224 The etiology of anxiety disorders

_________________________________________________________________________________________________________
Review / Derleme

The etiology of anxiety disorders

Orhan DOĞAN1
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ABSTRACT
Anxiety disorders are a growing health problem world-wide. They are very important from point of view of community
mental health because they cause functional impairment, decrease quality of life, and have the high comorbidity.
Although there are many investigations about the etiology of anxiety disorders, the causative factors, etiology, and
underlying mechanisms of anxiety disorders, as for most psychiatric disorders, remain relatively poorly understood. In
this article, it has been reviewed that the etiological factors of anxiety disorders such as biological, psychological,
Cognitive and Behavioral, and social factors. (Anatolian Journal of Psychiatry 2012; 13:224-231)
Key words: anxiety disorders, epidemiology, prevalence, rsik factors

Anksiyete bozukluklarının etiyolojisi

ÖZET
Anksiyete bozuklukları tüm dünyada giderek büyüyen bir sağlık sorunudur. Anksiyete bozuklukları işlevsel bozukluğa
neden olduğu, yaşam kalitesini düşürdüğü ve yüksek komorbidite gösterdiği için toplum ruh sağlığı açısından çok
önemlidir. Anksiyete bozukluklarının etiyolojisiyle ilgili çok sayıda araştırma olmakla birlikte, birçok psikiyatrik bozuk-
lukta olduğu gibi görece yeterli düzeyde anlaşılmadan kalmıştır. Bu yazıda, anksiyete bozukluklarının biyolojik, ruhsal,
bilişsel-davranışçı ve sosyal etkenler gibi etiyolojik etkenleri gözden geçirilmiştir. (Anatolian Journal of Psychiatry
2012; 13:224-231)
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INTRODUCTION Classification of Diseases-Classification of Mental

and Behavioural Disorders, Chapter V), the anxi-
Anxiety disorders are common and important ety disorders have been stated in heading neuro-
psychiatric disorders because cause considerable tic, stress-related and somatoform disorders as
functional impairment, decrease the quality of life, phobic anxiety disorders, other anxiety disorders
have the high prevalence rates and the high co- (panic disorder, generalized anxiety disorder
morbidity with psychiatric disorders and physical mixed anxiety and depressive disorder, and the
illnesses.1-3 DSM-IV-TR (Diagnostic and Statistical others), obsessive-compulsive disorder, reaction
Manual of Mental Disorders, fourth ed., text to severe stress and adjustment disorders, disso-
revised) include panic disorder (with and without ciative disorders, somatoform disorders, other
agoraphobia), social phobia (social anxiety disor- neurotic disorders.5
der), specific phobias, obsessive compulsive dis-
order (OCD), generalized anxiety disorder (GAD), THE ETIOLOGY OF ANXIETY DISORDERS
and posttraumatic stress disorder (PTSD) as
major anxiety disorders.4 In this chapter, the epi- Anxiety disorders have multiple etiological factors,
demiology and etiology of these major anxiety dis- and recently it is agreed that the biopsychosocial
orders will be presented. In ICD-10 (International factors are important in the etiology of anxiety
_________________________________________________________________________________________________________
1
Prof.Dr., Üsküdar Üniversitesi, İstanbul
Yazışma adresi / Address for correspondence:
Prof.Dr. Orhan DOĞAN, Feneryolu Poliliniği, Bağdat Cad. 109/A, Feneryolu-Kadıköy/İstanbul
E-mails: ordogan@gmail.com, odogan@uskudar.edu.tr
Geliş tarihi: 08.09.2011, Kabul tarihi: 22.12.2012

Anatolian Journal of Psychiatry 2012; 13:224-231

 Doğan 225
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disorders. These factors will be reviewed as gen- tor is linked to a GABA receptor, the neural trans-
eral firstly, and then biological, psychological, so- mission slows.3 The role of GABA to the patho-
cial factors will be explained for every disorder genesis of panic disorder has been shown:3 re-
duced saccadic eye movement velocity in re-
Biological Factors sponse to diazepam in patients with panic disor-
der,22 panicogenic response to the benzodiaze-
Genetics
pine antagonist flumazenil23 but a study not.24
Anxiety disorders tend to run in families. The
Phobic disorders: The relationship between GABA
family and twin studies provide evidences in these
-benzodiazepine receptor system and social pho-
issue.3,6 Genetic factors may affect brain develop-
bia is unclear and the findings are inconsistent.25
ment (neurotrophic factors), and modify neuro-
transmission. The genetic investigations have Serotonin (5-hydroxytryptamine, 5-HT): Sero-
focused on genes for target receptors, receptor tonin plays role in mediating some psychological
subunits, and neurotransmitters.6 The role of ge- processes such as arousal, impulsivity, suicidality,
netic factors is thought that have moderate genet- aggression, reward-punishment, attention, memo-
ic influences in anxiety disorders.3 ry.3,6 There are two important serotonergic sys-
tems in the brain: defensive or coping response to
Panic disorder: Some family and twin studies have
aversive and threatening events. The aversive
supported that there are moderate genetic influ-
stimulation activates the central projections of
ences in the expression of panic disorder7 but the
brain stem dorsal raphe nucleus (DRN) and cause
genetic influence may be more heterogeneous in
release of 5-HT onto neurons in the amygdala,
panic disorder.6 There are many positive studies in
frontal cortex, and basal ganglia.6 The role of 5-
related to putative genetic markers and candidate
HT2C receptors is important in mediating response
genes for panic disorder.3,8-9
to fear and anxiety in DRN, whereas 5-HT1A in
Phobic disorders: Fyer et al.10 found familial trans- median raphe nucleus (MRN).
mission for specific phobias whereas Skre et al.11
Panic disorder: It is accepted that serotonergic
did not find a genetic influence in their twin study
system modulates the dysregulated responses
for specific and social phobias. The presence of
because the serotonin reuptake inhibitors are
social phobia in parent is an important risk factor
efficient in treatment of panic disorder.3 Radio-
for adolescents.12 The results of genetic molecular
ligand PET neuroimaging studies provide evi-
studies of social phobia are inconsistent.13
dence about the role of serotonergic system in
OCD: The family studies,14 twin studies,15 candi- panic disorder: the decreased 5-HT1A receptor
date gene studies,16 linkage studies17 have been binding in the cingulate cortex and dorsal raphe in
revealed that OCD is a complex genetic disorder. patients with panic disorder,26 the decrease in
serotonin transporter binding in the midbrain, tem-
GAD: There is modest genetic influence for GAD.
poral lobes, and thalamus in patients with panic
The twin studies,18 Hollander and Simeon3 stated
disorder.27
that minimal molecular genetic studies of GAD
suggested associations to polymorphisms of the Phobic disorders: Although the role of serotonin in
dopamine D2 receptor gene, the serotonin trans- social phobia has not been investigated largely,
porter gene, and the monoamine oxidase-A gene. the altered serotonergic sensitivity is suggested.28
The improvement by selective serotonin reuptake
PTSD: It has been found that parental PTSD was
inhibitors in social phobia may due to increased
a risk factor as independent from a presence of a
serotonin availability.29
traumatic event for PTSD.3,18
OCD: Many studies provide evidence of the role of
Neurotransmitters and neural circuits
serotonergic system in the pathogenesis of OCD:3
It has been suggested that three neurotransmitter there are antiobsessional effects of potent seroto-
receptor systems are associated with anxiety dis- nin reuptake inhibitors such as clomipramine in
orders: GABAA-benzodiazepine receptor system,19 contrast to the ineffectiveness of noradrenergic
the serotonergic system,20 and noradrenergic sys- antidepressants. The improvement of OCD was
tem.21 found to correlate with a decrease a platelet sero-
tonin level30 and in cerebrospinal fluid (CSF) 5-
Gamma-amino butyric acid (GABA): GABA is
hydroxyindolacetic acid.31 Adams et al.32 has been
an inhibitory neurotransmitter. GABA suppresses
reported the increased 5-HT2A receptor binding in
the neuronal activity in the serotonergic and nor-
the caudate nuclei in patients with OCD.
adrenergic systems, and therefore the effects of
GABA exert.6 GAD: The role of serotonergic dysregulation may
partially be in GAD.3,33
Panic disorder: When the benzodiazepine recep-
Anadolu Psikiyatri Derg 2012; 13:224-231
226 The etiology of anxiety disorders
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PTSD: There is the role of serotonergic deficit in findings are inconsistent and contradictory.3
impulsive aggression, and the symptomatology of
Sodium lactate: Sodium lactate provocation of
PTSD may be related to serotonergic deficit. The
panic attacks may help to understanding the pa-
effectiveness of serotonin reuptake inhibitors in
thogenesis of spontaneous panic attacks. Lactate-
PTSD provides an indirectly evidence of dysregu-
provoked panic attacks are specific to patients
lated serotonergic system in PTSD.3
with panic disorder ‘10 mL/kg of 0.5 molar sodium
Noradrenaline (NA): Acute stress and aversive lactate infused over 20 minutes provoke a panic
stimulation increase the release of NA like 5-HT. attack in most patients with panic disorder but not
NA increases arousal and attention. It is sug- in healthy subjects.’3,42
gested that there is lability or abnormal regulation
Carbon dioxide hypersensitivity: A mixture of
of noradrenergic systems in anxiety disorders.6
5% CO2 in room air to breath causes panic at-
Panic disorder: The role of NA in the pathogenesis tacks43 and this finding appears specific to pa-
of panic disorder is only modest, but β-adrenergic tients with panic disorder.44 ‘CO2, lactate, and
blockers are not effective in blocking spontaneous bicarbonate cause panic attacks. CO2 is a meta-
panic attacks.3 The locus coeruleus is important in bolic product of lactate and bicarbonate, and
the pathogenesis in panic disorder because it con- crosses blood-brain barrier, cause cerebral hyper-
tains more than 50% of all noradrenergic neu- capnia. Hypercapnia causes hyperventilation and
rons.3 panic. According to these knowledge and findings,
Klein45 suggested that patients with panic disorder
PTSD: NA has an important role of the pathogen-
are hypersensitive to CO2’.3 It has been found that
nesis in PTSD and there are some evidences: the
the response to CO2 inhalation in patients with
increased urinary NA and epinephrine and plasma
specific phobias is not hypersensitive.46
NA levels in patients with PTSD,34 the increased
CSF NA level in men with chronic PTSD.35 Neurocircuitry of fear: According to Hollander
and Simeon,3 ‘the neurocircuitry of fear model is
The other neurotransmitters
suggested that panic attacks are analogous to
Dopamine (DA): Social phobia, especially comor- animal fear and avoidance responses and these
bid panic disorder may be associated with a de- conditions may be manifestations of dysregulation
creased dopaminergic activity.3 There are some in the brain circuits.’ Panic is an abnormally sensi-
evidences that dopaminergic dysregulation is tive fear network that originated in the amygdala.
associated with the pathogenesis of OCD: the as- Neuroimaging studies of panic disorder contain
sociation between OCD and Tourette’s disorder, locus coeruleus, brain stem, hypothalamus, HPA
the exacerbation of symptoms with chronic stimu- axis, and cortex. A PET functional neuroimaging
lants, the blunted growth hormone response to the study revealed the increased metabolic rate in the
DA agonist apomorphine, decreased DA D2 re- bilateral amygdala, hippocampus, thalamus, mid-
ceptor binding in the caudate nucleus in patients brain, caudal pons, medulla, and cerebellum in
with OCD.36 patients with panic disorder47 and in the right
Glutamate: Glutamate is an excitatory neurotrans- amygdala and hippocampus in a functional mag-
mitter. In the last years, it has been suggested netic resonance imaging (fMRI) study.48 Yoo et
that glutamatergic dysregulation may be associ- al.46 have been reported that structural volumetric
ated with the pathogenesis of OCD. The in- studies have been found decreased gray matter
creased glutamate level was determined in sev- volumes bilaterally in the putamen of patients with
eral brain regions37 and in CSF.38 panic disorder.

Neuropeptides: Many studies have been shown Neuroimaging and neuronal circuits: In the last
that some neuropeptide abnormalities may be as- years, many neuroimaging studies were con-
sociated with OCD:3 abnormalities in CSF vaso- ducted about brain structures and their functions
pressin,31 CSF somatostatin,39 and CSF oxyto- and circuits. These studies have been exerted the
cin.40 Geracioti et al.35 found the increased CSF important data about pathogenesis of anxiety dis-
substance P in patients with PTSD. One study orders.
found that neuropeptide Y plasma levels are asso- Panic disorder: Neuroimaging studies has been
ciated with degree of symptom improvement, conducted to revealed for the role of GABA to the
positive coping.41 pathogenesis of panic disorder: decreased benzo-
Hypothalamic-pituitary-adrenal (HPA) axis: diazepine receptor binding in hippocampus by
HPA axis is main importance in response to SPECT (single photon emission computed tomo-
stress. It is suggested that HPA axis dysregulation graphy),50 a global decrease in benzodiazepine
may be associated with panic disorder, but the receptor binding by PET (positron emission tomo-

Anatolian Journal of Psychiatry 2012; 13:224-231

 Doğan 227
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graphy,51 decrease in total occipital GABA lev- Psychodynamic theories

els.52 The first explanations of anxiety disorders (neuro-
Phobic disorders: There are dysfunctional brain sis) were interested in psychodynamic theories.
circuits in social phobia, consistently. According to According to psychodynamic theory, anxiety
study using SPECT, generalized social phoba emerges as result of unconscious conflicts (es-
imay be associated with low binding of DA D2 re- pecially sexually and aggressive). According to
ceptors in the striatum.53 In another study using Freud (in the structural theory), anxiety is ex-
SPECT, it is found that social phobia was asso- perienced in the ego and functions as a signal
ciated with a significant decrease in dopamine alerting the ego across to internal threats. There-
transporter site density on striatum.54 Many stud- fore, the libidinal energy transforms from physic-
ies of social phobia, using fMRI and PET has ological to somatic symptoms of anxiety.3,6 From
been found the greater blood flow in all areas point of this view, anxiety and anxiety disorders
involved emotional processing but not amygdala,55 occur when defense mechanisms are over-used.
heightened amygdala activation,56 increased sub- Psychoanalytic theorists after Freud, such as
cortical activity,57 the greater anterior cingulate Melanie Klein, Joachim Flescher made significant
activation,58 using MR spectroscopy higher gluta- contributions to the understanding of anxiety and
mate levels in the anterior cingulate.56 anxiety disorders. The psychoanalytic theory
helps to the understanding and treatment of
In patients with animal phobia, a volumetric study
patients with anxiety disorders but not all.3
has been shown increased cortical thickness in
paralimbic and sensory cortical areas.59 In pa- In the last decades, the different forms of anxiety
tients with spider phobia, an fMRI study has been such as separation anxiety, annihilation anxiety
revealed heightened activation in the prefrontal were added in literature as addition former forms
cortex, cingulate, and insula.60 such as id anxiety, superego anxiety, castration
anxiety, and loss anxiety. In particular, in the
OCD: A neuroethological model of OCD is in the
understanding of separation anxiety, the attach-
based on orbitofrontal-limbic-basal ganglia.3 Volu-
ment theories (Klein, Bowlby) from infant and child
metric imaging studies have been shown abnor-
researches made significant contribution to gene-
mal volumes in the orbitofrontal-limbic-basal gang-
sis of psychopathology.3 However, in a longitude-
lia circuits:3 reduced orbitofrontal and amygdala
nal study Aschenbrand et al.73 has not been found
volumes,61 smaller basal ganglia,62 enlarged thala-
an association between panic disorder and agora-
mus.63 Some studies have been found increased
phobia in adulthood and separation anxiety disor-
or decreased gray matter in various brain
der in childhood. In children with school phobia, it
fields.61,64 Two studies have been shown higher
has been found that the fear of separation from
metabolic activity in some brain fields or struc-
their mothers was usually the basis of refusing to
tures.65 After successfully treatment of OCD with
go to school, therefore it has been hypothesized
serotonin reuptake inhibitors or behaviour therapy,
that there is an associated between childhood
the structural brain changes have been deter-
separation anxiety and panic disorder and agora-
mined: decreased in hyperactivity or activation in
phobia in adulthood.73
some brain structures;66-67 after successfully treat-
ment of OCD with serotonin reuptake inhibitors, a Panic disorder: In patients with panic disorder has
decrease of thalamic size,63 a decrease caudate been found to be important the experiences of
glutamate levels.68 separation anxiety in childhood, neurophysiologi-
cally predisposed to early fearfulness, as addition
GAD: Tiihonen et al.54 have been found that ben-
this fearfulness the exposure to parental behavi-
zodiazepine receptor binding was significantly
ors, the real or threatened loss of a significant
decreased in the left temporal pole in patients with
relationship.3,6
GAD.
Phobic disorders: The phobic symptom formula-
PTSD: Functional neuroimaging studies of PTSD
tion is based on Freud’s Little Hans case. The in-
have been shown some abnormalities in brain
ner unconscious conflict and the anxiety emerged
structures: decreased blood flow, hyperactivation
of it displaces and projects onto relatively neutral
in amygdala,56,69 prefrontal hypoactivation.79
and easily avoidable objects (stimulus, situation or
Structural neuroimaging studies of GAD have
social function). This explanation is also valid for
been shown changes in brain structures: de-
specific phobia. The psychodynamic work of pho-
creased hippocampal volume70 but in a study the
bias focuses on the symbolic meanings.3,6 In
larger hippocampi;71 and in another study de-
agoraphobia with panic attacks, it has been found
creased anterior cingulate volume.72
that the recollection of an anxiety attack, the
Psychological Factors experiences of separation anxiety in childhood, -

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228 The etiology of anxiety disorders
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her or his the belief cannot escape from special There is excessively negative value of trauma and
condition, castration anxiety, a distrustful environ- memory disturbance in PTSD.82
ment, excessive fear of object loss are important.3
Behavioral factors
In understanding phobic disorders, especially
agoraphobia, the libidinal wishes and castration Behaviour theorists use learning theory to under-
anxiety may be important.3 stand and explain the development of anxiety dis-
orders. Behaviour theorists believed in that anxi-
OCD: According to psychodynamic theory, OCD is
ety is conditioned by the fear of an environmental
a continuum with obsessive compulsive character
stimulus. Relatively neutral stimuli become to
pathology. OCD develops if the unconscious de-
evoke fear and avoidance behaviour by classic
fense mechanisms fail to alleviation anxiety due to
conditioning; avoidance behaviour temporarily re-
sexual and aggressive impulses. In OCD, there is
duces anxiety and is reinforced and maintained by
a regression from the oedipal phase to the earlier
operant conditioning.3,6
anal phase.3
According to behaviour theorists, the anxiety at-
GAD: According to psychodynamic theory, GAD is
tacks are conditioned responses to fearful stimuli.
thought as the result of unconscious and unac-
The onset of panic disorder is usually paired of
ceptable sexual and aggressive impulses.6
some traumatic events but this is not always seen.
Cognitive and Behavioral Factors It is accepted that anxiety occurring in phobic
Cognitive and neurocognitive factors disorders is a conditioned response to the phobic
object with a noxious experience. Avoidance of
Sharpe et al.6 stated that ‘cognition refers to how the phobic object prevents or reduces anxiety, and
information is interpreted, stored and recalled’. then this result is perpetuated.3 Another model of
Cognitive factors are important in the etiology of specific phobias is the nonassociative learning
anxiety disorders and the interpretation of anxiety model; it is described as the converse of the con-
experiences. Panic disorder is a good example for ditioned model.83
the role of cognitive factors: ‘benign bodily sense-
tions are catastrophically misinterpreted as evi- In OCD, anxiety is conditioned to an environment-
dence of life-threatening disease, leading to anxie- tal stimulus and anxiety may be alleviated by a
ty, more bodily sensations and more catastrophic compulsive ritual.3,6
cognitions.’6 Neurocognitive models suggest that Peri et al.84 suggested that “there is a disturbance
amygdala-prefrontal circuitry is important in the of conditioned responses in PTSD. Autonomic
processing of emotional information, such as se- response to both innocuous and aversive stimuli is
lective attention to threat, the acquisition and ex- elevated”.3
tinction of conditioned fear, interpretation of ambi-
guous emotional stimuli in a negative manner.6,74 Social Factors
Patients with panic disorder experience more cog- For anxiety disorders, it can be said that there are
nitions concerned with physical catastrophes while social isolation, lack of support, unemployment,
patients with GAD experience more cognitions poverty, major adverse life events, abuse and
such as competence, acceptance, and other per- neglect in childhood among social factors.6
sons.3 It has been suggested that insecure attach-
Panic disorder: In various studies, it has been
ment relationship and ambivalence toward care-
found that traumatic events or relationships, such
givers in genesis of GAD.75 For GAD, the emoti-
as interpersonal trauma, unfavorable parental
onal dysregulation model has been suggested.76
attitudes, physical and sexual abuse in childhood
The core problem in patients with social phobia is were associated with panic disorder.3,85
to have a negative representation of one’s social
Phobic disorders: In genesis of social phobia, it is
self. It has been found that there are a number of
thought that some social events and social envi-
cognitive distortions such as attentional and imply-
ronment are important: the exposure to socially
cit memory bias,77 negative interpretations of am-
traumatic events, vicarious learning, reared social-
biguous social events,78 diminished perception of
ly anxious children, lack of adequate exposure to
control over anxiety-related symptoms79 in pa-
social situations, modeling of socially anxious be-
tients with social phobia.
haviors, lack of a close relationship with an adult,
Some cognition such as responsibility, intrusive abuse in childhood.3,12
and cognitive processes are important in the
GAD: The insecure and anxious early attachments
symptom formation, in the genesis and mainte-
in childhood may contribute to development of
nance of OCD.3 In patients with OCD, there are
anxiety and GAD.75
memory biases,80 selective attention deficits.81
Anatolian Journal of Psychiatry 2012; 13:224-231
 Doğan 229
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PTSD: Some social factors have been stated as ents, educational level, unemployment and pover-
important factors in the development of PTSD: ty but to be realizing these, the arrangements in
stressful life events, prior traumatic experiences, some issues such as the social, educational,
childhood conduct problems, male gender but economic, and political are necessary.
conflicting, physical abuse, in childhood, family
Anxiety disorders have multiple etiological factors.
history of anxiety, parental PTSD.86
There are biological factors such as genetics,
biochemical, structural, neurocircuits, the findings
CONCLUSIONS
of neuroimaging; psychological factors such as
psychodynamic, cognitive and neurocognitive, be-
Anxiety disorders as a group are the most pre-
havioral; social factors such as educational level,
valent of all psychiatric disorders. The having high
unemployment, poverty, lack of support among
prevalence rates, the high comorbidity rates with
etiological factors of anxiety disorders.
psychiatric disorder and physical illnesses, being
cause functional impairment, decreasing quality of In a result, it can be said that anxiety disorders are
life increase the importance of them. The preva- a community health problem. Firstly, before every-
lence rates of anxiety disorders can especially thing as psychiatrists, we have to understand
change in related to age and gender. anxiety disorders correctly and sufficiently be-
cause patients with any anxiety disorder respond
There are some evidence and known that anxiety
to proper treatments and return to previously level
disorders are commonly seen in primary care
of functioning.3 Secondly, as university teacher or
settings.2 What a shame that the rate of the re-
trainers, we have to adequately train to medical
cognition correctly and treating favorable of these
students and general practitioners about anxiety
disorders is very low in primary care settings,
disorders, and we have not to forget that general
whereas anxiety disorders are seen the mostly
practitioners are in health of general population.
prevalent in primary care settings.87
Thirdly, we have to correctly inform to the general
Anxiety disorders have a lot of risk factors such as population about the symptoms and what can be
demographic and social factors. Some of these applied. As finally, we are obliged to be the best
factors are easily determinable and controllable physicians.
such as the rearing children, the attitudes of par-

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