Combined pharmacotherapy and psychological therapies for
post traumatic stress disorder (PTSD) (Review)
Hetrick SE, Purcell R, Garner B, Parslow R
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 7
http://www.thecochranelibrary.com
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Combined SSRI plus CBT versus SSRI alone (adults), Outcome 1 PTSD symptom severity
(clinician rated) post intervention (final scores SIP). . . . . . . . . . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Combined SSRI plus CBT versus SSRI alone (adults), Outcome 2 Drop outs. . . . .
Analysis 1.3. Comparison 1 Combined SSRI plus CBT versus SSRI alone (adults), Outcome 3 Depression severity (self
rated) post intervention (change scores). . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.4. Comparison 1 Combined SSRI plus CBT versus SSRI alone (adults), Outcome 4 Anxiety severity (self rated)
post intervention (change scores). . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.1. Comparison 2 Combined SSRI plus CBT versus PE alone (adults), Outcome 1 PTSD symptom severity
(clinician rated) post intervention (change scores SPRINT). . . . . . . . . . . . . . . . . . .
Analysis 2.2. Comparison 2 Combined SSRI plus CBT versus PE alone (adults), Outcome 2 Drop outs. . . . . .
Analysis 3.1. Comparison 3 Combined SSRI plus TFCBT versus TFCBT alone (children/adolescents), Outcome 1 Drop
outs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Combined SSRI plus TFCBT versus TFCBT alone (children/adolescents), Outcome 2
Functioning CGAS.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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i
[Intervention Review]
Combined pharmacotherapy and psychological therapies for
post traumatic stress disorder (PTSD)
Sarah E Hetrick1 , Rosemary Purcell2 , Belinda Garner2 , Ruth Parslow3
1
Centre of Excellence in Youth Mental Health, Orygen Youth Health Research Centre, Centre for Youth Mental Health, University of
Melbourne, Melbourne, Australia. 2 Department of Psychiatry, Orygen Youth Health Research Centre, Melbourne, Australia. 3 Australian
Centre for Posttraumatic Mental Health, University of Melbourne, East Melbourne, Australia
Contact address: Sarah E Hetrick, Centre of Excellence in Youth Mental Health, Orygen Youth Health Research Centre, Centre for
Youth Mental Health, University of Melbourne, Locked Bag 10, 35 Poplar Road, Parkville, Melbourne, Victoria, 3054, Australia.
shetrick@unimelb.edu.au.
Editorial group: Cochrane Depression, Anxiety and Neurosis Group.
Publication status and date: New, published in Issue 7, 2010.
Review content assessed as up-to-date: 8 June 2010.
Citation: Hetrick SE, Purcell R, Garner B, Parslow R. Combined pharmacotherapy and psychological therapies for post
traumatic stress disorder (PTSD). Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD007316. DOI:
10.1002/14651858.CD007316.pub2.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
PTSD is an anxiety disorder related to exposure to a severe psychological trauma. Symptoms include re-experiencing the event, avoidance
and arousal as well as distress and impairment resulting from these symptoms.
Guidelines suggest a combination of both psychological therapy and pharmacotherapy may enhance treatment response, especially in
those with more severe PTSD or in those who have not responded to either intervention alone.
Objectives
To assess whether the combination of psychological therapy and pharmacotherapy provides a more efficacious treatment for PTSD
than either of these interventions delivered separately.
Search strategy
Searches were conducted on the trial registers kept by the CCDAN group (CCDANCTR-Studies and CCDANCTR-References) to
June 2010. The reference sections of included studies and several conference abstracts were also scanned.
Selection criteria
Patients of any age or gender, with chronic or recent onset PTSD arising from any type of event relevant to the diagnostic criteria were
included. A combination of any psychological therapy and pharmacotherapy was included and compared to wait list, placebo, standard
treatment or either intervention alone. The primary outcome was change in total PTSD symptom severity. Other outcomes included
changes in functioning, depression and anxiety symptoms, suicide attempts, substance use, withdrawal and cost.
Data collection and analysis
Two or three review authors independently selected trials, assessed their ’risk of bias’ and extracted trial and outcome data. We used
a fixed-effect model for meta-analysis. The relative risk was used to summarise dichotomous outcomes and the mean difference and
standardised mean difference were used to summarise continuous measures.
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Main results
Four trials were eligible for inclusion, one of these trials (n =24) was on children and adolescents. All used an SSRI and prolonged
exposure or a cognitive behavioural intervention. Two trials compared combination treatment with pharmacological treatment and
two compared combination treatment with psychological treatment. Only two trials reported a total PTSD symptom score and these
data could not be combined. There was no strong evidence to show if there were differences between the group receiving combined
interventions compared to the group receiving psychological therapy (mean difference 2.44, 95% CI -2.87, 7.35 one study, n=65)
or pharmacotherapy (mean difference -4.70, 95% CI -10.84 to 1.44; one study, n = 25). Trialists reported no significant differences
between combination and single intervention groups in the other two studies. There were very little data reported for other outcomes,
and in no case were significant differences reported.
Authors’ conclusions
There is not enough evidence available to support or refute the effectiveness of combined psychological therapy and pharmacotherapy
compared to either of these interventions alone. Further large randomised controlled trials are urgently required.
PLAIN LANGUAGE SUMMARY
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
PTSD is a potentially debilitating anxiety disorder triggered by exposure to a traumatic experience such as an interpersonal event like
physical or sexual assault, exposure to disaster or accidents, combat or witnessing a traumatic event. There are three main clusters of
symptoms: firstly, those related to re-experiencing the event; secondly, those related to avoidance and arousal; and thirdly, the distress
and impairment caused by the first two symptom clusters.
Both psychological therapy and pharmacotherapy have been used to treat PTSD and guidelines suggest that a combination of both
may mean people recover from PTSD more effectively. Four trials including 124 participants were included in this review. One of these
trials (n =24) was on children and adolescents. The trials all used SSRIs and prolonged exposure or a cognitive behavioural intervention.
Only two trials reported on total PTSD symptoms but the data could not be combined.
In this review, there are too few studies to be able to draw conclusions about whether a combination of psychological therapy and
pharmacotherapy result in better outcomes for patients than either of these treatments alone.
BACKGROUND
Description of the condition
PTSD is an anxiety disorder related to exposure to a severe psychological trauma. PTSD was first brought to public attention by
combat veterans. It was formally recognised as a clinical disorder in
1980, when its description and diagnostic criteria were specified in
the Diagnostic and Statistical Manual of Mental Disorders Version
III (DSM-III) (APA 1980). The disorder stands alone in psychiatry in having the requirement of an external stimulus, the traumatic experience, which then results in PTSD symptoms. Re-experience of the event is common to both major diagnostic systems
(DSM and ICD) as is avoidance and arousal. In DSM, distress or
impairment are also required (Lopez-Ibor 2002). DSM is stricter
in its definition of PTSD. It has been argued that these clinical
decision rules for diagnosis of PTSD may be too restrictive and fail
to recognise morbidity and associated impairment of functioning
commonly reported by individuals with sub-threshold symptoms,
particularly those who experience these over a long period of time
(Mylle 2004). To address this limitation, various modifications
have been proposed for DSM, such as Disorders of Extreme Stress,
Not Otherwise Specified (DES-NOS), which is described under
PTSD ’associated features’. DES-NOS includes symptoms relating to affect dysregulation, attention and consciousness (e.g. dissociation), disturbances in self perception, relations with others,
somatization and disturbances in systems of meaning.
Finally, PTSD has been differentiated from Acute Stress Disorder
(ASD) (another modification to DSM since the introduction of
PTSD) in which distressing re-experiencing, avoidance and arousal
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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symptoms are reported within two days to four weeks of experiencing a trauma, but persist for no longer than four weeks. For this
reason, it is now recommended that treatment for PTSD should
not be considered until four weeks after symptoms are first reported (Ballenger 2004).
The estimated life time prevalence of PTSD in community samples ranges between five and ten per cent (ACPMH 2007). It affects women more than men. PTSD in men is more commonly
related to combat exposure, and in women it is more commonly
related to sexual assault and other forms of interpersonal violence
(Kessler 1995). The reasons for higher rates in women are not fully
understood but may be related to the type of trauma, younger age
of exposure to trauma, stronger perceptions of threat and loss of
control and biological reactions to trauma, to name a few (Olff
2007). On the other hand, gender differences have been noted for
ICD-10 but not DSM-IV (APA 1994) diagnostic systems, due
to the different endorsement of symptoms by males and females,
and different configuration of symptoms in each diagnostic system
(Peters 2006). There is some evidence of genetic vulnerability for
PTSD (Yehuda 1999). The prognosis is often poor, with up to a
third of patients not recovering after many years (Kessler 1995).
Description of the intervention
Psychological interventions
Treatments for PTSD were primarily focused on psychological interventions in the years immediately following its formal recognition. Clinicians of this orientation argued that relief of PTSD
symptoms achieved with pharmacological interventions was superficial at best, and at worst, could hinder full resolution of the
trauma. They also argued that it encouraged patients’ early withdrawal from their longer-term psychological treatment (Friedman
1988).
Pharmacological interventions
Initially, pharmacological interventions, such as tricyclic antidepressants (TCAs) and mono-amine oxidase inhibitors (MAOIs),
were regarded only as an adjunct to long-term psychotherapy, usually to address the symptoms of comorbid depression experienced
by those with PTSD (Boehnlein 1985). By 1992, this position
had changed considerably. It was argued that effective treatment
of PTSD often required use of pharmacological interventions, although clinicians’ awareness of the efficacy of these treatments was
generally limited (Davidson 1992). Antidepressants, particularly
selective serotonin reuptake inhibitors (SSRIs), have been the most
commonly used pharmacological intervention (Davidson 1999;
Davidson 2000). While few RCTs exist, antipsychotic medication
is also used, most often in the case of patients who do not respond
adequately to antidepressants and psychotherapy (Hamner 2005).
How the intervention might work
Psychological interventions are primarily based on cognitive processing theories that contend that it is not the nature of the event
per se that affects subsequent psychological functioning, but the
individual’s appraisal of the event and the significance they attach to it (e.g., Foa 1989; Creamer 1992). Trauma-focused CBT,
including forms of exposure, emerged from cognitive processing
theories and is now recommended treatment for the clinical management of PTSD (ACPMH 2007).
Pharmacotherapy may work by correcting imbalances in neurotransmitters thought to play a role in causing and/or maintaining
PTSD symptoms (Stein 2000).
The combination of the two interventions may further enhance
treatment outcomes, particularly in those with comorbid conditions, with pharmacotherapy making exposure therapy more tolerable (Marshall 2000).
Why it is important to do this review
Clinical expert opinion on the treatment of PTSD has been revised
considerably during the past six years.
A consensus statement on PTSD treatment in 2000 recommended
psychotherapy (exposure therapy, stress inoculation training and
cognitive therapy) for mild PTSD and a combination of psychotherapy and pharmacotherapy for moderate to severe cases of
this disorder (Ballenger 2000). Recommendations made in the
most recent update of this statement focus on the early use of
SSRIs and/or CBT within 3 to 4 weeks of presentation of substantial, persistent PTSD symptomatology. This revised statement
advised that treatment for chronic PTSD may be most effective
in the longer term when both SSRIs and CBT are included in the
treatment plan (Ballenger 2004) .
A number of systematic reviews have been prepared about psychological interventions for preventing and treating PTSD. Neither
single session (Rose 2002) nor multiple session (Roberts 2009) interventions were recommended as interventions to prevent PTSD.
Bisson 2007, in a Cochrane systematic review, concluded that
trauma-focused cognitive behavioural therapy (CBT), as individual or group therapy, eye movement desensitisation and reprocessing (EMDR) and stress management were effective in reducing
PTSD symptoms. These reviews are of adults; a Cochrane protocol (Gillies 2007) aims to examine the effectiveness of psychological interventions to prevent and treat PTSD in children and
adolescents.
A Cochrane review of pharmacotherapy in adults with PTSD concluded that pharmacotherapy can be effective in treating symptoms, and that SSRIs should be first line agents for this disorder
(Stein 2006).
While combination treatments for PTSD are recommended by
clinical expert opinion as potentially effective, a systematic review
of the literature is required to appraise and assemble the evidence
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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for this. This review also adds to the programme of Cochrane
reviews on the prevention and treatment of PTSD.
Types of interventions
Intervention
OBJECTIVES
The purpose of this review was to assess:
1. whether the combination of psychological therapy and pharmacotherapy provides a more efficacious treatment for PTSD than
either of these interventions delivered separately
2. whether combination treatment is tolerable to patients with
diagnosed PTSD.
Combination of any type of pharmacotherapy and any type of psychological therapy were included, including individual and group
therapies. Categories of pharmacotherapy include SSRIs, SNRIs,
tricyclic antidepressants, anxiolytic medication, mood stabilizers,
atypical antipsychotics and other. Categories of psychological therapy comprise cognitive and/or behavioural approaches (including exposure therapy and trauma-focused CBT), eye movement
desensitisation and reprocessing (EMDR), interpersonal therapy,
supportive counselling and psychodynamic treatments.
Control conditions
METHODS
Criteria for considering studies for this review
Types of studies
Randomised controlled trials were included. Cluster randomised
controlled trials and cross over trials would have been included,
however, none were identified. Quasi-randomised controlled trials
were not included.
Types of participants
Patients of any age or gender with a primary diagnosis of PTSD,
diagnosed by a clinician using a structured or semi structured
interview based on DSM (APA 1994) or ICD (WHO 1992).
Participants with sub-clinical symptoms were also included. Subclinical symptoms were defined as at least one symptom in each of
the three symptom clusters (re-experiencing, avoidance, arousal)
or any acceptable definition adopted by the trialist. Definitions
were noted and described in Characteristics of included studies.
Trials of interventions for those with ASD were not included.
Chronic (>2 years or as defined by the trialist) and recent onset
(<2 years or as defined by the trialist) PTSD with any length of
untreated illness, and of any severity (as defined by the trialist usually as a score on a PTSD scale), arising from any type of event relevant to the diagnostic criteria, including and grouped according
to: 1. interpersonal events; 2. disaster or accidents; 3. combat; and
4. witnessing an event, were included. Those with psychiatric comorbidity, except psychotic illness, were included. These aspects
of the population were recorded, given their potential effect on
the treatment outcome.
1. Waitlist control
2. Pharmacotherapy placebo (which may be used in conjunction
with psychological therapy)
3. Standard treatment
4. Pharmacotherapy alone
5. Psychological therapy alone
Trials that combined two pharmacological interventions within a
trial or two psychological therapies within a trial were excluded.
Trials were also excluded where the combined treatment was usual
care and psychological therapy or pharmacological therapy.
Main comparisons
The main comparisons made included:
1. Combination psychological and pharmacological
intervention vs waitlist control;
2. Combination psychological and pharmacological
intervention vs pharmacotherapy placebo;
3. Combination psychological and pharmacological
intervention vs standard treatment;
4. Combination psychological and pharmacological
intervention vs pharmacotherapy alone;
5. Combination psychological and pharmacological
intervention vs psychological therapy alone
Separate meta-analyses were undertaken for children/adolescents
using these comparisons.
In future versions of this review, we anticipate reducing the number of comparisons and outcomes given the large number of analyses these may result in (which increase the chances of spurious
findings). In the update we will include the following comparisons
only:
• Combination psychological and pharmacological
intervention vs pharmacotherapy alone
• Combination psychological and pharmacological
intervention vs psychological therapy alone
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Types of outcome measures
Primary outcomes
1. Change from baseline to endpoint (or endpoint scores) of PTSD
symptom severity using valid and reliable clinician-rated scales
(e.g. The Clinician-Administered PTSD Scale, CAPs, Blake 1990;
the Short PTSD Rating Interview, SPRINT (Davidson 2001))
2. Number of withdrawals due to adverse events (number of
events)
Secondary outcomes
1. Change from baseline to endpoint (or endpoint scores) of PTSD
symptom severity using valid and reliable self-rated scales (e.g. The
Child PTSD Rating Scale, CPSS, Foa 2001)
2. Change (or endpoint) in Global Functioning scores using valid
and reliable scales (e.g. The Global Assessment of Functioning
score, GAF APA 1994)
3. Change from baseline to endpoint (or endpoint scores) of comorbid depression/anxiety using valid and reliable (a) clinicianrated and (b) self-rated scales (e.g. the Beck Depression Inventory
Beck 1961; The State Trait Anxiety Inventory Spielberger 1970)
4. Change from baseline to endpoint (or endpoint scores) of suicidal ideation using valid and reliable scales (e.g. The Scale for
Suicidal Ideation, SSI, Beck 1979)
5. Suicide attempt (reported in number of events)
6. Comorbid substance use (reported in number of events or on
valid and reliable scales) (e.g. Penn Alcohol Craving Scale Flannery
1999)
7. Vocational and social functioning (either in number of events
e.g. return to full time work or on valid reliable scales e.g. The
Work and Social Adjustment Scale, Mundt 2002)
8. Quality of life using valid and reliable scales (e.g. The Quality
of Life Scale, Burckhardt 2003)
9. Cost of treatment
While originally listed as a primary outcome in the protocol of
this review, Global Functioning scores and self-rated PTSD scores
were moved to secondary outcomes in the review. The number
of withdrawals due to adverse events was moved to the primary
outcomes according to the Cochrane Handbook (Higgins 2008).
As with the comparisons, we anticipate that in future updates we
will reduce the number of outcomes in order to reduce the likelihood of multiple analyses generating spurious results. Outcomes
will be limited to:
1. Change from baseline to endpoint (or endpoint scores) of PTSD
symptom severity (clinician-rated standardised, validated, reliable
rating scales)
2. Change from baseline to endpoint (or endpoint scores) of PTSD
symptom severity (self-rated standardised, validated, reliable rating
scales)
3. Change (or endpoint) in Global Functioning scores (standardised, validated, reliable rating scales)
4. Change from baseline to endpoint (or endpoint scores) of comorbid depression/anxiety (standardised, validated, reliable rating
scales)
5. Number of withdrawals due to adverse events (number of
events)
Search methods for identification of studies
The Cochrane Depression, Anxiety and Neuorosis Group (CCDAN) maintains two clinical trials registers at their editorial base
in Bristol, UK, a references register and a studies based register.
The CCDANCTR-References Register contains over 24,500 reports of trials in depression, anxiety and neurosis. Approximately
70% of these references have been coded to individual trials. These
coded trials are held in the CCDANCTR-Studies Register (which
contains over 11,000 records). Records are linked between Registers through the use of unique Study ID tags. Coding of trials is
based on the EU-Psi coding manual.
References to trials for inclusion in the Group’s registers are collated from routine (weekly) generic searches of MEDLINE, EMBASE and PsycINFO; quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review specific
searches of additional databases (PSYNDEX, LILACS, AMED,
CINAHL). Details of CCCDAN’s generic search strategies can
be found in the ‘Specialized Register’ section of the Cochrane
Depression, Anxiety and Neurosis Group’s module text.
Details of trials are also sourced from international trials registers c/o the World Health Organisation’s trials portal (http://
apps.who.int/trialsearch/), drug companies, the hand-searching of
key journals, conference proceedings and other (non-Cochrane)
systematic reviews and meta-analyses.
Electronic searches
a) In 2007 and in June 2010, the CCDAN trial registers were
searched by Hugh McGuire and (later) Sarah Dawson, CCDAN
Trials Search Co-ordinators (TSC) using the following terms:
CCDANCTR-Studies
Diagnosis = Post-Traumatic Stress Disorders
And
Intervention = “Combined Modality”
The TSC screened search results to exclude studies which combine
two pharmacological interventions within a trial or two psychological therapies within a trial. Studies were also excluded where
the combined treatment was usual care and psychological therapy
or pharmacological therapy
CCDANCTR-References
Keyword = “stress disorder*”
Or
Full-text = PTSD or “trauma* stress”
Again, results were screened in a similar way to above and references
obviously not relevant were excluded.
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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The reference section of each included trial was searched.
3. Outcome measures: description of measures used, timing of
administration, continuous/dichotomous nature, psychometric
properties, references.
4. Results: point estimates and measures of variability and frequency counts for dichotomous variables.
One review author compiled all comparisons and entered outcome
data into the Review Manager software program for meta-analysis.
A second review author performed double-data entry to ensure
accuracy of results. We sought to obtain missing data from trial
authors wherever possible.
Personal communication
Assessment of risk of bias in included studies
In order to ensure that as many as possible RCTs were identified,
the authors of the included trials and other experts in the field were
consulted to find out if they knew of any published or unpublished
RCTs in the area which had not been identified in the search.
Two review authors independently assessed the risk of bias of
the included trials using a descriptive approach as advocated by
the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2008). Potential for bias, including selection, performance, attrition and detection bias, was considered using the following criteria:
Any published or unpublished (including unpublished abstracts
and reports) were eligible for inclusion. There were no date or language of publication restrictions applied in the search or selection.
Searching other resources
Reference lists
Data collection and analysis
Sequence generation
Selection of studies
Two review authors independently selected trials for possible inclusion in the study. Firstly, the titles and abstracts of trials identified from the search were independently reviewed. Secondly, each
review author independently examined the full text of all studies
that they considered to be of possible relevance. Each review author
compiled a list of studies, which they believed met the inclusion
criteria. The content of each review author’s list was compared,
and any discrepancies discussed. Any disagreement was resolved
by discussion and consensus between all of the review authors.
Data extraction and management
Two review authors independently extracted data using specially
developed data extraction forms. Information was collected on:
1. Participants: age, gender, ethnicity, incident episode, length of
time since episode, length of time since onset of PTSD, severity of
PTSD, previous treatment for PTSD or other mental health disorders, type and severity of comorbid substance use disorder(s) and
other psychiatric comorbidities and suicide-related behaviours.
2. Interventions and comparisons: description of medication including planned and actual dose, length of treatment and description of psychological intervention including type, whether it is delivered to groups or individuals, whether it was manualised, who
delivered it and for how long, and the actual amount of therapy
received. Information on other adjunctive interventions was also
collected. The number of participants randomised to each group,
as well as total drop-outs and drop-outs due to adverse effects, was
extracted.
Was the allocation sequence adequately generated?
Allocation concealment
Was the allocation adequately concealed?
Blinding of participants, personnel and outcome assessors
Were the allocated interventions adequately blinded during the
study? (participant/care provider)? How did you know that blinding was maintained? (In this review, given psychological treatment
is one of the interventions, it was not possible for the participant and provider to be blinded). Were the outcome assessors adequately blinded to the allocated interventions?
Incomplete outcome data
Were dropouts and exclusions adequately addressed? (Were losses
to follow-up described?) Were intention-to-treat analyses used?
Selective outcome reporting
Have authors reported on all the outcomes they set out to? To
assess reporting bias, we recorded which of the review outcomes
were available with usable data from each included trial as well
as noting which of the review outcomes were only reported in
terms of whether there were significant differences between groups.
Additionally the other outcomes (not collected for the review)
reported by the trialists in the paper publication(s) were compiled.
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
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Other sources of bias
Dealing with missing data
Was the study apparently free of other problems that could mean
a high risk of bias e.g. early stopping, baseline imbalance, choice
of design, evidence of carry over effect, funding?
Each criterion was graded as yes, no or unclear, and scored as adequate (A), unclear (B) or inadequate (C), according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). When criteria were scored as unclear,
one review author attempted to obtain further information from
the authors of the trial. The review authors discussed any disagreement in the assessment of risk of bias to reach a consensus.
Trial authors were contacted for any missing data. Missing data
were imputed in order that standard deviations could be obtained.
Data from intention-to-treat (ITT) were extracted in the first instance with the type of imputation carried out by trialists noted. If
it had been possible, observed case (OC) data (as well as last observation carried forward data) would have been extracted and results
compared with ITT data, with results compared in the context of
the assumptions inherent in both these types of data.
Measures of treatment effect
For dichotomous outcomes, such as ’response’, results from each
trial were expressed as a Risk Ratio (RR) with 95% confidence
intervals, and combined in meta-analysis.
Continuous outcomes, such as symptom measures, may be presented in several ways. When absolute values of post-treatment
means and standard deviations (SD) were given, using the same
rating scale across studies, these were used to calculate the mean
difference (MD) and 95% confidence intervals. If different scales
were used to measure the same outcomes the standardised mean
difference (SMD) was calculated with 95% confidence intervals
and then combined for meta-analysis.
Unit of analysis issues
Cross-over trials were eligible for inclusion only when possible to
extract data from the first treatment period; or when inclusion of
data from both treatment periods is justified by a sufficiently long
wash-out period to minimise the effects of ’carry-over’. Data from
both periods can only be included when it is possible to determine
the correlation between participants’ responses to interventions in
the different phases (Elbourne 2002).
Had studies that randomise or allocate clusters (professionals or
health care organisations) been included that did not account for
clustering during analysis they would have been reanalysed using
the intraclass correlation coefficient (ICC), noting from where this
ICC was obtained.
There were no multiple arm trials included in the current review.
Should multiple treatment group trials be included in any update,
unit of analysis errors will be avoided by combining all relevant
experimental intervention groups of the study into a single group,
and combining all relevant control intervention groups into a single control group.
Review authors also checked for and report where skewed data
exist (in updates if there is skewed data, these will be reported in
additional tables). This was checked by comparing whether the
standard deviation for an observed mean was larger than the mean.
Assessment of heterogeneity
We ensured clinical homogeneity by only combining studies when
participants, interventions and outcome measures were considered to be similar. As such, studies of adults and children/adolescents were considered too different to combine. All studies included SSRIs but in future updates it may be necessary to stratify analyses by medication category as different medications may
have differing effects (Categories of pharmacotherapy include SSRIs, SNRIs, tricyclic antidepressants, anxiolytic medication, mood
stabilizers, atypical antipsychotics and other). In future studies it
may be necessary to stratify analyses by psychotherapy type (Categories of psychological therapy comprise cognitive and/or behavioural approaches (including exposure therapy and traumafocused CBT), eye movement desensitisation and reprocessing
(EMDR), interpersonal therapy, supportive counselling and psychodynamic treatments). For trials that were clinically heterogeneous or presented insufficient information for pooling, a descriptive analysis of main results was performed. Statistical homogeneity was assessed using the I-squared (I2 ) statistic (Higgins 2003).
As a rough guide the review authors used the following:
0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.
Additionally, the importance of the observed value of I2 depends
on (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity (e.g. P value from the chi-squared test,
or a confidence interval for I2 ) and these factors were taken into
consideration. Given the small number of studies, analysis of heterogeneity is limited.
Assessment of reporting biases
We aimed to investigate the potential for publication bias using a
funnel plot for the primary outcomes relating to PTSD diagnosis
and/or symptoms. However, given so few studies were included
in the review, this was not feasible. Publication bias has long been
associated with funnel plot asymmetry, however asymmetry may
be due to reasons other than publication bias and is difficult to
assess in the case of a small number of trials.
An assessment of the risk of reporting bias was also included as
stated above.
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Data synthesis
Description of studies
When appropriate, meta-analysis was performed and pooled effect
estimates obtained, using the Review Manager statistical software
program.
For all meta-analyses a fixed-effect (Mantel 1959) meta-analysis was used in the first instance. Where statistical heterogeneity
was found, it was examined by subgroup and sensitivity analyses.
Where this did not account for heterogeneity, we used the randomeffects models (DerSimonian 1986). When the pooled summary
statistic using the random-effects model differed from that using
the fixed-effect model, it was reported.
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of ongoing studies.
See also Characteristics of included studies.
Subgroup analysis and investigation of heterogeneity
If statistical heterogeneity was found, the aim was to examine it
by the following subgroup analyses, should there be a sufficient
number of studies.
1. Short term (acute) (<2 years) vs chronic PTSD (>2 years)
2. Mild vs severe PTSD (according to established scores on validated symptom severity measures)
3. Comorbid substance use disorders (SUD) vs no comorbid SUD
(diagnosed according to DSM or ICD)
There were insufficient studies however to undertake these subgroup analyses.
In future updates of the review, the number of subgroup analyses
will be reduced to avoid the large number of analyses these may
result in (which increase the chances of spurious findings). The
following subgroup analysis will be included:
1. Acute (<2 years) vs chronic PTSD (>2 years)
Sensitivity analysis
The aim was to perform sensitivity analyses to assess the robustness
of findings to decisions made about the risk of bias in studies. The
following groups were defined:
1. Allocation concealment is rated as yes, no or unclear (and attempts to clarify with authors fail) (A)
2. Blinding of outcome assessment is rated as yes, no or unclear
(and attempts to clarify with authors fail) (B)
3. Intention-to-treat analysis is rated as yes, no or unclear (and
attempts to clarify with authors fail) (C).
These criteria for assessing the risk of bias have been shown to
influence estimates of treatment effect (Juni 2001). The aim was
to perform sensitivity analyses in which studies categorised as A,
B or C were excluded, however, there were too few studies for this
to be meaningful.
In the future sensitivity analysis will be conducted removing those
studies where imputation of data was carried out.
RESULTS
Results of the search
Over time, two searches were run on the CCDAN registers by
TSCs Hugh McGuire (HM) in 2007 and Sarah Dawson (SD)
in 2010. The first set of searches were screened by HM and 11
studies and 3 uncoded references were sent to authors. Separate
searches run by authors at the time identified 111 citations from
MEDLINE and 9 from PsycINFO. When combined (and excluding duplicates) a total of 123 citations were retrieved; 106 were
excluded following scrutiny of the title/abstract and the full paper
of 17 possibly included studies were retrieved for closer inspection. Of these, 11 were excluded, 4 (Cohen 2007; Otto 2003;
Rothbaum 2006;Simon 2008) were included, some with multiple
publications, and one (Pai 2004) was an ongoing trial.
In the 2010 searches conducted by SD, 122 references were identified. Following screening at the editorial base, reports of 10 new
studies were sent to authors, of which one was judged irrelevant,
five were formally excluded and four placed in the ’Ongoing studies’ section of the review.
Included studies
Four trials were completed and published, although data for metaanalysis were not available from all of these trials for all outcomes.
The size of the trials varied between 10 (Otto 2003) and 65
(Rothbaum 2006) participants. The trials were undertaken in
Cambodia ( Otto 2003) and the USA (Cohen 2007; Rothbaum
2006 Simon 2008). Three of the included studies were of adults
and one was of children and adolescents (Cohen 2007). This study
was of females only, as was one of the adult studies (Otto 2003).
Participants
In all of the adult trials, PTSD was the primary diagnosis. In
all trials PTSD was diagnosed using a structured clinical interview for PTSD based on the DSM-IV (Cohen 2007; Otto 2003;
Rothbaum 2006) or the Mini International Neuropsychiatric Interview (MINI) (Simon 2008).The index trauma in Otto 2003
was exposure to the Pol Pot regime in Cambodia (including starvation, overwork, execution, threat of death, torture, severe physical deprivation and physical and/or sexual violence); in Simon
2008 and Rothbaum 2006 the predominant type of index trauma
was exposure to physical and/or sexual abuse. Comorbid anxiety
and depression symptoms were evident in the participants in each
of the trials, but other comorbidities, notably substance use and
suicidality were not documented.
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In the trial of Cambodian refugees (Otto 2003), inclusion was on
the basis of previous failure to response to clonazepam. In Simon
2008,participants were included in the trial if they remained symptomatic after eight weekly 90 to 120 minute sessions of prolonged
exposure. In no trial was there description of treatments that had
been received by participants prior to involvement in the studies.
In the trial of children and adolescents (Cohen 2007), all participants had sexual-abuse related PTSD symptoms (defined as
at least 5 symptoms on the Schedule for Affective Disorders and
Schizophrenia in School Aged Children, K-SADS-PL) with at least
one symptom in each of the three clusters. They were required to
have had these symptoms for at least two years. 68.2% met criteria
for comorbid diagnoses (72.7% in the combined pharmacotherapy and psychological therapy group; 63.5% in the psychological
therapy and placebo group) with all but one experiencing major
depressive disorder. Details of other comorbidities were not reported, but it was noted by the trialist that of those with at least
one comorbid diagnosis some had a diagnosis of substance abuse
not otherwise specified (Cohen 2007).
addition to sertraline over this period.
In the third adult trial (Simon 2008), patients were randomised
to receive paroxetine CE (mean 45.8mg) or placebo as augmentation to an additional five sessions of prolonged exposure (delivered
every second week). Few details are given about the prolonged
exposure treatment. It was delivered according to a standard protocol developed by one of the authors. The prolonged exposure
treatment was delivered less intensively in the intervention than it
had been delivered prior to randomisation to augmentation with
paroxetine (every two weeks rather than weekly).
In the trial of children and adolescents (Cohen 2007), participant
(all females) were randomly assigned to sertraline (up to 200mg/
day) and 12 sessions of trauma-focused CBT or placebo and 12
sessions of trauma-focused CBT. Parents were included in the
psychological intervention which included parenting skills, psychoeducation, relaxation, affect modulation, cognitive processing,
trauma narrative, in vivo mastery of trauma reminders, conjoint
child-parent session, and enhancing safety, healthy sexuality, and
future development. Therapists were master’s degree level social
workers.
Interventions
In the smaller trial of Cambodian refugees (Otto 2003), the
psychological intervention added to pharmacotherapy was CBTbased and covered the following elements: (1) information on the
symptoms and nature of PTSD from a cognitive-behavioural perspective, (2) clarification of the difference between PTSD symptoms and culturally-distinct fears of death or disability associated
with somatic symptoms, (3) exposure to somatic sensations associated with PTSD and anxiety, (4) exposure to memories of
specific trauma events with rehearsal of emotional acceptance and
cognitive coping strategies, (5) progressive muscle relaxation and
diaphragmatic breathing skills, and (6) self-care skills and assignment of pleasant events. This treatment was provided in a group
setting over 10 sessions. The length of this intervention period is
unclear (Otto 2003). Information on training of therapist(s) who
provided this treatment is not given. The pharmacotherapy comprised their existing dosage of the benzodiazepine, clonazepam,
and a titrated dosage of sertraline (up to 200mg/day) commenced
at the beginning of the trial period (trial period unspecified).
In the trial by Rothbaum 2006, prolonged exposure treatment was
given and comprised: psychoeducation about common reactions
to trauma, breathing retraining, in vivo exposure, prolonged imaginal exposure and homework. Prolonged imaginal exposure consisted of reliving the traumatic event in imagination and recounting the memory in the present tense for 45-60 minutes per session.
Participants received 10 twice-weekly sessions, each lasting 90120 minutes (Rothbaum 2006). Therapists at all three sites had at
least a master’s degree in clinical psychology. All participants that
had had a 10 week course of sertraline were randomly assigned to
remain on sertraline alone (up to 200mg/day) for a further five
weeks or to receive 10 sessions of prolonged exposure therapy in
Outcomes
A range of outcome measures were used in the included trials.
In the study of Cambodian refugees (Otto 2003), a total PTSD
score was not given, but rather subscale scores from the Clinician Administered PTSD Scale (CAPS) including re-experiencing, avoidance and arousal were used. Rothbaum 2006 used the
Structured Interview for PTSD (SIP) which yields a total severity
score. Simon 2008 used the clinician rated Short PTSD Rating
Interview (SPRINT). Simon 2008 also provided data from the
Clinical Global Impression-Severity of Illness scale (CGI-S). Otto
2003 measured depression and anxiety on the Hopkins Symptom Checklist-90. Rothbaum 2006 measured depression using
the Beck Depression Inventory and anxiety using the State-Trait
Anxiety Inventory with the state anxiety scale being used. Both of
these trials provided appropriate data for depression and anxiety
symptoms for meta-analysis. None of the adult studies provided
data on functioning.
In the trial of children and adolescents the K-SADS-PL - PTSD
section and the Children’s PTSD Symptoms Scale (CPSS) was
used. A total PTSD symptom score for the K-SADS-PL was not
provided for each of the intervention and comparison groups, nor
were scores provided for the CPSS. Cohen 2007 measured depression using the Beck Depression Inventory and the Mood and
Feeling Questionnaire and measured anxiety with the Screen for
Children’s Anxiety Related Disorders (SCARED); however no usable data was provided. Cohen 2007 did provide data on functioning, using the CGAS. All of the above instruments are welldocumented with good psychometric properties.
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Excluded studies
See also table of Excluded studies.
In two of the excluded studies, interventions comprised only
psychological treatments with no regulation of medications used
during the study period (Kessler 2003; Wright 2003). In one
study, participants were allocated to three groups: psychological treatment alone, psychological treatment plus medication, or
medication alone. The use of medication was not regulated and
could have included anxiolytics and/or tricyclic antidepressants
(Drozdek 1997). Two studies by Hinton (Hinton 2004; Hinton
2005) were also excluded, both on the basis that the psychological treatment (CBT) was used as an add-on to existing medication treatment that was not regulated over the period of the intervention. One study was not an RCT (Oflaz 2008). One study
examined the effects of pharmacological treatments for sleep in
addition to other treatments for PTSD (Abramowitz 2008); another was a dose-finding trial (Bouso 2008). Several studies featured non-pharmacological treatments that could not be described
as ’psychological’ in nature e.g. ’script driven traumatic imagery’
(Brunet 2008); ’collaborative care’ (Chan 2008), ’rTMS’ (Osuch
2009) and ’biofeedback’ (Zucker 2009) did not meet criteria for
psychological therapy for this review. The final studies did not include a group receiving combined medication and psychological
intervention (Clark 2008; Cottraux 2008; Resnick 2008; van der
Kolk 2007).
Only one trial gave details of the randomisation generation, stating that a computer generated random number sequence was generated (Cohen 2007). No details were provided in the other trials.
There were no details given about the concealment of allocation
in any of the published reports; however Simon 2008 did provide
additional information confirming allocation was concealed.
Blinding
It was not possible to blind care providers or participants to the
interventions in two of the adult trials, but in the Simon 2008
study where paroxetine CR was added, providers and participants
were blinded due to use of a placebo pill. In the trial of children
and adolescents, the use of a placebo pill also allowed blinding.
Outcome assessors were blind to treatment allocation in Cohen
2007, Rothbaum 2006 and Simon 2008 but not in the small trial
conducted in Cambodia (Otto 2003).
Incomplete outcome data
Rothbaum 2006 described drop outs and reported using intention-to-treat analysis; Simon 2008 described drop-outs and reported use of intention-to-treat analysis for 23 of the initial 25
randomised participants, but the remaining studies (Cohen 2007;
Otto 2003) did not provide detail.
Ongoing Studies
Five studies appear in this review’s list of currently ongoing studies
which may or may not meet final inclusion for updates of this
review. See also table of Characteristics of ongoing studies.
One ongoing study (Pai 2004) was identified that examines the
effectiveness of several interventions for adults with comorbid
PTSD and alcohol dependence. The study uses a 2 (naltrexone vs.
placebo) X 2 (CBT: prolonged exposure vs. no-prolonged exposure) design to assess the efficacy of naltrexone (NAL), prolonged
exposure (PE), and their combination (NAL + PE), vs. pill placebo
(PBO). One study (Gamito 2005) appears to involve a three-way
comparison between virtual reality exposure (VRE), drug treatment; and VRE + drug treatment. A third involves the administration of an antibiotic d-cycloserine in addition to CBT (Guay
2007); a fourth, the addition of fluoxetine to veterans already receiving psychological treatment (Hicks 2009) and the final study
(McAllister 2009) appears to involve venlaflaxine in addition to
CBT, although the number of arms in this trial is not clear.
Risk of bias in included studies
Allocation
Selective reporting
It is difficult to assess reporting bias given limited access to trial
protocols to assess a priori outcomes.
It should be noted that there were very little usable data for PTSD
symptom outcomes. In two trials, PTSD total scores were not
reported for each group (Cohen 2007; Otto 2003) and Cohen
2007 did not report all measures stated as being used.
Simon 2008 reports data obtained from one centre only of a larger
four-centre trial. Data from the other three centres have not yet
been published. We also noted that in Simon 2008 the SPRINT
is the only a priori outcome mentioned in the methods, but the
CGI-S outcomes are reported, raising the possibility that other
outcomes were measured and not reported.
Other potential sources of bias
The studies were generally small (ranging from 10 to 65 participants). In the trial by Cohen 2007 participants were not formally
diagnosed with PTSD but were entered into the trial if they had
PTSD symptoms (defined as at least 5 symptoms on the Schedule
for Affective Disorders and Schizophrenia in School Aged Children, K-SADS-PL).
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Effects of interventions
PTSD symptom severity (self-rated)
Few data from any included trial could be used in meta-analysis.
Data pooling for the PTSD outcome was impossible. Despite attempts to contact all authors, we were only able to secure additional data for one included trial (Rothbaum 2006), and one ongoing trial (Pai 2004) (although no outcome data were provided
given this study is yet to be completed).
Three trials included sertraline alone (Cohen 2007; Otto 2003;
Rothbaum 2006) and compared it to sertraline plus individual
prolonged exposure (Rothbaum 2006) or sertraline plus group
CBT (Otto 2003) or sertraline plus trauma focused CBT (Cohen
2007). The fourth trial examined prolonged exposure and compared it to prolonged exposure plus paroxetine CR (Simon 2008).
There were only trials available for two comparisons (with results
for adults and children/adolescents reported separately; hence,
three comparisons in total).
• Combination psychological and pharmacological
intervention vs pharmacotherapy alone
• Combination psychological and pharmacological
intervention vs psychological therapy alone
Neither study reported data for this outcome.
Global Functioning
Neither study reported data for this outcome.
Depression
Both studies in this comparison (Otto 2003; Rothbaum 2006)
reported depression severity scores. There were no statistically significant differences between the groups (SMD -0.40, 95% CI 0.86 to 0.07) (Analysis 1.3).
Anxiety
Both studies in this comparison (Otto 2003; Rothbaum 2006)
reported anxiety severity scores. There were no statistically significant differences between the groups (SMD -0.39, 95% CI -0.85
to 0.07) (Analysis 1.4).
1) Combination psychological and pharmacological
intervention vs pharmacotherapy alone
Suicidal ideation
PTSD symptom severity (clinician rated)
Suicide attempt
Two studies (Otto 2003 and Rothbaum 2006) compared psychological and pharmacological intervention versus pharmacotherapy
alone.
One study (Rothbaum 2006, n = 65) reported a total PTSD symptom score. In Rothbaum 2006 there were no statistically significant differences between the group receiving both an SSRI and
psychotherapy and those receiving an SSRI alone (mean difference -4.70, 95% CI -10.84 to 1.44) based on final scores on the
Structured Interview for PTSD (SIP).
Otto 2003 (n = 10) did not report on the significance of findings,
but reported “effect sizes indicative of consistent advantages” of
combined treatment compared to sertraline alone. However, in
this case, the numbers were very small and standard deviations
were noted to be much larger than the means reported, suggesting
the data were skewed and not appropriate for analysis.
Neither study reported data for this outcome.
Neither study reported data for this outcome.
Substance use
Neither study reported data for this outcome.
Vocational and social functioning
Neither study reported data for this outcome.
Quality of life
Neither study reported data for this outcome.
Cost of treatment
Neither study reported data for this outcome.
Withdrawals
Withdrawals due to adverse effects were not reported but authors
extracted data on drop outs as a surrogate. One of the two included trials within this comparison, with a total of 65 participants
(Rothbaum 2006), provided data on dropouts and showed no statistically significant differences between the groups (RR 5.47, 95%
CI 0.70 to 42.93).
3) Combination psychological and pharmacological
intervention vs psychological therapy alone
One trial including 25 participants (Simon 2008) compared
psychological and pharmacological intervention vs psychological
therapy alone.
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PTSD symptom severity
Quality of life
In Simon 2008 there were no statistically significant differences
between the group receiving both prolonged exposure and paroxetine CR and those receiving prolonged exposure alone (mean
difference 2.44, 95% CI -2.87, 7.35) on a total PTSD symptom
score.
No data were reported for this outcome.
Withdrawals
Withdrawals due to adverse effects were not reported but authors
extracted data on drop outs as a surrogate.
In Simon 2008 (N=25) there were no statistically significant differences between groups (RR 1.91 95% CI 0.38 to 9.51).
Cost of treatment
No data were reported for this outcome.
2) Combined SSRI plus TFCBT versus TFCBT alone
(children/adolescents)
One trial including 24 participants who were either children or
adolescents (Cohen 2007) compared psychological and pharmacological intervention vs psychological therapy alone.
PTSD symptom severity (self-rated)
The single included study (Simon 2008) did not report data for
this outcome.
Global Functioning
In this study (Simon 2008), the authors also report no significant
differences between groups on CGI-S or Clinical Global Impressions-Improvement scale (CGI-I) and low rates of remission in
both groups, with no differences between the groups in rates of
remission.
Depression
PTSD symptom severity (clinician rated)
While no usable data were reported, Cohen 2007 stated there were
no significant differences in PTSD symptoms between groups at
the end of treatment on the K-SADS-PL-PTSD and no differences in the numbers in each group who moved into a ’no PTSD
diagnosis’ category.
Withdrawals
In the study of children and adolescents (Cohen 2007; N=24)
there were no statistically significant differences between groups
(RR 0.50 95% CI 0.05 to 4.81) (both were due to residential
relocation).
No data were reported for this outcome.
PTSD symptom severity (self-rated)
Anxiety
No data were reported for this outcome.
The single included study (Cohen 2007) did not report data for
this outcome.
Suicidal ideation
Global Functioning Scores
No data for were reported for this outcome.
Data for this outcome related to functioning were provided using
the Children’s Global Assessment Scale (CGAS). There were no
statistically significant differences between the groups (mean difference 7.09, 95% CI -1.19 to 15.37).
Suicide attempt
No data were reported for this outcome.
Depression
Substance use
No data were reported for this outcome.
Vocational and social functioning
No data were reported for this outcome.
No data were reported in a form suitable for RevMan 5 (i.e. means
and SDs). Trialists reported that “on the MFQ, nine participants
scored in the nonclinical range (score < 27) at prettreatment (three
TF-CBT + sertraline; six TF-CBT + placebo); at posttreatment 13
additional participants had improved into the nonclinical range
(eight TF-CBT + sertraline and five in the TF-CBT plus placebo).”
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Anxiety
No data were reported in a form suitable for RevMan 5 (i.e. means
and SDs). Trialists reported that “on the SCARED, four participants (two in each group) scored in the nonclinical range (score <
25) at prettreatment; at posttreatment 13 additional participants
had improved into the nonclinical range (eight TF-CBT + sertraline and five in the TF-CBT plus placebo).”
Suicidal ideation
Trialists reported “at pre-treatment, 5 participants responded
’True’ to the question ’I thought about killing myself ’ (four in the
TF-CBT + sertraline and one in the TF-CBT plus placebo). At
post-treatment, no participants responded ’True’ to this question.”
Suicide attempt
and while three of the four included trials reported on drop outs,
the results were heterogeneous, with drop outs varying according
to intervention type across each study (for example, there were
fewer drop outs in the combined treatment arm in Cohen 2007,
in the SSRI alone treatment arm in Rothbaum 2006, and in the
psychological treatment only group in Simon 2008).
In the absence of evidence, it is not clear whether combination
treatments provide any advantage over a single modality alone.
One clinically appropriate approach for all age groups might be
to begin treatment with a single modality, before more intense
approaches are trialled. In light of the controversy surrounding
the use of SSRIs in children and adolescents (Hammad 2006),
beginning treatment with a psychological treatment may be the
preferred approach. The addition of medication should be cautious and well monitored for this age group (Bridge 2007).
No data were reported for this outcome.
Substance use
No data were reported for this outcome.
Vocational and social functioning
No data were reported for this outcome.
Quality of life
No data were reported for this outcome.
Cost of treatment
No data were reported for this outcome.
DISCUSSION
Summary of main results
There were four trials included in the review, one of which included children and adolescents (N=24) and three involving adults
participants (N=100).
As there were few trials, and very little data included in the review,
definitive conclusions are difficult to draw. Overall there is insufficient evidence to assess whether or not a combination of pharmacotherapy and psychotherapy is more effective in treating PTSD
than either of these interventions alone. In terms of the severity of
PTSD symptoms as an outcome measure, no pooling of data was
possible, although each trial alone appeared to suggest that there
was no benefit of combination therapy. Some pooling was possible
for depression and anxiety outcomes, but again there was no benefit of combination therapy. No trial reported on adverse outcomes,
Overall completeness and applicability of
evidence
With so few trials and data available for the review, there is a
paucity of information available about the effectiveness of combination interventions for PTSD. A major weakness in the included
trials was the lack of measurement and/or reporting of total PTSD
symptom outcome scores. PTSD symptoms were only measured
using clinician-rated tools, and functional outcomes were not reported in any case. Adverse events were not measured, including
suicide-related behaviours, nor was comorbid substance use, which
is considered an important and common comorbid condition in
PTSD.
Variants of CBT and exposure therapy were used in all the included
trials, with sertraline and paroxetine the only medications studied.
The study populations varied in each trial, although sexual and
physical violence were the most common precipitating traumatic
events. There were no trials with a focus on combat related trauma,
accidents or disasters. The included trials focused predominantly
on participants with chronic PTSD symptoms. Only one trial included participants who were eligible for inclusion due to having
PTSD symptoms, although trialists considered this to be equivalent to diagnosis. No trial that described participants as having
sub-clinical symptoms were located for inclusion in the review.
There were no data on long-term outcomes.
Quality of the evidence
There were few included trials, and the trials ranged in size between
10 and 65 participants. The quality of included trials was difficult
to evaluate given inadequate description of the methodological
details, which hampered the assessment of their internal validity.
Of note is the lack of reporting of outcomes in sufficient detail or in
a usable format for meta-analysis. Of the data that were available,
there was evidence of skew. Meta-analytic techniques frequently
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Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
13
face the problem of managing non-parametric data. While there
is not a clear consensus regarding the resolution of this statistical
issue, we note the limitations of our analysis in accounting for
skewed data. The consistency of results cannot be evaluated here
given the small number of trials and the lack of usable data.
Potential biases in the review process
Many of the aims of the review could not be addressed due to the
limited number of included trials and the lack of usable data. The
review team made all efforts to locate all published and unpublished trials by writing to the trial authors of included as well as
ongoing studies, and in every case attempted to obtain additional
data, both relating to the conduct of the trials and to the outcomes.
As we are aware of several ongoing trials for which we could not
yet obtain outcome data, the review will be updated to include
these subsequently published trials.
Agreements and disagreements with other
studies or reviews
In an earlier review, Marshall 2000 advocated the use of combined
approaches for the clinical management of PTSD, given that ongoing residual symptoms were frequently observed in trials utilising
single modality treatments. However, no data about the efficacy
of combined approaches were provided in Marshall’s review, given
the relative novelty at that time of this field of enquiry. In contrast,
a more recent review (Davis 2006) has highlighted potential risks
of combination treatment, citing evidence that pharmacotherapy
can lessen the efficacy of psychotherapy. Davis points to the possible efficacy of newer pharmacological agents that may improve
the effect of psychotherapy because of their impact on learning.
AUTHORS’ CONCLUSIONS
Implications for practice
There is currently insufficient evidence regarding the potential
benefits and risks of combined pharmacotherapy and psychotherapy for PTSD compared with either modality alone. The findings
are far from robust, are based on a small number of trials and
are largely unrepresentative of the many differing presentations of
PTSD seen in clinical practice. There is not enough evidence to be
able to determine if there is any advantage of combined treatment
over a single modality alone in patients with long-standing PTSD
symptoms.
Although this review could not determine the benefit of combined
interventions in children and adolescents specifically, given the
controversy about the use of antidepressants in this age group making judicious use of such medications is crucial and psychotherapy
may be preferred as the first line treatment. It may also be that
those who present for treatment in the early stages of illness, or
those with symptoms that do not yet meet the full threshold for
a diagnosis of PTSD, would benefit from a trial of psychotherapy
in the first instance, given the results of the Cochrane Systematic
review. The trials included in this review mostly pertain to the
treatment of chronic populations with no detail about intervention strategies that had already been trialled. It is possible however
that if effective (even if more simple) interventions were delivered
earlier in the course of illness, the outcomes may be more positive
(McGorry 2006).
Implications for research
Further research into the clinical management of PTSD is required, including larger trials that use (i) reliable and clinically
meaningful outcome measurements, such as remission of PTSD,
(ii) consistent measures of PTSD symptom reduction and (iii)
functional outcomes, including those related to social and occupational functioning. The impact of, and outcomes related to, substance use and suicidal ideation should be subject to more evaluation.
There is also a need for trials within homogenous patient populations, such as those exposed to combat-related trauma and disasterrelated trauma, in addition to larger studies of those with interpersonal-related violence and trauma. Trials in specific populations
such as children and adolescents are also required, and trials of
participants with sub-threshold PTSD or sub-clinical symptoms
would be valuable.
A consistent approach to stepped care models should be tested, for
example with medication introduced subsequent to the trial of a
psychological intervention. A range of commonly used and newer
psychotherapies and pharmacotherapies should also be trialled.
Finally, greater attention to the methodological and reporting requirements for RCTs, as specified in the CONSORT statement
(Moher 2001) is warranted in all future research in this field.
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
14
REFERENCES
References to studies included in this review
Cohen 2007 {published data only}
∗
Cohen JA, Mannarino AP, Perel JM, Staron V. A pilot
randomized controlled trial of combined trauma-focused CBT and
sertraline for childhood PTSD symptoms. Journal of the American
Adademy of Child and Adolescent Psychiatry 2007;46(7):811–9.
Tucker P, Davis L, Cohen J. Pharmacotherapy of PTSD: Trauma
and neurotransmitters across the lifespan. 20th Annual Meeting:
International Society for Traumatic Stress Studies. New Orleans,
LA, 2004; Vol. Nov 14–18.
Otto 2003 {published data only}
∗
Otto MW, Hinton D, Korbly NB, Chea A, Ba P, Gershuny BS,
Pollack MH. Treatment of pharmacotherapy-refractory post
traumatic stress disorder among Cambodian refugees: a pilot study
of combination treatment with cognitive-behavior therapy vs
sertraline alone. Behaviour Research and Therapy 2003;41:
1271–1276.
Rothbaum 2006 {published data only}
Connor M, Rothbaum B, Foa EB, Davidson JRT, Cahill S, Clary
C. A controlled trial of combined sertraline and prolonged exposure
therapy in posttraumatic stress disorder. European
Neuropsychopharmacology 2002;12(Suppl 3):s335.
Davidson JRT, Payne VM, Connor KM, Foa EB, Rothbaum BO,
Hertzberg MA, Weisler RH. Trauma, resilience and saliostasis:
effects of treatment in post-traumatic stress disorder. International
Clinical Psychopharmacology 2005;20:43–48.
∗
Rothbaum BO, Cahill SP, Foa EB, Davidson JRT, Compton J,
Connor KM, Astin MC, Hahn C. Augmentation of sertraline with
prolonged exposure in the treatment of post traumatic stress
disorder. Journal of Traumatic Stress 2006;19(5):625–638.
Rothbaum BO, Foa EB, Davidson JRT, Cahill SP, Connor KM.
Augmentation of sertraline with cognitive-behavioral therapy in the
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NR513]
Simon 2008 {published data only}
Davidson J. Randomized Trial of Paroxetine-CR for the Treatment
of Patients With Post-Traumatic Stress Disorder (PTSD)
Remaining Symptomatic After Initial Exposure Therapy.
Clinicaltrials.gov. [: NCT00215163]
Simon N. Randomised trial of paroxetine-CR for the treatment of
patients with post traumatic stress disorder remaining symptomatic
after initial exposure therapy. controlled-trials.com 2006.
∗
Simon NM, Connor KM, Lang AJ, Rauch S, Krulewicz S,
LeBeau RT, Davidson JR, Stein MB, Otto MW, Foa EB, Pollack
MH. Paroxetine CR augmentation for posttraumatic stress disorder
refractory to prolonged exposure therapy. Journal of Clinical
Psychiatry 2008;69(3):400–5.
References to studies excluded from this review
Abramowitz 2008 {published data only}
Abramowitz EG, Barak Y, Ben-Avi I, Knobler HY. Hypnotherapy
in the treatment of chronic combat-related PTSD patients suffering
from insomnia: A randomized, zolpidem-controlled clinical trial.
International Journal of Clinical and Experimental Hypnosis 2008;56
(3):270–80.
Bouso 2008 {published data only}
Bouso JC, Doblin R, Farre M, Alcazar MA, Gomez-Jarabo G.
MDMA-assisted psychotherapy using low doses in a small sample
of women with chronic posttraumatic stress disorder. Journal of
Psychoactive Drugs 2008;40(3):225–36.
Brunet 2008 {published data only}
Brunet A, Orrb SP, Tremblay J, Robertson K, Naderd K, Pitmanc
RK. Effect of post-retrieval propranolol on psychophysiologic
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Chan D. Depression and comorbid PTSD in veterans: Evaluation of
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Seattle: University of Washington, 2007.
Clark 2008 {published data only}
Clarke SB, Rizvi SL, Resick PA. Borderline personality
characteristics and treatment outcome in cognitive-behavioral
treatments for PTSD in female rape victims. Behavior Therapy
2008;39(1):72–8.
Cottraux 2008 {published data only}
Cottraux J, Note I, Yao SN, de Mey-Guillard C, Bonasse F,
Djamoussian D, Mollard E, Note B, Chen Y. Randomized
controlled comparison of cognitive behavior therapy with Rogerian
supportive therapy in chronic post-traumatic stress disorder: a 2year follow-up. Psychotherapy & Psychosomatics 2008;77(2):101–10.
Drozdek 1997 {published data only}
Drozdek B. Follow-up study of concentration camp survivors from
Bosnia-Herzegovina: three years later. Journal of Nervous and
Mental Disease 1997;185(11):690–4.
Hinton 2004 {published data only}
Hinton DE, Pham T, Tran M, Safren SA, Otto MW, Pollack MH.
CBT for Vietnamese refugees with treatment-resistant PTSD and
panic attacks: a pilot study. Journal of Traumatic Stress 2004;17(5):
429–33.
Hinton 2005 {published data only}
Hinton DE, Chhean D, Pich V, Safren SA, Hofmann SG, Pollack
MH. A randomized controlled trial of cognitive-behavioral therapy
for Cambodian refugees with treatment-resistant PTSD and panic
attacks: a cross-over design. Journal of Traumatic Stress 2005;18(6):
617–29.
Kessler 2003 {published data only}
Kessler RA. The differential impact of thought field therapy as a
treatment modality for male perpetrators of domestic violence
diagnosed with posttraumatic stress disorder. Dissertations Abstracts
International 2003;63(12-B):6097.
Oflaz 2008 {published data only}
Oflaz F, Hatipoglu S, AAydin H. Effectiveness of psychoeducation
intervention on post-traumatic stress disorder and coping styles of
earthquake survivors. Journal of Clinical Nursing 2008;17(5):
677–87.
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
15
Osuch 2009 {published data only}
Osuch EA, Benson BE, Luckenbaugh DA, Geraci M, Post RM,
McCann U. Repetitive TMS combined with exposure therapy for
PTSD: A preliminary study. Journal of Anxiety Disorders 2009;23
(1):54–9.
Resnick 2008 {published data only}
Resick PA, Galovski TE, O’Brien Uhlmansiek M, Scher CD, Clum
GA, Young-Xu Y. A randomized clinical trial to dismantle
components of cognitive processing therapy for posttraumatic stress
disorder in female victims of interpersonal violence. Journal of
Consulting & Clinical Psychology 2008;76(2):243–58.
van der Kolk 2007 {published data only}
van der Kolk BA, Spinazzola J, Blaustein ME, Hopper JW, Hopper
EK, Korn DL, Simpson WB. A randomized clinical trial of eye
movement desensitization and reprocessing (EMDR), fluoxetine
and pill placebo in the treatment of posttraumatic stress disorder:
treatment effects and long-term maintenance. Journal of Clinical
Psychiatry 2007;68(1):37–46.
Wright 2003 {published data only}
Wright TP. The effectiveness of behavioral activation group
therapy: Treating comorbid depression on a specialized inpatient
posttraumatic stress disorder unit for combat veterans. Dissertations
Abstracts International 2003; Vol. 64, issue 1–B:0436.
Zucker 2009 {published data only}
Zucker TL, Samuelson KW, Muench F, Greenberg MA, Gevirtz
RN. The effects of respiratory sinus arrhythmia biofeedback on
heart rate variability and posttraumatic stress disorder symptoms: A
pilot study. Applied Psychophysiology Biofeedback 2009;34(2):
135–143.
References to ongoing studies
Gamito 2005 {published data only}
Gamito P, Pacheco J, Ribeiro C, Pablo C, Saraiva T. Virtual war
PTSD--A methodological thread. Annual Review of CyberTherapy
and Telemedicine 2005;3:173–8.
Guay 2007 {published data only}
∗
Guay S. RCT of CBT combined with d-cycloserine for treating
PTSD or comparative study of the efficacy of a cognitive-behavioral
therapy for post-traumatic stress disorder with or without dcycloserine [NCT00452231]. Clinical-Trials.gov 2007.
Hicks 2009 {published data only}
Hicks PB, Adams ML, Litz B, Young K, Goldart J, Velez T, Penk
W//Kotrla K. Predictors of Treatment Response to Fluoxetine in
PTSD Following a Recent History of War Zone Stress Exposure.
Military Health Research Forum, Kansas City, MO. August 31September 3, 2009 [Conference Abstracts]. 2009.
McAllister 2009 {published data only}
McAllister TW, Fann J, Chard K. Venlafaxine and CBT for
Psychological Distress After TBI: A Randomized Controlled Trial.
Military Health Research Forum, Kansas City, MO. August 31September 3, 2009 [Conference Abstracts]. 2009.
Pai 2004 {published data only}
∗
Pai A, Riggs D, Volpicelli J, Imms P, Foa E. The role of
attributions in PTSD symptom severity and alcohol use. 20th
Annual Meeting, International Society for Traumatic Stress Studies.
New Orleans, LA, 2004; Vol. Nov 14–18.
Riggs D, Pai A, Volpicelli J, Imms P, Foa B. Treating co-morbid
PTSD and alcohol dependence: Early symptom changes. 20th
Annual Meeting: International Society for Traumatic Stress Studies.
New Orleans, LA, 2004; Vol. Nov 14–18.
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∗
Indicates the major publication for the study
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
18
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Cohen 2007
Methods
RCT
Participants
Setting: Unclear
Recruitment strategy: Consecutively referred
Country: USA
N: Number randomised 24 (12 to each treatment)
Exclusion criteria: non-English speaking; schizophrenia or other active psychotic disorder;
mental retardation or pervasive developmental disorder (all due to the requirement to receive
TF-CBT, a cognitive-oriented psychotherapy); or taking current psychotropic medications.
Current substance dependence.
Primary diagnosis? PTSD
How was PTSD measured? At least five PTSD symptoms on the Schedule for Affective
Disorders and Schizophrenia for School-Age Children-Present and Lifetime version [K-SADSPL] with at least one symptom in each of the three PTSD clusters and clinically significant
impairment
Index trauma? contact sexual abuse that was confirmed by Child Protective Services
Time since incident episode: Total only provided - mean months since most recent abuse
22.9(SD 35.6)
Previous treatment for PTSD: Not stated
Previous treatment for other mental disorders? Not stated
Age Total Range only provided 5 x 10-11yrs; 10 x 12-14yrs; 7 x 15-17yrs
Sex: 100% Female
Ethnicity: total only - 17 white; 5 African American
Comorbid substance use: Not stated
Suicidality: Not stated
Comorbidity: 68.2% met criteria for comorbid diagnoses (TF-CBT+Sert =72.7%; TFCBT+Placebo = 63.5%). All but one had MDD; other diagnoses included general anxiety
disorder, substance abuse not otherwise specified, oppositional defiant disorder, panic disorder,
and anorexia nervosa.
Interventions
Comparison Group 1
Type: Pharmacotherapy and Psychotherapy combined
Pharmacotherapy: Sertraline: started at 25mg and titrated to 50mg - 200mg day as clinically indicated
Length of pharmacotherapy: 12 weeks
Other treatments being used: None
Psychotherapy: Trauma focused CBT - (TF-CBT)
Individual/group: Individual
Manualised: There are two published books and a web-based learning course
Delivered by: One of two randomly assigned clinicians who were licensed masters level social
workers
Length of sessions: Unclear.
Number of sessions: 12
Length of intervention: 12 weeks
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
19
Cohen 2007
(Continued)
How many sessions actually delivered: Unclear
Was it intended as intervention or control: As intervention condition with Sertraline/
placebo control condition
Comparison Group 2
Type: Psychotherapy and placebo
Pharmacotherapy: Placebo pill
Psychotherapy: As above
Outcomes
PTSD symptoms (K-SADS-PL and CPSS)
Global impairment (CGAS)
Depression (MQF)
Anxiety symptoms (SCARED)
Suicidal ideation
Child-abuse related attributions and perceptions (The Childrens Attributions and Perceptions Scale)
Childrens’ behaviour and symptoms (CBCL)
Parental depression (BDI)
Parental emotional distress (The Parent’s Emotional Reaction Questionnaire)
Parental support (the Parental Support Questionnaire)
Sertraline side effects (SEF-CA)
Notes
Risk of bias
Item
Authors’ judgement
Description
Adequate sequence generation?
Yes
...“randomised according to a computerized random number
sequence” (p. 814)
Allocation concealment?
Unclear
No statement
Blinding?
Outcome assessor
Yes
...“double-blind procedure whereby no one directly involved in
the study (i.e., parents, children, independent evaluator, therapists, or child and adolescent psychiatrist) knew which condition the children were assigned to throughout the course of
treatment” (p. 814)
Incomplete outcome data addressed?
All outcomes
Unclear
Number dropped out: 1 TF-CBT + Sertraline; 1 TF-CBT +
Placebo
ITT analysis not undertaken, unclear description of reason for
drop-outs
Free of selective reporting?
No
All a-prior outcomes described in methods were reported on
but not in a usable format for meta-analysis; e.g. total PTSD
symptoms were not reported on for the sertraline and placebo
groups separately
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
20
Cohen 2007
(Continued)
Free of other bias?
No
Low recruitment rate; large number refused due to medication
concerns
Otto 2003
Methods
RCT
Participants
Setting: Unclear
Recruitment strategy: Unclear
Country: USA (but participants are Cambodian refugees)
N: Randomised 10
Exclusion criteria: Not stated
Primary diagnosis? Current PTSD, failure to respond to clonazepam
How was PTSD measured? Structured interview for PTSD ? DSM-IV
Severity:
CAPS re-experiencing:
Intervention: 21.4 (6.3); Control: 15.2 (6.2)
CAPS avoidance/numbing
Intervention: 24.4(12.1); Control:21.4(14.7)
CAPS hyperarousal:
Intervention: 18.8(10.1); Control:20.6 (9.8)
Index trauma: Pol Pot regime with exposure to starvation, overwork, illness, or execution. In
addition many survivors were subjected to the constant threat of death, torture, severe physical
deprivation, physical and sexual violence, and physical displacement
Time since incident episode: Total only provided : Approx 21-25 years ago
Previous treatment for PTSD: Total only provided: Pharmacotherapy: Clonazapam, SSRI
(not Sertraline)
Previous treatment for other mental disorders? Not stated
Age: Total only provided 47.2 years
Sex: 100% female
Ethnicity: All Cambodian
Comorbid substance use: Not stated
Suicidality: Not stated
Comorbid anxiety:
HSCL-90 anxiety:
Intervention: 29.2 (8.5);Control: 31.4 (6.2)
Anxiety sensitivity index (ASI)
Intervention:38.8 (11.0);Control 37.6 (15.2)
ASI-Khmer items:
Intervention: 37.6 (15.2);Control: 51.4 (7.8)
Comorbid depression
HSCL-90 depression:
Intervention: 34.4 (7.6);Control: 38.2 (9.2)
HSCL-90 somatisation:
Intervention: 36.2 (9.4);Control: 26.2 (6.1)
Interventions
COMPARISON GROUP 1
Type: Pharmacotherapy alone
Pharmacotherapy: Sertraline: 25mg/d for Week 1; 50mg/d for Week 2; with titration up
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
21
Otto 2003
(Continued)
by 50mg/d to a maximum of 200 mg/d.
Length of pharmacotherapy: Unclear
Other treatments being used: Unclear; however, ‘clonazepam treatment was held constant
0.5-1mg, BID; adjunctive treatment with benzodiazepam also use.
COMPARISON GROUP 2
Type: Pharmacotherapy and Psychotherapy combined
Pharmacotherapy: As above
Psychotherapy: CBT - culture specific
Individual/group: Group
Manualised: Unclear
Delivered by: Unclear
Length of sessions: Unclear.
Number of sessions: 10
Length of intervention: Unclear
How many sessions actually delivered: Unclear
Was it intended as intervention or control: As intervention added on to Sertraline (control
condition)
Outcomes
PTSD symptoms (CAPS re-experiencing, avoidance/numbing and hyperarousal symptoms)
Measures of comorbid anxiety (HSCL-90 anxiety, ASI, ASI-Khmer)
Measures of comorbid depression (HSCL-90 depression; HSCL-90 somatisation)
Notes
Risk of bias
Item
Authors’ judgement
Description
Adequate sequence generation?
Unclear
No statement
Allocation concealment?
Unclear
No statement
Blinding?
Outcome assessor
Unclear
No statement
Incomplete outcome data addressed?
All outcomes
Unclear
No statement
Free of selective reporting?
No
Total PTSD symptom scores not reported by group
Free of other bias?
Unclear
Small trial; some baseline imbalance in symptom severity
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
22
Rothbaum 2006
Methods
RCT
Participants
Setting: Outpatient
Recruitment strategy: Advertisements, referrals from professionals
Country: USA
N = Number randomised = 65 for phase 2
Exclusion criteria: History of psychotic, bipolar disorder; prior failure with Sertraline, medical contraindications to taking sertraline; current administration of psychiatric medication
Primary diagnosis? Primary psychiatric diagnosis of PTSD, duration >=3 months
How was PTSD measured? Structured clinical interview for DSM-IV Severity:
Intervention: Wk 10 Mean (SD) SIP 16.16 (10.64)
Control: Wk 10 Mean (SD) SIP 14.5 (11.65)
Index trauma? The most common index traumas were sexual assault, including childhood
sexual abuse (37%); nonsexual assault, including childhood physical abuse (25%); and the
death (not combat-related) of another person (22%), usually someone of significance to the
participant (i.e., child, parent, sibling, spouse or romantic partner).Another 9% reported
being in a motor-vehicle accident as the index trauma.
The remaining traumas coded as other were one case each of the following: combat exposure,
house fire, airplane crash, discovering a parent after a nonfatal overdose, and a police officer
who felt he came very close to shooting an unarmed suspect.
Time since incident episode: Total only provided (n=43) 8.1 years (11.77SD)
Previous treatment for PTSD: not stated
Previous treatment for other mental disorders? open label treatment with sertraline for
10 weeks as part of protocol (called Phase 1)
Age: Total only provided mean (SD) = 39.3 (10.69)
Sex: Total only provided 35.4% male; 64.6% female
Ethnicity: Total only provided 80% White; 18.5% Afr-Am; 1.5% Other
Comorbidity: 63% had current major depression, dysthymia or both; 52% had one or more
anxiety disorder
Comorbid substance use: not stated
Suicidality: not stated
Comorbid anxiety:
STAI-S Mean (SD) Wk 10
Intervention:43.0(13.21); Control:39.2(13.90)
Comorbid depression
BDI Mean (SD) Wk 10
Intervention: 11.2(8.94);Control: 9.5 (7.57)
Interventions
COMPARISON GROUP 1
Type: Pharmacotherapy alone
Pharmacotherapy: 10 weeks of open-label Sertraline, 200mg/day or maximum tolerated
dose; followed 5 weeks of Ssertraline, started at 25 mg/day increased to 200mg or maximum
tolerated dose per day. The average dose was 173.1 mg/day at the beginning of week 10 and
173.5mg/day at week 15.
COMPARISON GROUP 2
Type: Pharmacotherapy and psychotherapy combined
Pharmacotherapy: As above
Psychotherapy: Prolonged exposure (PE) therapy
Individual/group: Individual
Manualised: Yes
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
23
Rothbaum 2006
(Continued)
Delivered by: Therapists trained in the use of PE
Length of sessions: 90-120 minutes.
Number of sessions: 10
Length of intervention: 5 weeks
How many sessions actually delivered: Unclear; 10 for completers unknown for noncompleters.
Was it intended as intervention or control: As intervention added on to sertraline (control
condition)
Outcomes
Reduction in PTSD symptoms (SIP)
Reduction in comorbid anxiety (STAI)
Reduction in comorbid depression (BDI)
Notes
For depression and anxiety scores, the SD has been imputed for each group from the
combined SD of the change score. Mean change scores for each group were calculated
from endpoint scores in Table 2.
Risk of bias
Item
Authors’ judgement
Description
Adequate sequence generation?
Unclear
No statement
Allocation concealment?
Unclear
No statement
Blinding?
Outcome assessor
Yes
“independent evaluators” p 630; “The independent evaluators
were not otherwise involved in participants’ treatment and were
kept blind to the treatment condition of those participants who
entered Phase II” p 631.
Additional information from the author:
“the only person who was kept blind to treatment condition
was the IE, and of course, the IE was only blind to whether the
person got PE or not during phase II. The IE was not blind
to the fact that the person was on sertraline. We instructed the
patient not to discuss therapy with the IE and we took steps to
prevent the IE from seeing the patient accompanied by a study
therapist (e.g., having IE behind office doors when the patient
was in for a therapy visit, taking the ”back route“ to a therapist’s
office to avoid the waiting room, changing the IE if the blind
was blown, excluding the IE from supervision of study cases)”
Incomplete outcome data addressed?
All outcomes
Yes
Drop outs described and ITT analysis undertaken; uneven drop
outs across groups (number dropped out: Intervention: 6 Phase
2 ; Control: 1 Phase 2)
Free of selective reporting?
Unclear
Usable data not fully reported
Free of other bias?
No
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
24
Simon 2008
Methods
RCT
Participants
Setting: Outpatient
Recruitment strategy: Advertisements and clinical referral
Country: USA
N: Intervention: 9; Control: 14
Exclusion criteria: Serious medical illness; pregnant or lactating women; concurrent use
of other psychotropic medication; lifetime diagnosis of schizophrenia or psychotic disorder;
mental retardation; organic mental disorders or bipolar disorder; OCD exhibited in last six
months; eating disorders; cutting or self-injurious behaviour or alcohol or substance abuse
disorders within the last 6 months; current primary diagnosis of MDD, dysthymia, social
anxiety disorder or GAD; history of hypersensitivity or poor response to paroxetine; Current
compensation of legal action related to effects of trauma, those with ongoing relationship with
assailant.
Primary diagnosis? PTSD with participants still symptomatic (greater than or equal to 6
on SPRINT and CGI-S greater than or equal to 3) after 8 sessions of prolonged exposure
How was PTSD measured? Mini International Neuropsychiatric Interview (MINI) for
DSM-IV
Severity: all participants remained symptomatic after 8 sessions of PE
SPRINT total score:
Intervention: 16.11 ; Control 17.00
CGI-S:
Intervention: 4.11 ; Control 4.00
Index trauma?
Physcial and/or sexual abuse: intervention 89%; control 57%
Exposure to war: intervention 0%; control 14%
Physical accident and/or medical trauma: intervention 11%; control 29%
Time since incident episode: Unclear
Previous treatment for PTSD: 8 sessions of Prolonged Exposure therapy as part of protocol
Previous treatment for other mental disorders? Unclear
Age Intervention mean 47.8; Control mean 44.2
Sex Intervention F=4 (44%) M=5 (56%); Control F=9 (64%) M=5(36%)
Ethnicity Intervention 71% white; Control 78% white
Comorbid substance use: unclear
Suicidality Those with cutting or self-injurious behaviour were excluded but no other detail
about baseline suicidality given
Comorbid anxiety/depression
Number with at least 1 mood or anxiety disorder:
Intervention: 8 (89%); Control: 11(79%)
Number with MDD:
Intervention: 3 (33%); Control: 9 (64%)
Interventions
COMPARISON GROUP 1
Type: Pharmacotherapy and Psychotherapy combined
Pharmacotherapy: Paroxetine-CR initiated at 12.5mg/day and flexibly titrated based on
efficacy and tolerability from 12.5mg/day to a maximum of 62.5mg/day for 10 weeks. Included
management by a study psychiatrist during 10-20 minute sessions weekly for first two weeks
and then once every two weeks.
Mean dose 45.8 (SD16.5)
Psychotherapy: Prolonged exposure (PE) therapy
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
25
Simon 2008
(Continued)
Individual/group: Individual
Manualised: Yes
Delivered by: Trained therapists who received certification in PE
Length of sessions: 90-120 minutes
Number of sessions: 5 once every two weeks
Length of intervention: 10 weeks
How many sessions actually delivered: not reported
Was it intended as intervention or control: as intervention added on to PE (control
condition)
COMPARISON GROUP 2
Type: Psychotherapy and placebo
Pharmacotherapy: placebo (mean dose 44.8 (SD15.5)
Psychotherapy: As above
Outcomes
Level of impairment ( CGI-S)
PTSD symptoms (SPRINT)
Notes
Risk of bias
Item
Authors’ judgement
Description
Adequate sequence generation?
Unclear
No description except that random assignment was blocked by
CGI-S score
Allocation concealment?
Yes
Additional information from author: “Study was double blind
with the study staff giving the patient a randomization number
that only the research pharmacy supplying the medication knew
was placebo or active medication”
Blinding?
Outcome assessor
Yes
Additional information from author: “Study was double blind”.
Paper describes a “rater blind to treatment assignment” pg 401
Incomplete outcome data addressed?
All outcomes
Yes
5 drop outs; two before starting medication and not included
in ITT analysis, 1 additional from medication group due to
inpatient admission for suicidal ideation; 2 from placebo group
due to dizziness/nausea (1) and noncompliance (1).
Free of selective reporting?
Unclear
No information about outcome measurement planned a-priori.
Free of other bias?
No
small study; some imbalance - more females in placebo group;
more participants in placebo group had MDD; more participants in medication group had index trauma of sexual abuse
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
26
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Abramowitz 2008
The study treatments are hypnotherapy and zolpidem aimed at the sleep difficulties being suffered by participants
with PTSD who are already medicated with an SSRI and receiving psychotherapy
Bouso 2008
Dose-finding (rather than effectiveness) trial
Brunet 2008
’Script driven traumatic imagery’ did not meet criteria for psychological therapy for this review
Chan 2008
Intervention ’collaborative care’; does not meet inclusion criteria
Clark 2008
Participants not randomised to a combined intervention
Cottraux 2008
Participants not randomised to a combined intervention
Drozdek 1997
Medication not controlled and not clear whether groups are randomised
Hinton 2004
Participants not randomised to a combined intervention
Hinton 2005
Participants not randomised to a combined intervention
Kessler 2003
No random assignment to combined treatment (no mention of pharmacotherapy); unlikely that participants
have a primary diagnosis of PTSD
Oflaz 2008
Not an RCT
Osuch 2009
The pharmacological component of the trial was delivered in combination with repetitive transcranial magnetic
stimulation (rTMS) and not a psychological therapy
Resnick 2008
Participants not randomised to a combined intervention
van der Kolk 2007
No combined intervention group
Wright 2003
No random assignment to combined treatment; 90% of participants already on prescribed medication; the
intervention targeted major depressive disorder
Zucker 2009
Biofeedback not an eligible psychological intervention
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
27
Characteristics of ongoing studies [ordered by study ID]
Gamito 2005
Trial name or title
Virtual war PTSD
Methods
3 armed RCT
Participants
Males with the diagnostic of War PTSD according to DSM-IV-TR who looked for treatment at Hospital
Julio de Matos in Lisbon, Portugal.
Interventions
Virtual reality exposure (VRE); Drug treatment; VRE + Drug Treatment. The adequate therapeutic dosage
of Sertraline (Zoloft, Pfeizer) will be administrated during 16 weeks to the Drug Treatment groups. VRE
groups will use a Head Mounted Device that enables fully immersive experience in the following war virtual
scenarios: mine deflagration, mine deflagration + ambush, ambush and assisting casualties and waiting for a
rescue helicopter.
Outcomes
CAPS, BDI, STAI, SCL-90, MCM-II for psychometric measures and TAS, DES, PQ, SUDS, heart rate and
blood pressure, ECG, EEG and ACTH for physiological measures are the evaluation procedures selected for
assessing the results.
Starting date
Contact information
Notes
Guay 2007
Trial name or title
Comparative Study of the Efficacy of a Cognitive-Behavioral Therapy for Post-Traumatic Stress Disorder
With or Without D-Cycloserine
Methods
RCT
Participants
Either gender, aged 18 to 65, clinical diagnosis of PTSD
Interventions
CBT with and without D-Cycloserine
Outcomes
Primary Outcome Measures: Clinician-administered measures collected at initial assessment, post-treatment
and six-months follow-up:
CAPS: PTSD symptoms
SCID: AXIS I disorders
Secondary Outcome Measures: Patient self-report forms collected at initial assessment, post-treatment and
six-months follow-up:
BDI: depression symptoms
BAI: anxiety symptoms
WHOQL-Bref: quality of life
Starting date
February 2007
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
28
Guay 2007
(Continued)
Contact information
Sarah Jane Parent: sparent.hlhl@ssss.gouv.qc.ca
Notes
Authors will have to consider their inclusion criteria as d-cycloserine
Hicks 2009
Trial name or title
Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent History of War Zone Stress
Exposure
Methods
Double blind placebo controlled prospective 12 week trial of fluoxetine in veterans already receiving usual
psychological treatment
Participants
Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans
Interventions
Double-blind, placebo-controlled prospective 12-week trial of fluoxetine in OEF/OIF campaign veterans. All
participants will (also) receive usual psychological treatment by mental health services of the Carl R. Darnall
Army Medical Center
Outcomes
PTSD symptom severity and related functional impairment, comorbid depression, anxiety symptoms, and
alcohol intake
Starting date
Enrolling from 2009
Contact information
Paul Hicks, Central Texas Veterans Health Care System, USA
Notes
McAllister 2009
Trial name or title
Venlafaxine and CBT for Psychological Distress After TBI: A Randomized Controlled Trial
Methods
12 week RCT
Participants
Veterans and service members who have mild to severe TBI and PTSD or MDD
Interventions
Venlafaxine XR (VFN), Cognitive Behavioral Therapy (CBT), and a placebo and psycho-educational control
(CTL)
Outcomes
Primary outcomes: PTSD and depression symptoms; secondary aims include comparing response, remission,
and relapse rates; determining if treatment is associated with greater improvement in neuropsychological
functioning, functional status, and post-concussive symptoms; examining tolerability and cost-effectiveness
of VFN and CBT for the treatment of PTSD and MDD; and exploring predictors of treatment response
Starting date
Enrolling in 2009
Contact information
Thomas W McAllister, Dartmouth Medical School, Dartmouth, New Hampshire, USA
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
29
McAllister 2009
(Continued)
Notes
Pai 2004
Trial name or title
Treating co-morbid PTSD and alcohol dependence
Methods
RCT
Participants
Setting: Community-Outpatient
Recruitment strategy: Newspaper advertisement, Veterans Administration
Country: USA
Exclusion criteria: Current DSM diagnosis of substance dependence other than alcohol, nicotine, cannabis; 2)
opiate use in past 30 days; 3) significant risk of violence/ history of serious violent behaviour in past 4 years; 4)
report assault as index trauma combined with continuing relation ship with perpetrator; 5) current treatment for
psychotropic medications(excl short-term use of benzodiazepines for detoxification); 6 unstable or serious medical
illness; 7) current severe psychiatric symptoms; 8) mental retardation or other pervasive developmental disorder; 9)
investigational medication in past 30 days; 10) for women, pregnant, nursing or non-use of reliable contraception
Primary diagnosis? PTSD and Alcohol dependence
Interventions
COMPARISON GROUP 1
Type: Pharmacotherapy and Psychotherapy combined
Pharmacotherapy: Naltrexone 50mg/morning for 3 days then 100mg/morning
Length of pharmacotherapy: 24 weeks
Psychotherapy: CBT ? prolonged exposure therapy
Individual/group: Individual
Manualised: Yes
Delivered by: Psychologists and a registered nurse
Number of sessions: 18 - 1/week for 12 weeks, then 1/fortnight for 12 weeks.
Length of intervention: 24 weeks
How many sessions actually delivered: ongoing study
Was it intended as intervention or control: As control condition with Naltrexone/placebo intervention condition
COMPARISON GROUP 2
Type: Psychotherapy and placebo
Pharmacotherapy: Placebo
Length of pharmacotherapy: 24 weeks
Psychotherapy: CBT ? prolonged exposure therapy
Individual/group: Individual
Manualised: Yes
Delivered by: Psychologists and a registered nurse
Number of sessions: 18 - 1/week for 12 weeks, then 1/fortnight for 12 weeks.
Length of intervention: 24 weeks
COMPARISON GROUP 3
Type: Placebo medication alone
Type of pharmacotherapy: Placebo pill
Outcomes
Alcohol consumption ( Days drinking; drinks per drinking day; alcohol craving using Timeline Follow-Back Interview and Penn Alcohol Craving Scale)
PTSD symptoms
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
30
Pai 2004
(Continued)
(PTSD Symptom Scale, PSS-I)
Starting date
Contact information
Professor E Foa Director, Director of the Center for the Treatment and Study of Anxiety
University of Pennsylvania
3535 Market Street, 6th Floor
Philadelphia, PA 19104, USA
Notes
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
31
DATA AND ANALYSES
Comparison 1. Combined SSRI plus CBT versus SSRI alone (adults)
Outcome or subgroup title
1 PTSD symptom severity
(clinician rated) post
intervention (final scores SIP)
2 Drop outs
3 Depression severity (self rated)
post intervention (change
scores)
4 Anxiety severity (self rated) post
intervention (change scores)
No. of
studies
No. of
participants
1
65
Mean Difference (IV, Fixed, 95% CI)
-4.70 [-10.84, 1.44]
1
2
65
74
Risk Ratio (M-H, Fixed, 95% CI)
Std. Mean Difference (IV, Fixed, 95% CI)
5.47 [0.70, 42.93]
-0.40 [-0.86, 0.07]
2
74
Std. Mean Difference (IV, Fixed, 95% CI)
-0.39 [-0.85, 0.07]
Statistical method
Effect size
Comparison 2. Combined SSRI plus CBT versus PE alone (adults)
Outcome or subgroup title
1 PTSD symptom severity
(clinician rated) post
intervention (change scores
SPRINT)
2 Drop outs
No. of
studies
No. of
participants
1
23
Mean Difference (IV, Fixed, 95% CI)
2.24 [-2.87, 7.35]
1
25
Risk Ratio (M-H, Fixed, 95% CI)
1.91 [0.38, 9.51]
Statistical method
Effect size
Comparison 3. Combined SSRI plus TFCBT versus TFCBT alone (children/adolescents)
Outcome or subgroup title
1 Drop outs
2 Functioning CGAS
No. of
studies
No. of
participants
1
1
24
22
Statistical method
Risk Ratio (M-H, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Effect size
0.5 [0.05, 4.81]
7.09 [-1.19, 15.37]
32
Analysis 1.1. Comparison 1 Combined SSRI plus CBT versus SSRI alone (adults), Outcome 1 PTSD
symptom severity (clinician rated) post intervention (final scores SIP).
Review:
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
Comparison: 1 Combined SSRI plus CBT versus SSRI alone (adults)
Outcome: 1 PTSD symptom severity (clinician rated) post intervention (final scores SIP)
Study or subgroup
Combined
Rothbaum 2006
Total (95% CI)
SSRI only
Mean Difference
N
Mean(SD)
N
Mean(SD)
34
10.2 (8.83)
31
14.9 (15.27)
34
Weight
IV,Fixed,95% CI
Mean Difference
IV,Fixed,95% CI
31
100.0 %
-4.70 [ -10.84, 1.44 ]
100.0 %
-4.70 [ -10.84, 1.44 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.50 (P = 0.13)
-4
-2
0
Favours combined
2
4
Favours SSRI alone
Analysis 1.2. Comparison 1 Combined SSRI plus CBT versus SSRI alone (adults), Outcome 2 Drop outs.
Review:
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
Comparison: 1 Combined SSRI plus CBT versus SSRI alone (adults)
Outcome: 2 Drop outs
Study or subgroup
Rothbaum 2006
Total (95% CI)
Combined
Single treatment
n/N
n/N
Risk Ratio
Weight
6/34
1/31
100.0 %
5.47 [ 0.70, 42.93 ]
34
31
100.0 %
5.47 [ 0.70, 42.93 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 6 (Combined), 1 (Single treatment)
Heterogeneity: not applicable
Test for overall effect: Z = 1.62 (P = 0.11)
0.01
0.1
Favours combined
1
10
100
Favours single
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
33
Analysis 1.3. Comparison 1 Combined SSRI plus CBT versus SSRI alone (adults), Outcome 3 Depression
severity (self rated) post intervention (change scores).
Review:
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
Comparison: 1 Combined SSRI plus CBT versus SSRI alone (adults)
Outcome: 3 Depression severity (self rated) post intervention (change scores)
Study or subgroup
Otto 2003
Rothbaum 2006
Total (95% CI)
Combined
SSRI alone
Std. Mean Difference
Weight
Mean(SD)
N
Mean(SD)
5
-8.6 (7.2)
5
-8.6 (6)
13.9 %
0.0 [ -1.24, 1.24 ]
34
-3.2 (7.52)
30
0.3 (7.52)
86.1 %
-0.46 [ -0.96, 0.04 ]
100.0 %
-0.40 [ -0.86, 0.07 ]
39
IV,Fixed,95% CI
Std. Mean Difference
N
IV,Fixed,95% CI
35
Heterogeneity: Chi2 = 0.46, df = 1 (P = 0.50); I2 =0.0%
Test for overall effect: Z = 1.68 (P = 0.093)
-4
-2
0
Favours combined
2
4
Favours SSRI alone
Analysis 1.4. Comparison 1 Combined SSRI plus CBT versus SSRI alone (adults), Outcome 4 Anxiety
severity (self rated) post intervention (change scores).
Review:
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
Comparison: 1 Combined SSRI plus CBT versus SSRI alone (adults)
Outcome: 4 Anxiety severity (self rated) post intervention (change scores)
Study or subgroup
Otto 2003
Rothbaum 2006
Total (95% CI)
Combined
SSRI alone
Std. Mean Difference
Weight
Mean(SD)
N
Mean(SD)
5
-8.4 (5.6)
5
-5.2 (5.3)
13.1 %
-0.53 [ -1.81, 0.74 ]
34
-3.9 (10.4)
30
0 (10.4)
86.9 %
-0.37 [ -0.87, 0.12 ]
100.0 %
-0.39 [ -0.85, 0.07 ]
39
IV,Fixed,95% CI
Std. Mean Difference
N
IV,Fixed,95% CI
35
Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0%
Test for overall effect: Z = 1.66 (P = 0.097)
-4
-2
Favours combined
0
2
4
Favours SSRI alone
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
34
Analysis 2.1. Comparison 2 Combined SSRI plus CBT versus PE alone (adults), Outcome 1 PTSD symptom
severity (clinician rated) post intervention (change scores SPRINT).
Review:
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
Comparison: 2 Combined SSRI plus CBT versus PE alone (adults)
Outcome: 1 PTSD symptom severity (clinician rated) post intervention (change scores SPRINT)
Study or subgroup
Combined
Simon 2008
Total (95% CI)
Psychotherapy only
Mean Difference
N
Mean(SD)
N
Mean(SD)
9
-2.33 (5.24)
14
-4.57 (7.24)
9
Weight
IV,Fixed,95% CI
Mean Difference
IV,Fixed,95% CI
100.0 %
14
2.24 [ -2.87, 7.35 ]
100.0 % 2.24 [ -2.87, 7.35 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.86 (P = 0.39)
-10
-5
0
Favours combined
5
10
Favours psychother alone
Analysis 2.2. Comparison 2 Combined SSRI plus CBT versus PE alone (adults), Outcome 2 Drop outs.
Review:
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
Comparison: 2 Combined SSRI plus CBT versus PE alone (adults)
Outcome: 2 Drop outs
Study or subgroup
Simon 2008
Total (95% CI)
Combined
Single treatment
n/N
n/N
Risk Ratio
Weight
3/11
2/14
100.0 %
1.91 [ 0.38, 9.51 ]
11
14
100.0 %
1.91 [ 0.38, 9.51 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 3 (Combined), 2 (Single treatment)
Heterogeneity: not applicable
Test for overall effect: Z = 0.79 (P = 0.43)
0.01
0.1
Favours combined
1
10
100
Favours single
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
35
Analysis 3.1. Comparison 3 Combined SSRI plus TFCBT versus TFCBT alone (children/adolescents),
Outcome 1 Drop outs.
Review:
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
Comparison: 3 Combined SSRI plus TFCBT versus TFCBT alone (children/adolescents)
Outcome: 1 Drop outs
Study or subgroup
Combined
Single treatment
n/N
n/N
1/12
2/12
100.0 %
0.50 [ 0.05, 4.81 ]
12
12
100.0 %
0.50 [ 0.05, 4.81 ]
Cohen 2007
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 1 (Combined), 2 (Single treatment)
Heterogeneity: not applicable
Test for overall effect: Z = 0.60 (P = 0.55)
0.01
0.1
1
10
Favours combined
100
Favours single
Analysis 3.2. Comparison 3 Combined SSRI plus TFCBT versus TFCBT alone (children/adolescents),
Outcome 2 Functioning CGAS.
Review:
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)
Comparison: 3 Combined SSRI plus TFCBT versus TFCBT alone (children/adolescents)
Outcome: 2 Functioning CGAS
Study or subgroup
Combined
Cohen 2007
Total (95% CI)
SSRI alone
Mean Difference
N
Mean(SD)
N
Mean(SD)
11
66.64 (10.12)
11
59.55 (9.7)
11
Weight
IV,Fixed,95% CI
Mean Difference
IV,Fixed,95% CI
11
100.0 %
7.09 [ -1.19, 15.37 ]
100.0 %
7.09 [ -1.19, 15.37 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.68 (P = 0.093)
-10
-5
Favours SSRI alone
0
5
10
Favours combined
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
36
HISTORY
Protocol first published: Issue 3, 2008
Review first published: Issue 7, 2010
Date
Event
Description
14 July 2008
Amended
Converted to new review format.
CONTRIBUTIONS OF AUTHORS
Ruth Parslow conceived the review. Ruth Parslow co-ordinated the development of the protocol with all authors contributing equally
to the design and development of the protocol. All authors were involved in the inclusion and exclusion of trials, data extraction, entry
and quality appraisal. BG compiled all of the information about the trials in the Tables. SH drafted the text of the review and responded
to editorial comments, with all authors providing comment and feedback.
DECLARATIONS OF INTEREST
No declarations of interest.
SOURCES OF SUPPORT
Internal sources
• ORYGEN Research Centre, University of Melbourne, Australia.
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
None known.
INDEX TERMS
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
37
Medical Subject Headings (MeSH)
Adolescent; Child Abuse, Sexual [psychology]; Clonazepam [therapeutic use]; Cognitive Therapy [∗ methods]; Combined Modality
Therapy [methods]; Paroxetine [therapeutic use]; Randomized Controlled Trials as Topic; Refugees [psychology]; Serotonin Uptake
Inhibitors [∗ therapeutic use]; Sertraline [therapeutic use]; Stress Disorders, Post-Traumatic [drug therapy; ∗ therapy]
MeSH check words
Adult; Child; Female; Humans; Male
Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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