisms of FKBP5 and
peritraumatic dissociation.(64) Very recently, four polymorphism of the same gene were found to
interact with the severity of child abuse in a sample of adults as a predictor of adult PTSD symptoms.
(65) Another promising approach to the identification of the genetic underpinnings of PTSD is gene
expression profiling of peripheral blood mononuclear cells.(66) Preliminary findings in adults indi-
cate that signature patterns of gene expression may enable early identification of trauma survivors
who go on to develop PTSD. These results are encouraging and pave the way for further investigation
of the predictive value of gene expression signatures in child trauma survivors.

Assessment

Accurate and thorough assessment of traumatized children and adolescents with PTSD is cru-
cial for the implementation of any appropriate intervention. However, information relating to
trauma exposure may not be spontaneously volunteered, and consequently, PTSD symptoms
Traumatic Stress Disorders in Children 153

may easily be missed. Moreover, youth with PTSD often carry other diagnoses (e.g., major
depression), making it difficult for clinicians to distinguish PTSD from overlapping symptoms.
Distinguishing youth with exposure to single discrete traumatic events from those with expo-
sure to chronic or pervasive trauma is also important, as youth with the former tend to present
with less complex symptomatology and are usually more responsive to treatment. Exposure
to repeated and pervasive trauma, also known as complex or developmental trauma, refers to
the cumulative effect of simultaneous or sequential occurrence of different forms of abuse and/
or maltreatment (e.g., physical abuse, sexual abuse, emotional abuse and neglect, witnessing
domestic violence).
Historically, measures and interviews designed for adults have been adapted for youth
by simplifying language and concepts.(67) While many of these are in existence, few are
based on DSM-IV criteria, standardized, and well validated. Arguably, with the exception of
the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA), there is no
widely accepted “gold” standard measure for making the diagnosis and/or assessing treat-
ment effects. The American Academy of Child and Adolescent Psychiatry (1) advocates for a
multiinformant approach to assessment. The level of agreement between child and parent (or
guardian) may be poor for PTSD and for ASD;(68) however, informants other than the child
may yield potentially valuable sources of information. In fact, Scheeringa et al. (69) found that
combined parent–child reports yielded significantly more symptoms and higher rates for reex-
periencing, avoidance, and hyperarousal criteria (almost a twofold increase) and for the overall
diagnosis of PTSD (37.5%) than parent report alone (4.2%). The almost ninefold increase in
diagnosis from combined reports suggests that the diagnostic rates for children who are unable
to endorse symptoms themselves may greatly underestimate the true numbers.
In addition to enquiring about the presence of PTSD symptoms, both child and parent
should be asked about symptom severity and functional impairment. Assessment should fur-
ther focus on family factors, in particular the response of the parents to the trauma and the
ability of the parents to communicate with the child and support and enhance coping, and the
impact of the trauma on the functioning of the family unit.(70) There are several challenges to
the assessment of PTSD in youth and these include the following:
(i) Assessment of multiple trauma—many measures require the child/adolescent to report on
a variety of traumatic events but only one traumatic event (either the most bothersome or
the most recent) is used as a basis for assessing current PTSD symptoms;
(ii) Difficulty in determining the nature and extent of certain traumatic experiences (e.g., expo-
sure to domestic violence);
(iii) Uncertainty about the suitability and utility of many of the assessment instruments across
multinational and multiethnic settings;
(iv) Optimal integration of information from multiple informants (e.g., self-report measures
may do well to capture internalizing symptoms; however, parents are often more reliable
informants about behavior and externalizing symptomatology) and optimal integration of
multimodal data points, namely, emotional, behavioral, physiological, genetics data.(67)
Measures for the assessment of trauma currently in use can be divided into four main
domains:
(i) Child/adolescent self-report measures that screen for a history of trauma exposure only
(e.g., Childhood Trauma Questionnaire, Survey of Exposure to Community Violence);
(ii) Child/adolescent self-report measures that screen for PTSD symptoms (Children’s Impact
of Traumatic Events-Revised [IES-R]),(71) Trauma Symptom Checklist for Children (72),
Child PTSD Symptom Scale (CPSS; 73), Child Post-Traumatic Stress Disorder Reaction
Index (CPTSD-RI; 74);
(iii) Child and adolescent clinician-administered diagnostic interviews that screen for both
trauma exposure and PTSD (Clinician-Administered PTSD Scale for Children and
Adolescents [CAPS-CA]; (75)), Kiddie Schedule for Affective Disorders and Schizophrenia
(K-SADS; (76)), Diagnostic Interview for Children and Adolescents- Revised (DICA-R;
(77)). The CAPS-CA is a semistructured comprehensive clinical interview intended for
children/adolescents aged 8 to 18 years . It is modeled on the adult CAPS, comprises 32
items, and evaluates trauma exposure, makes diagnoses of current and lifetime PTSD,
154 Seedat

and assesses symptom severity. The K-SADS is similarly a semistructured interview for
children/adolescents aged 6 to 18 years that, in addition to assessing for present and life-
time PTSD, provides diagnoses on a range of other psychiatric disorders;
(iv) Child/adolescent self-report measures that screen for associated symptoms, for example,
dissociation and resilience (e.g., Adolescent Dissociative Experiences Scale [A-DES], (78);
Connor-Davidson Resilience Scale [CD-RISC], (79)). The A-DES is a 30-item self-report
measure of a variety of dissociative experiences for youths aged 12 to 18 years that may
be useful in examining dissociative experiences and psychopathological dissociation in
clinical and nonclinical samples of adolescents.(80) The CD-RISC, a 25-item self-report
measure with sound psychometric properties may also be useful in clinical and research
settings, as well as in investigations of the neurobiology of resilience and in the assessment
of interventions to enhance resilience. However, there is limited data on its use in children
and adolescents and on its use across different cultures.(55, 81)
No single measure is ideally suited to every child and situation. Self-report measures usu-
ally take a shorter time to administer than clinician-administered instruments. Instruments also
differ with respect to the PTSD symptom “time frame” that they measure (i.e., 1 week, 1 month).
Ultimately, the choice of instrument will depend on the context and the purpose for which it is
being used (whether research or clinical), its psychometric properties and user friendliness, the
age of the child being assessed, its validation across cultural settings, and cost and accessibility
(for comprehensive reviews see (79, 82)). In very young children, elicitation of information could
also be aided by a variety of verbal and nonverbal strategies, including storytelling, drawing,
play, and the use of dolls and toys.(70)
Other psychiatric and medical conditions may mimic the symptoms of PTSD and these
need to be ruled out. For example, avoidant symptoms (social withdrawal and emotional
numbing) and hyperarousal symptoms (sleep difficulties, irritability) may mimic major depres-
sive disorder. Similarly, PTSD can be mistaken for another anxiety disorder, including general-
ized anxiety disorder, social anxiety disorder, or obsessive compulsive disorder, because of the
overlap of symptoms such as irritability, physiological and psychological hyperarousal upon
reexposure to feared stimuli, sleep problems, hypervigilance, increased startle reaction, and
avoidance. PTSD can be misdiagnosed as an alcohol or drug use disorder, as alcohol and/or
drugs may be used by youth as self-medication to produce affective dulling and as a means
of avoiding trauma reminders. PTSD should also be differentiated from a psychotic disorder,
which it can mimic through symptoms such as flashbacks, hypervigilance, paranoia, sleep
difficulties, restricted affect, and/or social withdrawal. Lastly, a number of general medical
conditions (e.g., asthma, epilepsy, migraine, hyperthyroidism) and medications (e.g., steroids,
antiasthmatics, diet pills, antihistamines) may mimic some of the symptoms of PTSD.

Treatment

Practice parameters developed by the American Academy of Child and Adolescent Psychiatry
(1), which are in the process of being revised, advocate for a multimodal prevention–intervention
approach. This encompasses triage for trauma-exposed children by strengthening coping skills
for any anticipated trauma responses and grief reactions and treatment of acute and chronic
PTSD and other disorders that may develop in the aftermath of trauma. One of the first steps
in management is education of the child and parent/s about the disorder. This should be done
in consultation with the relevant primary care physician/s and school personnel. Inclusion of
parents in treatment is important for symptom resolution and allows parents to monitor their
child’s symptoms, learn behavior management techniques, and work with their own emotional
distress related to the trauma. The choice of treatment modality for a given child will depend on
(i) symptom severity and associated impairment, (ii) presence of comorbid conditions and asso-
ciated risk factors, (iii) developmental age and cognitive functioning of the child, (iv) treatment
preference of the child/parents, and (v) availability and affordability issues. In the main, inter-
ventions comprising psychotherapy (including trauma-focused cognitive–behavior therapy and
family therapy) and pharmacotherapy are widely used. The AACAP guidelines (1) recommend
that treatment of mild PTSD should begin with psychotherapy.
Traumatic Stress Disorders in Children 155

1. Psychotherapies
Trauma-Focused Cognitive–Behavior Therapy (CBT) and CBT
There are now several validated models of psychotherapy in use for childhood PTSD. Individual
trauma-focused cognitive–behavior therapy (TF-CBT) has the best empirical evidence as a benefi-
cial treatment for child and adolescent PTSD. Several rigorous controlled trials of TF-CBT and CBT
have examined efficacy in children 3 to 17 years of age, in various trauma contexts (particularly in
sexually abused children), with symptoms ranging from PTSD to other anxiety, mood, and behav-
ioral disorders.(35) In general, TF-CBT interventions include the following components: psychoe-
ducation, parenting skills, relaxation (e.g., progressive muscle relaxation, focused breathing), affect
awareness and regulation (e.g., identification of emotions, positive self-talk), cognitive restructur-
ing (recognizing the relationship between thoughts, feelings, and behaviors, correcting irrational
thoughts), trauma narrative (developing a narrative of the traumatic events), in vivo graded expo-
sure, conjoint child–parent sessions, and planning for future safety and development.
In a large multisite study, Cohen et al. (83) compared TF-CBT with child-centered therapy
(CCT). Children aged 8 to 14 years and their primary caretakers were randomly assigned to
either of the aforementioned treatments, which consisted of 12 weekly sessions of 45 minutes
for the child individually and 45 minutes for the parent, although 3 of the weekly sessions
involved 30 minutes of joint parent–child therapy. All of the children had significant symptoms
of PTSD, with 89% meeting full PTSD criteria. Specific elements of TF-CBT included skills in
emotional expression, training in coping skills, gradual exposure, cognitive processing of the
trauma, some psychoeducation, joint parent–child sessions, and parent management skills.(83)
CCT was supportive in nature, allowing the child or parent to guide the structure and content
of their own treatment, whereby children were encouraged to formulate their own personal
strategies for change. At treatment follow-up, children who received TF-CBT exhibited signifi-
cantly greater improvements on measures of PTSD, depression, behavior problems, and associ-
ated symptoms (abuse-related attributions and shame) than those who received CCT.
King et al. (84) randomly assigned 36 sexually abused children and adolescents to indi-
vidual CBT, family CBT, or a wait-list control condition and found that children in both active
conditions had a significantly superior response in PTSD symptoms and self-reports of fear and
anxiety compared with the wait-list condition. In a study to assess the durability of TF-CBT,
82 sexually abused children aged 8 to 15 years who were assigned to TF-CBT or nondirective
supportive therapy (NST) delivered over 12 sessions were followed up over 12 months. Among
the 49 treatment completers, children in the TF-CBT group had significantly greater improve-
ment in PTSD, dissociative symptoms, depression, and social competence than children who
received NST.(85) Similarly, Kolko (86) randomly assigned 55 physically abused or physically
maltreated youth to one of three conditions: individual child and parent CBT, family therapy
(FT), or routine community services (RCS). CBT was similar in format to TF-CBT used in other
studies. CBT and FT were composed of twelve 1-hour sessions per week, while the total dura-
tion of RCS varied but involved more weekly therapist contact hours than the other two condi-
tions. CBT produced significantly greater improvement than both FT and RCS on measures of
externalizing symptoms, conflict, and global assessment of functioning.
At least two studies provide support for the efficacy of school-based CBT for children who
are similarly exposed to traumatic events.(87, 88) In one of these, Stein et al. (2003) randomized
sixth-grade students who were exposed to community violence and experiencing posttraumatic
stress symptoms to either Group Cognitive-Behavioral Intervention (CBITS) or a 3-month wait-list
control condition. Components of CBITS included psychoeducation, graded exposure (e.g., writing,
drawing), cognitive and coping skills training (e.g., thought stopping, relaxation), and social skills
training, with 10 weekly group session (5–8 students). CBITS compared with wait listing produced
significant improvements in PTSD symptoms, depression, and psychosocial function. Treatment
gains on all measures were maintained at the 6-month follow-up in CBITS-treated youth. In the first
cluster randomized trial of a school-based intervention for children exposed to armed conflict in a
low-income setting in Indonesia, 15 sessions of a manualized group intervention administered by
paraprofessionals was compared with a wait-listed condition.(89) The intervention, over 5 weeks,
integrated CBT techniques (trauma-processing activities) with cooperative play and creative-
expressive exercises (drama, dance and music). Girls benefited more from the intervention than
boys, with reductions in PTSD symptoms and improvements in hope and functioning.
156 Seedat

Although data are few, there is some emerging evidence that TF-CBT may be efficacious
in youth exposed to complex trauma. Feather and Ronan (90) assessed a manualized, 16-
session TF-CBT in four youth aged 9 to13 years who were multiply traumatized (exposed to
childhood physical abuse, childhood sexual abuse, emotional abuse, interpersonal violence,
and domestic violence). All four children reported a decrease in PTSD symptoms and an
increase in coping posttreatment.
In a meta-analysis of 21 psychosocial treatment studies for pediatric PTSD, TF-CBT met well-
established criteria for efficacy; school-based CBT met criteria for probably efficacious, and other treat-
ments (including CBT, EMDR, family therapy, and child–parent psychotherapy) met criteria for
possibly efficacious.(91) Specifically cognitive–behavior grounded therapies were superior to non-
cognitive behavior therapies in reducing posttraumatic stress symptoms, depression anxiety, and
externalizing behavior problems. However, studies of the relative efficacy of different modalities
(i.e., individual vs. group) and dismantling studies of the critical components of treatment (e.g.,
exposure vs. cognitive restructuring) are needed.(92) Treatment studies suggest that 12 sessions
of TF-CBT is acceptable in children and adolescents with uncomplicated PTSD, although a small
number of children and adolescents may require longer-term treatment. The child/adolescent’s
response to therapy will determine the timing and pacing of sessions. As far as possible, an integrated
approach should be adopted in the treatment of any comorbid conditions (e.g., major depression,
substance abuse).

Eye Movement Desensitization and Reprocessing (EMDR)

EMDR is possibly an efficacious treatment in children and adolescents with PTSD (91), although
the majority of studies to date have had serious methodological shortcomings. A group of
6- to 16-year-old children (N = 33) with a DSM-IV diagnosis of PTSD were randomly assigned
to 8 weekly EMDR sessions or to a wait list group. Posttreatment scores of the EMDR group
were significantly lower than the wait-list group, with improvement in reexperiencing symp-
toms the most significant between-group difference over time (Ahmad et al. 2007). Relative
efficacy of CBT and EMDR was compared in a study in 12-13-year-old sexually abused girls
who were randomly assigned to receive up to 12 sessions of either treatment. Both treatments
produced significant improvement in PTSD symptoms and general behavior although EMDR
produced faster improvements. However, interpretation of these findings are limited by the
small sample (N = 14). Another non-CBT study compared individual brief psychoanalytic
therapy with group therapy that included a psychoeducational component.(93) The authors
reported substantial improvements in both treatment groups, although the individual brief
psychoanalytic condition led to a greater improvement in PTSD symptoms. However, as the
individual therapy condition consisted of 30 weeks while the group treatment received 18 ses-
sions, results may be confounded by the difference in treatment dose.

Prevention of PTSD and Early Identification of At-Risk Youth

Although widely used, the preventive benefits of single-session psychological interventions
(e.g., psychological debriefing) in adults are controversial. Psychological debriefing may inter-
fere with the natural course of adjustment and recovery by sensitizing the child to trauma
reminders without providing ample opportunity to process the experience and, in so doing,
produce negative outcomes.(94) Current evidence does not support the role of single-session
debriefing as a routine early intervention for children of any age. Stallard et al. (95) com-
pared single-session debriefing with supportive talk in children aged 7 to 18 years involved
in motor vehicle accidents. Interventions were initiated within 2 weeks of the accident occur-
ring. Although children in both groups made significant improvements on measures of PTSD
severity, depression, and anxiety at the 8-month follow-up assessment, it was unclear whether
the improvements were better or worse than what might have been expected from natural
recovery rates. In contrast, TF-CBT has been shown to be an effective early intervention 1 to
6 months posttrauma for symptomatic children, although its beneficial effects as a very early
intervention in the first 4 weeks posttrauma has yet to be demonstrated.(96) Coupled with
this is the issue of early screening. Empirically supported triage for psychological referral and
intervention in acute trauma settings is consistent with current thinking about prevention prac-
tices. For example, the STEPP (Screening Tool for Early Predictors of PTSD) is a triage screening
Traumatic Stress Disorders in Children 157

tool that was developed for use in acute care settings to alert clinicians to injured children and
their parents who are at high risk of posttraumatic stress. Its brevity (4 dichotomous questions
asked each of the child and parent and 4 readily available pieces of information from medi-
cal records), simple scoring rule, and excellent psychometric properties make it suitable for
administration in acute care settings.(97, 98)

2. Pharmacotherapies
Currently, little is known about the effectiveness of pharmacotherapeutic agents in pediatric
PTSD, and there are few controlled studies to make firm pharmacological treatment recommen-
dations. The NICE guidelines state that drug treatments should not be routinely prescribed for
children and adolescents with PTSD as “at present there is too little evidence from RCTs (ran-
domized controlled trials), open-label studies or case-control studies to recommend the use of
any psychotropic medication to treat PTSD in children and young adults”.(99) Many experts
would agree that there is a lack of data to support the use of medication alone, in the absence of
psychotherapy. Early open trials in children and adolescents with PTSD have reported benefits
with propranolol,(100) clonidine,(101) guanfacine,(102) carbamazepine,(103) tricyclics (e.g.,
imipramine), novel antipsychotics (e.g., risperidone, olanzapine), opiates (e.g., morphine; 104),
and citalopram,(105) among others. In a prospective double-blind, pilot study of acute stress
disorder (ASD), 25 children (aged 2 to 19 years) who had sustained serious burns were ran-
domly assigned to imipramine or chloral hydrate treatment.(106) Imipramine was significantly
more effective than chloral hydrate in treating ASD symptoms. Saxe et al. (104, 107) conducted
a naturalistic study to investigate the relationship between the dose of morphine administered
during a child’s hospitalization for acute burns and the course of posttraumatic stress disorder
(PTSD) symptoms over the 6-month period following discharge from the hospital. Children
who received higher doses of morphine had a greater reduction in PTSD symptoms over 6
months. The authors conducted pathway analyses to test the potential mediating roles of pain
reduction, noradrenergic attenuation, and separation anxiety on the association between mor-
phine and PTSD. Their results suggested that a reduction in separation anxiety may medi-
ate the association between morphine administration and PTSD symptom reduction at the
3-month follow-up.(107) The first controlled trial of divalproex sodium (an antikindling agent
with potential usefulness in reducing aggression in PTSD) in conduct-disordered youth with
PTSD provides preliminary evidence for its short-term efficacy in PTSD.(108) Twelve partici-
pants were randomized into either a high-dose (500–1,500 mg per day or therapeutic plasma
levels for seizure control between 50–120 ng/ml) or low dose (up to 250 mg/day) condition. At
the end of 8 weeks of treatment, patients in the high-dose condition had significantly greater
improvement and fewer core PTSD symptoms.
Clinicians have tended to rely on clinical experience and extrapolation of data from adult
populations to inform their choice of medications in this population.(109) Based on an earlier
survey of child psychiatrists by Cohen et al.(110), 95% of psychiatrists said that they had used
pharmacotherapy to treat childhood and adolescent PTSD. Medications most frequently used
were selective serotonin reuptake inhibitors and α-adrenergic agonists. Selective serotonin
reuptake inhibitors (SSRIs) were rated by respondents as being most effective for treating over-
all PTSD symptoms, including reexperiencing symptoms and avoidance numbing symptoms.
Alpha-adrenergic agonists were rated as most effective for hyperarousal symptoms. Seedat
et al. (105) compared improvement in 24 child and adolescent subjects to 14 adult subjects pro-
vided with 20–40 mg/day of citalopram in an open-label study and demonstrated equivalent
improvements between the groups. A Turkish open trial of fluoxetine also showed effective-
ness in improving PTSD symptoms (earthquake-related) among 26 participants aged 7 to 17
years.(111) One study assessed the potential benefits of adding an SSRI, sertraline, versus pla-
cebo, to TF-CBT in a double-blind design to 10-to-17-year-olds (N-24) who had PTSD second-
ary to sexual abuse.(112) Both groups experienced significant improvement, but there was little
benefit to adding sertraline to TF-CBT.
Selective serotonin reuptake inhibitors have been shown to be effective for children and
adolescents with other anxiety disorders (e.g., social phobia, generalized anxiety disorder, sep-
aration anxiety disorder; 113) and a review of nine randomized double-blind studies on the
efficacy of pharmacotherapy for generalized anxiety disorder, separation anxiety disorder, and
158 Seedat

social phobia found strong evidence for the efficacy of SSRIs for the treatment of these anxiety
disorders with standardized effect sizes varying between medium and large.(114) Children
and adolescents with PTSD who also have comorbid mood and anxiety disorders are likely to
benefit from an SSRI.
Recently the use of the SSRIs in children and adolescents has come under scrutiny owing
to concerns about the increased risk of suicidal ideation and behavior in youth treated for
depression.(115, 116) This led to a reanalysis of published and unpublished studies by the US
Food and Drug Administration and the UK’s Medicines and Healthcare products Regulatory
Agency (MHRA). A systematic review by Hetrick et al. (116) concluded that “it is unclear what
the effect of SSRIs is on suicide completion. While untreated depression is associated with
the risk of completed suicide and impacts on functioning, it is unclear whether SSRIs modify
this risk in a clinically meaningful way.” However, other data suggest that the SSRIs (e.g.,
fluoxetine, paroxetine, sertraline, and citalopram) exhibit both safety and efficacy in pediatric
depression, with no evidence for increased suicidality after commencement of treatment.(117)
While concerns regarding the use of SSRIs in pediatric depression may not apply to the treat-
ment of PTSD, it is prudent that children and adolescents with PTSD who are commenced on
SSRIs be carefully monitored, particularly in the initiation phase of treatment.

Conclusions

Pediatric PTSD is a prevalent and disabling disorder that is characterized by complex and
unique neurobiological and developmental alterations. Although findings with respect to the
directions of these alterations have been mixed, studies that have examined early biological
predictors of PTSD in children and adolescents have been relatively consistent. Accurate assess-
ment of PTSD in this population, and early identification of those children at risk, is crucial in
order to target interventions appropriately. Despite the lack of randomized controlled studies
to inform pharmacological management, the field is now in a better position to discriminate
the effectiveness of specific treatment approaches in this age group. At the same time, more
rigorous and larger-scale psychosocial and pharmacological trials that examine both treatment
predictors and mediating and moderating elements are needed. Finally, studies that evaluate
whether psychoeducation, CBT, and pharmacological manipulations (e.g., propranolol) may
be usefully implemented in children and adolescents at very early time points, following expo-
sure to traumatic events, would be of great importance.

References

  1. American Academy of Child and Adolescent Psychiatry. Practice parameters for the assessment and
treatment of children and adolescents with posttraumatic stress disorder. J Am Acad Child Adolesc
Psychiatry 1998; 37(Suppl): 4S–26S.
  2. Perry BD, Azad I. Posttraumatic stress disorders in children and adolescents. Curr Opin Pediatr
1999; 11(4): 310–6.
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th ed.
text revision. American Psychiatric Association: Washington, DC; 2000.
  4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 3rd ed.
American Psychiatric Association: Washington, DC; 1980.
  5. McFarlane A. Posttraumatic phenomena in a longitudinal study of children following a natural
disaster. J Am Acad Child Adolesc Psychiatry 1987; 26(5): 764–9.
  6. Cuffe SP, Addy CL, Garrison CZ et al. Prevalence of PTSD in a community sample of older
adolescents. J Am Acad Child Adolesc Psychiatry 1998; 37(2): 147–54.
  7. Carrion VG, Weems CF, Ray R, Reiss AL. Toward an empirical definition of pediatric PTSD: the
phenomenology of PTSD in youth. J Am Acad Child Adolesc Psychiatry 2002a; 41(2): 166–73.
  8. Scheeringa M, Zeanah C, Myers L, Putnam F. Predictive validity in a prospective follow-up of PTSD
in preschool children. J Am Acad Child Adolesc Psychiatry 2005; 44(9): 899–906.
  9. Scheeringa MS. Developmental considerations for diagnosing PTSD and acute stress disorder in
preschool and school-age children. Am J Psychiatry 2008; 165(10): 1237–9.
10. Meiser-Stedman R, Smith P, Glucksman E, Yule W, Dalgleish T. The posttraumatic stress disorder
diagnosis in preschool- and elementary school-age children exposed to motor vehicle accidents. Am
J Psychiatry 2008; 165(10): 1326–37.
Traumatic Stress Disorders in Children 159

  11. Scheeringa MS, Peebles CD, Cook CA, Zeanah CH. Toward establishing procedural criterion and
discriminant validity for PTSD in early childhood. J Am Acad Child Adolesc Psychiatry. 2004; 40(1):
52–60.
  12. Lavigne JV, Gibbons RD, Christoffel KK et al. Prevalence rates and correlates of psychiatric disorders
among preschool children. J Am Acad Child Adolesc Psychiatry 1996; 35(2): 204–14.
  13. Reinherz HZ, Giaconia RM, Lefkowitz ES, Pakiz B, Frost AK. Prevalence of psychiatric disorders in a
community population of older adolescents. J Am Acad Child Adolesc Psychiatry 1993; 32(2): 369–77.
  14. Saigh PA, Green BL, Korol M. The history and prevalence of post-traumatic stress disorder with special
reference to children and adolescents. J Sch Psychol 1996; 34(2): 107–31.
  15. McNally RJ. Assessment of posttraumatic stress disorder in children and adolescents. J Sch Psychol
1996; 3(2): 133–45.
  16. Fletcher K. Childhood posttraumatic stress disorder. In: Mash EJ, Barkley RA, eds. Child
Psychopathology, 2nd edn. Guilford Press: New York, 2003; 330–71.
  17. McLeer SV, Deblinger E, Atkins MS, Foa EB, Ralphe DL. Posttraumatic stress disorder in sexually
abused children. J Am Acad Child Adolesc Psychiatry 1988; 27: 650–4.
  18. Kiser LJ, Ackerman BJ, Brown E et al. Posttraumatic stress disorder in young children: a reaction to
purported sexual abuse. J Am Acad Child Adolesc Psychiatry 1988; 27:645–9.
  19. Schwarz ED, Kowalski JM. Posttraumatic stress disorder after a school shooting: effects of symptom
threshold selection and diagnosis by DSM-III, DSM-III-R, or proposed DSM-IV. Am J Psychiatry
1991; 148: 592–7.
  20. Terr LC. Chowchilla revisited: the effects of psychic trauma four years after a school bus kidnapping.
Am J Psychiatry 1983; 140: 1543–50.
  21. Arroyo W, Eth S. Children traumatized by Central American Warfare. In: Eth S, Pynoos RS, eds. Posttraumatic
stress disorder in children. Washington, DC: American Psychiatric Association, 1985; 101–20.
  22. Saigh PA. On the development of posttraumatic stress disorder pursuant to different modes of
traumatization. Behav Res Ther 1991; 29: 213–6.
  23. Handford HA, Mayes SD, Matterson RE et al. Child and parent reaction to the three mile island
nuclear accident. J Am Acad Child Adolesc Psychiatry 1986; 25: 346–56.
  24. Earls F, Smith E, Reich W, Jung KG. Investigating psychopathological consequences of a disaster in
children: a pilot study incorporating a structured diagnostic interview. J Am Acad Child Adolesc
Psychiatry 1988; 27: 90–95.
  25. Shannon MP, Lonigan CJ, Finch Jr AJ, Taylor CM. Children exposed to disaster: I. Epidemiology of
posttraumatic stress symptoms and symptom profiles. J Am Acad Child Adolesc Psychiatry 1994;
33: 80–93.
  26. Lonigan CJ, Shannon MP, Taylor CM, Finch AJ, Sallee FR. Children exposed to disaster: risk factors
for the development of posttraumatic symptomatology. J Am Acad Child Adolesc Psychiatry 1994;
33: 94–105.
  27. Bryant RA. Early predictors of posttraumatic stress disorder. Biol Psychiatry 2003; 53(9): 789–95.
  28. Kassam-Adams N, Winston FK. Predicting child PTSD: The relationship between acute stress
disorder and PTSD in injured children. J Am Acad Child Adolesc Psychiatry 2004, 43: 403–11.
  29. Meiser-Stedman R, Yule W, Smith P, Glucksman E, Dalgleish T. Acute stress disorder and
posttraumatic stress disorder in children and adolescents involved in assaults or motor vehicle
accidents. Am J Psychiatry 2005; 162: 1381–3.
  30. Dalgleish T, Meiser-Stedman R, Kassam-Adams N et al. Predictive validity of acute stress disorder
in children and adolescents. Br J Psychiatry 2008; 192(5): 392–3.
  31. Bryant RA, Salmon K, Sinclair E, Davidson P. The relationship between acute stress disorder and
posttraumatic stress disorder in injured children. J Trauma Stress 2007; 20(6): 1075–9.
  32. Task Force on Research Diagnostic Criteria- Infancy and Preschool: Research diagnostic criteria
for infants and preschool children: the process and empirical support. J Am Acad Child Adolesc
Psychiatry 2003; 42: 1504–12.
  33. Mylle J, Maes M. Partial posttraumatic stress disorder revisited. J Affect Disord 2004; 78(1): 37–48.
  34. Horowitz K, McKay M, Marshall R. Community violence and urban families: experiences, effects,
and directions for intervention. Am J Orthopsychiatry 2005; 75(3): 356–68.
  35. Pine DS, Cohen JA. Trauma in children and adolescents: risk and treatment of psychiatric sequelae.
Biol Psychiatry 2002; 51(7): 519–31.
  36. Copeland WE, Keeler G, Angold A, Costello EJ. Traumatic events and posttraumatic stress in
childhood. Arch Gen Psychiatry 2007; 64(5): 577–84.
  37. Giaconia RM, Reinherz HZ, Silverman AB et al. Traumas and posttraumatic stress disorder in a
community population of older adolescents. J Am Acad Child Adolesc Psychiatry 1995; 34(10):
1369–80.
  38. Koenen KC, Moffitt TE, Caspi A et al. The developmental mental-disorder histories of adults with
posttraumatic stress disorder: a prospective longitudinal birth cohort study. J Abnorm Psychol 2008;
117(2): 460–6.
160 Seedat

  39. Pervanidou P. Biology of post-traumatic stress disorder in childhood and adolescence.

J Neuroendocrinol 2008; 20(5): 632–8.
  40. Meewisse ML, Reitsma JB, de Vries GJ, Gersons BP, Olff M. Cortisol and post-traumatic stress
disorder in adults: systematic review and meta-analysis. Br J Psychiatry 2007; 191: 387–92.
  41. Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage associated with prolonged
glucocorticoid exposure in primates. J Neurosci 1990; 10(9): 2897–902.
  42. Gould E, Tanapat P. Stress and hippocampal neurogenesis. Biol Psychiatry 1999; 46(11): 1472–9.
  43. De Bellis MD, Baum AS, Birmaher B et al. Developmental traumatology. Part I: Biological stress
systems. Biol Psychiatry 1999a; 45(10): 1259–70.
  44. Carrion VG, Weems CF, Ray RD et al. Diurnal salivary cortisol in pediatric posttraumatic stress
disorder. Biol Psychiatry 2002b; 51(7): 575–82.
  45. Carrion VG, Weems CF, Reiss AL. Stress predicts brain changes in children: a pilot longitudinal study
on youth stress, posttraumatic stress disorder, and the hippocampus. Pediatrics 2007; 119(3): 509–16.
  46. De Bellis MD, Keshavan MS, Clark DB et al. Developmental traumatology. Part II: Brain development.
Biol Psychiatry 1999b; 45(10): 1271–84.
  47. De Bellis MD, Keshavan MS, Shifflett H et al. Brain structures in pediatric maltreatment-related
posttraumatic stress disorder: a sociodemographically matched study. Biol Psychiatry 2002; 52(11):
1066–78.
  48. Carrion VG, Weems CF, Eliez S et al. Attenuation of frontal asymmetry in pediatric posttraumatic
stress disorder. Biol Psychiatry 2001; 50(12): 943–51.
  49. Delahanty DL, Nugent NR. Predicting PTSD prospectively based on prior trauma history and
immediate biological responses. Ann N Y Acad Sci 2006; 1071: 27–40.
  50. De Bellis MD, Kuchibhatla M. Cerebellar volumes in pediatric maltreatment-related posttraumatic
stress disorder. Biol Psychiatry 2006; 60(7): 697–703.
  51. Jackowski AP, Douglas-Palumberi H, Jackowski M et al. Corpus callosum in maltreated children with
posttraumatic stress disorder: a diffusion tensor imaging study. Psychiatry Res 2008; 162(3): 256–61.
  52. Pervanidou P, Kolaitis G, Charitaki S et al. The natural history of neuroendocrine changes in
pediatric posttraumatic stress disorder (PTSD) after motor vehicle accidents: progressive divergence
of noradrenaline and cortisol concentrations over time. Biol Psychiatry 2007; 62(10): 1095–102.
  53. Young EA, Breslau N. Cortisol and catecholamines in posttraumatic stress disorder: an epidemiologic
community study. Arch Gen Psychiatry 2004; 61(4): 394–401.
  54. Yehuda R, Siever LJ, Teicher MH et al. Plasma norepinephrine and 3-methoxy-4-hydroxyphenylglycol
concentrations and severity of depression in combat posttraumatic stress disorder and major
depressive disorder. Biol Psychiatry 1998; 44(1): 56–63.
  55. Connor KM, Zhang W. Recent advances in the understanding and treatment of anxiety disorders.
Resilience: determinants, measurement, and treatment responsiveness. CNS Spectr 2006; 11(10
Suppl 12): 5–12.
  56. Storr CL, Ialongo NS, Anthony JC, Breslau N. Childhood antecedents of exposure to traumatic
events and posttraumatic stress disorder. Am J Psychiatry 2007; 164(1): 119–25.
  57. Singer MI, Anglin TM, Song LY, Lunghofer L. Adolescents’ exposure to violence and associated
symptoms of psychological trauma. JAMA 1995; 273(6): 477–82.
  58. Olff M, Langeland W, Draijer N, Gersons BP. Gender differences in posttraumatic stress disorder.
Psychol Bull 2007; 133(2): 183–204.
  59. Langeland W, Olff M. Psychobiology of posttraumatic stress disorder in pediatric injury patients: a
review of the literature. Neurosci Biobehav Rev 2008; 32(1): 161–74.
  60. Nugent NR, Christopher NC, Delahanty DL. Emergency medical service and in-hospital vital signs
as predictors of subsequent PTSD symptom severity in pediatric injury patients. J Child Psychol
Psychiatry 2006; 47(9): 919–26.
  61. Yehuda R, Halligan SL, Bierer LM. Cortisol levels in adult offspring of Holocaust survivors: relation to
PTSD symptom severity in the parent and child. Psychoneuroendocrinology 2002; 27(1–2): 171–80.
  62. Yehuda R, Engel SM, Brand SR et al. Transgenerational effects of posttraumatic stress disorder in
babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol
Metab 2005; 90(7): 4115–8.
  63. Nugent NR, Amstadter AB, Koenen KC. Genetics of post-traumatic stress disorder: informing
clinical conceptualizations and promoting future research. Am J Med Genet C Semin Med Genet
2008; 148C(2): 127–32.
  64. Koenen KC, Saxe G, Purcell S et al. Polymorphisms in FKBP5 are associated with peritraumatic
dissociation in medically injured children. Mol Psychiatry 2005; 10(12): 1058–9.
  65. Binder EB, Bradley RG, Liu W et al. Association of FKBP5 polymorphisms and childhood abuse with
risk of posttraumatic stress disorder symptoms in adults. JAMA 2008; 299(11): 1291–305.
  66. Segman RH, Shefi N, Goltser-Dubner T et al. Peripheral blood mononuclear cell gene expression
profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol Psychiatry
2005; 10(5): 500–13, 425. Erratum in: Mol Psychiatry 2005; 10(5): 514.
Traumatic Stress Disorders in Children 161

  67. Hawkins SS, Radcliffe J. Current measures of PTSD for children and adolescents. J Pediatr Psychol
2006; 31(4): 420–30.
  68. Meiser-Stedman R, Smith P, Glucksman E, Yule W, Dalgleish T. Parent and child agreement for acute
stress disorder, post-traumatic stress disorder and other psychopathology in a prospective study of
children and adolescents exposed to single-event trauma. J Abnorm Child Psychol 2007; 35(2): 191–201.
  69. Scheeringa MS, Wright MJ, Hunt JP, Zeanah CH. Factors affecting the diagnosis and prediction of
PTSD symptomatology in children and adolescents. Am J Psychiatry 2006; 163(4): 644–51.
  70. Salmon K. Remembering and reporting by children: the influence of cues and props. Clin Psychol
Rev 2001; 21(2): 267–300.
  71. Weiss DS, Marmar CR. The impact of events scale-revised. In: Wilson JP, Keane T, eds. Assessing
Psychological Trauma and PTSD. Guilford Press: New York; 1987.
  72. Briere J. Trauma Symptom Checklist for Children (TSCC). Odessa, FL: Psychological Assessment
Resources; 1996.
  73. Foa EB, Riggs DS, Dancu DV, Rothbaum BO. Reliability and validity of a brief instrument for
assessing post-traumatic stress disorder. J Trauma Stress 1993; 6: 459–73.
  74. Pynoos RS, Frederick C, Nader K et al. Life threat and posttraumatic stress in school-age children.
Arch Gen Psychiatry 1987; 44: 1057–63.
  75. Newman E, Weathers FW, Nader K et al. Clinician-Administered PTSD Scale for Children and
Adolescents (CAPS-CA). Los Angeles: Western Psychological Services; 2004.
  76. King NJ, Tonge BJ, Mullen P et al. Treating sexually abused children with posttraumatic stress
symptoms: a randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2000; 39(11): 1347–55.
  77. Reich W, Leacock N, Shanfield C. Diagnostic Interview for Children and Adolescents-Revised
(DICA-R). St. Louis, MO: Washington University; 1994.
  78. Armstrong JG, Putnam FW, Carlson EB, Libero DZ, Smith SR. Development and validation of a
measure of adolescent dissociation: the adolescent dissociative experiences scale. J Nerv Ment Dis
1997; 185(8): 491–7.
  79. Connor KM, Davidson JR. Development of a new resilience scale: the Connor-Davidson Resilience
Scale (CD-RISC). Depress Anxiety 2003; 18: 76–82.
  80. Ohan JL, Myers K, Collett BR. Ten-year review of rating scales. IV: scales assessing trauma and its
effects. J Am Acad Child Adolesc Psychiatry 2002; 41(12): 1401–22.
  81. Jørgensen IE, Seedat S. Factor structure of the Connor-Davidson resilience scale in South African
adolescents. Int J Adolesc Med Health 2008; 20(1): 23–32.
  82. Strand VC, Sarmiento TL, Pasquale LE. Assessment and screening tools for trauma in children and
adolescents: a review. Trauma Violence Abuse 2005; 6(1): 55–78.
  83. Cohen JA, Deblinger E, Mannarino AP, Steer RA. A multisite, randomized controlled trial for children
with sexual abuse-related PTSD symptoms. J Am Acad Child Adolesc Psychiatry 2004; 43(4): 393–402.
  84. Kaufman J, Birmaher B, Brent D et al. Schedule for affective disorder and schizophrenia for school-
age children-present and lifetime version (K-SADS-PL): Initial reliability and validity data. J Am
Acad Child Adolesc Psychiatry 1997; 36: 980–8.
  85. Cohen JA, Mannarino AP, Knudsen K. Treating sexually abused children: 1 year follow-up of a
randomized controlled trial. Child Abuse Negl 2005; 29(2): 135–45.
  86. Kolko DJ. Individual cognitive behavioral treatment and family treatment and family therapy for
physically abused children and their offending parents: A comparison of clinical outcomes. Child
Maltreatment 1996; 1: 322–42.
  87. Kataoka SH, Stein BD, Jaycox LH et al. A school-based mental health program for traumatized
Latino immigrant children. J Am Acad Child Adolesc Psychiatry 2003; 42(3): 311–8.
  88. Stein BD, Jaycox LH, Kataoka SH et al. A mental health intervention for school children exposed to
violence: a randomized controlled trial. JAMA 2003; 290(5): 603–11.
  89. Tol WA, Komproe IH, Susanty D et al. School-based mental health intervention for children affected
by political violence in Indonesia: a cluster randomized trial. JAMA 2008; 300(6): 655–62.
  90. Feather JS, Ronan KR. Trauma-focused cognitive-behavior therapy for abused children with
posttraumatic stress disorder: a pilot study. NZ J Psychol 2006; 35: 132–45.
  91. Silverman WK, Ortiz CD, Viswesvaran C et al. Evidence-based psychosocial treatments for children
and adolescents exposed to traumatic events. J Clin Child Adolesc Psychol 2008; 37(1): 156–83.
  92. Nikulina V, Hergenrother JM, Brown EJ et al. From efficacy to effectiveness: the trajectory of the
treatment literature for children with PTSD. Expert Rev Neurother 2008; 8(8): 1233–46.
  93. Trowell J, Kolvin I, Weeramanthri T et al. Psychotherapy for sexually abused girls: psychopathological
outcome findings and patterns of change. Br J Psychiatry 2002; 180: 234–47.
  94. Rose S, Bisson J, Wessely S. A systematic review of single-session psychological interventions
(‘debriefing’) following trauma. Psychother Psychosom 2003; 72(4): 176–84.
  95. Stallard P, Velleman R, Salter E et al. A randomised controlled trial to determine the effectiveness of
an early psychological intervention with children involved in road traffic accidents. J Child Psychol
Psychiatry 2006; 47(2): 127–34.
162 Seedat

  96. Cohen JA. Treating acute posttraumatic reactions in children and adolescents. Biol Psychiatry 2003;
53(9): 827–33.
  97. Ward-Begnoche WL, Aitken ME, Liggin R et al. Emergency department screening for risk for post-
traumatic stress disorder among injured children. Inj Prev 2006; 12(5): 323–6.
  98. Winston FK, Kassam-Adams N, Garcia-España F, Ittenbach R, Cnaan A. Screening for risk of
persistent posttraumatic stress in injured children and their parents. JAMA 2003; 290(5): 643–9.
  99. NICE. National Institute for Clinical Excellence: Post-traumatic Stress Disorder. The management of
PTSD in adults and children in primary and secondary care. Royal College of Psyhiatrists. Cromwell
Press Limited, Trowbridge, Wiltshire, 2005.
100. Famularo R, Kinscherff R, Fenton T. Propranolol treatment for childhood posttraumatic stress
disorder, acute type: a pilot study. Am J Dis Child 1988; 142(11): 1244–7.
101. Harmon RJ, Riggs PD. Clinical perspectives: clonidine for posttraumatic stress disorder in preschool
children. J Am Acad Child Adolesc Psychiatry 1996; 35(9): 1247–9.
102. Horrigan JP, Barnhill LJ. Risperidone and PTSD in boys. J Neuropsychiatry Clin Neurosci 1999; 11:
126–7.
103. Looff D, Grimley P, Kuller F, Martin A, Shonfield L. Carbamzepine and PTSD. J Am Acad Child
Adolesc Psychiatry 1995; 34(6): 703–4.
104. Saxe G, Stoddard F, Courtney D et al. Relationship between acute morphine and the course of PTSD
in children with burns. J Am Acad Child Adolesc Psychiatry 2001; 40(10): 915–21.
105. Seedat S, Stein DJ, Ziervogel C et al. Comparison of response to selective serotonin reuptake inhibitor
in children, adolescents, and adults with PTSD. J Child Adolesc Psychopharmacol 2002; 12(1): 37–46.
106. Robert R, Blakeney PE, Villarreal C, Rosenberg L, Meyer WJ 3rd. Imipramine treatment in pediatric
burn patients with symptoms of acute stress disorder: a pilot study. J Am Acad Child Adolesc
Psychiatry 1999; 38(7): 873–880.
107. Saxe G, Geary M, Bedard K et al. Separation anxiety as a mediator between acute morphine
administration and PTSD symptoms in injured children. Ann N Y Acad Sci 2006; 1071: 41–5.
108. Steiner H, Saxena KS, Carrion V, et al. Divalproex sodium for the treatment of PTSD and conduct
disordered youth: a pilot randomized controlled clinical trial. Child Psychiatry Hum Dev 2007;
38(3): 183–93.
109. Stein DJ, Ipser JC, Seedat S. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane
Database Syst Rev 2006; 1: CD002795.
110. Cohen J, Mannarino A, Rogal S. Treatment practices for childhood posttraumatic stress disorder.
Child Abuse Negl 2001; 25: 123–35.
111. Yorbik O, Dikkatli S, Cansever A, Sohmen T. The efficacy of fluoxetine treatment in children and
adolescents with posttraumatic stress disorder symptoms (Turkish). Klinik Psikofarmakoloji Bulteni
2001; 11: 251–6.
112. Cohen JA, Mannarino AP, Perel JM, Staron V. A pilot randomized trial of combined trauma-focused
CBT and sertraline for childhood PTSD symptoms. J Am Acad Child Adolesc Psychiatry 2007; 46(7):
811–9.
113. Research Unit on Pediatric Psychopharmacology Anxiety Study Group. Fluvoxamine for the
treatment of anxiety disorders in children and adolescents. N Engl J Med 2001; 344(17): 1279–85.
114. Dieleman GC, Ferdinand RF. Pharmacotherapy for social phobia, generalised anxiety disorder and
separation anxiety disorder in children and adolescents: an overview. Tijdschr Psychiatr 2008; 50(1):
43–53.
115. Scahill L, Hamrin V, Pachler ME. The use of selective serotonin reuptake inhibitors in children and
adolescents with major depression. J Child Adolesc Psychiatr Nurs 2005; 18(2): 86–9.
116. Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M. Selective serotonin reuptake inhibitors (SSRIs)
for depressive disorders in children and adolescents. Cochrane Database Syst Rev 2007; 18(3):
CD004851.
117. Sharp SC, Hellings JA. Efficacy and safety of selective serotonin reuptake inhibitors in the treatment of
depression in children and adolescents: practitioner review. Clin Drug Investig 2006; 26(5): 247–55.
12 Ethnocultural issues
Alexander McFarlane and Devon Hinton

There is an objective truth—which she might call historical fact as opposed to historical
interpretation. And you have to reach for it . . . the most important thing any human
being can do is to be as objective as possible about the past, that is the only thing on
which a secure identity—individual or society—can be based. And linked to this is the
feeling that doing it is a virtual impossibility. Because the moment you try, all the forces
of delusion, self-aggrandizement, guilt, brain-washing by public perceptions, conspire to
distort the past almost as soon as it has happened.
(Interview with Pat Barker, The Guardian, October 1998) (1)

Introduction

Posttraumatic stress disorder (PTSD) is a unique disorder because it conveys how the envi-
ronment and the process of adjustment to severe traumatic stress can be extremely det-
rimental to an individual’s adaptation. The process of interaction between internal and
social resources brings into focus how individuals’ experience and the meaning that they
assign to an event play a critical role in psychological outcome. The attribution of meaning
involves looking at the individuals’ personal relationships in the context of society and
culture. This embeddedness of experience implies that PTSD is not an illness implicit to the
individual alone as it also involves an interaction with the sociocultural environment over
time.(2) The belief that individuals can control their own destiny is only a relatively recent
notion and is one of the dimensions in which cultural expectations define the impact of
experience on psychological well-being. Religion and the prevailing cultural norms about
restitution and dealing with grief are cultural domains where resources can mitigate the
impact of trauma.(3)
This chapter will discuss these issues while accepting the importance of the role of neu-
robiology and the universality of the psychological stress response.(4) These form the stage on
which ethnic and cultural factors are played out. Perhaps most important to this process is the
dimension of intrusion and avoidance in the traumatic stress response.(5) These axes of reac-
tion are manifest in both individuals’ cognitive and affective domains and the way that society
at large contains and relives trauma.(6) The critical aspect of this process is the subtle manner
in which the past often comes to be played out in the future and moulds the shape and affect of
current reactions and attitudes without the roots being recognized.
The role of culture is easy to lose in the world of objectivity and statistically based research
with the current ascendancy of biological observations. The stated importance of an ethnocul-
tural perspective can be dismissed as platitudinous in the world of reductionism because of
few facts and many assertions. The contributions that it makes do not have the same focused
objective dimensions as does research into changes in specific domains of neurotransmitter
systems, for example. However, there is a great need to look at the relevance of more empiri-
cally based observations about trauma to the lives of traumatized people and the meaning they
ascribe to their suffering.(7, 8)

Definition of Culture

Culture is a phenomenon that has several dimensions: It is the distinctive practices and beliefs
as well as a development or improvement of the intellect or behavior due to education, train-
ing, or experience. The idea that it is a process that involves active development and change
is implicit in the use of the word to describe the act of processing of cultivated land, animals,
164 McFarlane and Hinton

and so on.(9) The definitions of culture are as many and varied as cultures that exist. One of the
primary characteristics of a culture is that it provides a context for survival. Rappaport (10) has
described a complex set of relationships between quite divergent variables in a society compar-
ing it to an ecosystem where the culture is defined as the system which is evolved to ensure the
survival of the population in the context of the resources available. Thus, culture has a regula-
tory function that is experienced as an ideology by the population, whereas its contribution to
survival is latent and unconscious among the members of the culture.(11)
Culture contributes divergent tensions, not the least of which comes from the human
need for dependence; therefore, its loss becomes traumatic.(3) Individuals who are strongly
identified with a culture and its values are protected and buffered by the support and sense
of identity that it provides, particularly at times of trauma.(3) The power of culture lies in
the fact that it is a protector, integrator, and security system.(12) This protection is at a cost
because it limits individuality and freedom of expression and the loss leaves a deep sense of
disorientation.
Culture provides a frame of belief that assists in dealing with illness and traumatic
events as well as their causes. This function has a dimension that persists and does not dis-
appear with treatment or the reconstruction of the damage after a disaster. Traumatic events
do have predictable consequences that are unavoidable, although they can be minimized
through preparation, training, and risk appraisal. Distress, loss, and sickness must, there-
fore, be managed and adapted to by both individuals and groups. Culture is the vehicle that
embodies the values enriching these processes and the rituals contributing to healing.(13, 14)
Suffering and illness are profound personal experiences as well as communications to the
group.(3)
The traumatic stress field is one that is especially influenced by these forces. The nature of
a traumatic experience is partly defined by cultural expectations about risk. Fatalistic cultures are
accepting of the existence of traumatic events because they have external and unmodifiable risks
and that these must be constantly faced. However, this belief system can undermine the potential
for successful mitigation of risk, although it provides a useful set of beliefs and constructs for
dealing with tragedy when it arises. The social system also provides valuable models for how to
adapt once the trauma has arisen.(15) The models of intervention that we propose in the face of
disaster, such as debriefing, are in part social movements that mobilize belief systems and sup-
port networks and give cultural permission to emote and seek help.(16) These belief systems help
overcome the natural resistance to asking for help and the cultural tradition of not showing pain
or distress. The advocacy for particular treatment approaches also comes from subcultural beliefs
about the benefits and superiority of one treatment over another in the context of competing
tribes of therapist. This internecine battle is often disguised with the language of science, which
emphasizes the differences between approaches rather than the nonspecific aspects of treatment
and the common origins of many competing approaches.
There are also often major cultural gulfs between clinicians and their patients. This divide
is summarized in this quote about the inability of the welfare professionals to document and
intervene in child abuse until recent times.

In England, a different factor was at work during those years, and that a mind-set pre-
vailed which allowed damage and abuse to go unrecognized. They were the years of
scrupulous professional regard for what was thought of as “working class culture.” In
their numbing desire to be “non-judgemental,” educated people in the welfare trade did
not “talk down” to the economically disadvantaged nor teach them how to live their
lives. So the dysfunctional became a model, and their expectations for their clients—of
stability and routine in childcare, for example—were low. They had every bit of jargon at
their fingertips, and liberal clichés bubbled on their lips; it was just in practical observa-
tion that they were deficient. (17)

Most discussion of culture and trauma focus on the comparison between different socie­
ties and the way that they adapt and create meaning in response to particular types of experi-
ence or the phenomenology of the stress response in culturally distinct groups. Victims’ status
itself creates a distinct cultural group and behavioral expectations. This latter dimension of the
forces and influence of culture is possibly of most significance to clinicians.
Ethnocultural Issues 165

The Cultural Determination of Meaning

The personal meaning of traumatic experience of the individual is influenced by the social con-
text in which it occurs. Victims and the significant people in their surroundings may have dif-
ferent and fluctuating assessments both of the reality of what has happened and of the extent
of their suffering.(18) As a result, victims and witnesses may have strongly conflicting agendas
in the need for repair: heal, forget, or take revenge. At the individual level, this dynamic can be
seen as one of the forces that is played out in the repressed memory debate, where the accused
have used scientific argument to alienate and deny the traumatic reality of the victims. These
conflicts between a trauma’s meaning to victims and witnesses create an environment for the
trauma to be perpetuated. When it comes to the conflict of nations, soon, not the trauma itself
but the allocation of blame and responsibility may become the central issue.
Many personal testimonies of trauma survivors describe the absence of support by the
people on whom they counted and being blamed for bringing horrendous experiences upon
themselves, which left deeper scars than the actual traumatic events themselves.(19) Similarly,
victims often feel ashamed and disgusted by their own failure to prevent what has happened.
(14) Thus, for many victims a violation of their self and social ideals becomes part of the trau-
matic experience. This is also true for nations who have been beaten in war. This sense of self-
betrayal is particularly acute if a nation was unprepared and did not anticipate the intentions
or strength of their enemy. Members of that nation may find it difficult to respect those who
fought or the leaders who played a part in the loss of national pride. The liberators and the
resistance fighters can become powerful reminders of this shame.
Once the period of a trauma is over there can be a dramatic shift in attitudes. Ironically,
both a victim of PTSD, and the larger society that may be expected to respond with compassion,
forbearance, or financial sacrifices have a stake in believing that the trauma is not really the cause
of the individual’s suffering. Society becomes resentful about having its illusions of safety and
predictability disturbed by people who remind them of how fragile security can be. One of the
reasons for this failure of empathy is the gulf between the experience of the victim and their abil-
ity to express it in language that provokes empathy in those who do not know the experience.

The Conflict between the Individual and Social Need

External validation of the reality of a traumatic experience in a safe and supportive context is
a vital aspect of preventing and treating posttraumatic stress. However, the creation of such a
context for recovery can become very complicated when the psychological needs of victims
are in conflict with their social network.(20) When victims’ helplessness persists, as in chronic
PTSD, or when the meaning of the trauma is secret, forbidden, or unacceptable, such as occurs
in intrafamilial abuse, or state violence, the trauma fails to elicit donation of resources, restitu-
tion, or metering out of justice. In the restoration of government at the end of a war, there may
be a conflict between the resistance leadership and the established holders of power who went
into the safety of exile. Validation of bravery of the resistance fighters may threaten a non-
democratic government that was installed at liberation because this enhances their legitimate
political profile. Lack of validation and support is likely to perpetuate the haunting traumatic
memories that evoke a sense of victimization and social alienation.
One of the paradoxes about the predicament of survivors (whether they be soldiers or
civilian victims) is that the larger social group often lacks any realistic understanding of their
predicament. Primo Levi, who was an Italian chemist who survived the death camps of Nazi
Germany, wrote passionately about the changed perception of the victims of this terrible incar-
ceration. In the years immediately following the war he described how: “I encountered peo-
ple who didn’t want to know anything, because the Italians, too, had suffered, after all, even
those who didn’t go to the camps! They used to say, ‘For heaven’s sakes, it’s all over,’ and so
I remained quiet for a long time.”(21)
In 1955 Levi noted that it had become “indelicate” to speak of the camps—“One risks
being accused of setting up as a victim, or of indecent exposure.” Thus was confirmed the ter-
rible, anticipatory dream of the victims, during and after the camps: that no one would listen,
and if they listened they wouldn’t believe. Once people did start to listen, and believe, the other
166 McFarlane and Hinton

obsession of the survivor began to eat away at Levi—the shame, and guilt, of survival itself,
made worse in his case by the embarrassment of fame. Why should he, Levi, have survived?
Had he made compromises that others had refused? Had others died in his place? His only
resource to ward off the enemies of memory was words. But “the trade of clothing facts in
words,” he wrote, “is bound by its very nature to fail.”
The importance of language, that we can communicate and we must communicate, that
language is vital to humanity, and that the deprivation of language is the first step of destruc-
tion of a man, was enforced within the camp (words were replaced by blows—“that was how
we knew we were no longer men”). (22)”
For the victims of individual and hidden traumas such as child abuse and domestic vio-
lence, the recurrence of the victimization and denial by the immediate social network is far
more insidious and hence harder to identify.(23) Due to the social stigma attached to these
forms of trauma, their occurrence is kept hidden, which means that there is very little chance of
any realistic social awareness emerging. This was also the lot of the “comfort women” enslaved
by the Japanese army.(24) The women’s movement has been the voice for these concerns and
has greatly contributed to the breaking down the social dismissal of sexual violence. This col-
lective advocacy has challenged the minimization of the dark and silent world of familial abuse
that shatters the advocated social ideals of modern conservative politicians.
Victims of trauma often become subjects of passionate concern from those around them,
concern that may have no direct reflection on their actual well-being. Often voiceless about
their innermost fears and becoming accustomed to passive acquiesce, victims of trauma are a
means for a variety of political and social ends, both for good and ill; they can be nurtured or
idealized, and just as easily spurned, stigmatized, and rejected. Between 1947 and 1982, Israeli
society moved from the latter to the former position in regards to its attitude toward Holocaust
survivors, without ever resting in the middle of the pendulum by treating them as fellow
human beings who had been exposed to the unspeakable.(25) Bloom (26) has described how
the field of traumatic stress emerged out of a political process advocating compassion for the
Vietnam veterans. They were seen as the victims of government policy and the resultant terror
of collective violence.

The Problem and the Nature of Traumatic Memory

The most dramatic achievement of human culture is language. It has no innate or indepen-
dent existence, yet it has driven an enormous amount of human evolution.(27) Language also
defines and binds cultures. It is challenging to consider that before the existence of the gramo-
phone, language could only be understood as a collective social memory. It is a phenomenon
that can only exist between individuals. As the sophistication of societies increases it becomes
the pervasive glue that creates the ties between groups and defines the boundaries that are
more or less permeable between cultures.
The limitation of language becomes apparent when experiences occur so infrequently
between individuals that there is no collective way of expressing the nature and consequences
of that event.(28) By definition these experiences have the capacity to fall outside the world of
the spoken culture. Hence, the expression of traumatic experience is a much more complex task
than appears at first hand. War is the greatest collective human trauma and the need to write
history and develop military tactics has necessitated its exploration. There is a variety of data
that suggest there is an immense difficulty in constructing a true representation of war.
Janet (29) highlighted that another of the critical dimensions of traumatic experience is
the difficulty of creating a representation of it in narrative memory. The event becomes trapped
in the primary sensory memories rather than developing a transformed and more symbolic
structure that has a linguistic base. Hence, the very nature of traumatic experience is its pro-
pensity to bypass linguistic representation.(30) Perhaps one way of conceptualizing this phe-
nomenon is to consider that traumatic experiences are defined by their capacity to disrupt the
use of language. Creative expression does not naturally emerge to convey these events. One of
the most boring jobs for the officers in the world War II was censoring the letters of the men,
who seemed to have enormous difficulty capturing the nature of terror and the chaos of com-
bat.(31) Siegfried Sassoon reflected the social consequences of this problem, conveying their
Ethnocultural Issues 167

experience in his peace statement that was published in The Times and read out in the House
of Commons (32).

I have seen and endured the sufferings of the troops, and I can no longer be a party to
prolong these sufferings for ends which I believe to be evil and unjust. I am not protesting
against the conduct of the War, but against the political errors and insincerities for which
the fighting men are being sacrificed. On behalf of those who are suffering now I make
this protest against the deception which is being practised on them; also I believe that
I may help to destroy the callous complacency with which the majority of those at home
regard the continuance of agonies which they do not share, and which they have not suf-
ficient imagination to realize. (p. 218) (33)

Grasping the nature of the trauma, therefore, requires a great deal of imagination and
empathy if the truth is not to be avoided. The listener or interpreter has to compensate for the
fact that most victims have impaired capacity to translate the intense emotions and perceptions
related to the trauma into communicable language. Not being able to give a coherent account of
the trauma to others, or even to oneself, without feeling traumatized all over again, makes it dif-
ficult for a culture to create representations of these experiences. The combination of the wish of
the bystander not to be disturbed by the raw emotions of injured people and the problems of vic-
tims articulating what they feel and need makes it extremely difficult to stay focused on working
through the impact of the trauma. Instead of clear-cut statements that convey the reality of what
has happened, traumatic memories start leading a life of their own as disturbing symptoms.(33)
When the memories of the trauma remain unprocessed, traumatized individuals tend to
become like Pavlov’s dogs: subtle reminders become conditional stimuli to reexperience fright-
ening feelings and perceptions belonging to the past. Hence social and cultural rituals that do
not process the experience have the capacity to sustain the trauma and inflict pain by touching
the wound that has not healed. This emphasizes that cultures should ideally provide some
symbolic transformation of an experience. To facilitate social healing they should provide hope
in the recall of horror. They must tell the story of suffering while not wounding the bereaved
by adding the dread of their memories of the dead. They must encourage reconciliation rather
than driving retribution and motivating a further cycle of violence by creating a universal
image of suffering where no one is spared the agony of violence. The message is to heal but not
through the romanticization of victors or the humiliation of those who were routed.
The awareness in a society of the memories that drive its values and the roots of its cul-
ture are critical to healthy identifications and preventing an acting out of old wounds in social
prejudices and victimizations. Grossman (34) has highlighted how the increasing distance we
have from birth and death in developed societies means that we have lost the experiences that
teach respect for life and death. Increasingly, Western cultural ideas are subject to distortions
through the media, which feasts on trauma and suffering, and the aggression depicted in the
cinema and video games. This portrays a far more aggressive and ruthless world than reality
demonstrates historically, as there have been tremendous prohibitions to killing even in war.
The identification of youth with this Hollywood culture and its implicit messages may explain
the spate of violent crime being committed by youth across the Western world. Previously,
the importance of submission as a strategy and an understanding that much aggression was a
threatening posture rather than a desire to kill was implicit cultural knowledge. The danger of
living in a media-driven culture is that it both misrepresents long-standing inhibitions against
violence and also destroys the cultural diversity that has been the core of the survival of social
groups.

Cross-cultural Studies

There are a variety of case reports that have examined the trauma response in particular minor-
ity groups.(11) These reports often convey unique and stark cultural comparisons, but the per-
spective of the heightened sensitivity to difference in the outside observer is what drives these
comparisons. When these perceived distinctions are subjected to scientific observation, what
is striking is  the relative lack of data suggesting cultural specificity in the trauma response,
168 McFarlane and Hinton

although the healing rituals vary greatly.(35) A sensitivity to this variance is an important
issue for the development of humanitarian aid to Third World disasters and civil wars. The
problems of ethnic conflict and the refugee crisis that often follows are going to be a growing
international problem emphasizing the importance of this body of knowledge.(36) The other
groups who have been of particular interest are refugees who have been resettled in new host
countries (37) and victims of torture (4) and gross human rights violations.(38) A critical step
in studying these populations has been the development of cross-cultural instruments such as
the Harvard trauma questionnaire.(1)
The large epidemiological studies of Vietnam veterans provide a particular insight into
outcome of minorities in response to one category of event. The National Vietnam Veterans’
Readjustment Study (NVVRS) (39) used several minority sample groups and found that in
contrast to the PTSD prevalence rate of 13.7% among Whites, Blacks had a rate of 20.6%, and
Hispanics 27.6%. There was also a suggestion that when they became ill there was a greater
degree of disability and social maladjustment. However, the increased rate of disorder in the
Blacks was accounted for by an increased combat exposure. These were analogous findings
to those of Laufer et al. (40) who similarly found greater impact of combat on Blacks. Similar
observations were made about Maori soldiers in the New Zealand army who served in Vietnam
where combat exposure level, rank, and combat role accounted for the greater morbidity.(41)
These findings are not representative of the general population. In the National Comorbidity
Study, Kessler et al. (42) found that Whites had the higher rates of traumatization and PTSD.
The most important cultural finding in this study was that for the same trauma, women had
double the rate of PTSD of men. The embeddedness of women in their culture and attachments
is one explanation for this vulnerability.(3) Trauma involves the carrying of the pain of those
around one, which is particularly costly if individuals have strong attachments.
Case studies have exemplified some dimensions of war having specific effects on minori-
ties.(43, 44) For example, Asian Americans fighting in the Vietnam War were more closely iden-
tified with the Viet Cong, which created many points of confusion in separating the self from
the victim.(45) This is the reverse of the phenomenon observed in Southeast Asian refugees in
the United States (46, 47), where the lack of social integration was an important stressor. Studies
of refugee populations that make prevalence estimates (7) are difficult to interpret because
the representativeness of the sample is often hard to determine, but they do demonstrate the
extreme traumatization of these people and the need for humanitarian concerns not to be lost
within the walls of cultural and geographical isolation.(48)
Natural disasters created by far the greatest devastation in Third World countries (49)
because of the lack of risk management and the poor quality of building materials and construc-
tion standards (97.5% of disaster victims are in developing countries, (50)). The 2005 Indian Ocean
Tsunami and its devastation are a potent reminder of the capacity of these events for devastation.
Yet these events have been given little attention in epidemiological research because of the imper-
atives of survival in these economies.(51) The prevalence studies that have been conducted are
generally difficult to interpret because of the nonrepresentative samples studied (e.g., the 1989
Mexico earthquake (52); the Amero mudslide (50)). Some important exceptions exist, including
the study of the Armenian earthquake and the Puerto Rico floods and mudslides that had been
previously sampled in the Epidemiological Catchment Area (ECA) study.(53) There are also a
series of more recent events that have been studied but few of the data have found their way
into the Western literature. The Kobe earthquake in Japan that killed thousands of people has
been extensively examined and demonstrated some of the methodological issues about under-
reporting symptoms due to the cultural tradition of bushido where there is great shame associ-
ated with inappropriate displays of emotion.(11) The Iraqi occupation of Kuwait has also been
studied using a strict epidemiological approach and demonstrated the similarities of response in
a Moslem and Western culture and that gender stereotyping seemed to have little impact.(54)
The similarities of the trauma response across cultures presents significant support for
the integrity of PTSD as a distinct diagnosis. A study of Khmer adolescent refugees suggested
that PTSD as a result of war trauma surmounted the barriers of culture and language.(55)
Implicit in PTSD is the notion that relatively independent of the nature of the traumatic stres-
sor, the context, and the culture, there is a similar phenomenology and epidemiology.(2) This
observation supports the idea of trauma as a unifying concept in contrast to the imperative of
focusing on individual groups of victims. What cross-cultural studies have identified is the
Ethnocultural Issues 169

impact of culture on the road to care and the nature of treatment that is acceptable to the
patient. For example, treatment-seeking Iranian torture victims living in Germany had poorer
knowledge of German.(56) A useful strategy is to work in collaboration with traditional healers
who address the health beliefs of the victims.(57) It appears the racial origin does not influence
the response to treatment in a Veterans Affairs system.(58) This is an example that should also
be followed in the context of Western society, where there is often a significant divide between
the health beliefs of the patient and the professional.(59) Studies of the mental health literacy of
populations demonstrates major divergences in the beliefs within a culture about the effective-
ness and appropriateness of different treatments.(60)

The way culture influences the presentation of symptoms

Studies of refugee populations have highlighted the propensity to somatization of PTSD in

non-Western groups.(61–63) The irony is that the majority of patients in First World settings
also present with these concerns, but the doctor’s apostolic role persuades the patient to avoid
this method of complaint and focus on the cognitive and affective symptoms.(64) The history
of trauma-related syndromes has focused on the role of somatization.(65) In the 1890s there
was a major focus on the investigation of hysteria and its multiple manifestations. During
World Wars I and II there were epidemics of conversion disorders, especially in battle situa-
tions where the soldiers were given little opportunity for the expression of their fear through
action. The description of the phenomenology of these reactions did not unravel the impor-
tance of the expression of the trauma in the symptoms. Latterly, following the Vietnam War,
there was the belief that the multiple ailments of the servicemen were due to their exposure to
the herbicide Agent Orange.(66) Predictably, following the 1990 War against Iraq, the Gulf War
syndrome rather than PTSD has emerged as the critical health issue where the somatic distress
of the servicemen is the critical concern.
The other force at work in these situations is the role of compensation and the impact
that litigation has on symptoms and their presentation. The suspicion of exaggeration and
malingered distress is one of the cultural stigmas that haunt the trauma victim. There are two
competing narratives in the legal arena that demonstrate how distress can be modified by the
context and the listener. The counsel for the defense has little compunction in voicing suspicion
and derision about the victim’s complaints in contrast to the plaintiff’s counsel who will subtly
encourage and seek out real and imagined complaints. The impact of the culture of the law
on the definition of the field and the public debate surrounding victims is a major social force.
The critic Robert Hughes in the Culture of Complaint (67) discussed the issue that how society
conceptualizes personal responsibility is dramatically influenced by the adversarial tradition.
In its extremes, these tensions become manifest in the false memory debate and concerns about
alien abduction and satanic ritual abuse. The multiple opinions that can be expressed about
victims demonstrate the depth of divergence within a dominant culture

The Impact of Trauma on Culture

The 20th century was marked by major international conflicts and unprecedented loss of life in
war. World War I was a cataclysm that partly occurred because of the failure of military tactics
to deal with the consequences of the new weapons and their destructive power. This conflict
challenged conventional forms of expression and the abstract art movement was strongly influ-
enced by a recognition that realism had failed to prepare people for what transpired.(68) The
uncertainty and the emergence of new forms of disaster such as the atomic bomb, AIDS, and
environmental degradation have left a pall of uncertainty and threat hanging over the world.
(69) The world of art and philosophy has tried to grapple with this new reality of chance. In
this way the threat of loss and the awareness of the brutality of the world have come to change
art and culture in dramatic ways. Perhaps the most dramatic shifts occurred in the social dis-
location and rebellion against authority at the time of the Vietnam War. Trauma is an abiding
theme of the 20th century and has dominated our attempts to find cultural and political iden-
tity. Trauma is the constant concern of the media and, as a major social preoccupation, becomes
170 McFarlane and Hinton

a powerful organizing force. The need remains to develop a cultural narrative for traumatic
situations that allows more effective organization to prevent the cycles of violence that we see
being played out in places such as Yugoslavia. The misrepresentation of conflict and its conse-
quences in romanticism and nationalism are major threats to peace and survival.
This indicates that the effect of trauma on culture is a bidirectional phenomenon. Just as
culture provides a social vehicle for healing, cultures are changed and subcultures arise in an
attempt to accommodate the effects of disasters, perceived social threats, and wars. Culture
represents the need that people have for stories to heal suffering. Scientifically proved treat-
ments are insufficient. There is a need for rituals to assist in healing. The rituals of bereavement
and the narratives that are used to contend with death take on many different forms, all serve
the same purpose—to integrate a person’s experience into the stream of social adaptation.
Thus, there are a series of ways in which culture can assist in the understanding of suffer-
ing and the healing of these wounds.(11)
1. The comparison of different cultures can assist in understanding the nature of trauma and
the ways of dealing with and resolving these traumas.
2. Studying groups who belong to minority cultures embedded in a larger social group can
assist in understanding the impact of belonging to one culture while being embedded in a
different host culture.(70)
3. The impact of a minority culture being overrun by an exogenous group can be a specific
type of trauma in its own right that can disrupt the normal healing rituals of the minority
culture and leave the entire group highly vulnerable to trauma.
To conclude this chapter, we would like to present some of the key questions that need to
be addressed when trying to understand the presentation of trauma-related disorder in cross-
cultural perspective and when attempting to develop culturally sensitive treatments:

Trauma-Related Disorder in Cross-Cultural Perspective: Some Key

Questions

1. Do traumatized members of other cultural groups meet the diagnostic criteria for posttraumatic stress
disorder (PTSD) as specified in the most current version of the DSM-IV?
It does seem that DSM-IV-defined PTSD symptoms occur in various cultural groups as
a consequence of trauma, for example, among Cambodian refugees (7) and among Xhosa-
speaking South African political detainees.(8)
2. Across cultural groups, do the salience of DSM-IV-defined PTSD symptoms and symptom clusters
(e.g., hyperarousal symptoms) vary?
Increased salience of DSM-IV-defined PTSD symptoms may result from any or all of the
following three causes: (a) the group’s cultural interpretation of the symptom as being particu-
larly dangerous or as being indicative of serious bodily, psychological, or spiritual problems;
(b) the nature of the trauma, as in prolonged exposure to traumas and situations of stress lead-
ing to prominent hyperarousal; or (c) the fact that the group lacks institutionalized means, as
in healing practices, to decrease those symptoms.
As an example, though two groups may initially have a similar severity of startle fol-
lowing a trauma, the two groups may have radically different interpretation of that symptom:
Among Cambodian refugees, startle is considered to be an indicator of a “weak heart,” (9) and
generates multiple fears––worry that the “soul” may be displaced. Among trauma survivors in
Mozambique, trauma-related dreams receive elaborate cultural explanation and lead to specific
ritual action (10); likewise, among Cambodian survivors of the Pol Pot period, trauma-related
nightmares are given elaborate interpretation, are considered an indicator of the physical and
spiritual strength of the dreamer (11)––a bad dream results in feelings of vulnerability and
increased anxiety and panic.
Studies have shown psychopathological dimensions to vary across cultural groups. For
example, hyperarousal symptoms seem to be more prominent among elderly so-called Whites
than among African Americans (12), and avoidance symptoms seem to be far less prominent
among Kalahari Bushmen compared to previously studied groups.(13) The reasons for these
differences have yet to be investigated.
Ethnocultural Issues 171

3. Are the rates of certain DSM-IV disorders, for instance, major depressive disorder or panic disorder,
greater in certain traumatized groups?
This would seem to be the case: Among Cambodian refugees (14), panic disorder is a very
prominent aspect of the reaction to trauma. Their high rate of panic disorder appears to result
from the severity of catastrophic cognitions about somatic and psychological symptoms, as
well as prominent trauma associations to autonomic arousal.
4. Across cultures, do the symptoms of non-PTSD disorders found in the DSM-IV have varying saliency
among trauma victims, or do differences only emerge when more extensive lists are used that tap those
constructs.
For example, trauma victims in two different cultures may have the same rate and sever-
ity of major depressive disorder, but the frequency of the actual symptoms of major depressive
disorder may vary, for example, there being more weight loss in one group and more negative
affect in another. These differences may only emerge if symptom lists are used that separately
assess symptoms clustered together for one criteria (e.g., insomnia and hypersomnia in the
major depressive disorder criteria). Or differences may only emerge if symptoms characteristic
of that construct, but not assessed in any of the criteria for that disorder, are assessed: tinnitus
among patients with panic-disorder-type panic attacks.
5. In other cultures, do certain symptoms and psychopathological dimensions not assessed in the DSM-IV
attain greater salience in trauma victims?
In various cultures, certain somatic symptoms seem to have more salience among persons
with trauma-related disorder––for example, dizziness among Chinese populations (15), tinnitus
among Cambodian refugees (16), gastrointestinal upset among Rwandan genocide survivors.(17)
Or to give an example of nonsomatic symptom, the rate of sleep paralysis in trauma-related dis-
order appears to be very high among Cambodian refugees.(11)
Yet still, psychopathological dimensions not specifically addressed (or minimally addressed)
in DSM-IV may be more prominent among trauma victims in certain cultural contexts, such as
somatization, panic attacks, low self-esteem, low cultural-esteem, impaired psychological flex-
ibility. To give another example, survival guilt is extremely salient among Rwandan genocide
owing to cultural beliefs about the need to bury the dead in a set period of time according to
traditional rites to assure the deceased’s transformation into a benevolent ancestor.(18, 19)
6. What is the local interpretation of trauma-caused symptoms? Are trauma-caused symptoms attrib-
uted to local cultural syndromes or spiritual causes? Do those cultural syndromes and spiritual explana-
tions of trauma-caused symptoms shape the local experience of trauma-related disorder?
One must investigate the local understanding of trauma-caused symptoms and psycho-
pathological dimensions, that is, how those symptoms and psychopathological dimensions are
thought to be generated in the culture in question. One must investigate local ways of talking
about––and experiencing––trauma-related disorder. As a result of these cultural frames, a patient
will interpret trauma symptoms in certain ways and will survey the body for evidence of having
certain cultural syndromes after being traumatized, of having certain spiritual-based problems.
Among Mozambique war victims, trauma-related disorder is frequently expressed in terms
of spirit possession.(20) In many cultures, certain somatic-type cultural syndromes are an impor-
tant part of trauma-related disorder: Among Spanish-speaking populations of the Caribbean,
ataque de nervios (21, 22); among Central Americans, a feeling of inner heat (23); and among civil
war victims in Sierra Leone, a “hypertension” (haypatεnsi) syndrome.(24) Among Cambodian
and Vietnamese refugees, weak heart is common way of understanding trauma-related symp-
toms. In these two cultures, weak heart is thought to cause a wide spectrum of symptoms: a
feeling of energy depletion, startle, uncontrollable worry. Weak heart also causes fear of death
from bodily dysfunction, especially cardiac arrest.(9, 25, 26) Among Cambodian refugees, vari-
ous culturally specific panic attacks are prominent among trauma victims: orthostatic panic, “hit-
by-the-wind” panic, neck-focused panic.(25–31) These panic attacks arise in large part due to
local catastrophic cognitions and misconceptions about the body’s physiology.
7. Does the factor structure of symptoms resulting from trauma vary across cultures?
In certain cultures, it may be that if you make an extensive list of symptoms––character-
istic of PTSD, somatization, and other disorders––and then run a factor analysis, the clustering
will radically vary across cultures. This clustering may result from the nature of the trauma
and from the cultural interpretation of symptoms. For example, the Cambodian syndrome of
weak heart will tend to cause panic symptoms, palpitations, and startle to be a prominent part
172 McFarlane and Hinton

of one factor. The structure of such factors will be clearer if the cultural syndrome, such as weak
heart, are also listed.
8. How do local cultural traditions aid in the recovery from trauma?
Studies document that certain cultural institutions may play a key role in recovering from
trauma: meditation among Cambodian refugees (32); ritual drumming in central Mozambique
(10); sweat lodge rituals among certain American Indian groups (for a review, see (33)); and the
transformation of iglata talk (drunken and boastful talk with peers) to waktoglaka talk (sober,
sometimes tearful talk about war experiences in ceremonial settings) among Northern Plains
Vietnam veterans, which is considered part of the process of “coming home.”(34)
9. How can state-of-the-art trauma treatments be adapted for patients in other cultural contexts?
For a treatment to be culturally acceptable and effective for a particular cultural group,
it should address prominent PTSD symptoms and dimensions (e.g., hyperarousal), comor-
bid DSM-IV conditions (e.g., panic disorder), psychopathological dimensions (e.g., low self-
esteem), and symptoms (e.g., sleep paralysis). And the treatment should specifically address
cultural syndromes prominent in trauma victims in that context, for example, ataque de nervios
among Puerto Rican groups, “wind overload,” neck-focused panic, and weak heart among
Cambodian refugees. Those syndromes may involve various pyschopathological dimensions:
depression, panic, anger. And for a treatment to be culturally acceptable and effective for a
particular cultural group, it may be that healing traditions of the culture in question should be
incorporated into treatment: Buddhist techniques for certain Asian populations.(32) Such treat-
ments may not only promote acceptability and increase personal and cultural self-esteem but
may also have important effects on specific dimensions of psychopathology.

Conclusion

In considering the effect of culture following traumatic events and describing its impact, there
are a series of potential misinterpretations that can occur. Kleinman (35) uses the term category
fallacy to refer to the mistake of assuming that our diagnostic categories will necessarily apply
to other groups, for instance, that the DSM-IV-defined PTSD adequately depicts the response to
traumatic events in other cultural groups. To avoid a category fallacy when studying trauma-
related disorder in another context, one must consider the questions we outlined above.
We use the term abstraction error to describe the error of assuming that if the members
of a cultural group are diagnosable as having PTSD then the relative prominence of DSM-IV
symptoms and their meaning is the same. Finding that a group is diagnosable as having PTSD
is just the beginning and not the end of the analysis.
We use the term content error to describe the mistake of assuming that the DSM-IV PTSD
symptoms adequately describe the full spectrum of trauma-caused symptoms in a certain cul-
ture. To attain “content validity” (36) in the conceptualization of trauma-related disorder for a
particular group, one needs to describe the full spectrum of trauma-related symptoms—and
syndromes––for that group. For example, dizziness and the cultural syndrome of weak heart
may be very prominent in certain cultural group and should be evaluated when assessing
trauma-related disorder (and treatment outcomes) for that group.
We suggest the term symptom fallacy to refer to the mistake of assuming that the meanings
associated with a certain symptom do not vary across groups, that the symptom meanings for
a person from a particular social, economic, and cultural position will apply exactly to a person
from a different social, economic, and cultural position. The identification of the presence of a
trauma-related symptom, such as anger, is just the beginning of the analysis; in addition, one
must identify the metaphors associated with the symptoms label (in the language in question),
trauma associations, the local understanding of the symptom, associated ethnophysiology, and
specific triggers (e.g., the acting-out behaviors of a gang-involved child).

References

  1. Barker P. 1998 (cited in Annan G). Ghosts, in New York Review; 1999.
  2. Bronfenbrenner U, Ceci SJ. Nature-nurture reconceptualized in developmental perspective: a
bioecological model. Psychol Rev 1994; 101(4): 568–86.
Ethnocultural Issues 173

  3. deVries. Trauma in cultural perspective, in traumatic stress: the effects of overwhelming experience
on mind, body and society, van der Kolk BA, McFarlane, AC, Wesiaeth L, ed. Guilford: New York,
1996: 398–413.
  4. Yehuda R, McFarlane AC. Conflict between current knowledge about posttraumatic stress disorder
and its original conceptual basis. Am J Psychiatry 1995; 152(12): 1705–13.
  5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed.
Washington DC; 1994.
  6. Hinton DE, Chhean D, Pich V et al. Assessment of posttraumatic stress disorder in Cambodian
refugees using the Clinician-Administered PTSD Scale: psychometric properties and symptom
severity. J Trauma Stress 2006; 19(3): 405–9.
  7. Wilson EO. Consilience: The Unity of Knowledge. Boston: Little, Brown; 1998.
  8. Norris FH, Weisshaar DL, Conrad ML et al. A qualitative analysis of posttraumatic stress among
Mexican victims of disaster. J Trauma Stress 2001; 14(4): 741–56.
  9. Heinemann Australian Dictionary. 4th ed. Victoria: Heinemann Educational Australia; 1992.
10. Rappaport RA. Ritual ecology and systems. New Haven, CT: Yale University Press, 1984: 1–7.
11. Chemtob CM. Posttraumatic stress disorder, trauma and culture, in International Review of Psychiatry.
Mak FL, Nadelson CC, ed. American Psychiatric Press: Washington DC, 1996; 257–92.
12. Brown GW, Prudo R. Psychiatric disorders in a rural and an urban population: Vol 1. Aetiology of
depression. Psychol Med 1981; 11: 581–99.
13. McCall GJ, Resick PA. A pilot study of PTSD symptoms among Kalahari Bushmen. J Trauma Stress
2003; 16(5): 445–50.
14. Devon H, Phalnarith BA, Sonith P; Khin UM. Panic disorder among Cambodian refugees attending a
psychiatric clinic. Prevalence and subtypes. Gen Hosp Psychiatry 2000; 22(6): 437–44.
15. Mainous AG 3rd, Smith DW, Acierno R, Geesey ME. Differences in posttraumatic stress disorder
symptoms between elderly non-Hispanic Whites and African Americans. J Natl Med Assoc 2005;
97(4): 546–9.
16. Raphael B, Meldrum L, McFarlane, Alexander C. Does debriefing after psychological trauma work?
Br Med J 1995; 310: 1479–80.
17. Mantel H. Killer Children. New York Rev Books, 1999: 4–5.
18. Winter J. Sites of Memory. Sites of Mourning. The Great War in European Cultural History. Cambridge:
Cambridge University Press; 1995.
19. Lifton RJ. Home from the War. New York: Basic Books; 1973.
20. Guarnaccia PJ, Canino G, Rubio-Stipec M, Bravo M. The prevalence of ataques de nervios in the
Puerto Rico disaster study. The role of culture in psychiatric epidemiology. J Nerv Ment Dis, 1993;
181(3): 157–65.
21. Caracciolo N ed. Uncertain refuge: Italy and the Jews during the holocaust. University of Illinois:
Illinois; 1995.
22. Judt T. The courage of the elementary. New York Rev Books, 1999: 31–8.
23. Herman J. Trauma and recovery. New York: Basic Books; 1992.
24. Buruma I. The wages of guilt: Memories of war in Germany and Japan. New York: Meridian Press;
1995.
25. Solomon Z. From denial to recognition: attitudes toward Holocaust survivors from World War II to
the present. J Trauma Stress 1995; 8(2): 215–28.
26. Bloom SL ed. Our hearts and our hopes are turned to peace: Origins of the International Society for
Traumatic Stress Studies. International Handbook of Human Response to Trauma, ed. Shalev AY,
Yehuda R, McFarlane AC. Kluwer/Plenum: New York, 2000; 27–50.
27. Deacon TW. The Symbolic Species. The Co-evolution of Language and the Brain. New York: WW
Norton; 1997.
28. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed.
Washington, DC: American Psychiatric Association; 1980.
29. Janet P. Les Medications Psychologiques. Paris: Felix Alcan; 1919.
30. Van Der Kolk BA, Burbridge JA, Suzuki J. The psychobiology of traumatic memory. Clinical
implications of neuroimaging studies. Ann N Y Acad Sci 1997; 821: 99–113.
31. Fussell P. The Great War and Modern Memory. London: Oxford University Press; 1975.
32. Sassoon S. Memoirs of an Infantry Officer. London: Faber and Faber; 1930.
33. Langer LL. Holocaust Testimonies: The Ruins of Memory. New Haven CT: Yale University Press;
1991.
34. Grossman D. On Killing: the psychological cost of learning to kill in war and society. Boston: Little,
Brown; 1997.
35. Frueh BC, Brady KL, de Arellano MA. Racial differences in combat-related PTSD: empirical findings
and conceptual issues. Clin Psychol Rev 1998; 18(3): 287–305.
36. de Girolamo G McFarlane AC, ed. Epidemiology of victims of international violence: a review of the
literature. Int Rev Psychiatry, ed. Mak FL, Nadelson CC. American Psychiatric Press: Washington DC,
1996; 2: 93–119.
174 McFarlane and Hinton

37. Hinton DE, Pich V, Chhean D, Pollack MH. ‘The ghost pushes you down’: sleep paralysis-type panic
attacks in a Khmer refugee population. Transcult Psychiatry 2005; 42(1): 46–77.
38. Silove D ed. Torture and refugee trauma; implications for nosology and treatment of posttraumatic
syndromes. International Review of Psychiatry, ed. Mak FL, Nadelson CC. American Psychiatric
Press: Washington DC, 1996; 211–32.
39. Kulka RA, Schlenger WE, Fairbank JA et al. Trauma and the Vietnam War Generation: Report of
Findings from the National Vietnam Veterans Readjustment Study. New York: Brunner/Mazel;
1990.
40. Laufer KS, Yager T, Frey-Wouters E et al. Comparative Adjustments of Veterans and their Peers, Vol
3. Post-war Trauma: Social and Psychological Problems of Vietnam Veterans in the Aftermath of the
Vietnam War. New York: Center for Policy Research; 1981.
41. MacDonald C, Chamberlain K, Long N. Race, combat, and PTSD in a community sample of New
Zealand Vietnam War veterans. J Trauma Stress 1997; 10(1): 117–24.
42. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National
Comorbidity Survey. Arch Gen Psychiatry 1995; 52(12): 1048–60.
43. Loo LM. An integrative-sequential treatment model for posttraumatic stress disorder: a case study of
the Japanese-American internment and redress. Clin Psychol Rev 1993; 13: 89–117.
44. Hamada, R, Chemtob CM, Sautner R, Sato R. Ethnic identity and Vietnam: a Japanese-American
Vietnam veteran with PTSD. Hawaii Med J 1988; 47(3): 100–2, 105–6, 109.
45. Loo CM, Karam S, Ray S, Bill K. Race-related stress among Asian American veterans: a model to
enhance diagnosis and treatment. Cult Divers Ment Health 1998; 4(2): 75–90.
46. Kinzie JD, Boehnlein JK, Leung PK et al. The prevalence of posttraumatic stress disorder and its
clinical significance among Southeast Asian refugees. Am J Psychiatry 1990; 147(7): 913–7.
47. Mattson S. Mental health of southeast Asian refugee women: an overview. Health Care Women Int
1993; 14: 155–65.
48. Kagee A. Do South African former detainees experience post-traumatic stress? Circumventing the
demand characteristics of psychological assessment. Transcult Psychiatry 2004; 41(3): 323–36.
49. Green BL ed. Cross-national and ethnocultural issues in disaster research. Ethnocultural aspects of
posttraumatic stress disorder: issues, research and clinical applications, ed. Marsella AJ, Friedman
MJ, Gerrity ET, Scurfield RM. American Psychological Applications: Washington DC, 1996: 341–61.
50. Lima BR, Pai S, Santacruz H. Psychiatric disorders in primary health care clinics one year after a
major Latin American disaster. Stress Medicine 1991; 7: 25–32.
51. Igreja V. ‘Why are there so many drums playing until dawn?’ Exploring the role of Gamba spirits and
healers in the post-war recovery period in Gorongosa, Central Mozambique. Transcult Psychiatry
2003; 40(4): 459–87.
52. de la Puente R. The mental health consequences of the 1985 earthquakes in Mexico. Int J Ment Health
1990; 19: 21–9.
53. Soloman SD, Canino GJ. Appropriateness of DSM-III-R criteria for posttraumatic stress disorder.
Compr Psych 1990; 31: 227–37.
54. McFarlane AC, van der Kolk BA. The long-term effect of psychological trauma: a public health issue
in Kuwait. Med Principles Pract 1996; 5: 59–75.
55. Sack WH, Seeley JR, Clarke GN. Does PTSD transcend cultural barriers? A study from the Khmer
Adolescent Refugee Project. J Am Acad Child Adolesc Psychiatry 1997; 36(1): 49–54.
56. Priebe S, Esmaili S. Long-term mental sequelae of torture in Iran--who seeks treatment? J Nerv Ment
Dis 1997; 185(2): 74–7.
57. Scurfield RM. Healing the warrior: admission of two American Indian war-veteran cohort groups to
a specialized inpatient PTSD unit. Am Indian Alsk Native Ment Health Res 1995; 6(3): 1–22.
58. Rosenheck R, Fontana A. Race and outcome of treatment for veterans suffering from PTSD. J Trauma
Stress 1996; 9(2): 343–51.
59. Schreiber S. Migration, traumatic bereavement and transcultural aspects of psychological healing:
loss and grief of a refugee woman from Begameder country in Ethiopia. Br J Med Psychol 1995; 68:
135–42.
60. Jorm AF, Korten AE, Jacomb PA et al. “Mental health literacy”: a survey of the public’s ability to
recognise mental disorders and their beliefs about the effectiveness of treatment. Med J Aust 1997;
166(4): 182–6.
61. Cheung P. Somatisation as a presentation in depression and post-traumatic stress disorder among
Cambodian refugees. Aust N Z J Psychiatry 1993; 27(3): 422–8.
62. Kirmayer LJ. ed. Confusion of the senses: implications of ethnocultural variations in somatoform
and dissociative disorders for PTSD. Ethnocultural aspects of posttraumatic stress disorder: issues,
research and clinical applications ed. Marsella AJ, Friedman MJ, Gerrity ET, Scurfield RM. American
Psychological Association: Washington DC, 1996; 131–63.
63. Uwanyiligira E. La Souffrance Psychologique des Survivants des Massacres au Rwanda: Approaches
Therapeutique. Nouvelle Revue d’Ethnopsychiatrie, 1997; 34: 87–104.
64. Balint M. The Doctor, his Patient and the Illness. London: Pitman; 1957.
Ethnocultural Issues 175

65. Showalter E. Hysterical Epidemics and Modern Culture. London: Picador; 1997.
66. Hall W. The Agent Orange controversy after the Evatt Royal Commission. Med J Aust 1986; 145(5):
219–25.
67. Hughes R. Culture of Complaint: The Fraying of America. New York: Oxford University Press; 1993.
68. Conrad P. Modern Times: Modern Places. Life and Art in the 20th Century. London: Thames and
Hudson; 1998.
69. Bagilishya D. Mourning and Recovery from Trauma; in Rwanda, Tears Flow Within. Transcult
Psychiatry 2000; 37: 337–53.
70. Hinton DE, Chhean D, Pich V, Hofmann SG, Barlow DH. Tinnitus among Cambodian refugees:
relationship to PTSD severity. J Trauma Stress 2006; 19(4): 541–6.
13 Posttraumatic stress disorder after disasters
Andrea R Maxwell and Sandro Galea

Introduction

In a national study of the U.S. population, 15% of women and 19% of men reported exposure
to a natural disaster during their lifetime.(1) Although a range of psychopathologies can occur
after these events (2, 3), posttraumatic stress disorder (PTSD) is the most commonly studied
and likely the sentinel psychopathology after exposure to a disaster.(3–6) In this chapter we
present (a) an overview of the current evidence in the field regarding PTSD and disasters,
(b) the challenges of postdisaster research with consideration of how these may influence our
understanding of the consequences of disasters, and (c) future research directions to strengthen
the field of PTSD and disasters. Before we embark on the chapter, we note two limitations.
First, we do not intend this chapter to be a comprehensive review of all current evidence in the
field of PTSD and disasters; instead, we provide a summary of some of this evidence, largely
drawing from previous reviews in the field.(3–6). Second, substantial debate exists in the peer-
reviewed literature as to what constitutes a disaster. We refer the reader to other work that has
considered this question in greater detail.(7) In the context of this chapter, we consider disasters
to be unexpected and acute events that can be human made, technological, or natural.(3, 7)

Summary of evidence regarding PTSD after disasters

We first consider the prevalence of PTSD after disasters among specific groups that are largely
defined by their type and intensity of exposure: survivors, rescue workers, the general popula-
tion, and children. This is followed by evidence from the literature regarding various sociode-
mographic covariates of PTSD after disasters—gender, social support, age, socioeconomic status,
and race or ethnicity. We also note—reflecting the predominant analytic mode of most disaster
literature—that we use the term prevalence rather than incidence to document the burden of PTSD
after disasters because very few studies have ensured predisaster PTSD was absent in their par-
ticipants. This convention is consistent with previous reviews in the literature.(4, 5)

Studies of human-made and technological disasters

In general, a high prevalence of PTSD has been documented among survivors of human-made
or technological disasters, ranging from approximately 20% to 75%.(4, 5) For example, a study
of the 1993 religious uprisings in Sivas, Turkey, found that the prevalence of PTSD 1 month
postdisaster was 20.3% among survivors.(8) At the other extreme, by retrospectively assessing
survivors of the 1998 Piper Alpha oil rig disaster 10 years postdisaster, Hull and colleagues
showed that the prevalence of PTSD was 73% among survivors 3 months postdisaster.(9)
Another study that assessed PTSD around 6 months after the 1995 Oklahoma City bombing
found that 34.3% of survivors had PTSD (10); a similar burden of PTSD was found 1 month
after the 1991 mass shooting in Killeen, Texas (11), 6 months after the 1992 Biljermeer plane
crash (12), and 13 months after the 1998 Lockerbie plane crash.(13)
A substantial burden of PTSD has also been found among rescue workers after disasters.
For instance, a substantial proportion of police officers were found to exhibit PTSD symptoms
1 to 2 years after the 1989 Hillsborough football stadium disaster in Sheffield, UK—44.3% exhib-
ited severe symptoms, while an additional 41.4% exhibited moderate symptoms.(14) Studies of
rescue workers after the September 11 terrorist attacks in New York City found that the preva-
lence of PTSD ranged from 22.5% at 2 weeks (15) to 20% 10 to 15 months after exposure.(16)
After the 1989 USS Iowa gun turret explosion, 11% of volunteer disaster workers suffered from
PTSD 1 month postdisaster.(17) Potentially complicating cross-study comparability of these
Posttraumatic stress disorder after disasters 177

results, the percent of rescue workers with PTSD may differ depending on the type of work
performed. A study that assessed the prevalence of PTSD among rescue workers 2 to 3 years
after the September 11 terrorists attacks in New York City found that the overall prevalence of
PTSD was 12.4% but that of unaffiliated volunteers and construction/engineer workers was
especially high—21.2% and 17.8%, respectively.(18)
Studies that have assessed the psychological burden of disasters among the general pop-
ulation have generally found, not surprisingly, a lower prevalence of PTSD than that of sur-
vivors or rescue workers.(4) After the Los Angeles civil disturbances, Hanson and colleagues
estimated that the prevalence of PTSD 6 to 8 months after these disturbances was 4.1% in the
general population.(19) Subsequent work of general populations collected within 12 months
of disasters such as the September 11 terrorist attacks in New York City (20–22), the 1989 Exxon
Valdez oil spill (23), and the 2004 train bombings in Madrid (24), found a similar burden of
PTSD in relevant areas.
Because only a small number of studies have evaluated the prevalence of PTSD among
children, few conclusions can be drawn as to the effect of disasters on them. After the 2001
chemical factory explosion in Toulouse, France, Godeau and colleagues found that 44.6% of
directly exposed children aged 11 to 13 years and 28.5% of directly exposed children aged 15 to
17 years had symptoms consistent with PTSD.(25) In addition, the prevalence of PTSD among
children was documented to be 38.4% 1 month after the 1984 school sniper attack in Los Angeles
(26); 27% 3 months after the 1993 World Trace Center Bombing (27); 11.9% 9 months after the
1991 industrial fire in Hamlet, North Carolina, (28); and 18.4% 6 months after the September 11
attacks in New York City.(29) For a comprehensive review of the literature surrounding chil-
dren and human-made disasters, see a review by Pfefferbuam and colleagues (30).
Although a wide range of correlates of PTSD after disasters have been examined, some fac-
tors have been studied repeatedly in the literature and merit brief comment. First, it is clear from the
body of postdisaster research that the single central predictor of PTSD after disasters is the degree of
exposure to the event.(2) As noted in our above summary of prevalences, the groups with the great-
est direct exposure to disasters are also those that have a greater likelihood of developing PTSD.
Similarly, within each exposure group, those with the most disaster-related traumatic events are the
persons who have the greatest risk of developing PTSD. In terms of sociodemographic correlates,
female gender has consistently been shown to be a risk factor for postdisaster PTSD.(23, 28, 31–34)
In fact, most studies suggest that women have a nearly a twofold greater risk than men of PTSD,
given comparable disaster-related exposure.(4) Some studies have also shown that social support
is protective after disasters.(35, 36) In contrast, the evidence as to the effect of age (37–39), socioeco-
nomic differences, such as the level of education (40–42), and race or ethnicity (20, 28, 43, 44) on the
prevalence of PTSD after disasters has been inconsistent.

Studies of natural disasters

Many of the observations that can be drawn from natural disasters are similar to those drawn
from technological and human-made disasters. For example, the prevalence of PTSD among
highly exposed survivors was 24% 3 months after a 2000 Icelandic earthquake (45), 18.3%
6 months after the 1989 Newcastle earthquake (46), and 23% 14 months after the 1999 earth-
quake in Turkey.(47) After the 1988 Armenian earthquakes, a much higher prevalence (92%)
was found among a nonrepresentative sample of survivors 2.5 years after exposure.(48)
Few studies have evaluated PTSD among rescue workers postdisaster, but in general, those
conducted have documented a high prevalence. For example, 7 to 13 weeks after the Hurricane
Katrina in 2005, 22% of firefighters and 19% of police officers in New Orleans met PTSD diag-
nostic criterion. (49) A comparable prevalence of PTSD was found among rescue workers both
after the 2003 Bingol, Turkey earthquake—23% 2 months postdisaster (50) and after the 1999
Taiwan earthquake—21.4% 5 months postdisaster.(51)
Among the general population, the prevalence is largely lower than that of survivors
or rescue workers. After the 2003 bushfires in Australia, 5% of young adults met criterion for
PTSD 5 to 18 months postdisaster (52); correspondingly, 3.7% of a community affected by the
1985 Puerto Rican floods suffered from PTSD 2 years postdisaster.(53) In a community 100 km
away from the epicenter of the 1999 Turkey earthquake, the prevalence of PTSD was 14% 14
months postdisaster (47); a similar prevalence was found in affected communities 6 months
after the 1999 Mexican floods (54) and 2 months after the 2004 tsunami in Asia.(55)
178 Maxwell and Galea

A number of studies have assessed the impact of natural disasters on children and have
largely showed a substantial burden of PTSD among this population. Six months after Hurricane
Mitch in 1998, the prevalence of PTSD among adolescents ranged from 14% to 90%, dependent
on the dose of exposure (56); another study found that the prevalence of PTSD ranged from 26%
to 95% in different communities 1.5 years after the 1988 earthquake in Armenia, with the preva-
lence again dependent on the level of exposure.(57) In addition, 56% of school-aged children
had moderate to very severe symptoms of PTSD 3 months after Hurricane Andrew in 1992 (58),
results that were comparable to a study conducted 6 months after Hurricane Floyd.(59)
Analogous to the evidence for technological and human-made disasters, women are
more likely than men to suffer from PTSD after disasters.(46, 60–63) Low social support may
also contribute to greater PTSD symptomatology.(64–66) However, the evidence regarding age
(63, 67), socioeconomic status (67–69), and race or ethnicity (61, 70, 71) remains inconclusive.

Methodological challenges of postdisaster research

The challenges of postdisaster research are many and greatly influence our understanding of
the mental health consequences of disasters. In examining some of these challenges, we start
with a discussion of how the aftermath of a disaster affects development of the research plan
and researchers themselves. We then turn our attention to issues surrounding sampling of the
affected community, defining and finding the population of interest and garnering participation.
This is followed by a consideration of how exposure and PTSD are characterized in individual
studies and the effect of these characterizations on cross-study comparability. We end with a dis-
cussion of the difficulties inherent in measuring and analyzing covariates and health indicators.

Research plans and researchers

By their nature, disasters are largely unanticipated and disruptive. The aftermath of a disas-
ter can be chaotic, with concurrent interruption of infrastructure ranging from telephone ser-
vice to hospitals. These are hardly optimal conditions under which to initiate a research study.
Research is typically long planned, completed under highly controlled circumstances, and
supported by a wide spectrum of resources—all characteristics that may not be possible in
a postdisaster setting. The effect of disasters on researchers themselves can also be complex.
Oftentimes researchers may effectively function as the first wave of responders in postdisas-
ter circumstances—an unfamiliar position for many that leads to complications. For example,
anecdotal evidence in the field suggests that researchers—especially mental health clinicians—
may identify with research participants affected by the disaster (57, 72), potentially limiting
their objectivity and compromising their research.

Sampling the affected community

The difficulty of launching a research plan after a disaster has led to a preponderance of con-
venience sampling in the field.(3, 6) In cases where no other sampling method was feasible,
convenience samples have contributed to the field and illuminated areas for further research.
(18, 73) Overall, though, the conclusions that can be drawn from such studies are limited. In
addition, the challenge of procuring a representative sample in postdisaster circumstances
has greatly limited cross-study comparability in the field.(4) Here we discuss three aspects of
recruiting a representative sample: defining the population of interest, finding this population,
and acquiring participants.
In the process of defining a population for study, not only must the level and type of
exposure—the “affected”—be delineated but also what constitutes the “who.” For example,
many studies have considered how disaster circumstances affect rescue workers, but who is
included in this definition? Many studies have exclusively focused on police workers and fire-
fighters, but Perrin and colleagues recently showed that unaffiliated volunteers, construction
workers, and engineers were affected more than their traditional counterparts.(18)
Finding a population can also be difficult in postdisaster circumstances, as persons may
be displaced and/or mobile after a disaster. A study that assessed the mental health of the
affected population after Hurricane Katrina had difficulties tracking participants due to their
mobility.(74) In addition, after Hurricane Katrina, many undocumented migrant workers left
Posttraumatic stress disorder after disasters 179

the area; as a result, studies that assessed the mental health burden after this event likely under-
counted these persons.(75)
Even after a population is defined and found, the difficulties in enrolling participants
can be considerable. Persons affected by the disaster may be hesitant to enroll in research not
related to service utilization; in some communities this may be compounded by a mistrust of
the medical and research field.(76) However, research has shown that those who do partici-
pate make favorable cost–benefits appraisals of their participation (77), and the majority are
not adversely affected by research participation.(78, 79) Language and cultural barriers may
also limit the ability of researchers to reach a community. For example, after the Marmara
earthquake in Turkey, the refusal rate of potential female participants was higher when the
interviewees were male as opposed to female.(47) All of these factors may limit the ability of
researchers to adequately sample a population and elicit the relevant information from these
communities.

Characterization of exposure and PTSD

Due to the heterogeneous nature of disasters, the resulting exposure after a particular disaster
is likely unique. Assuming that the nature of exposure is related to broad categories of disasters
such as “natural disasters” may even be problematic, as one natural disaster may differ greatly
from another. Instead, specific dimensions such as duration and intensity may be more rele-
vant for characterization of the exposure. For example, a disaster that unfolds slowly over time
such as the Chernobyl disaster (80) may be characterized by prolonged exposure, while the
exposure after a mass shooting—a “point” event—may be characterized as acute.(81) Because
of the unique nature of exposure, drawing generalizations across studies in the literature must
be performed carefully with consideration of these limitations.
The changing definitions of PTSD over the years may also affect the ability to compare
results among studies in the field of PTSD and disasters. As is documented elsewhere in this
book, the definition of PTSD has changed since its introduction under the auspices of DSM-III
in 1980.(82) Meaningful differences have been introduced in the revised edition of the DSM-III
(DSM-III-R) published in 1987 (83) and in the DSM-IV criterion, introduced in 1994.(84) While
this changing definition of PTSD is a challenge to all PTSD research, it is particularly important
in the context of disaster-related research where only a handful of studies may be conducted
after any given disaster. This results in comparisons across DSM eras being near inevitable in
the field for the purposes of drawing generalizable inference.

Covariate assessment
The challenges associated with assessing covariates that may influence the central associations
of interest are not unique to postdisaster research but are greatly heightened by the scarcity of
research after any particular disaster. The covariates assessed frequently differ from study to
study, limiting the ability to determine the covariates most important for predicting psychopa-
thology and to compare studies both within disasters and across disasters. Certain covariates
like gender are regularly measured by postdisaster studies (68, 85), but others like perievent
emotional reactions are not.(86) Effects of additional covariates such as socioeconomic status,
social support, racial identity, and other demographical characteristics remain to be illuminated.
In addition, studies frequently use different models to assess the relationship between covariates
and psychopathology; because of this, their association is often obscured.(4, 5, 87) For example,
Weismann and colleagues found that it was not gender itself but rather the underlying social
and economic circumstances that explained the relationship between gender and PTSD observed
in most studies.(88) Clearly, much more work needs to be carried out to aid our understanding
of correlates for PTSD. In nondisaster research, the abundance of studies often overcomes these
limitations, but studies of disasters are limited in number, accentuating these difficulties.

Assessing incident disorders

One of the central difficulties in assessing psychopathology after disasters is demonstrating
that the case is a “new”—or incident—case. Due to the unpredictability of disasters, predisaster
measures of mental disorders such as PTSD are rarely available. Some exceptions exist (89, 90),
but these are largely where preexisting studies were in place. For a case to be potentially caused
180 Maxwell and Galea

by a disaster, its onset must occur after the event; unfortunately, most disaster studies have
limited access to the timeline of disease onset due to the lack of preexisting data. For a further
discussion of the problems of postonly studies and approaches to address them, we refer the
reader to other resources.(91)
Another challenge to measuring health indicators after disasters is characterizing the full
breadth of psychopathology that may occur. While PTSD is likely the sentinel disaster psycho-
pathology (92) and the focus of most postdisaster research, (3, 6) it may often manifest with con-
current comorbidity.(93) Studies of disasters increasingly need to consider these comorbidities
to fully assess the mental health burden after disasters and the patterns of PTSD manifestation
postdisaster. For example, a number of studies have found a higher prevalence of depression
among those affected by postdisaster PTSD as compared to controls.(10, 47, 57, 94–96) Some
studies have also shown postdisaster PTSD to be associated with anxiety disorders (94–96),
substance abuse (31, 97), somatization (98), and functional impairment.(10, 99, 100) However,
most of this evidence remains inconclusive due to the limited number of comparable studies.
Lastly, postdisaster studies are increasingly incorporating biological measures into their
measurements to elucidate the relationship between mental disorders and the underlying bio-
chemical and genetic factors.(101, 102) Including these measures creates another dimension
of issues for disaster research, such as the reliability of these measures and their feasibility in
postdisaster circumstances. This area of research will likely become increasingly important in
the coming years.

Research directions

We suggest that there are four central directions for future research in the field: (a) compre-
hensive research for comorbid disorders, (b) studies concerned with the nature of disaster
exposure, (c) inquiry about the course of PTSD, and (d) interventional studies and the need to
determine effective treatments of PTSD after disasters.

Comorbid disorders
As shown earlier, PTSD may manifest with concurrent comorbid disorders such as depression,
substance abuse, and anxiety disorder. However, studies have yet to fully characterize what
these comorbid disorders may be and the longitudinal course of them in conjunction with
PTSD. In addition, the long-term physical consequences of PTSD need to be examined to fully
assess the burden of the disease. For example, a recent study showed that PTSD might increase
the risk of cardiovascular disease.(103) Further studies similar to this need to be conducted, to
confirm this finding and explore other potential physical manifestations of PTSD.

Exposure
As we note in this review, overall, evidence from the literature and reviews of this evidence show
that a higher disaster-related exposure is associated with a higher prevalence of PTSD.(4, 5, 21,
22, 25, 47, 55, 80, 104) For instance, those closest to the site of the disaster have been documented
to have a higher prevalence of PTSD than those further away.(22, 25, 47, 80) In addition, as seen
above, the prevalence of PTSD is typically highest among survivors, followed by rescue workers,
with the general population having the lowest prevalence of PTSD. These three types of samples
represent the heterogeneous nature of exposure among the affected population. For example,
survivors directly experienced the attack itself, while rescue workers directly experienced the
aftermath of the attack. In contrast, the exposure for the general population is typically indirect:
Some people may have lost a friend or family member, suffered a poor outcome from the disaster
such as displacement or employment loss, or experienced the disaster through the media.
Whether indirect exposure is sufficient for causing psychopathology in the general popu-
lation is currently in debate in the literature. In a study of primary care patients, Neria and col-
leagues found that indirect exposure was not related to the risk of PTSD.(44) However, studies
of national populations after September 11 (22, 105) and population in an area far from the
Oklahoma City bombing (106) indicate that a relation may exist between the two. Models that
have been suggested to mediate this relation include widespread media exposure to mediums
Posttraumatic stress disorder after disasters 181

such as television (107, 108) and perceived threat and relative risk appraisal.(109) Future work
that examines the relation between PTSD and indirect exposure, as well as potential mecha-
nisms that mediate this relation, is well indicated.
In addition, the concept of indirect exposure raises important considerations about the
burden of PTSD after disasters. Because a greater number of people are indirectly exposed to
disasters rather than directly exposed, the overall health burden may be weighted toward those
who are indirectly exposed and show signs of partial PTSD rather than survivors who have full
PTSD.(4, 5) This may have important implications for public health policies after disasters.

Course of PTSD and longitudinal studies

The uncertainty surrounding the exact trajectory of PTSD after disasters reveals the need for
more longitudinal studies in the field, as the risk factors for persistent PTSD and the course
of delayed-onset PTSD have yet to be determined. Typically, postdisaster studies have relied
on cross-sectional studies (6) that provide an illustration of a population at one point in time,
thereby estimating the burden of mental health, which is useful to both researchers and public
health officials.(110) However, establishing how this burden evolves over time is very difficult
with this type of study.
In general, researchers have found that the prevalence of PTSD decreases over time.(5)
A study of survivors of a mass shooting found that the prevalence of PTSD decreased from 28%
1 to 2 months after the incident to 17% 1 year later.(81) A similar decline was found in studies
of the NYC population after the September 11 attacks (111), a community affected by the 1988
Lockerbie disaster (13), survivors of the 2004 Asian earthquake and tsunamis (55), and survi-
vors of the 1989 Newcastle earthquake.(112) Among children, La Greca and colleagues found
that 3 months after Hurricane Andrew, 29.8% experienced severe to very severe symptoms of
PTSD; this declined to 18.1% at 7 months and 12.5% at 10 months.(65) A similar decrease was
found by a study that assessed the functioning of children after the 1993 World Trade Center
attacks.(27) Studies of rescue workers after the 1988 Piper Alpha oil rig disaster (90) and the
USS Iowa gun turret explosion (17) have also documented a decline in the prevalence of PTSD
over time. Furthermore, a study of the general U.S. population after the September 11 attacks
showed a decrease in PTSD from 17% at 2 months to 5.8% at 6 months, indicating that the
prevalence of PTSD may also decrease among indirectly exposed persons.(105)
However, the persistence of PTSD in some populations has yet to be fully character-
ized. Norris and colleagues found that the prevalence of PTSD among survivors of Hurricane
Andrew slightly increased from 26% at 6 month to 29% 30 months postdisaster.(113) Similarly,
a study after a 1998 earthquake in Northern China found that the prevalence of PTSD increased
between 3 and 9 months in 2 affected villages.(114) Delayed-onset PTSD may also compli-
cate the projected course of PTSD, as McFarlane found in a study of firefighters after the 1983
Australian bush fire.(115) Future work may fruitfully examine the course of PTSD and corre-
lates of persistent PTSD.

Interventional studies
We address the topic of interventional studies for postdisaster treatment of PTSD briefly, refer-
ring the interested reader to a more complete review of interventional treatments.(116) Most
research to date has considered survivors of traumatic events in general, rather than focusing
on survivors of disasters. Even drawing from this wider arena of research, the evidence is
inconsistent. In fact, a recent meta-analysis showed that single-session critical-incident debrief-
ing—once a commonly used clinical intervention—may actually be harmful.(117) Overall,
cognitive–behavioral therapy (CBT) may currently be the most promising psychosocial inter-
vention, as indicated by research.(116) Studies have shown that CBT initiated within the first
month after a trauma may prevent psychological sequelae as compared to other interventional
methods such as supportive counseling or repeated assessments.(118–120) For pharmacother-
apy, SSRIs are often used as the first-line medications for the treatment of PTSD.(121)
The evidence regarding effective treatments, specifically after disasters, is sparse, as few
studies have been conducted in postdisaster circumstances.(122, 123, 124) Many therapies,
ranging from psychological to pharmacological, have yet to be evaluated in the postdisaster
context, thereby limiting the ability of communities and governments to mitigate the mental
health consequences of disasters.
182 Maxwell and Galea

Conclusion

Many methodological challenges are inherent in the study of postdisaster mental health con-
sequences. Because of these challenges, several aspects of postdisaster PTSD remain largely
underdeveloped in the literature. For example, the prevalence of PTSD after disasters has been
well characterized in some populations; however, in others such as children or those of low
socioeconomic status, further work needs to be conducted. More important, while the course
of PTSD after disasters is still a nascent area of research, more longitudinal studies of represen-
tative populations could greatly assist in the determination of trajectories of PTSD such as the
occurrence of delayed-onset PTSD. Furthermore, the field has yet to fully determine the effect
of comorbid disorders and indirect exposure on the burden of PTSD. Future work also needs
to explore the role of different interventions in mitigating PTSD after disasters. These subjects
represent integral areas of inquiry for the improvement of both the postdisaster research field
and postdisaster public health practice.

References

   1. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the
national comorbidity survey, Arch Gen Psychiatry 1995; 52: 1048–60.
   2. Neria Y, Gross R, Marhsall R eds. 9/11: Mental Health in the Wake of Terrorist Attacks. Cambridge
University Press: New York; 2006.
   3. Norris FH, Elrod CL. Psychosocial consequences of disaster: a review of past research. In: Norris FH,
Galea S, Friedman MJ, Watson PJ, eds. Methods for Disaster Mental Health Research. The Guilford
Press: New York, 2006: 20–42.
   4. Galea S, Nandi A, Vlahov D. The epidemiology of post-traumatic stress disorder after disasters.
Epidemiol Rev 2005; 27: 78–91.
   5. Neria Y, Nandi A, Galea S. Post-traumatic stress disorder following disasters: a systematic review,
Psychol Med 2008; 38: 467–80.
   6. Norris FH, Friedman MJ, Watson PJ. 60,000 disaster victims speak: Part I, An empirical review of the
empirical literature, 1981–2001, Psychiatry 2002; 65: 207–39.
   7. McFarlane AC, Norris FH. Definitions and concepts in disaster research. In: Norris FH, Galea S,
Friedman MJ, Watson PJ, eds. Methods for Disaster Mental Health Research. The Guilford Press:
New York, 2006; 3–19.
   8. Sungur M, Kaya B. The onset and longitudinal course of a man-made post-traumatic morbidity:
survivors of the Sivas disaster. Int J Psychiatry Clin Pract 2001; 5: 195–202.
   9. Hull AM, Alexander DA, Klein S. Survivors of the Piper Alpha oil platform disaster: long-term
follow-up study. Br J Psychiatry 2002; 181: 433–8.
  10. North CS, Nixon SJ, Shariat S et al. Psychiatric disorders among survivors of the Oklahoma City
bombing. JAMA 1999; 282: 755–62.
  11. North CS, Smith EM, Spitznagel EL. Posttraumatic stress disorder in survivors of a mass shooting.
Am J Psychiatry 1994; 151: 82–8.
  12. Carlier IV, Gersons BP. Stress reactions in disaster victims following the Bijlmermeer plane crash.
J Trauma Stress 1997; 10: 329–35.
  13. Scott RB, Brooks N, McKinlay W. Post-traumatic morbidity in a civilian community of litigants: a
follow-up at 3 years. J Trauma Stress 1995; 8: 403–17.
  14. Sims A, Sims D. The phenomenology of post-traumatic stress disorder. A symptomatic study of 70
victims of psychological trauma. Psychopathology 1998; 31: 96–112.
  15. Fullerton CS, Ursano RJ, Reeves J, Shigemura J, Grieger T. Perceived safety in disaster workers
following 9/11, J Nerv Ment Dis 2006; 194: 61–3.
  16. Centers for Disease Control and Prevention, Mental health status of World Trade Center rescue and
recovery workers and volunteers - New York City, July 2002-August 2004, MMWR Morb Mortal
Wkly Rep 2004; 53: 812–5.
  17. Ursano RJ, Fullerton CS, Kao TC, Bhartiya VR. Longitudinal assessment of posttraumatic stress
disorder and depression after exposure to traumatic death. J Nerv Ment Dis 1995; 183: 36–42.
  18. Perrin MA, DiGrande L, Wheeler K et al. Differences in PTSD prevalence and associated risk factors
among World Trade Center disaster rescue and recovery workers, Am J Psychiatry 2007; 164: 1385–94.
  19. Hanson RF, Kilpatrick DG, Freedy JR, Saunders BE. Los Angeles County after the 1992 civil disturbances:
degree of exposure and impact on mental health. J Consult Clin Psychol 1995; 63: 987–96.
  20. Adams RE, Boscarino JA. Differences in mental health outcomes among Whites, African Americans,
and Hispanics following a community disaster. Psychiatry 2005; 68: 250–65.
Posttraumatic stress disorder after disasters 183

  21. Galea S, Ahern J, Resnick H et al. Psychological sequelae of the September 11 terrorist attacks in New
York City. N Engl J Med 2002; 346: 982–7.
  22. Schlenger WE, Caddell JM, Ebert L et al. Psychological reactions to terrorist attacks: findings from
the national study of Americans’ reactions to September 11. JAMA 2002; 288: 581–8.
  23. Palinkas LA, Petterson JS, Russell J, Downs MA. Community patterns of psychiatric disorders after
the Exxon Valdez oil spill. Am J Psychiatry 1993; 150: 1517–23.
  24. Miguel-Tobal JJ, Cano-Vindel A, Gonzalez-Ordi H et al. PTSD and depression after the Madrid
March 11 train bombings. J Trauma Stress 2006; 19: 69–80.
  25. Godeau E, Vignes C, Navarro F et al. Effects of a large-scale industrial disaster on rates of symptoms
consistent with posttraumatic stress disorders among schoolchildren in Toulouse. Arch Pediatr
Adolesc Med 2005; 159: 579–84.
  26. Pynoos RS, Frederick C, Nader K et al. Life threat and posttraumatic stress in school-age children.
Arch Gen Psychiatry 1987; 44: 1057–63.
  27. Koplewicz HS, Vogel JM, Solanto MV et al. Child and parent response to the 1993 World Trade
Center bombing. J Trauma Stress 2002; 15: 77–85.
  28. March JS, Amaya-Jackson L, Terry R. Posttraumatic symptomatology in children and adolescents
after an industrial fire. J Am Acad Child Adolesc Psychiatry 1997; 36: 1080–8.
  29. Hoven CW, Duarte CS, Lucas CP et al. Psychopathology among New York city public school children
6 months after September 11. Arch Gen Psychiatry 2005; 62: 545–52.
  30. Pfefferbaum B, Pfefferbaum RL, Gurwitch RH et al. Children’s response to terrorism: a critical
review of the literature. Curr Psychiatry Rep 2003; 5: 95–100.
  31. Grieger TA, Fullerton CS, Ursano RJ. Posttraumatic stress disorder, alcohol use, and perceived safety
after the terrorist attack on the pentagon. Psychiatr Serv 2003; 54: 1380–2.
  32. Pulcino T, Galea S, Ahern J. Posttraumatic stress in women after the September 11 terrorist attacks in
New York City, J Womens Health (Larchmt) 2003; 12: 809–20.
  33. Schuster MA, Stein BD, Jaycox L et al. A national survey of stress reactions after the September 11,
2001, terrorist attacks. N Engl J Med 2001; 345: 1507–12.
  34. Green BL, Korol M, Grace MC et al. Children and disaster: age, gender, and parental effects on PTSD
symptoms. J Am Acad Child Adolesc Psychiatry 1991; 30: 945–51.
  35. Dalgleish T, Joseph S, Thrasher S, Tranah T, Yule W. Crisis support following the Herald of Free-
Enterprise disaster: a longitudinal perspective. J Trauma Stress 1996; 9: 833–45.
  36. McCarroll JE, Fullerton CS, Ursano RJ, Hermsen JM. Posttraumatic stress symptoms following
forensic dental identification: Mt. Carmel, Waco, Texas. Am J Psychiatry 1996; 153: 778–82.
  37. Gregg W, Medley I, Fowler-Dixon R et al. Psychological consequences of the Kegworth air disaster.
Br J Psychiatry 1995; 167: 812–7.
  38. Luce A, Firth-Cozens J. Effects of the Omagh bombing on medical staff working in the local NHS
trust: a longitudinal survey. Hosp Med 2002; 63: 44–47.
  39. Trautman R, Tucker P, Pfefferbaum B et al. Effects of prior trauma and age on posttraumatic stress
symptoms in Asian and Middle Eastern immigrants after terrorism in the community. Community
Ment Health J 2002; 38: 459–74.
  40. Cardenas J, Williams K, Wilson JP, Fanouraki G, Singh A. PSTD, major depressive symptoms, and
substance abuse following September 11, 2001, in a midwestern university population. Int J Emerg
Ment Health 2003; 5: 15–28.
  41. Johnson SD, North CS, Smith EM. Psychiatric disorders among victims of a courthouse shooting
spree: a three-year follow-up study. Community Ment Health J 2002; 38: 181–94.
  42. Epstein RS, Fullerton CS, Ursano RJ. Posttraumatic stress disorder following an air disaster: a
prospective study. Am J Psychiatry 1998; 155: 934–8.
  43. Galea S, Vlahov D, Tracy M et al. Hispanic ethnicity and post-traumatic stress disorder after a disaster:
evidence from a general population survey after September 11, 2001. Ann Epidemiol 2004; 14: 520–31.
  44. Neria Y, Gross R, Olfson M et al. Posttraumatic stress disorder in primary care one year after the 9/11
attacks. Gen Hosp Psychiatry 2006; 28: 213–22.
  45. Bodvarsdottir I, Elklit A. Psychological reactions in Icelandic earthquake survivors. Scand J Psychol
2004; 45: 3–13.
  46. Carr VJ, Lewin TJ, Webster RA et al. Psychosocial sequelae of the 1989 Newcastle earthquake: I,
Community disaster experiences and psychological morbidity 6 months post-disaster. Psychol Med
1995; 25: 539–55.
  47. Basoglu M, Kilic C, Salcioglu E, Livanou M. Prevalence of posttraumatic stress disorder and
comorbid depression in earthquake survivors in Turkey: an epidemiological study. J Trauma Stress
2004; 17: 133–41.
  48. Najarian LM, Goenjian AK, Pelcovitz D, Mandel F, Najarian B. The effect of relocation after a natural
disaster. J Trauma Stress 2001; 14: 511–26.
  49. Centers for Disease Control and Prevention (CDC). Health hazard evaluation of police officers
and firefighters after Hurricane Katrina--New Orleans, Louisiana, October 17–28 and November
30-December 5, 2005. MMWR Morb Mortal Wkly Rep 2006; 55: 456–8.
184 Maxwell and Galea

  50. Ozen S, Sir A. Frequency of PTSD in a group of search and rescue workers two months after 2003
Bingol (Turkey) earthquake. J Nerv Ment Dis 2004; 192: 573–5.
  51. Chang CM, Lee LC, Connor KM et al. Posttraumatic distress and coping strategies among rescue
workers after an earthquake. J Nerv Ment Dis 2003; 191: 391–8.
  52. Parslow RA, Jorm AF, Christensen H. Associations of pre-trauma attributes and trauma exposure
with screening positive for PTSD: analysis of a community-based study of 2,085 young adults.
Psychol Med 2006; 36: 387–95.
  53. Canino G, Bravo M, Rubio-Stipec M, Woodbury M. The impact of disaster on mental health:
prospective and retrospective analyses. Int J Ment Health 1990; 19: 51–69.
  54. Norris FH, Murphy AD, Baker CK, Perilla JL. Postdisaster PTSD over four waves of a panel study of
Mexico’s 1999 flood. J Trauma Stress 2004; 17: 283–92.
  55. van Griensven F, Chakkraband ML, Thienkrua W et al. Mental health problems among adults in
tsunami-affected areas in southern Thailand. JAMA 2006; 296: 537–48.
  56. Goenjian AK, Molina L, Steinberg AM et al. Posttraumatic stress and depressive reactions among
Nicaraguan adolescents after Hurricane Mitch. Am J Psychiatry 2001; 158: 788–94.
  57. Goenjian AK, Pynoos RS, Steinberg AM et al. Psychiatric comorbidity in children after the 1988
earthquake in Armenia. J Am Acad Child Adolesc Psychiatry 1995; 34: 1174–84.
  58. Vernberg EM, Silverman WK, La Greca AM, Prinstein MJ. Prediction of posttraumatic stress
symptoms in children after Hurricane Andrew. J Abnorm Psychol 1996; 105: 237–48.
  59. Russoniello CV, Skalko TK, O’Brien K et al. Childhood posttraumatic stress disorder and efforts to
cope after Hurricane Floyd. Behav Med 2002; 28: 61–71.
  60. Shannon MP, Lonigan CJ, Finch AJ Jr, Taylor CM. Children exposed to disaster: I, Epidemiology of post-
traumatic symptoms and symptom profiles, J Am Acad Child Adolesc Psychiatry 1994; 33: 80–93.
  61. Garrison CZ, Bryant ES, Addy CL et al. Posttraumatic stress disorder in adolescents after Hurricane
Andrew. J Am Acad Child Adolesc Psychiatry 1995; 34: 1193–201.
  62. Caldera T, Palma L, Penayo U, Kullgren G. Psychological impact of the Hurricane Mitch in Nicaragua
in a one-year perspective. Soc Psychiatry Psychiatr Epidemiol 2001; 36: 108–14.
  63. Durkin ME. Major depression and post-traumatic stress disorder following the Coalinga and Chile
earthquakes: a cross-cultural comparison. J Soc Behav Pers 1993; 8: 405–20.
  64. Norris FH, Kaniasty K. Received and perceived social support in times of stress: a test of the social
support deterioration deterrence model. J Pers Soc Psychol 1996; 71: 498–511.
  65. La Greca A, Silverman WK, Vernberg EM, Prinstein MJ. Symptoms of posttraumatic stress in children
after Hurricane Andrew: a prospective study. J Consult Clin Psychol 1996; 64: 712–23.
  66. Weiss DS, Marmar CR, Metzler TJ, Ronfeldt HM. Predicting symptomatic distress in emergency
services personnel. J Consult Clin Psychol 1995; 63: 361–8.
  67. Norris FH, Kaniasty K, Conrad ML, Inman GL, Murphy AD. Placing age differences in cultural
context: a comparison of the effects of age on PTSD after disaster in the United States, Mexico, and
Poland. J Clinical Geropsychology 2002; 8: 153–73.
  68. Catapano F, Malafronte R, Lepre F et al. Psychological consequences of the 1998 landslide in Sarno,
Italy: a community study. Acta Psychiatr Scand 2001; 104: 438–42.
  69. Kilic C, Ulusoy M. Psychological effects of the November 1999 earthquake in Turkey: an epide­
miological study. Acta Psychiatr Scand 2003; 108: 232–8.
  70. La Greca AM, Silverman WK, Wasserstein SB. Children’s predisaster functioning as a predictor of
posttraumatic stress following Hurricane Andrew. J Consult Clin Psychol 1998; 66: 883–92.
  71. Perilla JL, Norris FH, Lavizzo EA. Ethnicity, culture and disaster response: identifying and explaining
ethnic differences in PTSD six months after Hurricane Andrew. J Soc Clin Psychol 2002; 21: 20–45.
  72. Steinberg AM, Brymer MJ, Steinberg JR, Pfefferbaum B. Conducting research on children and
adolescents after disaster. In: Norris FH, Galea S, Friedman MJ, Watson PJ, eds. Methods for Disaster
Mental Health Research. The Guilford Press: New York, 2006: 243–53.
  73. North CS, Pfefferbaum B, Narayanan P et al. Comparison of post-disaster psychiatric disorders after
terrorist bombings in Nairobi and Oklahoma City. Br J Psychiatry 2005; 186: 487–93.
  74. Kessler RC, Galea S, Jones RT, Parker HA. Hurricane Katrina Community Advisory Group, Mental
illness and suicidality after Hurricane Katrina. Bull World Health Organ 2006; 84: 930–9.
  75. Galea S, Brewin CR, Gruber M et al. Exposure to hurricane-related stressors and mental illness after
Hurricane Katrina. Arch Gen Psychiatry 2007; 64: 1427–34.
  76. Corbie-Smith G, Thomas SB, St George DM. Distrust, race, and research. Arch Intern Med 2002; 162:
2458–63.
  77. Newman E, Kaloupek DG. The risks and benefits of participating in trauma-focused research
studies. J Trauma Stress 2004; 17: 383–94.
  78. Newman E, Walker EA, Gefland A. Assessing the ethical costs and benefits of trauma-focused
research. Gen Hosp Psychiatry 1999; 21: 187–96.
  79. Galea S, Nandi A, Stuber J et al. Participant reactions to survey research in the general population
after terrorist attacks. J Trauma Stress 2005; 18: 461–5.
Posttraumatic stress disorder after disasters 185

  80. Havenaar JM, Rumyantzeva GM, van den Brink W et al. Long-term mental health effects of the
Chernobyl disaster: an epidemiologic survey in two former Soviet regions. Am J Psychiatry 1997;
154: 1605–7.
  81. North CS, Smith EM, Spitznagel EL. One-year follow-up of survivors of a mass shooting. Am J
Psychiatry 1997; 154: 1696–702.
  82. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 3rd edn.
American Psychiatric Association: Washington, DC; 1980.
  83. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 3rd edn,
revised. American Psychiatric Association: Washington, DC; 1987.
  84. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th edn.
American Psychiatric Association: Washington, DC; 1994.
  85. Stuber J, Resnick H, Galea S. Gender disparities in posttraumatic stress disorder after mass trauma.
Gend Med 2006; 3: 54–67.
  86. Pfefferbaum B, Stuber J, Galea S, Fairbrother G. Panic reactions to terrorist attacks and probable
posttraumatic stress disorder in adolescents. J Trauma Stress 2006; 19: 217–28.
  87. Galea S, Ahern J. Invited commentary: considerations about specificity of associations, causal
pathways, and heterogeneity in multilevel thinking. Am J Epidemiol 2006; 163: 1079–82.
  88. Weissman MM, Neria Y, Das A et al. Gender differences in posttraumatic stress disorder among primary
care patients after the World Trade Center attack of September 11, 2001. Gend Med 2005; 2: 76–87.
  89. Asarnow J, Glynn S, Pynoos RS et al. When the earth stops shaking: earthquake sequelae among
children diagnosed for pre-earthquake psychopathology. J Am Acad Child Adolesc Psychiatry 1999;
38: 1016–23.
  90. Alexander DA. Stress among police body handlers, a long-term follow-up. Br J Psychiatry 1993; 163:
806–8.
  91. Galea S, Maxwell AR. Methodological challenges in studying the mental health consequences of
disasters, In: Neria Y, Galea S, Norris FH, eds. Mental Health Consequences of Disasters. Cambridge
University Press, in press.
  92. Brunello N, Davidson JR, Deahl M et al. Posttraumatic stress disorder: diagnosis and epidemiology,
comorbidity and social consequences, biology and treatment. Neuropsychobiology 2001; 43:
150–62.
  93. Breslau N, Chase GA, Anthony JC. The uniqueness of the DSM definition of post-traumatic stress
disorder: implications for research. Psychol Med 2002; 32: 573–6.
  94. Brooks N, McKinlay W. Mental health consequences of the Lockerbie disaster. J Trauma Stress 1992;
5: 527–43.
  95. Green BL, Lindy JD, Grace MC, Leonard AC. Chronic posttraumatic stress disorder and diagnostic
comorbidity in a disaster sample. J Nerv Ment Dis 1992; 180: 760–6.
  96. McFarlane AC, Papay P. Multiple diagnoses in posttraumatic stress disorder in the victims of a
natural disaster. J Nerv Ment Dis 1992; 180: 498–504.
  97. Stewart SH, Mitchell TL, Wright KD, Loba P. The relations of PTSD symptoms to alcohol use and
coping drinking in volunteers who responded to the Swissair Flight 111 airline disaster. J Anxiety
Disord 2004; 18: 51–68.
  98. Foa EB, Stein DJ, McFarlane AC. Symptomatology and psychopathology of mental health problems
after disaster. J Clin Psychiatry 2006; 67(2): 15–25.
  99. Pfefferbaum B, North CS, Doughty DE et al. Posttraumatic stress and functional impairment in
Kenyan children following the 1998 American Embassy bombing. Am J Orthopsychiatry 2003; 73:
133–40.
100. North CS, Tivis L, McMillen JC et al. Coping, functioning, and adjustment of rescue workers after
the Oklahoma City bombing. J Trauma Stress 2002; 15: 171–5.
101. Galea S, Acierno R, Ruggiero K et al. Social context and the psychobiology of posttraumatic stress.
Ann NYAcad Sci 2006; 1071: 231–41.
102. Kilpatrick DG, Koenen KC, Ruggiero KJ et al. The serotonin transporter genotype and social support
and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am J
Psychiatry 2007; 164: 1693–9.
103. Kubzansky LD, Koenen KC, Spiro A 3rd, Vokonas PS, Sparrow D. Prospective study of posttraumatic
stress disorder symptoms and coronary heart disease in the Normative Aging Study. Arch Gen
Psychiatry 2007; 64: 109–16.
104. Tucker P, Pfefferbaum B, Nixon SJ, Dickson W. Predictors of post-traumatic stress symptoms in
Oklahoma City: exposure, social support, peri-traumatic responses. J Behav Health Serv Res 2000;
27: 406–16.
105. Silver RC, Holman EA, McIntosh DN, Poulin M, Gil-Rivas V. Nationwide longitudinal study of
psychological responses to September 11, JAMA 2002; 288: 1235–44.
106. Pfefferbaum B, Seale TW, McDonald NB et al. Posttraumatic stress two years after the Oklahoma
City bombing in youths geographically distant from the explosion. Psychiatry 2000; 63: 358–70.
186 Maxwell and Galea

107. Ahern J, Galea S, Resnick H, Vlahov D. Television images and probable posttraumatic stress disorder
after September 11: the role of background characteristics, event exposures, and perievent panic,
J Nerv Ment Dis 2004; 192: 217–26.
108. Ahern J, Galea S, Resnick H, Kilpatrick D, Bucuvalas M. Television images and psychological
symptoms after the September 11 terrorist attacks, Psychiatry 2002; 65: 289–300.
109. Marshall RD, Bryant RA, Amsel L et al. The psychology of ongoing threat: relative risk appraisal, the
September 11 attacks, and terrorism-related fears, Am Psychol 2007; 62: 304–16.
110. Verger P, Dab W, Lamping DL et al. The psychological impact of terrorism: an epidemiologic study
of posttraumatic stress disorder and associated factors in victims of the 1995–1996 bombings in
France. Am J Psychiatry 2004; 161: 1384–9.
111. Galea S, Vlahov D, Resnick H et al. Trends of probable post-traumatic stress disorder in New York
City after the September 11 terrorist attacks. Am J Epidemiol 2003; 158: 514–24.
112. Carr VJ, Lewin TJ, Webster RA et al. Psychosocial sequelae of the 1989 Newcastle earthquake:
II, Exposure and morbidity profiles during the first 2 years post-disaster. Psychol Med 1997; 27:
167–78.
113. Norris FH, Perilla JL, Riad JK, Kaniasty K, Lavizzo EA. Stability and change in stress, resources, and
psychological distress following natural disaster: findings from hurricane andrew. Anxiety Stress
Coping 1999; 12: 363–96.
114. Wang X, Gao L, Shinfuku N et al. Longitudinal study of earthquake-related PTSD in a randomly
selected community sample in north China. Am J Psychiatry 2000; 157: 1260–6.
115. McFarlane AC. The longitudinal course of posttraumatic morbidity. The range of outcomes and their
predictors. J Nerv Ment Dis 1988; 176: 30–9.
116. Gibson LE, Hamblen JL, Zvolensky MJ, Vujanovic AA. Evidence-based treatments for traumatic
stress: an overview of the research with an emphasis on disaster settings, In: Norris FH, Galea S,
Friedman MJ, Watson PJ, eds. The Guilford Press: New York, 2006: 208–25.
117. van Emmerik AA, Kamphuis JH, Hulsbosch AM, Emmelkamp PM. Single session debriefing after
psychological trauma: a meta-analysis. Lancet 2002; 360: 766–71.
118. Bryant RA, Moulds ML, Nixon RV. Cognitive behaviour therapy of acute stress disorder: a four-year
follow-up. Behav Res Ther 2003; 41: 489–94.
119. Bryant RA, Harvey AG, Dang ST, Sackville T, Basten C. Treatment of acute stress disorder: a
comparison of cognitive-behavioral therapy and supportive counseling. J Consult Clin Psychol
1998; 66: 862–6.
120. Ehlers A, Clark DM, Hackmann A et al. A randomized controlled trial of cognitive therapy, a self-
help booklet, and repeated assessments as early interventions for posttraumatic stress disorder.
Arch Gen Psychiatry 2003; 60: 1024–32.
121. Davis LL, Frazier EC, Williford RB, Newell JM. Long-term pharmacotherapy for post-traumatic
stress disorder. CNS Drugs 2006; 20: 465–76.
122. Basoglu M, Salcioglu E, Livanou M. A randomized controlled study of single-session behavioural
treatment of earthquake-related post-traumatic stress disorder using an earthquake simulator.
Psychol Med 2007; 37: 203–13.
123. Chemtob CM, Nakashima J, Carlson JG. Brief treatment for elementary school children with disaster-
related posttraumatic stress disorder: a field study, J Clin Psychol 2002; 58: 99–112.
124. Gillespie K, Duffy M, Hackmann A, Clark DM. Community based cognitive therapy in the treatment
of posttraumatic stress disorder following the Omagh bomb. Behav Res Ther 2002; 40: 345–57.
14 Symptom exaggeration in posttraumatic
stress disorder
Alzbeta Juven-Wetzler, Rachel Sonnino, Danit Bar-Ziv, and Joseph Zohar

Introduction

Posttraumatic stress disorder (PTSD) is unique among psychiatric disorders as, per definition,
the trigger is known; the critical event is part of the core diagnosis. Because there is an external
event, in many cases PTSD is linked to compensation; for example, in case of car accidents
compensation is sought from the insurance company, while in other cases (such as war-related
PTSD) the address is the Ministry of Defense, and so on.
As in most of the cases the compensation, level of disability, and subsequently the finan-
cial gain, is based on a combination of symptom severity and functioning, the patient might
have an inherent incentive to exacerbate the symptoms. Moreover, as the patients often feel as
though they are a victim, they also feel justified in using this approach (“They are responsible
for this, they need to pay for it”).
The authors are by no means suggesting that PTSD is merely a “compensation neurosis,”
rather they propose to face the uniqueness of PTSD described above and to examine the moni-
toring of PTSD through a prism aimed to illuminate the issue of symptom exacerbation.
Cofactoring with an “exacerbation index” is important not only for getting an accurate
clinical picture of the actual (factual) status of a given patient but it is also important in order to
increase the validity of the diagnosis of PTSD. Mingling intentional exacerbation with genuine
PTSD may prevent proper diagnosis and treatment of patients who really suffer from PTSD
and for whom it may be hard to pass the barriers of disbelief rooted by cases of intentional
exacerbation. If ways can be found to better identify this fraction of patients with symptom
exaggeration, who are often quite vocal and demanding, and to separate them from cases of
genuine PTSD, it would boost the validity and confidence in the diagnosis of PTSD.

Malingering vs. Exaggeration

Noting the Diagnostic and Statistical Manual of Mental Disorders (DSM), 4th edition defini-
tion of malingering as “the intentional production of false or grossly exaggerated physical or
psychological symptoms, motivated by external incentives” (1, p. 683), we prefer to use the
term exaggerators rather than malingerers, in order to include those whose exaggeration is not
consciously intentional. As we shall see in the following sections, the distinction between
intentional and nonintentional is less pertinent when considering the implications of symptom
exaggeration, although it does come into play when discussing how to recognize cases of
exaggeration and how to deal with them once identified.

Clinical and Social Implications of Symptom Exaggeration

The severity of PTSD has been monitored initially for two primary purposes—clinical and
research purposes. Clinical monitoring of severity is intended to quantify the patient’s status
and to help the clinician get a more accurate impression of how a particular patient responds
to a given treatment. For research purposes, a severity score is sometimes used as a stricter
inclusion criterion than the diagnostic threshold, and repeated measures allow statistical com-
parison of different treatment trials and control groups.
However, the severity of PTSD has another, financial, implication—that of disability sup-
port and/or compensation. Monetary benefits available to PTSD patients include various wel-
fare-based disability allowances to compensate for the patient’s inability to function normally in
his or her everyday lives—inability to hold a job, to continue social activities, and so on.(2) These
188 Juven-Wetzler, Sonnino, Bar-Ziv, and Zohar

benefits depend heavily on the severity of the PTSD symptoms as assessed by a psychiatrist.
The monetary implication of the severity of PTSD (as assessed by a clinician) is rooted in the
very characteristic that makes PTSD unique among psychiatric disorders—that the disorder is
triggered by an external event in a defined time. If a certain party can be held responsible for the
traumatic event, and the resulting impaired function can be confirmed by a mental health profes-
sional, litigation is possible for compensation from the relevant organization.
In addition, a further repercussion of a PTSD diagnosis rated at a given severity level
is that of the “social reaction” to the disorder. The social benefits of assuming a sick role may
provide sympathy, care, and attention otherwise not forthcoming from family members and
friends. Depending on the nature of the triggering traumatic event, the associated stigma of
a mental health problem may be outweighed by the accompanying “hero” role that can be
assumed by having survived certain ordeals, especially with growing public awareness and
acceptance of this disorder.
One might assume that for clinical or research purposes patients would have no vested
interest in influencing the severity score of their PTSD symptoms. However, the monetary and
social incentives described above are unfortunately entwined in the process, as the severity of
PTSD as outlined by the clinician or the researcher may be quoted and relied on in applications
for monetary benefits/legal actions.
The desire to have their PTSD assessed as more severe than it actually is may prompt
some individuals to misreport their symptoms in order to portray them as harsher and more
disabling. As the diagnosis of posttraumatic stress disorder (PTSD), like most but not all psy-
chiatric disorders, is based in large part on the patient’s report of subjective symptoms; this is
possible in a way that would not be the case in some physical diseases, where objective testing
(e.g., EMR for a patient complaining of muscle weakness) would refute unfounded claims of
illness and would help to give a complementary evaluation of the severity of the symptoms.

The Epidemiological and Research Impact of Symptom Exaggeration

Determining the prevalence of PTSD is difficult because any baseline sample screened for the
“true” rate of PTSD is itself potentially tainted with exaggerators. However, large epidemio-
logical studies, in which the sample was not chosen following exposure to traumatic events,
and participants were anonymous, (and, therefore, can be expected to have been more honest
about symptoms) are most likely to attain accurate prevalence rates, with the least contamina-
tion from exaggerator data. One such study, the U.S. National Comorbidity Study (3) found
PTSD to have a prevalence of 7.8%.
The financial loss caused by symptom exaggeration in PTSD is perhaps the most prom-
inent of consequences when examined from a public interest point of view, but the effect
exaggeration has on research must also be considered. Patients who expect the severity of
their PTSD as measured in clinical research to serve other purposes, whether monetary or
social, or even those who have a specific reason for wanting to be included in a particu-
lar study (either to access an otherwise unavailable or expensive treatment or to sidestep
a lengthy waiting list in regular treatment clinics), may give inflated descriptions of symp-
toms, and the implications for PTSD research are manifold. First, prevalence rates of PTSD,
if they include exaggerators, may be grossly inflated. Rosen (4) points out high prevalence
of PTSD in studies where malingering was not ruled out, in comparison with epidemiologi-
cal data (where exaggeration can be assumed minimal), and Summerfield (5) points out that
these inflated prevalence rates, if published as accurate, can then mislead others. In fact, a
vicious circle can ensue, whereby an initially exaggeration-tainted sample gives rise to esca-
lated prevalence rates, which in turn lure subsequent researchers into a false sense of security
regarding the purity of their samples (given that the prevalence rate matches the prevalence
found in previous research), and these results, if published, merely serve to strengthen the
notion that finding a prevalence such as this does not require further investigation of the pos-
sibility of exaggeration. In addition to elevated prevalence figures, as most research stipu-
lates a certain level of PTSD severity as an inclusion criterion, exaggeration in the screening
process would result in less severe cases entering the sample, skewing subsequent biological
and clinical measures and analyses (e.g., in a study looking at a biological parameter that is
Symptom Exaggeration in PTSD 189

specific to PTSD, including non-PTSD or mild cases of PTSD might hamper the interpreta-
tion of the biological results). Furthermore, in the majority of studies examining potential or
current treatments for PTSD, severity is used as a measure of the treatment’s success. Any
participant who exaggerates symptoms at the baseline measurement in such a study would
be expected to do the same at the follow-up phase, thus creating a flat effect of no response,
data contamination, and a blurring of the clinical signal.

Why Does Symptom Exaggeration in PTSD Go Unnoticed?

Since the diagnosis of PTSD was introduced into the DSM (6), concerns have been voiced that
the symptoms of the disorder were relatively easy to simulate.(7–10) Concerns such as these
led to the addition of a note regarding malingering in the discussion of PTSD in DSM-IV (1):
“Malingering should be ruled out in those situations in which financial renumeration, benefit
eligibility, and forensic determinations play a role” (p. 467). A study performed in 2002 dem-
onstrated how difficult it can be to recognize symptom fabrication by professional actors.(11)
This makes the more subtle task of identifying exaggeration, cases in which genuine symptoms
are reported as more severe than truly experienced, seem even more daunting. Not only is the
difference between the experience and presentation more subtle but some cases involve “ama-
teur dramatics” as well, as in the case of survivors of the sinking of the Aleutian Enterprise
(12), who later admitted being advised by their attorneys regarding symptoms they may have,
presumably in an attempt to manipulate diagnosis or severity rating of PTSD. Particularly tell-
ing is the case of one fisherman survivor who wanted to go back to work but was told by his
attorney that it would “look better” if he did not.
In the face of such obstacles, it is not surprising that the possibility of exaggeration (or
malingering, as required by DSM-IV) is at best discussed in general terms with regard to the
entire sample and very rarely examined in detail. This is despite the fact that studies specifically
investigating PTSD in the context of compensation claims and lawyer involvement have found
connections between these and PTSD severity.(13, 14) However, although the findings arouse
suspicion, these studies do not actually imply that the litigation status influences patients to por-
tray their symptoms as more disruptive and disturbing, rather than the symptom severity being
the cause of the litigation. Indeed, several studies have failed to demonstrate an “improvement”
in PTSD symptoms, following finalization of compensation claims.(13, 15, 16) Yet this lack of
improvement does not necessarily mean all cases were genuine and can be interpreted in two
other ways. One possibility is that the patients are still suspicious and refrain from admitting that
they have a deliberate exacerbation. The other possibility is that the process of symptom exag-
geration in itself is not harm free, and the long time that patients present themselves with certain
symptoms might have resulted in “adapting” or “imprinting” of these symptoms (something
along the lines of disuse atrophy—if an arm is not used for several weeks—let alone months or
even years—then it is very difficult, if not impossible, to bring it back to full function). Hence, the
possibility of exaggeration in cases with such large financial rewards at stake needs to be ruled
out carefully and certainly should not be swept under the carpet.

Identification of symptom exaggerators

The identification of PTSD patients suspected of exaggerating their symptoms in order to attain
secondary benefits is a difficult task. One interesting study took advantage of changes in Croatian
legislation regarding compensation for veterans in 2001.(17) This group observed a change in
symptom reports of compensation-seeking veterans, following reforms of the national regulations
for compensation criteria in Croatia. Distribution of diagnoses (based on reported symptoms)
changed between the years 2000 and 2002 in a manner tending toward the better compensation
rates awarded to certain PTSD-related diagnoses by the 2001 reform. This would imply some
level of reporting bias on the part of compensation seekers, be it conscious or not.
However, such a method can be applied only in unique circumstances, where changes in
the legislation governing compensation rights offer an opportunity to examine patients before
and after the reform. Furthermore, it gives a picture from a prevalence point of view, but still
190 Juven-Wetzler, Sonnino, Bar-Ziv, and Zohar

no answer regarding individual patients. For specific, everyday purposes, a simpler method is
needed. We will review here techniques examined and proposed for detecting symptom exag-
geration, including the use of clinical interview, psychological scales, cognitive testing, and
physiological measures.
Identifying a suspected malingerer/exaggerator is possible in several ways.(18, 19) Some
of these methods are more suitable for conscious malingerers who are deliberately trying to
pull the wool over the eyes of the clinician, whereas others are appropriate for more subtle
cases, where symptom exaggeration is suspected, and where it is uncertain whether the patient
is even aware himself of embellishing the description of his symptoms.
The exact methods used to identify suspected cases of symptom exaggeration are usually
kept confidential to a great extent, as knowledge of how the techniques work can give deliber-
ate exaggerators an opportunity to prepare in advance and possibly alter their performance so
as to evade detection.

Clinical Interview and Corroboration of data

Although we will briefly review psychological, cognitive, and physiological methods for detect-
ing symptom exaggeration in PTSD, one should not overlook the classical basic approach, that
is, comprehensive clinical interview in which inconsistencies and atypical presentation might
direct us to focus and carefully investigate overreporting.
The clinician should not show open signs of suspicion or incredulity (which risks arousing
an exaggerator’s suspicion, thus increasing his efforts to appear sincere), yet symptom reports
should not be taken at face value. Given the high success rates for PTSD-naive subjects in feigning
PTSD symptoms using a symptom checklist (8, 9), the use of open-ended questions, at least ini-
tially, is prudent (18), and the patient’s responses can then be explored in more detail. Examples
of instances in which a particular symptom was manifest should be requested and, where pos-
sible, corroborated with reports from family members and friends or other sources.
The clinical interview can also serve as an opportunity to observe the patient, which
can provide insights as to the veracity of the symptoms reported (e.g., a patient claiming lack
of concentration who does not display any difficulty concentrating during the interview or a
claim of extreme irritability that is not evident in the patient’s behavior). However, given the
subjectivity of both administering and interpreting the clinical interview, it is a good idea to
combine it with more standardized testing for symptom exaggeration for a fuller picture.

Scales to Identify Symptom Exaggeration

There are no specific scales formulated for the detection of malingering or symptom over-
reporting in PTSD alone. General scales attempting to detect symptom exaggeration usu-
ally include questions about both genuine and improbable symptoms, under the premise
that those who are fabricating or overreporting their symptoms will be more suggestible
to the decoy items than patients who respond accurately and according to their actual
experience.(20)
The Minnesota Multiphasic Personality Inventory (MMPI-2) has been used to detect
symptom feigning in a range of disorders, including PTSD. The D and F-K scales are often
used to detect malingering in general, and, less commonly, the PK and PS scales for combat-
PTSD specifically. Detection methods in MMPI-2, as with scales in general, tend to focus on
overendorsement of symptoms, with a suspiciously high number of symptoms overall or of
rare symptoms. An additional focus is on certain more subtle symptoms that may be missed
by an exaggerator not sufficiently knowledgeable about the intricacies of the disorder’s symp-
toms.(21) The advantage of the MMPI-2 scale in identifying symptom overreporting is that the
length (it is estimated to take 1-2 hours to complete) makes it difficult for individuals attempt-
ing to portray an untrue presentation to keep up the pretense in a convincing way. Studies
using the MMPI-2 in PTSD populations have uncovered high rates of symptom exaggera-
tion, particularly in individuals involved in compensation claims/litigation.(22) However, its
immense length is one of the MMPI-2’s downfalls as well. Not every situation is conducive
Symptom Exaggeration in PTSD 191

to administering such a lengthy test, and the results are not easily interpreted (only a trained
individual can score and interpret the results). This kind of investment of time and effort may
be worthwhile in individual cases, perhaps in forensic and legal settings, and although not
foolproof, could contribute to the overall picture of whether a supposed PTSD patient is indeed
such. However, for a clinician with a hunch that something is amiss with a particular patient’s
description of PTSD symptoms, or for use in clinical trials that seek to ensure that all partici-
pants do indeed suffer from the necessary severity of PTSD, more specific as well as shorter
and simpler methods are needed.
The Structured Interview of Reported Symptoms (SIRS, 20) consists of 172 items and looks
at trends such as endorsement of rare or absurd symptoms, or improbable symptom combina-
tions. It also includes items that lean toward detection of feigned cognitive dysfunction.
The SIRS was found to successfully distinguish between simulators and genuine PTSD
patients in a study examining the feigning of a number of disorders.(20) A study looking at the
effectiveness of the SIRS in detecting feigned symptoms in PTSD compensation and disability
claimants also found it effective.(23)
The Miller Forensic Assessment of Symptoms (M-FAST) is relatively short (takes 10 to
15 minutes to administer), measuring endorsement of rare symptom combinations, atypical
symptoms, and excessive reporting. It has been successful at differentiating nonpatients pro-
vided with diagnostic information from a clinical sample of PTSD patients.(24)
The Trauma Symptom Inventory (TSI) was not developed as a tool for detecting malin-
gering but rather as an assessment of the sequelae of traumatic events. However, it comprises
three subscales that point toward possible symptom exaggeration and have been found effec-
tive in detecting coached feigners of PTSD.(25)

Cognitive Testing and Symptom Exaggeration

There is no conclusive evidence to suggest that PTSD patients demonstrate deficits in most cog-
nitive functions.(26, 27) First, it is unclear whether deficits found reflect a preexisting vulner-
ability to PTSD or a deficit brought about by the disorder itself.(28) In addition, any cognitive
deficits observed could stem not from the PTSD but rather from a comorbid disorder, such as
depression, which is commonly comorbid with PTSD.(29)
Whether or not PTSD patients actually suffer a decline in cognitive function and whether
this is caused directly by PTSD or by a comorbid disorder, cognitive testing can potentially be
used to detect symptom exaggeration in PTSD, particularly in cases where a decline in cognitive
function is reported. No cognitive dysfunction should result in an individual performing worse
than if he were to guess the answers on a particular test. Several cognitive tests have been used
to identify individuals who are “working hard” to appear to have low cognitive abilities. For
instance, in forced choice questions (where the subject is asked to choose the answer to each ques-
tion from two or more options, only one of which is correct), even a patient who is unable to work
out the answer to the question should attain a score comparable to the guess rate, determined by
the number of options for each question. Improbable patterns of performance can also be identi-
fied as a person trying to “fake bad.” The detection of a probable case of symptom exaggeration
by this method was described by Rosen and Powel (30) in their case description of a patient who,
claiming to suffer memory deficits as part of his PTSD symptomatology, completed a forced
choice memory test with an accuracy of only 31%, where the two-choice design set the chance
rate at 50%. Through the use of this test it was apparent that the patient was making a concerted
effort to perform badly rather than that he had genuine memory deficits.
Despite the potential use of cognitive testing in detecting symptom exaggeration for
patients claiming cognitive deficits, a paradoxical finding in a neuropsychological study is
that issuing a warning prior to the test, that they should complete the test honestly because the
testers are able to identify malingering, actually hampers the test’s ability to detect feigning,
as patients seeking to mislead do so in a less pronounced way, making it harder to detect the
effect.(31, 32) This can be expected in PTSD patients as well, implying that attempts to identify
exaggerators should not be made known to the patient.
Other cognitive phenomena can be utilized in detecting patients who are exaggerat-
ing their symptom severity. For instance, the primacy and recency effects observed in intact
192 Juven-Wetzler, Sonnino, Bar-Ziv, and Zohar

memory performance (the tendency to remember more words from the beginning and end of
a list than from the middle) are also present in memory-deficient patients, yet these effects are
hard to emulate by individuals who are reporting less than they truly recall from what they
were asked to remember.(33)

Physiological Measures and Symptom Exaggeration

The idea of being able to use physiological measures to confirm a patient’s symptom descrip-
tions is very interesting. Just as a blood test can help us to measure physiological attributes, a
person’s physiological measures might be harnessed to help us to answer as to whether a par-
ticular individual has PTSD. Several studies have attempted to find such a measure, examining
heart rate, blood pressure, skin conductance, and so on, both at baseline and after traumatic
stressors; however, Gerardi et al. (34) found that only diastolic blood pressure differentiated
PTSD from a control group trying to fake PTSD symptoms. Thus, it appears that physiological
measures that were examined so far were not particularly effective in differentiating between
genuine and faked PTSD.
A further issue with the use of some of the physiological measures is related to their
specificity and validity. For instance, in a 6-year follow-up of survivors of the Oklahoma City
bombing, although exposed individuals were found to have a more pronounced autonomic
response to trauma reminders than nonexposed individuals, this pronounced autonomic
response was not correlated to whether or not they had developed PTSD.(35) Thus, it would
appear that physiological measures used here (heart rate and blood pressure) were not dis-
criminative enough to differentiate between trauma survivors with and without PTSD, imply-
ing that the current measures available would not be effective in identifying cases of symptom
exaggeration. Rare cases of individuals claiming to have PTSD when in fact they did not even
experience the trauma they claim to have suffered might perhaps offer a further physiological
measure as a potential additional diagnostic reliner, but the subtlety of overreporting appears
to require a less direct approach.

Conclusion

Because per definition there is an external and known trigger, PTSD is linked to compensation
proportionally more than other psychiatric disorders. Although PTSD should not be reduced
to a compensation neurosis, the issue of symptom exaggeration need not be swept under the
carpet. The search for differentiating individuals with genuine PTSD vs. those who are inten-
tionally or nonintentionally exacerbating their symptoms is important in clinical practice as
well as in clinical research, as the participants who fake PTSD are weakening the validity and
the confidence of the diagnosis in PTSD.
There is a fine line that clinicians should walk when exploring the various ways to iden-
tify symptom overreporting. An individual who is intentionally pretending to have developed
PTSD should be neither diagnosed, treated, nor granted benefits. On the other hand, handling
of overreporters needs to be much more delicate, as it might include a group of genuine PTSD
sufferers who are, for whatever reason, and at different levels of consciousness, exaggerating
or embellishing their symptoms. Even for those who are deliberately doing this, the diagnosis
of PTSD may still be valid based on their genuine symptoms and they have a right to be treated
and to receive compensation in line with the severity of their true symptoms.
Reviewing the current literature suggests three major avenues that were explored in
order to aid the clinician in identifying overreporting. The methods that have been examined
were scales (such as MMPI-2 and SIRS), cognitive tests (such as forced-choice and free-recall
memory tests), and physiological measures (which include heart rate, blood pressure, GSR,
etc.). Unfortunately, all of these methods were not found to have either the specificity or the
validity required from a respected diagnostic test.
As the awareness of PTSD is growing and subsequently there is a parallel growth in the
compensation related to PTSD, the need to find appropriate tools to aid the clinician in differ-
ential diagnosis of symptom exacerbation in PTSD is growing.
Symptom Exaggeration in PTSD 193

The authors believe that modern technologies (like brain imaging) and better cognitive
solutions will be instrumental in developing the appropriate tools to differentiate between
symptom exacerbation and genuine PTSD.

References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed.).
Washington, DC: Author; 1994
  2. Kessler RC. Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry
2000; 61 (5):4–12.
  3. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National
Comorbidity Survey. Arch Gen Psychiatry 1995; 52(12):1048–60.
  4. Rosen GM. DSM’s cautionary guideline to rule out malingering can protect the PTSD data base.
Anxiety Disorders 2006; 20: 530–535.
  5. Summerfield D. A critique of seven assumptions behind psychological trauma programmes in
war–affected areas. Social Science and Medicine 1999; 48: 1449–1462.
  6. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (3rd ed.).
Washington, DC: Author; 1980.
  7. Eldridge G. Contextual issues in the assessment of posttraumatic stress disorder. Journal of Traumatic
Stress 1991; 4: 7–23.
  8. Lees–Haley P, Dunn J. The ability of naïve subjects to report symptoms of mild brain injury, post–
traumatic stress disorder, major depression, and generalized anxiety disorder. Journal of Clinical
Psychology 1994; 50: 253–256.
  9. Burges C, McMillan T. The ability of naïve participants to report symptoms of post–traumatic stress
disorder. British Journal of Clinical Psychology 2001; 40(2): 209–214.
10. McNally R. Progress and controversy in the study of posttraumatic stress disorder. Annual Review of
Psychology 2003; 54:229–252.
11. Hickling EJ, Blanchard EB, Mundy E, Galovski TE. Detection of malingered MVA related posttraumatic
stress disorder: An investigation of the ability to detect professional actors by experienced clinicians,
psychological tests and psychophysiological assessment. Journal of Forensic Psychology Practice
2002; 2: 33–54.
12. Rosen GM. The Aleutian Enterprise sinking and posttraumatic stress disorder: Misdiagnosis in clinical
and forensic settings. Professional Psychology: Research and Practice 1995; 1: 82–87.
13. Blanchard EB, Hickling EJ, Taylor AE et al. Effects of litigation settlements on posttraumatic stress
symptoms in motor vehicle accident victims. Journal of Traumatic Stress 1998; 11(2): 337–354.
14. Ehlers A, Mayou RA, Bryant B. Psychological predictors of chronic posttraumatic stress disorder after
motor vehicle accidents. Journal of Abnormal Psychiatry 1998; 107(3):508–19.
15. Sayer NA, Spoont M, Nelson DB, Clothier B, Murdoch M. Changes in psychiatric status and service
use associated with continued compensation seeking after claim determinations for posttraumatic
stress disorder. Journal of Traumatic Stress 2008; 21(1): 40–48.
16. Fontana A, Rosenheck R. Effects of compensation–seeking on treatment outcomes among veterans
with posttraumatic stress disorder. Journal of Nervous and Mental Disease 1998; 186(4): 223–230.
17. Kozarić-Kovaćić D, Bajs M, Vidošić S et al. Change of diagnosis of posttraumatic stress disorder
related to compensation–seeking. Croatian Medical Journal 2004; 45(4): 427–433.
18. Knoll J, Resnick PJ. The detection of malingered post–traumatic stress disorder. Psychiatric Clinics of
North America 2006; 29: 629–647.
19. Resnick PJ. My favorite tips for detecting malingering and violence risk. Psychiatric Clinics of North
America 2007; 30: 227–232.
20. Rogers R, Kropp PR, Bagby RM, Dickens SE. Faking specific disorders: a study of the Structured
Interview of Reported Symptoms (SIRS). Journal of Clinical Psychology 1992; 48(5):643–8.
21. Rogers R, Sewell KW, Martin MA, Vitacco MJ. Detection of feigned mental disorders: A meta–analysis
of the MMPI–2 and malingering. Assessment 2003; 10(2): 160–177.
22. Gold PB, Frueh BC. Compensation–seeking and extreme exaggeration of psychopathology among
combat veterans evaluated for posttraumatic stress disorder. Journal of Nervous and Mental Disease
1999; 187(11):680–684.
23. Rogers R, Payne JW, Berry DTR, Granacher RP Jr. Use of the SIRS in compensation cases: an
examination of its validity and generalizability. Law Hum Behav. 2009; 33(3):213–24.
24. Guy LS, Kwartner PP, Miller HA. Investigating the M–FAST: psychometric properties and utility to
detect diagnostic specific malingering. Behavioral Sciences & the Law 2006; 24(5): 687–702.
25. Guriel J, Yanez T, Fremouw W et al. Impact of coaching on malingered posttraumatic stress symptoms
on the M–FAST and the TSI. Journal of Forensic Psychology Practice 2004; 4(2): 37–56.
194 Juven-Wetzler, Sonnino, Bar-Ziv, and Zohar

26. Moore SA. Cognitive abnormalities in posttraumatic stress disorder. Current Opinion in Psychiatry
2008; 22:19–24.
27. Elsesser K, Sartory G. Memory performance and dysfunctional cognitions in recent trauma victims and
patients with posttraumatic stress disorder. Clinical Psychology and Psychotherapy 2007; 14:464–474.
28. Parslow RA, Jorm AF. Pretrauma and posttrauma neurocognitive functioning and PTSD symptoms
in a community sample of young adults. American Journal of Psychiatry 2007; 164: 509–515.
29. Johnsen GE, Kanagaratnam P, Asbjornsen AE. Memory impairments in posttraumatic stress disorder
are related to depression. Journal of Anxiety Disorders 2008; 22:464–474.
30. Rosen GM, Powel JE. Use of a symptom validity test in the forensic assessment of posttraumatic
stress disorder. Anxiety Disorders 2003; 17: 361–367.
31. Youngjohn JR, Lees–Haley PR, Binder LM. Comment: Warning Malingerers Produces More
Sophisticated Malingering. Archives of Clinical Neuropsychology 1999; 14(6): 511–515.
32. Youngjohn JR. Confirmed attorney coaching prior to neuropsychological evaluation. Assessment
1995; 2: 279–283.
33. Bernard LC. The detection of faked deficits on the Rey Auditory Verbal Learning Test: the effect of
serial position. Archives of Clinical Neuropsychology 1991; 6(1–2):81–8.
34. Gerardi RJ, Blanchard EB, Kolb LC. Ability of Vietnam veterans to dissimulate a psychophysiological
assessment for posttraumatic stress disorder. Behavior Therapy 1989; 20: 229–243.
35. Tucker PM, Pfefferbaum B, North CS et al. Physiologic reactivity despite emotional resilience several
years after direct exposure to terrorism. American Journal of Psychiatry 2007; 164(2):230–5.
15 Future directions
Joseph Zohar, Murray B Stein, and David Nutt

This second volume of our posttraumatic stress disorder (PTSD) book allows us to see how far
we have come over the past 7 years. It is clear that some aspects of knowledge regarding PTSD
have progressed significantly, whereas others have moved on only a little. In this chapter we
pick up some of the critical issues relating to knowledge gaps and future research needs.

The brain mechanisms of PTSD

One of the major advances in research in PTSD has been in identifying the brain circuits that
underpin the disorder. The Liberzon chapter pulls together a significant body of work that has
defined a circuitry of emotion and its dysregulation in PTSD, showing relevant overlaps with
brain regions involved in other anxiety disorders and in emotional regulation. The emerg-
ing evidence for some dysregulation of cortical function in the medial PFC is potentially very
exciting. What is now needed is to know to what extent this region directs the full panoply of
symptom expression in PTSD, that is, is it linked to the three symptom clusters or preferentially
to one such as memory? Moreover, we need to know the origins of the fMRI abnormalities. One
exciting possibility is that they might reflect alterations in GABA-A receptor function as sug-
gested by the PET imaging data detailed in the chapter also.
A deficiency of GABA-A benzodiazepine receptors could lead to local PFC regulation as
reported in the PET scans. How can we reconcile this with the fact that drugs that might be pre-
dicted to rectify this binding deficit, the benzodiazepines, seem to be ineffective in preventing
PTSD development or in its treatment (see chapter 10). One reason for this might be that the ben-
zodiazepines tend to produce adaptive changes in their binding sites that lead to a reduction in
their function over time, thus undermining any therapeutic actions (see 1). If this is the case then
there are potential ways to investigate such possibilities; in particular, one would predict that
in animals that had been given a course of a benzodiazepine, with the course suspended after a
specific period, the receptors would be in a state that could predispose to PTSD. An effective rat
model of PTSD has now been developed (see chapter 10) so testing this theory is now possible.
Of course, a GABA-A benzodiazepine deficit might be amenable to treatment with other new
agents that do not suffer from the long-term problems that the traditional benzodiazepines cause.
Such new drugs include subtype-selective agonists such for the a2 and a3 subtypes of the recep-
tor.(2) These drugs are being trialed in the treatment of GAD and panic disorder, so exploring
their action in PTSD is a possibility. Moreover, as these two specific subtypes have rather specific
distribution in brain, being particularly located in circuits that regulate emotion and sleep, abnor-
malities of them might well be candidates for the pathogenesis of symptom generation in PTSD;
such studies would again be amenable to investigation in animal models where both whole brain
imaging and localized receptor mapping could be carried out.
The other main neurotransmitter in the cortex is glutamate, which is almost certainly
involved in the learning of traumatic memories. Although imaging glutamate is currently not
possible in humans, there are new tracers in development that may allow this in future years.
Again animal studies might point to the best direction—would a marker of the ion-channel–
linked (ionotropic) receptors be more informative than one for the metabotropic ones? One
can make credible cases for either ionotropic or metabotropic receptors, or indeed both, being
involved in PTSD, and there is some research underway, manipulating each of these in anxiety
as well as other brain disorders. In particular, the work to augment ionotropic glutamate func-
tion with drugs that mimic the cotransmitter glycine (e.g., D-cycloserine) is well established
in both animal and human models of stress learning. It is now established that learning to
overcome stress-related anxiety in animals, for example, extinction of fear-based behavior,
196 Zohar, Stein, and Nutt

requires new learning, and this can be enhanced by D-cycloserine (see chapter by 9). Early
human studies in phobic humans found similar results and so there are ongoing studies now in
patients with PTSD who are engaging in psychotherapy treatment. Results should be available
in a year or two, so watch this space!

How do current treatments work?

It is now generally agreed (see 3) that SSRIs are the preferred first-line treatment of PTSD.
However, they do not work immediately; usually it takes 3 or more weeks for a clear therapeu-
tic action to emerge. The usual explanation for this is that the immediate action of SSRIs is to
increase 5HT levels; this increase in 5HT then stimulates the 5HT1A autoreceptors on the raphe
cell bodies and dendrites. As these are inhibitory receptors, the firing rate of the 5HT neurones
is slowed down, limiting the potential increase of 5HT in the synaptic cleft that reuptake block-
ade can produce. However, over time the 5HT1A autoreceptors desensitize; thus the firing rate
returns to normal and the 5HT released from cell firing cannot be taken up due to the SSRI
effects, which leads to increased postsynaptic 5HT function. Subsequently, there may be adap-
tive changes in postsynaptic processes such as receptors, second messengers, gene products,
and even new neurones (neurogenesis) that may produce the final therapeutic outcome.
In the treatment of depression with SSRIs there is considerable discussion about the
role of synaptic versus postsynaptic mechanisms in the action of antidepressants. Although
postsynaptic changes are well described in rodent models, they are harder to demonstrate
in humans, possibly for technical reasons. One exception is the paroxetine study reported in
chapter 5, which found that long-term treatment of PTSD with paroxetine increased hippocam-
pal volume, suggesting some neurogenerating actions of 5HT. This increase in size was also
associated with improved memory function. In another anxiety disorder, that is, panic disor-
der, clinical recovery on SSRI treatment has been found to restore the deficit in 5HT1A recep-
tors found on PET scanning in untreated patients.(4) Again this suggests some role for 5HT in
restoring normal neuronal function.
However, it may be that persistent elevations of 5HT are necessary for the therapeutic effects
of SSRIs, for if brain 5HT is depleted using the tryptophan depletion paradigm then the antide-
pressant efficacy of SSRIs is undermined (5–7), although the same effect was not seen in OCD.
(8) Recently we have shown that in panic (9) social anxiety disorder (10) tryptophan depletion
produces relapse in patients who recovered using SSRIs suggesting that tonic 5HT function is nec-
essary to maintain wellness in recovery. Since then we have been able to conduct a similar study in
PTSD.(11) A total 10 patients who had made a good recovery on SSRIs (so they were rated fully or
very markedly recovered on the CGI) underwent tryptophan depletion or sham depletion in a ran-
domized crossover design. At the time of peak depletion (5 hours), patients were exposed to their
traumas using autobiographical scripts. These provoked the full range of PTSD anxiety symptoms
with physiological changes in blood pressure and heart rate despite the patients all being recov-
ered. However, on the tryptophan depletion day, all measures of symptoms and physiology were
significantly enhanced compared with the control day. This suggests that 5HT is critical to restrain-
ing the expression of anxiety in PTSD when treated with SSRIs and that there may be commonali-
ties of action of the SSRIs across the range of anxiety disorders. It would be very interesting to see
whether similar reductions in 5HT1A receptors are found in untreated PTSD as found in panic (4)
and social anxiety (12) and whether they recover on successful treatment.

Antistress treatments?

One of the great goals of PTSD medicine is to find preventative mechanisms. Of course, such
agents would be challenging to develop due to the relatively small percentage of exposed indi-
viduals going on to develop PTSD (though in incidents like rape this is the majority) and the
need to ensure that other sequelae of trauma, especially depression, were also remedied or at
least prevented from getting worse than the existing state.
Therefore, what are the processes that underlie the development of PTSD that could be
amenable to early intervention? In essence, they are those relating to memory formation, that
Future Directions 197
Figure 1
Psychological stress

NMDA-R
Corticosterone Dentate gyrus
granule neuron
Cell membrane

Ca2+

Nuclear membrane

Histone tail

Gene
transcription
(e.g. c-Fos)

Nuclesome Memory formation of

the stressful event

Figure 15.1  The necessary confluence of cortisol [through GR receptors] and glutamate [through NMDA recep-
tors] in the production of memory.(15)

is, glutamate and GABA, and those related to emotional processing (noradrenaline 5HT) and
those related to stress (cortisol plus related central regulators of this axis, for example, CRF and
ACTH). The potential role of glutamate drugs in “unlearning” PTSD has been discussed briefly
in the chapter on treatment (chapter 9), but even if this is successful, there is still the question
of whether antiglutamate drugs could prevent the acquisition of the traumatic memories in the
first place.(13)
As we have seen in Bisson et al.’s (chapter 10), GABA-A drugs, in particular the benzodiaz-
epines, are not effective as prophylaxis; however, so far only nonselective benzodiazepines have
been used. Given the multiple subtypes of the GABA-A/benzodiazepine receptor and new selec-
tive agents that are now being studied in humans, at some stage, it would be sensible to see whether
these might have utility in PTSD prevention; certainly they seem to have less disadvantages in
terms of tolerance abuse liability and withdrawal than the nonselective benzodiazepines.(2)
As Bisson et al mentioned in chapter 10, antinoradrenaline drugs, especially beta block-
ers and the a1 antagonist prazosin, have already been considered. A very recent paper extends
the studies on b-blockers, describing the finding that a dose of 40 mg propranolol has been
shown to “erase the expression of the fear memory” when given prior to the fear memory
being reactivated.(14) If such an effect could be demonstrated in patients with PTSD then it
could have significant clinical utility.
Another approach is to use established treatments but earlier in the course of the ill-
ness. The potential prophylactic role of the SSRI escitalopram is under investigation in a
major Israeli study led by Shalev that will soon report its findings. But what of anticortisol
agents? The central regulation and actions of cortisol are well understood and provide new
treatment targets. Cortisol release is controlled by CRF (corticotrophin-releasing factor), a
peptide found in a number of brain regions that regulates aspects of behavior such as groom-
ing, eating, sexual drive, and sleep as well as stimulating ACTH release from the hypo-
thalamus. ACTH then stimulates cortisol production and release from the adrenal glands,
sending feedback onto the brain, to the inhibition of both CRF and ACTH release through
two receptors, namely, the mineralocorticoid (MR) and glucocorticoid (GR) receptors. These
198 Zohar, Stein, and Nutt

receptors are highly expressed in limbic brain regions and regulate emotional as well as
endocrine responses to cortisol. In the hippocampus, they are necessary coreceptors with glu-
tamate receptors to regulate stressful memory encoding.(15 – see figure 15.1) Anti-GR drugs
have been developed as potential new treatments of depression (16) that, therefore, could
potentially be explored in the treatment of PTSD.
A complementary approach is to reduce CRF activation using CRF antagonists, several
of which exist and which are being tested in depression also.(17) We have shown that a new
CRF 1 receptor antagonist reduces anxiety in a stress model in normal volunteers involved in
a 20-minute CO2 inhalation procedure.(18) It would be of great interest to test these agents in
PTSD as soon as possible. Given the proviso that the cortisol system in chronic PTSD may be
subfunctioning, the primary target would need to be prophylactic rather than curative.

An opportunity for early intervention?

Following a cerebrovascular accident (CVA), there is a 3-hour “window” from the onset in which
“clot-busting” drugs can be administered to relieve thrombosis. After a myocardial infarction
(“heart attack”), reperfusion of the infarct-related artery in the very first hour significantly reduces
mortality rates. The common denominator is that immediate intervention is given in order to pre-
vent/decrease the impending (usually devastating) sequelae of those events, which often trigger
a chain of pathological processes. The concept is that if the right intervention is given during the
“window of opportunity,” it might dramatically improve the outcome.
Is there a “golden hour” in psychiatry? Can intervention right after exposure to traumatic
events attenuate the pathological response that we refer to as PTSD?
PTSD is unique among other psychiatric disorders in that the trigger is well defined, not
only with regard to time (we can often know exactly when it started) but also with regard to
cause (a “Criterion A” traumatic event). Hence, it would be quite straightforward to develop
an animal model, as one can induce PTSD, for example, by exposure of animal to the predator
(19), and carefully monitoring behavior afterwards. What is unique for PTSD is that most of the
individuals who are exposed to traumatic events eventually recover from it, and only a minor-
ity (10–20%; 20) develop PTSD. An animal model has been developed that involves exposing
the rat to its natural predator (a cat) and also mimics PTSD by setting apart the minority of
those affected (via cutoff behavioral criteria; 21–23 and chapter 7 of this book). This animal
model of PTSD may be unique among animal models of psychiatric disorders because in PTSD
it is feasible to create a situation that might eventually lead to the disorder (this is certainly not
the case for any other psychiatric disorder, in which neither the precipitating event, nor the
timing of the disorder is defined).
The authors submit that use of translational research, in which a valid animal model will
be used, might be able to provide better insight with regard to beneficial versus harmful inter-
ventions in this narrow (albeit as yet poorly defined as to whether it is hours or days) window
of opportunity. We anticipate that the pendulum in PTSD research will shift from treatment
of established (and often very chronic) PTSD to innovative approaches aiming at limiting the
development of PTSD (and other related forms of psychopathology, such as depression) fol-
lowing trauma exposure. Such approaches will focus at administering preventive interven-
tions during these golden hours.
Actually, there are some initial encouraging data pertaining to administration of phar-
macological agents early in the aftermath of traumatic stress, such as cortisol (22), galanin (24),
and oxytocin.(24) There are also some hints regarding the potential benefit of early admin-
istration of SSRIs (25), opiate agonists such as morphine (26), and possibly betaadrenergic
blocking agents such as propranolol (27); the list will probably be expanded. It might be that,
ultimately, PTSD will be the first psychiatric disorder in which the focus could be on preven-
tion as opposed to treatment. This of course will depend on whether the field will be able to
develop effective interventions in the golden hours— the first few hours immediately after the
traumatic event. Animal models suggest that targeting the consolidation or reconsolidation of
the traumatic event will be instrumental for such treatments. If we can manage to interfere with
the consolidation or maintenance of the traumatic memory during the golden hours (28, 29), it
may be possible to prevent the development of PTSD.
Future Directions 199

Along these lines, sophisticated psychotherapeutic approaches aimed at altering or

reducing the impact of the traumatic memories could be another potential approach to be fol-
lowed. There are, in fact, strong data supporting the use of cognitive–behavioral approaches in
the aftermath of trauma to prevent the development (or reduce the progression into chronicity)
of PTSD.(30) It may someday be possible to use pharmacotherapy to augment the effects of
exposure on extinction of fear.(14) For those individuals whose minds are trapped in traumatic
pasts, the future is bright!

References

  1. Nutt DJ. Death and dependence: current controversies over the selective serotonin reuptake inhibitors.
J Psychopharmacol 2003; 17: 355–64.
  2. Nutt DJ. GABA-A receptors: subtypes, regional distribution and function. In J Clin Sleep Med 2006;
2(2): 5–11.
  3. Stein D, Cloitre M, Nemeroff CB et al. Cape Town Consensus on Posttraumatic Stress Disorder. CNS
Spectr 2008; 13: 12 (Suppl 19).
  4. Nash JR, Sargent PA, Rabiner EA et al. A positron emission tomography study of serotonin 5-HT1A receptor
availability in untreated and recovered patients with panic disorder. Br J Psychiatry 2008; 193: 1–6.
  5. Delgado PL, Charney DS, Price LH et al. Serotonin function and the mechanism of antidepressant
action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch
Gen Psychiatry 1990; 47: 411–8.
  6. Hood SD, Bell CJ, Nutt DJ. Acute tryptophan depletion part 1: rationale and methodology: Australia
and New Zealand. J of Psychiatry 2005; 39: 558–64.
  7. Bell CJ, Hood SD, Nutt DJ. Acute tryptophan depletion part 2: Australia and New Zealand. J of
Psychiatry 2005; 39: 565–74.
  8. Barr LC, Goodman WK, McDougle. Tryptophan depletion in patients with obessive compulsive
disorder who respond to SSRIs. Arch Gen Psychiatry 2004; 51: 309–17.
  9. Bell C, Forshall S, Adrover M et al. Does 5-HT restrain panic? A tryptophan depletion study in panic
disorder patients recovered on paroxetine. J Psychopharmacol 2002; 16: 5–14.
10. Argyropoulos S, Hood SD, Adrover M et al. Tryptophan depletion reverses the therapeutic effect
of selective serotonin reuptake inhibitors in social anxiety disorder. Biological psychiatr 2004; 56:
503–9.
11. Corchs F, Nutt DJ, Hood S, Bernik M. 5HT and sensitivity to trauma-related exposure in
SSRI-recovered PTSD. Biol Psychiatry 2009; Biol Psychiatry 2009; 66(1):17–24.
12. Lanzenberger RR, Mitterhauser M, Spindelegger C et al. Reduced serotonin-1A receptor binding in
social anxiety disorder. Biol Psychiatry 2007; 61: 1081–9.
13. O’Brien M, Nutt D. Loss of consciousness and post-traumatic stress disorder. A clue to aetiology and
treatment. Br J Psychiatry 1998; 173: 102–4.
14. Kindt M, Soeter M, Vervliet B. Beyond extinction: erasing human fear responses and preventing the
return of fear. Nat. Neurosci 2009; 12(3): 256-8.
15. Reul H and Nutt DJ. Cortisol and glutamate—a critical confluence in PTSD? J Psychopharmacol 2008;
22:469–72.
16. Schatzberg AF, Lindley S. Glucocorticoid antagonists in neuropsychotic disorders. Eur J Pharmacol
2008; 583: 358–64.
17. Ising M, Holsboer F. CRH1 receptor antagonists for the treatment of depression and anxiety. Exp Clin
Psychopharmacol 2007; 15(6): 519–28.
18. Bailey JE, Papadopoulos A, Diaper A et al. Preliminary Evidence of Efficacy of a CRF1 Receptor
Antagonist in the7.5% CO2 Model of Anxiety. Journal of Psychopharmacology Summer meeting
supplement 2008.
19. Adamec RE, Shallow T. Lasting effects on rodent anxiety of a single exposure to a cat. Physiol Behav
1993; 54: 101–9.
20. Yehuda R, McFarlane AC. Conflict between current knowledge about posttraumatic stress disorder
and its original conceptual basis. Am J Psychiatry 1995; 152(12): 1705–13.
21. Cohen H, Zohar J, Matar M. The Relevance of differential response to trauma in an animal model of
post-traumatic stress disorder. Biological Psychiatry 2003; 53: 463–73.
22. Cohen H, Matar MA, Buskila D, Kaplan Z, Zohar J. Early post-stressor intervention with high-dose
corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress
disorder. Biol Psychiatry 2008; 64(8): 708–17.
23. Cohen H, Matar M, Zohar J. Animal models of posttraumatic stress disorder. In: P.M. Conn (Ed)
Sourcebook of Models for Biomedical Research. Humana Press 2008; 591–602.
200 Zohar, Stein, and Nutt

24. Kozlovsky N, Matar MA, Kaplan Z, Zohar J, Cohen H. The role of the galaninergic system in
modulating stress-related responses in an animal model of posttraumatic stress disorder. Biol
Psychiatry 2009; 65(5): 383–91.
25. Matar MA, Cohen H, Kaplan Z, Zohar J. The effect of early poststressor intervention with sertraline on
behavioral responses in an animal model of posttraumatic stress disorder. Neuropsychopharmacology
2006; 31(12):2610–8.
26. Bryant RA, Creamer M, O’Donnell M, Silove D, McFarlane AC. A study of the protective function of
acute morphine administration on subsequent posttraumatic stress disorder. Biol Psychiatry 2009;
65(5): 438–40.
27. Brunet A, Orr SP, Tremblay J et al. Effect of post-retrieval propranolol on psychophysiologic
responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder.
J Psychiatr Res 2008; 42(6): 503–6.
28. Kozlovsky N, Kaplan Z, Zohar J et al. Protein synthesis inhibition before or after stress exposure
results in divergent endocrine and BDNF responses disassociated from behavioral responses. Depress
Anxiety 2008; 25(5): E24–34.
29. Cohen H, Kozlovsky N, Matar MA, Kaplan Z, Zohar J. Mapping the brain pathways of traumatic
memory: inactivation of protein kinase M zeta in different brain regions disrupts traumatic memory
processes and attenuates traumatic stress responses; submitted.
30. Bryant RA, Moulds ML, Nixon RVD. Cognitive behaviour therapy of acute stress disorder: a four-
year follow-up. Behav Res Ther 2003; 41(4): 489–94.
 Index

Page numbers in italics refer to tables; those in bold to figures.

[123I]iomazenil 46 behavioral sensitization 54

99mTc hexamethylpropyleneamineoxime see enhanced stress sensitivity
(HMPAO) SPECT 37 benzodiazepine 95, 121
blood oxygen level–dependent method
acute PTSD 7–8 (BOLD) signal 37
acute stress disorder 7 brain circuits
and pediatric PTSD 148–9 cognitive appraisal 52
symptoms 7 default network 62
adrenergic agents 122 finding
afferent sensory input 52 memory function 52–3
Alprazolam 95 neuroimaging
amnesia 52 functional study 58
amygdala 40, 52, 59–60 activity 58–9
aversive conditioning 43 neurological working model 51–2
animal genetic studies 80–1 fear behavior 52
knockout models 80 performance 57–8
animal model 88 traumatic memory
behavioral assessments 89 formation of 54–7
cutoff behavioral criteria brain mechanisms 195
classifications 89–91 brain-derived neurotrophic
selective study 91–5 factor gene 76
Anisomycin 95 Brodmann Area 32 52
anterior cingulate gyrus 52 Bupropion 119
anticonvulsants 120–1
antidepressants 116–20 catecholamines 55
selective serotonin reuptake childhood
inhibitors 116–18 abuse in 28
dual reuptake inhibitors 118 see also pediatric PTSD
tricyclic antidepressants 118–19 Chromatin 54
Bupropion 119 chronic PTSD 7–8
monoamine oxidase inhibitors 119 Clinician-Administered PTSD
Mirtazapine 119–20 Scale (CAPS) 103
antipsychotics 121–2 Cochrane Database review 101
antistress treatments 196–8 cognitive activation studies 39
anxiety disorders 105, 109 cognitive appraisal 44–5
anxiety 56 cognitive reappraisal 45
anxiogenic’ memories 55 cognitive–behavioral therapy (CBT)
apolipoprotein E gene 76 anxiety management techniques (AMT)
avoidance symptoms 30–1 105
exposure therapy 101–4
behavior therapy eye movement desensitization and
anxiety disorders 109 reprocessing 106–7
202 index

pediatric PTSD 155–6 efficacy of 131

systematic desensitization 105–6 multiple session interventions 132–40
virtual reality exposure earthquake imagery 38
therapy 104–5 emotion regulation 44
cognitive–emotional interactions 44–6 emotions 28–9
comorbid disorders enhanced stress sensitivity 54
and genetics 79–80 ethnoculture
pediatric PTSD 149–50 cross-cultural study 167–9
postdisasters 180 culture, definition 163–4
comorbidity 6 individual and social
mental health 20–1 conflicts 165–6
physical health conditions 21–2 meaning of 165
suicidal behavior 21 symptoms, presentation of 169
and trauma spectrum 33 trauma, impact on 169–70
corticosteroid 94 traumatic memory 166–7
cross-cultural study 167–9 exposure
ethnoculture 167–9 characterization of 179
trauma-related disorder 170–2 postdisasters 180
culture 163 exposure therapy 101–4
trauma on 169 extreme behavioral response 89
see also ethnoculture extreme fear 52
cutoff behavioral criteria (CBC), 90, 91 eye movement desensitization and
classification 89–90 reprocessing (EMDR) 106
minimal behavioral response 89 pediatric PTSD 156
extreme behavioral response 89
time factor 91 fear conditioning
physiological data 91–2 inhibition of 109
strain/genetic studies 92 extinction 56–7
molecular neurobiology, FK506 binding protein 5 (FKBP5)
correlation 93 gene 77–8
drug study 93–5 frontal cortical areas 53
functional imaging techniques 58
D-cycloserine (DCS) 109 functional magnetic resonance imaging
delayed-onset PTSD 8 (fMRI) 36–7
Diagnostic and Statistical Manual of Mental and receptor imaging 46
Disorders 12
diagnostic dilemmas, in assessment gamma-aminobutyric acid gene (GABA)
of trauma 26–9 46, 76–7, 195
symptoms 29–32 gene expression 78–9
structured instrument 33 General Health Questionnaire 103
dissociative symptoms 32 general population studies
Dopamine-related genes 72, 75 on PTSD 12, 13
dual reuptake inhibitors lifetime and prevalence of 14
duloxetine 118 on traumatic events 12
dynamic psychotherapy 100–1 genes 54
genetic mechanism 70
early interventions 198–9 animal genetic studies 80
theoretical models 128 apolipoprotein E gene 76
social models 128 brain-derived neurotrophic factor
psychological models 128–9 gene 76
biological models 129–30 comorbidity 79–80
types of 130–1 Dopamine-related genes 72, 75
index 203

familial aggregation studies 70–1 N methyl D aspartase (NMDA) 54

FK506 binding protein 5 (FKBP5) natural disasters 168, 177–8
gene 77–8 Nefazodone 120
gamma-aminobutyric acid neural activation 38
gene 76–7 neural circuitry 51–2
gene expression 78–9 fear behavior 52
glucocorticoid receptor gene 77 sensitization 54
molecular studies 71–2 neuroimaging 36
monoamine oxidase gene 75–6 of brain 58–9
neuropeptide Y gene 78 cognitive activation study 39–41
serotonin transporter gene 75 cross-sectional symptom
twin studies 71 severity 38–9
glucocorticoid dysregulation functional connectivity
mechanisms 123 analyses 41
glucocorticoid receptor gene 77 functional magnetic resonance imaging
glucocorticoids 55 (fMRI) 36–7
functions 41–2
hippocampus 43, 52, 60 symptom provocation study 37–8
horror 28 threat-related process 43–4
human-made disaster 176–7 neuropeptide Y gene 78
hyperarousal symptoms 31–2 neurotrophins 93
hypnosis 99 novel agent 122–3
hypnotherapy 99
hypnotics 121 olfactory sensory input 52
orbitofrontal cortex (OFC) 52
Impact of Event Scale (IES) 99
incident disorders parahippocampus 61
postdisaster, assessment of 179–80 parietal cortex 53
Institute of Medicine 101 pediatric PTSD
interventional studies community surveys 147–8
postdisasters 181 and acute stress disorder 148–9
comorbidity 149–50
longitudinal study neurobiology 150–1
postdisasters 181 risk and resilience 151–2
assessment 152–4
malingering 187 treatment 154
medial prefrontal cortex (MPF) 53 psychotherapies 155–7
memories 54 pharmacotherapies 157–8
see also traumatic memories selective serotonin reuptake inhibitors
mental health comorbidities 20–1 157–8
Miller Forensic Assessment of Symptoms pharmacotherapy
(M-FAST) 191 adrenergic agents 122
minimal behavioral response 89 anticonvulsants 120–1
Minnesota Multiphasic Personality antidepressants 116–20
Inventory 190–1 antipsychotics 121–2
Mirtazapine 119–20 benzodiazepines 121
molecular genetic studies 71–2 hypnotics 121
monoamine oxidase gene 75–6 novel agent 122–3
monoamine oxidase inhibitors 119 pediatric PTSD 157–8
motor cortex 53 physical health comorbidities 21–2
MPFC 59–60 Positive Feedback Cycle 130
multiple traumatic events 15 positron emission tomography (PET) 36
204 index

postdisasters Screening Tool for Early Predictors 156–7

human-made and technological disasters early identification 156–7
176–7 secondary traumatization 28
interventional studies 181 selective serotonin reuptake
longitudinal studies 181 inhibitors (SSRI) 196
methodological changes 178–80 pediatric PTSD 157–8
natural disasters 177–8 treatment, duration 117–18
research directions 180–1 Sertraline 93
posterior cingulate cortex 53 sensitization
posttraumatic stress disorder (PTSD) serotonin transporter gene 75
association studies 73–4 serotonin/norepinephrine reuptake
course of 181 inhibitors 118
definition 1 severity 187
diagnosis 2 exacerbation 6
heterogeneity 62 sex differences
mental and physical in prevalence of PTSD 18–19
comorbidities 20–2 traumatic events 15–16
neuroanatomical impairments 39 single-photon emission tomography
neuroimaging studies 36 (SPECT) 36
population studies 12 spider phobia 110
prevalence of 17–18 Sertraline 93
sex difference 18–19 startle reflex 56
process implicated 43–4 stress inoculation training (SIT)
risk factors for 20 102, 105
time course 6, 43 striatum 53
habituation and extinction 43–4 Structured Interview of Reported
and traumatic events 12 Symptoms 191
types 7–8 suicidal behavior 21
precuneus 61 symptom exaggeration
predator-scent stress paradigm 88–9 classical basic approach 189
PSS 89 clinical and social
prolonged exposure 102 implications 187–8
psychosocial treatments cognitive testing 191–2
anxiety management techniques (AMT) financial loss 188–9
105 identify 189–90
combined treatment approaches 107–10 scales 190–1
exposure therapy 101–4 obstacles 189
psychotherapy 108–10 physiological measures 192
virtual reality exposure vs. malingering 187
therapy 104–5 symptom severity
psychotherapy 108–10, 155 correlation with 38–9
pediatric PTSD 155–7 symptoms assessment 29
PTSD symptoms 5 for acute stress disorder 7
avoidance symptoms 30–1
rape 28, 102 dissociative symptoms 32
anxiety management techniques 105 hyperarousal symptoms 31–2
conditions, in PTSD 102 reexperience symptoms 29–30
receptor imaging 46 systematic desensitization 105–6
on inhibitory systems 46
reexperience symptoms 29–30 technological disaster 177
regional cerebral blood flow thalamus 61
(rCBF) 37 threat-related neurocircuitry 43
index 205

time course 6 risk factors 16

trauma sex difference 15–16
childhood abuse 28 traumatic memories 52
DSM-IV extinction, failure of 56–7
diagnostic criteria 26 fear conditioning 55–6
definition 27 traumatic memory
trauma-focused cognitive–behavior therapy ethnoculture
pediatric PTSD 155–6 problem and nature 166–7
trauma-induced personality grasping 167
changes 8 in children 148
trauma-related disorder 170–2 neurological working model
cross-cultural study 167–9 features 51–2
trauma spectrum traumatic stress–induced disorders
and comorbidity 33 time factor 91
Trauma Symptom Inventory (TSI) 191 tricyclic antidepressants 118–19
traumatic cues 55
traumatic events U.S. National Comorbidity Study 6
amnesia 52
definition 12 Venlafaxine 118
dilemmas, in assessment 26–27 vicarious traumatization 28
exposures 19–20 Vietnam veterans 104
methods of assessing 12 virtual reality exposure therapy 104–5
multiple traumatic events 15
population studies 13 World War I 169
prevalence of 13–15, 17–18 World War II 169