Anxiety Disorders in Women

Psychiatr Clin N Am 26 (2003) 621–672
Anxiety disorders in women

Teresa A. Pigott, MD
Clinical Trials Division, Department of Psychiatry, University of Florida
College of Medicine, L4-100, PO Box 100256, Gainesville, FL 32611-0256, USA
Data obtained from large-scale epidemiological studies of psychiatric

illnesses suggest that anxiety disorders afflict 15.7 million people in the
United States each year and 30 million people at some point in their lives [1].
Generalized anxiety disorder (GAD), panic disorder (PD), simple phobia,
social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and
posttraumatic stress disorder (PTSD) are all classified as anxiety disorders in
DSM-IV [2]. Estimates based on data from the Epidemiological Catchment
Area (ECA) study, one of the largest investigations of the prevalence of
mental disorders ever completed, reveal a nearly 15% lifetime prevalence
rate for anxiety disorders. Three of the anxiety disorders (phobic disorders,
OCD, and panic disorder) were among the seven most frequent psychiatric
disorders identified in the United States. Over 6% of men and 13% of
women respondents met 6-month criteria for a DSM-III anxiety disorder in
the ECA study. The ECA data also provided strong evidence that anxiety
disorders were much more prevalent in women than in men [3–9].
Subsequent large-scale population surveys have also indicated that anxiety
disorders are extremely common in modern society, especially among
women. Conducted after the ECA study, the National Comorbidity Survey
(NCS) was the first community survey to administer a structured psychiatric
interview to a national probability sample of the US population [10]. Based
on lifetime prevalence estimates from the NCS data, the most common
psychiatric disorders in the United States were major depression (17.1%),
alcohol dependence (14.1%), SAD (13.3%), and simple phobia (11.3%).
Approximately 1 in every 4 of the respondents met lifetime criteria for at
least one anxiety disorder in the NCS. One of the surprising findings from
the NCS was that the 12-month prevalence of anxiety disorders (17%) was
significantly greater than the 12-month prevalence of substance use
disorders (11%) or affective disorders (11%) [10]. Data from the NCS
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622 T.A. Pigott / Psychiatr Clin N Am 26 (2003) 621–672
confirmed that anxiety disorders were not only common but that their
associated chronicity exceeded that of the most prevalent psychiatric
disorders, depression, and substance use disorders.
In the ECA sample, over 13% of women compared with 6% of men met
criteria for a DSM-III anxiety disorder within the past 6 months [3]. The
NCS data also demonstrated that women were much more likely to have
anxiety disorders than men. Prevalence estimates based on the NCS data
indicate that one of every three women meet criteria for at least one anxiety
disorder during their lifetime [10]. Prevalence estimates based on the NCS
data also indicated that women are one and a half to two times more likely
than men to meet lifetime criteria for PD (5.0% versus 2.0%), GAD (6.6%
versus 3.6%), agoraphobia (7.0% versus 3.5%), simple phobia (15.7%
versus 6.7%), PTSD (11.3% versus 6.0%), and SAD (15.5% versus 11.1%).
Although prevalence estimates for OCD were not included in the NCS data,
lifetime prevalence estimates based on the ECA revealed that women (3.1%)
were at least one and a half times as likely as men (2.0%) to meet criteria for
OCD during their lifetime [11]. Population surveys conducted on an
international basis and using similar methodology have also substantiated
that anxiety disorders are common, particularly in females, on a worldwide
basis [12–16]. Although anxiety disorders occur more frequently in women
throughout the life span, there is some evidence that the observed gender
difference in prevalence rates may narrow with advanced age (after the age
of 65) [17]. However, prevalence rates in geriatric populations are often
difficult to interpret because multiple factors may contribute artifacts, in-
cluding the cumulative effects of anxiety-related mortality, attenuating
hormonal influences, and increasing rates of cognitive impairment [17].
Women also have a nearly twofold greater lifetime risk for major de-
pression than men. Several lines of evidence suggest that the increased
prevalence rates for anxiety disorders in women may also convey an
increased risk for depression. In the ECA study, almost half (47%) of the
respondents meeting lifetime criteria for major depression also met criteria
for a coexisting anxiety disorder [8]. The ECA data also revealed that the
mean age of onset for an anxiety disorder (16 years) was much earlier than
depression (23 years) in the respondents with depression and comorbid
anxiety disorders [8]. The presence of an anxiety disorder was also as-
sociated with an increased risk for major depressive disorder in the NCS
[10]. Breslau and colleagues [18] examined the potential relationship between
preexisting anxiety disorders and subsequent risk for depression in a
longitudinal study of young adults from the Detroit, Michigan, area.
Although they found a twofold increase in lifetime prevalence rates of major
depression in the females, the observed gender difference in depression
prevalence rates was largely due to an elevated occurrence of respondents
with major depression and coexisting anxiety disorders. Moreover, the
history of an anxiety disorder was associated with an increased risk for
major depression in men and women in the study. These results suggest that
T.A. Pigott / Psychiatr Clin N Am 26 (2003) 621–672 623
the early onset and elevated occurrence of anxiety disorders in women

account in large part for the increased prevalence rate of depression
observed in women [18].
In addition to conveying increased susceptibility to depression, the
presence of an anxiety disorder is also associated with other adverse
consequences, including an increased risk of functional impairment,
diminished occupational opportunities, impaired occupational performance,
and elevated morbidity and mortality rates [19–30]. Limited academic
achievement and reduced educational opportunities have also been linked to
a diagnosis of an anxiety disorder. In fact, the strongest predictor of
premature school termination in female respondents was the presence of an
anxiety disorder in the NCS [20]. The presence of an anxiety disorder is also
associated with elevated use rates for emergency medical and mental health
care services [3,31–36]. The economic burden estimated for anxiety disorders
is enormous. Greenberg and colleagues [37] calculated the cost of anxiety
disorders in the United States at $42 billion per year. One third of this
annual cost reflected the estimated cost of psychiatric treatment (31%) and
prescription pharmaceuticals (2%). The remaining two thirds is based on
the estimated costs associated with nonpsychiatric medical treatment (54%
or $23 billion), mortality-related expenses (3% or $1.2 billion), and indirect
costs that result from lost productivity and other adverse functional
consequences (1% or $4.1 billion). The highest (primarily nonpsychiatric)
use rates among the anxiety disorders were associated with a diagnosis of
PTSD and panic disorder, respectively. However, PD, OCD, GAD, SAD,
and PTSD diagnoses were all associated with significant impairment in
work-related performance [37]. Despite the substantial burden associated
with anxiety disorders, few individuals meeting anxiety disorder criteria
receive any type of treatment [33,38–41]. Moreover, most estimates suggest
that only 20% tp 30% receive effective treatment [10,42–46]. Numerous
studies have demonstrated that individuals meeting criteria for an anxiety
disorder are most likely to initially present in primary care and emergency
care settings, which, in turn, are associated with consistently low recognition
and effective treatment rates (see references [25,35,36,47–49]).
Various genetic, biological, developmental, and environmental factors
have been implicated in the finding of increased anxiety prevalence in
women compared with men. Kendler and colleagues have used female twin
studies to extensively investigate the potential role of genetic factors in the
development of certain anxiety disorders in women, especially GAD. Their
work has provided strong evidence that GAD and depression may share
a common genetic diathesis [50–52], whereas the other anxiety disorders
appear to be characterized by less genetic homogeneity [53–56]. Devel-
opmental and environmental factors, such as childhood trauma and early
separation anxiety, may also be instrumental in increasing the risk of anxiety
disorders during adulthood in both sexes [57–60]. There is some intriguing
evidence, however, that women may be particularly susceptible to the
adverse consequences that arise from childhood abuse. Breslau and

colleagues [61–69] have extensively investigated the potential relationship
between gender, trauma exposure, and PTSD in a number of seminal
studies. Results from such investigations have suggested that even when
trauma exposure rates are similar between men and women, women remain
at a much greater risk for PTSD development. A history of childhood
trauma also appears to be a more reliable predictor of PTSD in women than
in men [67]. Gender may also have a substantial impact on the type of
anxiety disorder that may develop in response to chronic environmental
stress. Galbaud and colleagues [70] found that a diagnosis of depression,
drug addiction, or antisocial personality disorder in a husband or wife
increased the chance that an anxiety disorder would be present in the
spouse. However, a gender difference was detected in the type of anxiety
disorder that was present in the spouse. For example, women were more
likely to meet criteria for PTSD if their husband had drug addiction,
whereas men were more likely to meet criteria for GAD if their wife was
addicted to drugs [70]. The profound fluctuations in estrogen and
progesterone concentrations that characterize the female reproductive
hormone cycle may also contribute to the elevated prevalence and increased
chronicity associated with the presence of anxiety disorders in women. With
these issues in mind, this article will provide a review of the available data
concerning the potential impact of female gender on the epidemiology,
phenomenology, clinical course, and treatment of anxiety disorders in
women throughout the life span.
Generalized anxiety disorder (GAD)

Population surveys estimate that the lifetime prevalence rate for GAD is
between 5% and 6% [10,71–73]. Women have a two to three times higher
lifetime risk for GAD compared with men [71,74,75]. Although the
prevalence of most anxiety disorders decreases with advanced age, GAD
remains at a constant prevalence rate throughout life. As a result, GAD is
one of the most prevalent anxiety disorders in the elderly (age greater than
60 years) [17,41,76]. In addition to female gender, GAD was associated with
an age greater than 24 years, being separated, widowed, or divorced, and
unemployment in the NCS study [71]. GAD is an especially common illness
in primary care settings [72]. The 1-month prevalence rate for GAD was 8%
in a recently completed 14-country, WHO-sponsored study conducted in
primary care settings. The presence of GAD in the primary care patients,
even in the absence of comorbid conditions, was associated with consider-
able social disability [77]. GAD was the most common anxiety disorder
present in primary care patients with chronic medical illnesses in a separate
report. GAD was present in 12% of the primary care patients with chronic
medical illness. In addition, over half (54%) of the depressed primary care
patients also met criteria for GAD in the same study. These results suggest
that primary care clinicians should always consider the possibility of GAD
in depressed patients with chronic medical illnesses [26]. In a national
sample of more than 500 primary care practices in the United States,
prevalence rates for GAD and major depression were comparable and both
were associated with the same degree of adverse consequences. Primary care
patients with GAD were more likely to be female, report onset of GAD
between the ages of 25 and 45 years, and experience a chronic clinical course
in the national survey of primary care patients. A diagnosis of GAD was
also associated with increased health care use rates, elevated rates of dis-
ability and social impairment, and an increased suicide rate [78,79].
Population surveys and clinical samples have demonstrated that
comorbid psychiatric disorders are extremely common in GAD (see
references [10,26,70,71,74,77,79–82]). The lifetime comorbidity risk was
90.4% in respondents with a history of GAD in the NCS study [71]. Mood
disorders are the most common lifetime comorbid disorders in GAD with
unipolar depression (67%), reported four times more common than bipolar
disorder (17%). The presence of comorbid mood disorders with GAD re-
sulted in a significant increase in associated disability and dysfunction [80].
Comorbid conditions are also common in clinical samples of patients with
GAD. Nearly three fourths (74%) of patients with primary GAD (n = 109)
had another lifetime psychiatric diagnosis. The most prevalent comorbid
diagnoses were social phobia (23%) and simple phobia (21%) [83]. In the
largest prospective study of anxiety disorders conducted to date, the
Harvard Anxiety Research Program (HARP) Study, panic disorder and
social anxiety disorder were the most commonly reported comorbid dis-
orders in patients with GAD (n = 164) [73]. Data from four community
surveys in the WHO International Consortium in Psychiatric Epidemiology
study revealed that the presence of simple phobia, either currently or in the
past, was associated with an increased risk of GAD. Simple phobia was the
only disorder that predicted the persistence of GAD, suggesting that a
history of simple phobia may be a risk factor for GAD [81].
Even in the absence of comorbid disorders, GAD is associated with
significant disability and dysfunction. The NCS data revealed that the
majority of people with GAD, whether comorbid or not, reported
substantial functional interference and a high degree of professional help-
seeking and increased medication use that they attributed to their GAD
symptoms [71,80]. A diagnosis of GAD was also linked to elevated rates of
medically unexplained symptoms, overuse of health care resources, and
increased psychotropic medication use compared with patients without
GAD [71]. Roy Byrne and Katon [36] suggest that the increase in health care
use associated with GAD occurs by an indirect mechanism. They
hypothesize that the presence of GAD serves as a catalyst that modifies
the presentation of other psychiatric disorders that more directly affect
health care costs [36]. GAD is generally characterized by a chronic clinical
course (see references [71,73,79,83,84]). Remission rates appear to be low in

GAD. For example, the likelihood of remission for patients with GAD in
the HARP study was 15% after 1 year and 25% after 2 years. Only 8% of
patients with GAD were considered to be in complete remission from all
psychiatric symptoms at the 2-year follow-up visit [73]. The HARP study
has also provided information about the relative rates of comorbid condi-
tions and treatment response in patients with primary versus secondary
(onset of GAD after another anxiety disorder) GAD. Patients with primary
GAD demonstrated significantly lower rates of agoraphobia, social anxiety
disorder, simple phobia, PTSD, alcohol use disorders, or MDD compared
with the patients with secondary GAD. However, remission rates and treat-
ment response were not significantly different between primary versus second-
ary GAD [85]. In a 5-year longitudinal study of GAD and panic disorder
patients, Woodman and colleagues [72] found that patients with GAD had
a significantly lower remission rate (18%) than patients with panic disorder
(45%). They also reported that GAD was associated with a significantly
earlier age of onset and a longer duration of illness than panic disorder [72].
These results suggest that GAD is a common, disabling, and chronic disorder
that primarily affects women. As discussed in the next section, a number of
gender differences have been identified in GAD.
Women and GAD

Kendler and colleagues [53] used data obtained from female twin pairs
(n = 1008) to examine the potential impact of parental loss or parental
marital disruption during childhood as a risk factor for subsequent
development of GAD during adulthood. Women who reported a childhood
history of parental marital separation or a childhood history of separation
from their mother or father were more likely to have GAD as adults [53].
Women with GAD are also more likely to have comorbid psychiatric
disorders than men with GAD. Depressive disorders, especially dysthymia,
are particularly common when women have GAD [71]. Because the presence
of depression in patients with GAD has been associated with increased
functional impairment and a greater risk of suicide, this may help to explain
why women have a more chronic course and greater symptom severity than
men with GAD [38,71,73]. Preliminary evidence also suggests that women
are more likely than men with GAD to seek treatment with a health care
professional, especially if comorbid diagnoses are also present [40,86].
The frequent occurrence of depression in women with GAD may also
provide an important clue in understanding the underlying pathophysiology
of GAD. Kendler and colleagues [50,52,56] have investigated the potential
role of genetic factors in the development of anxiety disorders in women by
analyzing data from bivariate female twin pairs. Their results suggest that
GAD is a moderately familial disorder that is largely or entirely the result of
genetic factors shared between relatives rather than to the effects of the
familial environment. Data from the female twin pairs suggest that genetic
factors account for approximately 30% of the risk of GAD development,
with environmental factors explaining the remainder of the variance [52].
The female twin pair data also suggests that the same or similar genetic
factors may determine liability for major depression and GAD. That is,
GAD and depression may arise from the same genotype and whether major
depression or GAD develops may be determined by environmental
experiences [50]. This data provides strong evidence for genetic transmission
as a critical mediating factor in GAD.
Disturbances in serotonergic, noradrenergic, and GABA-ergic neuro-
transmission have all been implicated in the pathophysiology of GAD
[74,87–89]. Results from a neuroimaging study conducted in patients with
GAD revealed a more homogeneous distribution of benzodiazepine
receptors throughout the cerebral hemispheres in patients with GAD versus
control subjects [90]. The authors of the study speculated that this finding
might represent evidence of reduced heterogeneity of cerebral blood flow in
GAD. Such results may be analogous to the reduced heterogeneity in
myocardial blood flow that is characteristic of ischemic heart disease [90].
Although gender differences have not been identified in neurobiological or
neuroimaging investigations conducted in GAD, few studies have specif-
ically addressed the potential impact of gender. Medications reported to be
effective in placebo-controlled trials for the treatment of GAD include
buspirone, benzodiazepine anxiolytics, venlafaxine, and the selective
serotonin reuptake inhibitors (SSRI) antidepressants [82,87,89]. Because
GAD is commonly complicated by comorbid depressive disorders, effective
antidepressant medications (venlafaxine, SSRIs) are generally recommended
as first-line pharmacotherapy for GAD. Analysis of data from the 8-week,
multicenter, double-blind comparison of the SSRI paroxetine (at 20 and 40
mg/day) and placebo for the treatment of GAD failed to reveal evidence of
any significant gender effect in treatment response [91]. Although significant
gender differences for treatment response in GAD have not been reported,
few studies have specifically provided information about gender and
treatment response. Data derived from animal models of anxiety suggest
that response to anxiolytic medication, especially benzodiazepine anxio-
lytics, may be significantly influenced by gender as well as the phase of
the estrous cycle [92]. However, controlled studies of benzodiazepine
anxiolytics for the treatment of GAD have thus far failed to provide
information about the potential influence of gender on treatment response
or tolerability issues.
There is ample evidence that women with GAD and other anxiety
disorders are more likely than men to be prescribed psychotropic medi-
cations, especially benzodiazepines. A survey conducted in over 60,000
patients seen in general practice settings revealed that women were twice
as likely as men to receive a first prescription for benzodiazepines regardless
of symptoms or diagnosis. The gender difference was continued in repeat

prescriptions for benzodiazepines [93]. Data from a 15-center, primary care
epidemiological survey also found that female gender predicted increased
prescription rates. Anxiolytics, hypnotics, and antidepressants each ac-
counted for approximately 20% of all prescriptions. Although over 50% of
patients diagnosed with a psychiatric illness were prescribed psychotropic
medication, only 8% of the patients with anxiety disorders, who were largely
female, were treated with antidepressant medication [94]. There is even more
of an extensive comorbidity between GAD with depression in geriatric
populations, but available data suggests that when treatment is given,
benzodiazepines are overused and antidepressants are underused [41,76].
These results suggest that women with anxiety disorders, including GAD,
are more likely to receive benzodiazepine medications than antidepressants.
This may have important implications because women with GAD have
increased risk for depressive disorders than men. In addition, animal data
suggests that gender and the estrous cycle may have a substantial effect on
response to benzodiazepine anxiolytics, whereas gender differences have
not been reported with antidepressant medications for the treatment of
GAD.
GAD and the female reproductive cycle

Women with GAD often report premenstrual worsening in GAD
symptoms. A prospective comparison of women with GAD (n = 21),
women with GAD and PMS (n = 41), and women controls (n = 19)
revealed that the women with GAD and premenstrual syndrome (PMS) had
more symptoms than the controls during both phases of the menstrual cycle
and during the premenstrual period. However, there was no significant
change in symptom severity during the menstrual cycle in the women with
GAD alone [95]. Further information about the impact of the menstrual
cycle, pregnancy, or menopause on the symptoms or course of GAD has not
been reported at this time. These findings indicate that gender differences
exist in the prevalence, clinical features, and comorbid conditions that may
complicate GAD. There is evidence that GAD symptom severity may be
influenced by female reproductive hormone cycles, but further information,
especially about the potential impact of pregnancy and the postpartum
period on GAD, is currently absent. Because preliminary evidence suggests
that women with GAD have a more chronic course and a worse outcome,
systematic data concerning gender differences in underlying pathophysiol-
ogy or treatment response is clearly needed. The emerging picture is that
GAD in women is more common and more likely to be chronic, complicated
by comorbid psychiatric disorder, and associated with more functional
impairment than in men. Yet, women with GAD are less likely than men to
receive first-line treatment with antidepressant medication.
Panic disorder and agoraphobia

Panic disorder (PD) was one of the most prevalent psychiatric disorders
identified in the ECA population survey. The lifetime prevalence for panic
disorder was estimated at 2.2%, and women were two and a half to three
times more likely than men to meet criteria for panic disorder during their
lifetime (3.4% versus 0.9%) [9]. The ECA data also demonstrated an
increased risk for panic disorder in those under the age of 45 years [96]. The
lifetime prevalence rate for panic disorder (3.5%) was even higher in the
NCS study than that reported for the ECA study. The lifetime prevalence
estimate for panic disorder was also two and a half times greater in women
(5%) than in men (2%) in the NCS study [10]. Panic disorder followed
a bimodal age distribution and was associated with lower educational
achievement as well as female gender in the NCS. A similar rate (50%)
was reported for the occurrence of panic disorder and panic disorder with
agoraphobia. The NCS data did not detect evidence of significant differences
in the sociodemographic correlates associated with the two diagnoses [97].
Similar lifetime prevalence estimates for panic disorder (1.5–3.0%) have
been reported from international epidemiological studies, such as the cross-
national epidemiology of panic disorder [98]. The only exception has been
the lifetime prevalence for panic disorder (0.4) reported in Taiwan; however,
most psychiatric disorders are reported to be rare in Taiwan. Women are
reported to have significantly higher prevalence rates for panic disorder on
a worldwide basis. The international data has also confirmed that panic
disorder is associated with an increased lifetime risk for agoraphobia and
major depression [16,98–101].
Data from clinical samples suggest that agoraphobia in the absence of
panic disorder is rare. However, results from population surveys suggest
that agoraphobia without panic disorder is not uncommon. Two thirds of
the ECA respondents with agoraphobia denied a history of panic disorder
[102]. Moreover, lifetime prevalence estimates for agoraphobia (5.3%)
exceeded that of panic disorder (3.5%) in the NCS study. Women (7%) were
twice as likely as men (3.5%) to meet criteria for agoraphobia without
panic disorder. Regardless of the prevalence of agoraphobia, there is fairly
consistent evidence that agoraphobia is associated with considerable dis-
ability and elevated levels of help-seeking behaviors. Data from the re-
cently published Australian National Survey suggests that the presence of
agoraphobia alone (ie, without panic) was associated with a similar degree
of functional impairment as the presence of panic disorder alone [39]. In the
same report, the presence of panic disorder with agoraphobia was associated
with an increased risk of comorbid disorders and a greater degree of
disability compared with the presence of either panic disorder alone or
agoraphobia alone [103].
The onset of panic disorder is typically during early to middle adulthood
and is rare after the age of 40 [98,100,104]. However, there is generally
a considerable delay between the onset of panic disorder and its effective
treatment. Available evidence suggests that only 1 out of 5 patients with
panic disorder will present for initial evaluation to a psychiatrist [105].
Instead most will present in a general medical setting, often with prominent
cardiovascular, respiratory, or gastrointestinal complaints that may lead to
unnecessary tests and diagnostic procedures [33]. Some 30% to 50% of
patients with recurrent chest pain and normal coronary arteries are reported
to meet criteria for panic disorder. In a study conducted in nearly 1000
primary care patients, almost one third of the patients with panic disorder
had been treated for emotional, alcohol, or drug-related problems in the 6
months before interview [106]. These results suggests that panic disorder
most often presents in medical rather than mental health settings, and the
failure to promptly diagnose panic disorder results in significant morbidity
and health care use, especially in primary care and cardiology settings
[31,32].
Comorbid psychiatric disorders are extremely common in panic disorder.
Major depressive disorder is the most common comorbid condition with
most estimates suggesting a 50% to 75% lifetime risk in panic disorder. A
diagnosis of panic disorder is also associated with an elevated risk of
comorbid substance use disorders and an increased rate of additional
anxiety disorder diagnoses [104]. Results from a Canadian national survey
(n = 3258) revealed that 90% of the respondents meeting criteria for panic
disorder also met criteria for another DSM-III diagnosis; the risk of
a comorbid disorder was 2.7 times higher in the respondents with panic
disorder compared with respondents without panic disorder. Similar to
results from previous population surveys, the Canadian data revealed that
major depressive episode (73%), alcohol abuse/dependence (54%), drug
abuse/dependence (43%), and phobia (44%) were the most common
comorbid conditions in panic disorder [100]. In addition to their frequent
co-occurrence, the presence of depression or agoraphobia may also have
important prognostic implications for patients with panic disorder.
Considerable evidence suggests that panic disorder complicated by either
depression or agoraphobia is associated with greater illness severity and an
elevated risk for additional comorbid disorders compared with panic
disorder alone [107,108]. For example, Starcevic and colleagues found
elevated rates of depression, dysthymia, SAD, GAD, and OCD in patients
with panic disorder and agoraphobia compared with patients with panic
disorder alone [108].
Panic disorder is generally considered to have a chronic clinical course
with complete or sustained remission a rare occurrence (see references
[47,96,104,107,109]). In a comprehensive review of panic disorder, Keller
and Hanks concluded that up to one third of patients with panic disorder
attained only minimal therapeutic benefits, despite years of treatment. They
also suggested that patients with panic disorder for 6 months or longer had
significantly more impairment that those with panic disorder for less than 6
months [107]. At 1 year of follow-up, 40% of the panic patients in the

HARP study were still receiving treatment. Extrapolating from this data,
30% to 40% of patients with panic disorder would be expected to require
long-term treatment [107]. Relapse and remission rates were also compared
in the HARP panic patients with or without agoraphobia (n = 309) [109].
At the 1-year point of observation, remission rates were two times greater
in the patients with panic disorder alone (39%) compared with those
with panic disorder and agoraphobia (17%). Relapse was common after
remission and occurred in both groups of patients with panic disorder
[109].
Panic disorder appears to be associated with the worst outcome of any of
the anxiety disorders. Adverse consequences linked to the presence of panic
disorder include psychosocial and occupational dysfunction, marital
disruption, alcohol abuse, financial dependency, and poor general medical
and emotional health. A panic disorder diagnosis is also associated with
increased medication use and elevated use rates for all types of medical
services (see references [24,28,29,104,110]). Panic disorder patients from the
HARP study reported significantly more medical problems than the
population at large including ulcers, angina, and thyroid disease [25].
Publication of the ECA data led to considerable speculation about a possible
association between panic disorder and an increased risk of suicide attempts
[24,111,112]. However, subsequent reanalyses of the ECA data as well as
several subsequent investigations suggest that the presence of comorbid
disorders with panic, rather than panic disorder alone, account for the
observed increase in suicide attempts in panic disorder [113–116].
SSRI antidepressants are generally recommended as first-line phar-
macotherapy for panic disorder. However, various other agents have
demonstrated efficacy in panic disorder in placebo-controlled trials, in-
cluding benzodiazepine anxiolytics and other classes of antidepressant
medications (tricyclic antidepressants and monoamine oxidase inhibitors)
[5]. The International Consensus Group on Depression and Anxiety rec-
ommended that pharmacotherapy for panic disorder should be continued
for at least 12 to 24 months and discontinuation of effective pharmaco-
therapy should be attempted slowly over a period of 4 to 6 months [117].
Despite the appearance of consensus treatment guidelines, considerable
evidence suggests that few individuals with panic disorder receive adequate
or appropriate treatment [33]. In a preliminary analysis of the HARP data,
Yonkers and colleagues [118] reported that patients with panic disorder
(n = 331) were more likely than patients without panic disorder to receive
treatment with a benzodiazepine. However, the presence of comorbid
depression was associated with an increased likelihood of antidepressant
treatment in the patients with panic disorder [118]. In a separate report
based on HARP data, Yonkers and colleagues [119] systematically assessed
the adequacy of pharmacotherapy in the patients with panic disorder. The
results were surprising in that only 54% of the most symptomatic panic
patients were considered to be receiving optimal pharmacological treatment;

in the less symptomatic panic patients, pharmacotherapy was considered to
be optimal in an even smaller percentage of the patients (43%) [119].
Because the HARP panic patients were all being treated by psychiatrists
from major teaching hospitals, these findings seem particularly alarming.
Women and panic disorder

In addition to the finding that panic disorder is two to three times more
common in women, panic attacks also occur more frequently in women than
in men [120]. Though panic attacks do not appear to be associated with the
same degree of morbidity as panic disorder, their occurrence may still herald
serious consequences [121]. The lifetime prevalence estimate for panic
attacks (4.3%) by DSM-IV criteria was twice that estimated for panic
disorder (1.6%) in a large-scale (n = 3000) community survey conducted in
adolescents and young adults. Moreover, the presence of panic attacks in
the adolescents or young adults in the survey was strongly related to the
subsequent development of a range of psychiatric disorders during
adulthood, especially in women. The conditional probability of developing
a psychiatric disorder in women with panic attacks was calculated at 40%.
These results suggest that panic attacks are more common in women than in
men and that their presence may well elevate the risk for the subsequent
occurrence of other psychiatric disorders [121]. The onset of panic disorder
may be earlier in women than in men [104] although this has not been
universally reported [98,100]. Hazard rates calculated from the NCS data
found that panic disorder was most prevalent between the ages of 25 and 34
years in women and between the ages of 30 and 44 years in men [104]. In one
of the largest clinical samples of panic patients examined for gender
differences (n = 673), Clayton and colleagues found that women had a later
age of onset compared with men with panic disorder [122]. Postmenopausal
women with panic disorder may also have less anticipatory anxiety, panic
attack frequency, and panic severity than younger women with panic
disorder [122].
Some phenomenological features identified in women with panic disorder
appear to be distinct from those noted in men with panic disorder. For
example, women meeting criteria for panic disorder reported more in-
dividual panic symptoms than men in the Edmonton (Canada) popula-
tion survey [100]. In the same survey, women with panic disorder had
significantly (a) greater levels of phobic avoidance; (b) more reliance on
family members as a means to enter fearful situations; and (c) more reports
of panic attacks being triggered by leaving home alone or by using public
transportation [100]. Significant gender differences have also been reported
in clinical samples of patients with panic disorder. Starcevic and colleagues
found that women with panic disorder were significantly more likely than
men to eschew transportation by bus and to avoid unfamiliar places when

alone. They also found that women were much more likely than men with
panic disorder to report that they needed a companion, especially their
spouse or children, to go outside the home [123]. This increased level of
dependence may help to explain the consistent finding that women with
panic disorder have a greater degree of functional impairment compared
with men with panic disorder [98,123,124].
Women with panic disorder also have an elevated lifetime risk for
comorbid psychiatric disorders compared with men [125]. Agoraphobia,
depression, GAD, simple phobia, and somatization disorder all appear to
occur more frequently in women than in men with panic disorder (see
references [73,103,110,125–128]). Several studies have specifically investi-
gated the potential impact of gender on presentation and clinical course in
patients with panic disorder and agoraphobia. Findings from such studies
indicate that women with panic disorder and agoraphobia report greater
phobic avoidance, more catastrophic thoughts, and a heightened awareness
of body sensations compared with men with panic disorder and
agoraphobia [23,124,129]. Women compared with men with panic disorder
and agoraphobia also appear to have a more severe illness and an increased
risk of comorbid SAD or PTSD [124,130]. An examination of gender
differences in the frequency of DSM-IV personality disorder diagnoses in
a sample of patients with panic disorder (n = 184) revealed that women
were more likely to meet criteria for histrionic and cluster C diagnoses,
particularly dependent personality disorder. In contrast, men with panic
disorder were significantly more likely to meet criteria for more severe
personality disorders, including schizoid and borderline personality disorder
[131]. Although men with panic disorder have higher rates of comorbid
alcohol abuse, women with panic disorder are more likely to have comorbid
alcohol abuse or dependence compared with women without panic disorder
(see references [10,122,129,132]). There is also some evidence that relatives
of women with panic disorder may have an increased risk for alcohol
dependence, suggesting a possible genetic link between panic disorder and
alcohol abuse in women [56,133].
The prevalence of panic disorder may be higher among female than male
suicides [134], although this finding appears more attributable to super-
imposed major depression, substance abuse, and personality disorders than
the presence of panic disorder alone [134]. Results from at least one study
suggest that men, but not women, with panic disorder may have an elevated
general mortality rate, especially as a result of circulatory disorders,
compared with control subjects [23]. A link has been suggested between
smoking behavior and panic disorder in women. That is, women with panic
disorder were reported to have a significantly higher smoking prevalence at
the onset of their illness (54%) than did control subjects (35%). The current
prevalence rate for smoking in the women with panic disorder (40%) was
also significantly higher than that demonstrated for control subjects (25%)
in the same report [135]. These findings suggest that women with panic
disorder have an elevated risk for comorbid psychiatric disorders in general
and certain comorbid disorders in particular. Because the presence of certain
comorbid disorders in panic disorder appears to have prognostic
significance, the gender differences identified may have important implica-
tions. For example, a less favorable outcome has been reported for panic
disorder with agoraphobia compared with panic disorder alone. Because
women with panic disorder are more likely to have agoraphobia, this may
represent a substantial factor in explaining the consistent observation that
panic disorder is more chronic and severe in women than in men (see
references [28,29,39,96,125]). Recent prospective data also suggests that if
a period of remission occurs during the course of panic disorder, women
have an increased risk for recurrence of panic disorder [125].
The etiology of panic disorder remains obscure, and it is difficult to
explain why women have a greater risk and a more malevolent course for
panic disorder than men. Numerous neurobiological and psychological
theories have been proposed for panic disorder. Most psychological theories
emphasize the importance of cognitive misinterpretation and ‘‘false threat
alarms’’ as the basis for the subsequent development of panic disorder [136].
Biological theories, in contrast, implicate altered brain function and an
abnormal ventilatory response in the pathophysiology of panic [137,138].
Neural circuits within the amygdala and its ascending cortical pathways are
most often speculated to represent the functional neuroanatomy of panic
disorder. Altered dysregulation of the ventilatory response and associated
neurovascular instability may also be important factors in the pathophys-
iology of panic disorder [139]. Physiological (eg, CO2 sensitivity) and
psychological (anxiety sensitivity) factors have been suggested as predis-
posing factors in the development of panic disorder [139,140]. Despite the
striking gender differences identified in the prevalence and clinical features
associated with panic disorder, evidence of significant gender differences in
the purported pathophysiology of panic disorder have not been extensively
investigated or reported.
Results from covariate female twin studies suggest that genetic or familial
factors play a role in panic disorder, although their contribution is estimated
to be modest [54,56]. The presence of a specific genetic polymorphism has
also been linked to an increased risk for panic disorder in women. Women
with panic disorder are reported to have a higher occurrence of a novel
repeat genetic polymorphism on chromosome X than control subjects [141].
This genetic polymorphism is thought to mediate expression of monoamine
oxidase A. Because monoamine-oxidase inhibiting antidepressants are
known to be effective antipanic agents, this finding has been interpreted
as evidence that altered monoamine oxidase A activity may be a risk factor
for panic disorder, at least in women [141]. Environmental influences have
also been linked to an increased risk of panic disorder, especially in women.
A history of childhood anxiety disorders, especially separation anxiety, has
also been linked to the presence of panic disorder during adulthood [142]. A
retrospective analysis of twin data suggested a substantial genetic
contribution to separation anxiety in females but not in males, although
environmental influences also appeared to be critical in both genders [143].
Results from a community survey that systematically compared trauma
exposure in patients with DSM-IV anxiety disorders (n = 125) to age- and
gender-matched control subjects (n = 125) revealed that reports of child-
hood physical and sexual abuse were significantly higher in those with
anxiety disorders than in the control subjects. Moreover, women with panic
disorder (60.0%) reported more sexual abuse than the women with other
anxiety disorders (30.8%). These findings confirm the association between
anxiety disorders and reported childhood physical and sexual abuse, but
also suggest that childhood sexual abuse may increase the risk of panic
disorder in women [57].
Panic disorder and the female reproductive cycle

The dramatic fluctuations in reproductive hormone cycles that occur
throughout the female lifecycle appear to have a substantial impact on the
clinical course of panic disorder in women. The dramatic decline in estrogen
and progesterone levels that characterizes the midluteal phase of the
menstrual cycle has been linked to the emergence or worsening of anxiety
symptoms in general, and panic disorder in particular [144]. Several reports
suggest that women with panic disorder experience an increase in their
anxiety and panic symptoms during the midluteal or premenstrual phase of
the menstrual cycle [145,146]. Women with panic disorder are also reported
to endorse more severe menstrual symptoms relating to bodily sensations,
anxiety sensitivity, state and trait anxiety, fear of body sensations, and
illness-related concerns compared with control subjects [147]. In addition,
a recent report examined the relationship between premenstrual exacerba-
tion and suicidal behavior in patients with panic disorder (n = 70).
Although most of the patients (60%) denied a premenstrual exacerbation in
panic, the patients with a premenstrual increase in panic anxiety also
reported significantly higher levels of suicidal ideation or behavior during
the premenstrual phase [148]. Though these findings are intriguing, these
studies were primarily retrospective. This may prove to be an important
distinction, because prospective studies reported to date have failed to detect
any significant association between menstrual cycle phase and ratings of
panic or anxiety symptoms in women with panic disorder [149,150]. Results
from biological challenge paradigms conducted in women with panic
disorder have detected evidence of changes in anxiety sensitivity across the
menstrual cycle. Acute ingestion of carbon dioxide (CO2) is often used as
a provocative challenge to precipitate anxiety and panic attacks in ex-
perimental conditions [146]. Women with panic disorder have been reported
to demonstrate evidence of menstrual cycle phase (follicular versus luteal)

dependent changes in anxiety sensitivity in at least one report [151]. That is,
women with panic disorder demonstrated elevated anxiety responses during
the midluteal phase of the menstrual cycle compared with the earlier
follicular phase when serially administered CO2. The women control
subjects did not demonstrate any significant relationship between CO2-
induced anxiety and phase of the menstrual cycle during the same study
[152]. In the same report, subsequent alprazolam treatment was associated
with apparent ‘‘normalization’’ of the CO2-induced anxiety response
[151].
Precipitous estrogen withdrawal, whether physiological or induced by
medication or surgical intervention, has also been linked to the subsequent
emergence of panic disorder. In a large study (n = 390) of perimenopausal
women with new-onset but ‘‘ill-defined’’ psychological and somatic
symptoms, 7% were found to meet criteria for panic disorder [153]. More-
over, another study suggests that a diagnosis of panic disorder should be
considered in perimenopausal women who present with hot flashes but fail
to respond to hormone replacement therapy [154]. Medical interventions
that have primary progesterone-like effects, such as birth control pills or
Norplant implants, have also been associated with the acute development of
panic disorder [155]. Ovarian suppressants used for the treatment of
endometriosis, such as leuprolide, may also elicit panic attacks and other
psychiatric disturbances [156]. These findings confirm that precipitous or
acute suppression of ovarian function (eg, perimenopause) may increase the
risk of panic disorder onset or exacerbation. However, there is less
information available about the potential impact of chronic or long-term
ovarian suppression (eg, postmenopause) on panic disorder prevalence or
course. Further analyses of data from the multicenter sertraline trials
conducted in panic disorder revealed that postmenopausal women reported
significantly fewer panic attacks, lower levels of anticipatory anxiety, and
less overall panic severity compared with younger women participating in
the trials [122]. Community surveys conducted in geriatric populations
(persons 60 years or older) have found that anxiety disorders in general are
less prevalent than in younger populations and that panic disorder, in
particular, is rare in the elderly [76]. These results suggest that the menstrual
cycle has a profound impact on the prevalence and course of panic disorder
in women.
Pregnancy is characterized by two- to threefold increases in estrogen and
a dramatic elevation (80–100) in progesterone concentration [157].
Estrogen’s biological actions are thought to convey some mood-enhancing
or antidepressant effects. In contrast, progesterone increases MAO enzyme
activity. Pregnanolone, a major metabolite of progesterone, enhances
GABA tone by way of its effects as an allosteric modulator at the GABA-
benzodiazepine receptor complex. Because GABA represents one of the
major inhibitors of neurotransmission within the CNS, progesterone’s
biological effects may convey an anxiolytic action [156,158,159]. Proges-

terone is also a potent stimulant for oxygen drive. With these actions in
mind, women with preexisting panic disorder might be expected to ex-
perience a substantial attenuation or remission in panic during pregnancy.
As summarized by Northcott, most of the available evidence suggests that
pregnancy has a highly variable influence on the course of panic disorder
[160]. Most estimates suggest that about half (40–45%) of women with
preexisting panic disorder will have no significant change in their panic
symptoms during pregnancy. Preexisting panic disorder will improve during
pregnancy in 30% to 35% of patients and substantially worsen in 20% to
30% of patients during the course of pregnancy [160–162]. In a more recent
report, Hertzberg analyzed the results from eight reported studies (n = 215
pregnancies) and concluded that (41%) experienced improvement in panic
disorder during pregnancy, whereas an onset or an exacerbation in panic
disorder was reported in 38% of the described pregnancies [163]. Although
data is limited, results from a large-scale cohort study revealed that women
who suffer a miscarriage (n = 299) were not at an increased risk for
developing panic disorder compared with control subjects (n = 230) in the
6 months following the loss [164]. Interestingly, women with panic disorder
appear unlikely to experience the same outcome (ie, worsening, improve-
ment, or no change) in subsequent pregnancies. That is, the course of panic
disorder during successive pregnancies is often markedly different [160–
162,165]. Postpartum worsening (35–63%) is a much more consistent
finding demonstrated in women with preexisting panic disorder [160–
162,166,167]. The postpartum period may also be associated with an
increased risk for the onset of panic disorder. According to available data,
11% to 29% of women with panic disorder report onset during the
postpartum period [167,168]. Because this rate is significantly greater than
the expected age-corrected rate for panic onset in women, it is unlikely to
represent a coincidental event [167]. In patients with preexisting panic
disorder, pregnancy does not appear to increase the likelihood that
medication for panic can be successfully discontinued [161,162]. Instead,
there is some support for continuing or restarting pharmacotherapy during
the latter part of pregnancy in patients with panic disorder who are
considered at a high risk for relapse in the postpartum period. Cohen and
colleagues demonstrated that pregnant women with preexisting panic
disorder who receive antipanic medication are significantly less likely to
experience a postpartum exacerbation than those who did not receive
treatment during pregnancy [161,162].
Selective serotonin reuptake inhibitors (SSRI), monoamine oxidase
inhibitors (MAOI), and tricyclic (TCA) antidepressants have all demon-
strated efficacy in the treatment of panic disorder [5,117,169]. High-potency
benzodiazepine medications, such as lorazepam, alprazolam, and clonaze-
pam, are also effective antipanic agents. Each of the antipanic medications
(SSRI, MAOI, TCA, and benzodiazepines) is associated with a similar rate
of improvement (60–70%) in panic symptomatology. However, buspirone

and other medications with primary serotonergic effects do not appear to be
more effective than placebo for panic disorder [137]. Little information is
available concerning the potential impact of gender on treatment response
in panic disorder. Results from one small study [170] suggest that the TCA
desipramine may be less effective in men than in women with panic disorder.
Pooled data from four double-blind, placebo-controlled treatment trials in
patients with DSM-III-R panic disorder (n = 338 women and 335 men)
was examined for potential impact of concomitant hormone therapy on
sertraline response or tolerability in women across the lifecycle. No signif-
icant effect on treatment response was found for younger women based on
oral contraceptive status or for postmenopausal women based on hormone
replacement therapy status. Sertraline was well tolerated, with women
reporting a higher incidence of diarrhea than men [122]. Although con-
ducted in women with depression (n = 61), results from a treatment trial
involving interpersonal psychotherapy and SSRI pharmacotherapy suggest
a possible relationship between a history of panic-agoraphobic symptoms
and treatment response. The authors found that women with high baseline
scores (35 or greater) on the Panic-Agoraphobic Spectrum Self-Report
(PASS) were less likely to respond to interpersonal psychotherapy alone and
also exhibited a delayed response (18 versus 10 weeks) to a subsequent SSRI
trial than women with low baseline PASS scores (less than 35) [171]. These
results suggest that future studies in pharmacological and nonpharmaco-
logical treatment response in women with panic disorder across the lifecycle
are indicated.
These findings indicate that important gender differences exist in the
prevalence, clinical features, and overall course of panic disorder. Women
are more likely to have panic disorder with comorbid conditions, especially
agoraphobia. They are also more likely than men to suffer a recurrence of
panic symptoms after remission of panic disorder. Available data also
suggests that the women reproductive cycle, especially pregnancy and the
postpartum period, can have an important impact on the course of panic
disorder. Moreover, declining women hormone levels associated with the
aging process or as a consequence of medical or surgical interventions can
precipitate or elicit an exacerbation in panic disorder. Although pre-
liminary evidence also suggests that treatment response may be different in
men versus women with panic disorder, further studies that focus on this
critical issue are clearly needed. The potential contribution of differential
avoidance strategies and other clinical characteristics that may influence
prognosis in panic disorder also requires further investigation. Important
gender differences in the presentation, clinical features, and overall course
of panic disorder have been identified. Women with panic disorder are
more likely to have agoraphobia and other comorbid conditions than men
with panic disorder. The elevated risk for comorbid conditions likely
contributes to the poorer prognosis reported for women than men with
panic disorder. However, the potential contribution of differential

avoidance strategies and other clinical characteristics that may influence
prognosis in panic disorder requires further study.
Simple phobia
Estimates based on the ECA and NCS data confirm that simple phobia is
one of the most common psychiatric disorders, with an 11% lifetime
prevalence rate [10,172]. Women are twice as likely as men to meet criteria
for simple phobias (see references [15,39,173,174]). Simple phobias
encompass a wide range of fears, including situation-related phobias (eg,
claustrophobia, acrophobia), animal-related phobias (eg, fear of spiders,
insects, snakes), and health care-related phobias (eg, fear of injections,
blood, dental procedures) [175]. Situational phobias represent the most
common simple phobias, followed by animal-related, and then health-
related phobias, respectively [175]. Population surveys suggest that the most
common fears reported in respondents with simple phobia include fears
related to heights, claustrophobia, riding on public transportation, being in
crowds, insects, bad weather, and of being in water (aquaphobia) [15].
Simple phobia is consistently reported to have the earliest age of onset
among the anxiety disorders. Most studies suggest that simple phobia begins
during adolescence with a mean age of onset around 15 years [172]. Simple
phobia tends to have a chronic course [39]. Comorbid psychiatric disorders
are fairly common in simple phobia. Given the early age of onset for simple
phobia, comorbid disorders generally occur after simple phobia is already
well established [172,176]. In an analysis of data obtained from surveys
conducted in the United States and three other countries, Kessler and
colleagues [81] found that respondents who met either current or lifetime
criteria for simple phobia had elevated rates of GAD. That is, even when
remitted, a history of simple phobia conveyed an increased risk for GAD.
The authors suggest that this finding is likely to represent a state-dependent
phenomena and that a history of simple phobia may represent a risk marker
for GAD [81]. The presence of simple phobia has been linked to a number of
serious consequences, including an increased vulnerability for subsequent
development of major depression and addictive disorders [8]. A diagnosis of
simple phobia has also been associated with lower socioeconomic status in
several population surveys [39]. Results from at least one report suggest that
the number of fears, independent of the type, are most predictive of the
degree of functional impairment in simple phobia [177]. The presence of
multiple fears within an individual with simple phobia was also associated
with an increased risk for comorbid conditions and a chronic clinical course
in the same report [177]. Most studies estimate that only 10% to 20% of
individuals meeting criteria for simple phobia receive appropriate treatment
[15,39].
Women and simple phobia

Women have a twofold higher lifetime risk for simple phobia than men
(26% versus 12%). In addition, results from a population survey conducted
in over 700 adults revealed that women were also much more likely than
men to meet lifetime criteria for situational phobias (17% versus 8.5%) and
animal phobias (12% versus 3%) [175]. Health-related phobias were re-
ported to have a similar prevalence rate in men and women (3.2% versus
2.7%). Women reported higher fear ratings for all objects and situations
than the men in the survey. The incidence of phobia related to flying
increased in women with increasing age, whereas the incidence of phobia
related to injections decreased with advancing age. No correlations between
the incidence of specific phobias and age were detected in men in the survey
[175]. In a population survey conducted in over 8000 adults, animal phobias
are reported to be the most common simple phobia in women, whereas
acrophobia (fear of heights) is reported as the most common simple phobia
in men [177]. Specific questions about blood-injection-injury phobia were
included in the ECA study. Results from this assessment revealed that
blood-injection-injury phobia was a common form of simple phobia and
that females had a higher prevalence rate than males. Respondents with the
blood-injection-injury form of simple phobia also were reported to have
a significantly higher than expected lifetime prevalence rates for other
psychiatric conditions, including marijuana abuse/dependence, major de-
pression, OCD, panic disorder, agoraphobia, social anxiety, and other
simple phobias. Although respondents with blood-injection-injury phobia
denied seeking any type of treatment for the simple phobia, diabetics
meeting criteria for the condition reported an increased rate of macro-
vascular complications [178]. Though numerous reports have confirmed that
women have an increased prevalence rate for simple phobia compared with
men, little additional information is available concerning the clinical
features or course of simple phobia in women. Data derived from twin
studies suggests that environmental influences may be more critical than
genetic factors in the development of simple phobia in women [51]. Data
about the possible relationship between female reproductive cycles and
simple phobia is also currently absent.
Social anxiety disorder (SAD)

Social anxiety disorder is one of the most common psychiatric disorders.
Estimates based on the NCS data suggest that the lifetime prevalence rate
for social anxiety disorder exceeds 13% [10,39,179–181]. Although the ECA
study failed to detect a significant sex difference in social anxiety disorder
prevalence rates [39], subsequent population surveys conducted in the
United States and abroad indicate a higher prevalence rate for women than
men (see references [10,14,16,182,183]). Public speaking-related anxiety
appears to be the most common form of social anxiety disorder. Anxiety

related to small-group activities, meeting strangers, eating in public, cashing
checks in public, and using public restrooms are also frequent fears in social
anxiety disorder [184]. Results from the cross-national survey of social
anxiety disorder revealed some variance in symptom profiles occurs across
the different countries (see references [10,14,182,184]). The onset of social
anxiety disorder is usually before the age of 18; onset after the age of 25 is
uncommon. Most evidence suggests that social anxiety disorder has
a chronic and unremitting clinical course. Reported risk factors for social
anxiety disorder include younger age (18–29 years), lower socioeconomic
status (SES) [39,185], lack of social support, and single marital status. The
presence of social anxiety disorder is associated with a number of
devastating consequences, including lower education attainment and ele-
vated rates of workplace impairment (see references [14,37,39,42,45,
172,179,182–187]). The presence of SAD has also been linked to working
fewer months, spending more months on welfare, and an increased reliance
on welfare rather than wages. These SAD-related consequences are reported
to be independent of the effects of depression [188].
Two subtypes of social anxiety disorder are recognized: generalized and
nongeneralized. Most studies suggest that about one third of individuals
with social anxiety disorder are classified as nongeneralized and two-thirds
as generalized social phobics [183,186]. Fear of public speaking is the most
common symptom in nongeneralized social anxiety disorder, whereas the
generalized subtype is characterized by multiple fears related to perform-
ance and interactions in social situations. The NCS data revealed similar
ages of onset and family histories for the two subtypes, but the generalized
subtype was associated with more chronicity, greater functional impair-
ment, and a higher risk of comorbid disorders than the nongeneralized
subtype of social anxiety disorder [181,186]. Results from a prospective
longitudinal community study of over 3000 subjects between the ages of 14
and 24 revealed that subjects with the generalized subtype had an earlier
age of onset, higher symptom persistence, greater impairment, and more
comorbidity than those with nongeneralized social anxiety disorder. In
addition, respondents with the generalized subtype were more likely to
have received psychiatric treatment and to have a parent with a history of
psychiatric disorders than respondents with nongeneralized social phobia
[183]. A number of studies suggest that the generalized subtype represents
a familial form of social anxiety disorder. For example, Stein and col-
leagues [189] conducted a direct family interview study in patients with
social anxiety disorder and found that there was a 10-fold increased risk of
generalized social anxiety disorder in first-degree relatives of probands
with generalized social phobia compared with first-degree relatives of com-
parison probands. In contrast, the risk for nongeneralized social phobia
was not significantly different between the two groups of first-degree
relatives. These results indicate that generalized social anxiety disorder
may characterize a familial form of the disorder [189]. Similar findings

were reported in an earlier study conducted in patients with social anxiety
disorder [190]. The generalized type of social anxiety disorder has a lower
chance of spontaneous recovery than the nongeneralized type. Although
the generalized subtype is more likely to receive psychiatric treatment,
both types of social phobia tend to be underdiagnosed and undertreated
[181,183].
Several studies have demonstrated that health care professionals,
especially physicians, are poor at identifying or correctly diagnosing social
anxiety disorder [191]. In a study of over 2000 primary care patients, 5%
met criteria for social anxiety disorder. In the absence of comorbid
depression, less than half (46%) of the patients meeting criteria for social
anxiety disorder were recognized as having a psychiatric disorder by the
general practitioners. Depressed social anxiety disorder patients were more
likely to be recognized by a general practitioner as having a psychiatric
illness (76%), but only 11% were correctly identified as having an anxiety
disorder [44,192]. Similar results were demonstrated in a more recent
study conducted by Stein and colleagues [42]. Patients meeting criteria for
SAD were not only common in primary care but they demonstrated
greater use of health care resources than other patients. However, less
than 20% of the patients with SAD were prescribed appropriate
psychotropic medication. Social phobia is highly comorbid with major
depression and with other anxiety disorders in the primary care setting
[42].
Comorbid mood (major depression, dysthymia), anxiety (simple phobia,
agoraphobia), and addictive disorders frequently occur in social anxiety
disorder. Data from community and clinical samples suggest a 60% to
80% lifetime risk for comorbid psychiatric conditions (see references
[10,45,176,179,182,184,186]). The NCS data indicated a strong association
between a lifetime diagnosis of SAD and an increased risk of major
depressive disorder (threefold increase), dysthymia (2.7-fold increase), and
bipolar disorder (sixfold increase). In primary care settings, SAD is
reported to be highly comorbid with major depression (50–70%), addictive
disorders, and other anxiety disorders, especially panic disorder, agora-
phobia, and GAD [42,192]. Because the onset of SAD generally precedes
that of other psychiatric disorders, there has been speculation that SAD
may predispose individuals to develop mood and addictive disorders [8]. In
addition to increasing the risk for subsequent development of mood
disorders, social anxiety has also been associated with the occurrence of
more severe and chronic mood disorders [45]. An increased risk of suicide
attempts has been reported in subjects with social anxiety disorder [112],
but this increased risk appears to be primarily attributable to the presence
of comorbid conditions [179]. SAD with comorbid disorders is associated
with greater clinical severity and increased treatment rates compared with
SAD alone [176]. Childhood behavioral inhibition is implicated as a
nonspecific risk factor for the development of an anxiety disorder in

adults. However, social anxiety disorder, in particular, is most strongly
associated with a history of behavioral inhibition during childhood [193].
Because there is considerable overlap in diagnostic criteria between avoi-
dant personality and SAD, it is not surprising that most studies indicate
that 70% and 90% of patients with generalized SAD have coexisting
avoidant personality disorder. The co-occurrence of social anxiety disorder
and avoidant personality disorder appears to convey an increased risk for
depressive disorder as well as a greater degree of functional impairment
compared with social anxiety alone [194]. Several reports suggest that
avoidant personality traits often improve or resolve with effective SAD
treatment [194,195].
The neurobiology of social anxiety disorder is poorly understood,
although preliminary research has identified evidence of several different
biological abnormalities. Challenge paradigms comparing social anxiety
disorder patients and control subjects after acute administration of carbon
dioxide, cholecystokinin, or caffeine have detected evidence of enhanced
sensitivity and potential cardiovascular and adrenergic abnormalities in the
patients with social anxiety disorder. Serotonergic dysfunction is implicated
by pharmacological challenge results as well as the efficacy of the SSRI
antidepressants in the treatment of social anxiety disorder [196–198].
Patients with social anxiety disorder administered serotonergic probes
demonstrate evidence of altered neuroendocrine and behavioral responses
compared with control subjects. Functional neuroimaging studies reveal
evidence of altered dopaminergic function in patients with social anxiety.
In particular, a significant reduction in striatal dopamine reuptake has
been detected in social anxiety disorder patients versus control subjects
[196].
Results from bivariate female twin studies suggest that social phobia
results from the combined effect of a slightly stronger genetic influence and
nonspecific environmental experiences [51]. Data derived from family
studies also provide support for the importance of genetic factors in the
development of generalized SAD (see references [51,55,56,140,181]). As
previously noted, patients with generalized SAD are 10 times more likely to
have relatives with SAD than control subjects. Results from the Stein and
colleagues study [189] also imparted strong support for the validity of
separating SAD into generalized versus nongeneralized groups for research
purposes. Data derived during the same study failed to support the role of
genetic or familial effects as primary factors in the transmission of the
nongeneralized form of SAD [189]. Data from family and twin studies also
reveal that SAD and depression share a number of etiologic factors that
may help to explain the substantial comorbidity between SAD and
depression. In contrast, genetic and familial data do not provide support
for shared genetic or familial factors in the association between SAD and
alcoholism [176].
A number of pharmacological treatments, including the MAOIs,

reversible inhibitors of MAO-A, beta blockers, high-potency benzodiaze-
pines, and the SSRIs have all demonstrated efficacy in the treatment of
social anxiety disorder [197–201]. In the largest multicenter, placebo-
controlled trial reported to date, paroxetine was more effective than placebo
in moderate and severe social anxiety disorder [200]. Pooled data from three
multicenter, placebo-controlled trials of paroxetine in SAD revealed that
there was no difference in treatment response in the patients with
generalized versus nongeneralized SAD. That is, paroxetine was effective
in both types of SAD [201]. Based on the International Consensus Treatment
Guidelines, SSRI antidepressants are considered first-line therapy for social
anxiety disorder. These guidelines also advocate long-term (greater than 12
months) treatment for patients with generalized social anxiety disorder that
have (a) persistent symptoms despite treatment; (b) a comorbid psychiatric
condition; (c) a history of relapse after treatment discontinuation; or (d)
a early onset of social anxiety disorder [197]. However, little information is
available concerning the potential impact of gender on treatment response
in social anxiety disorder.
Women and social anxiety disorder

Evidence of significant gender differences has been reported in patients
with SAD. Women’s risk for SAD (15.5%) is slightly higher than that of
men (11.1%). Despite this finding, there have been few studies that have
specifically examined the potential impact of gender on the presentation or
course of SAD. Turk and colleagues [202] investigated potential gender
differences in a clinical sample of patients with SAD. According to their
report, women had greater SAD symptom severity than men. Some
significant differences in SAD phenomenology were also identified. The
women with SAD reported more severe phobic anxiety than the men with
SAD in a wide range of social activities, including talking to authority
figures, acting/performing/speaking/working in front of others or while
being observed, being the center of attention, expressing disagreement or
disapproval to unfamiliar people, and hosting parties. The women were also
more likely to cite attending a party as one of their social anxiety-related
fears. The only social anxiety-related fears identified as more common in
men than in women were urinating in public bathrooms and returning goods
to a store. No evidence of gender differences in the prevalence of the
generalized versus nongeneralized type of SAD, the occurrence of comorbid
disorders, or in the clinical course of SAD were identified in the study [202].
However, several other studies have reported that women with SAD have an
increased risk for agoraphobia compared with men with SAD [174,192,203].
An examination of alcoholics with concurrent SAD who were enrolled in an
alcohol treatment study (n = 110) revealed that women had elevated rates
of comorbid psychiatric disorders than the men. Moreover, the women

reported more distress related to family and social functioning then the
males in the study [204].
A recent report used the NCS data to explore the potential association
between the onset of phobias and the occurrence of adverse experiences
during childhood. The onset of SAD was found to be associated with the
occurrence of two adverse experiences during childhood: sexual assault by
a relative and chronic exposure to verbal outbursts between parents. No
significant correlations were identified between the onset of SAD and
adverse experiences in men [205]. As previously noted, data from bivariate
female twin studies provide support for the importance of genetic and to
lesser extent, environmental experiences, in the development of SAD [51].
Little has been reported about the impact of gender on treatment in SAD.
There is some evidence that men are more likely than women to seek
treatment for SAD [206]. Reich and colleagues [207] examined potential
predictors of clinical course in SAD patients participating in the HARP
study. At 65 weeks of follow-up, there was no evidence of gender differences
in the clinical course or outcome of the patients with SAD [207]. In a more
recent analysis of the HARP data, Yonkers and colleagues [208] compared
the clinical course and characteristics of the SAD patients (n = 176) after
8 years of observation. Only 38% of the women and 32% of the men
experienced a complete remission during the 8-year study; there was no
gender difference in remission rates detected. Although a larger proportion
of the women than the men had generalized SAD, the difference was not
significantly different. The women with SAD were more likely to have
concurrent agoraphobia, and the men with SAD were more likely to have
comorbid substance use disorders. The women with SAD, poor baseline
functioning, and history of suicide attempts had a more chronic course for
SAD than men with SAD who had the same characteristics. Women with
SAD were more impaired in household functioning than men with SAD
[208]. In a pooled analysis of data from the three multicenter, placebo-
controlled paroxetine trials in SAD, women were found to have a sig-
nificantly greater prevalence of generalized SAD than men. There was no
evidence of a gender difference in response rates reported from the
paroxetine trial data [201]. Information about the impact of female
reproductive cycle events on SAD is currently absent.
These results suggest that women are more likely than men to meet
lifetime criteria for SAD. Women with SAD appear to have a greater
number of social anxiety-related fears and perhaps greater overall symptom
severity than men with SAD. Women with SAD also have an increased risk
of comorbid agoraphobia. Most evidence suggests that women are more
likely than men to have the generalized type of SAD. Because the
generalized form of SAD is associated with increased symptom severity,
a more chronic course, and greater functional impairment, further
investigations that focus on gender differences in SAD are warranted.
Obsessive-compulsive disorder (OCD)

Results from the ECA study and the Cross-National OCD Collaborative
Group Study estimate that the lifetime prevalence rate for OCD is between
2% and 3% worldwide. These large-scale population surveys also dem-
onstrate that women are one and a half times more likely than men to meet
lifetime criteria for OCD [11,209]. The onset of OCD is early—usually
during adolescence or young adulthood. Peak ages of onset appear to be
from 10 to 19, closely followed by the ages of 20 and 29 [210]. The most
common obsessive symptoms relate to aggression, contamination, sym-
metry, saving/collecting, sexual impulses, or religious matters. The most
common compulsive rituals include checking, cleaning, counting, ordering,
and hoarding rituals [211–214]. Results from population surveys indicate
that many respondents meeting criteria for OCD experience only obsessions,
whereas some only manifest compulsive behaviors. Even when obsessions
and compulsions are present, their relative predominance appears to vary
across different geographic regions (see references [11,209,210,215]). In
contrast, OCD patients from clinical samples are more likely to endorse
multiple obsessions and compulsions. Given the wide range of symptoms
present, numerous investigators have proposed various classification
schemes for OCD in the hopes of identifying distinct subgroups that may
share similar clinical courses, prognosis, or treatment response. The primary
symptom classifications most commonly proposed as distinct subgroups
within OCD include symmetry/ordering, contamination/cleaning, obses-
sions/checking, and hoarding [212,216,217]. Another proposed classification
scheme suggests that core dimensions, such as abnormal risk assessment or
incompleteness may be useful in identifying homogeneous OCD subgroups
with distinct treatment responses [218]. Unfortunately, there has yet to be
any significant relationship demonstrated between the various symptom-
based classification schemes and treatment response in OCD.
Historically, most studies have indicated that OCD symptoms tend to
change over time within an individual patient [211,213,214,218]. However,
results from a recent investigation suggest that OCD symptoms may be
more stable than previously surmised; that is, any alterations detected in
OCD symptom presentations over time tend to reflect subtle changes within,
rather than between, the primary OCD symptom constellations [219]. The
majority of OCD patients appear to have a chronic clinical course. An
episodic clinical course may occur in a small subgroup of OCD patients
[211,220–222]. The episodic clinical course was associated with lower rates
of checking rituals and an increased risk of relatives with mood disorders in
one study [220]. Sustained remissions in OCD are fairly rare [27,47,223].
Two long-term, prospective studies have generated remarkably similar
results concerning remission rates in OCD [224]. In a 5-year prospective
study (n = 110), only 20% of the OCD patients achieved full remission in
their symptoms, although 50% were considered to have at least a partial
remission. Partial remission was associated with being married and having
a lower baseline global OCD severity score, whereas coexisting major
depression was marginally predictive of poorer outcome in the OCD
patients during the study [222]. Results from a 2-year prospective study of
OCD patients (n = 66) yielded similar results. Over the 2-year period of
observation, 12% attained full remission and 47% were considered to have
at least a partial remission. The probability of relapse after remission was
high at 48%. No specific factors were associated with remission or outcome
during the second study [224].
The vast majority (60–70%) of patients with OCD experience severe
impairments in psychosocial and occupational functioning [21,27,223]. A
diagnosis of OCD is also associated with elevated use rates for medical and
mental health services [27,35,223]. The economic burden associated with
OCD is estimated at $8 billion per year in the United States [225]. Much of
this cost is attributable to poor recognition rates and substantial treatment
delays for patients with OCD. Results from the largest nationwide survey of
OCD sufferers conducted by Hollander and colleagues [27] revealed an
average 17-year delay between the onset of OCD symptoms (mean age 14.5)
and the initiation of appropriate treatment interventions (mean age 31.5).
The majority of the OCD survey respondents felt that their illness had
directly resulted in impaired academic achievement (58%), lowered career
aspirations (66%), and disrupted family relationships (73%). In addition,
13% of the respondents reported a history of suicide attempts [27].
OCD is characterized by an increased lifetime risk for several psychiatric
disorders, including major depressive disorder (60–80%) [214], additional
anxiety disorder diagnoses (30–50%), (see references [211,218,226,227]),
eating disorders (10–20%) (see references [213,214,218,228–230]), and
Tourette’s disorder (8–15%) [214,231–233]. A lifetime diagnosis of OCD
is also associated with an increased likelihood of substance abuse, schizo-
phrenia, body dysmorphic disorder, hypochondriasis, and personality dis-
orders (see references [11,209–211,213,214,218,222,223,226,227,230,234]).
OCD may also be associated with an increased risk of bipolar disorder.
Perugi and colleagues conducted two studies examining the relationship
between OCD and bipolar disorder [220,235]. In the first study of over 300
patients with OCD, the lifetime risk for bipolar disorder was 16%. The
OCD patients with lifetime bipolar disorder reported a more gradual onset
and more episodic course for OCD. They were also more likely to endorse
obsessions with sexual and religious content than the patients with OCD
alone [220]. In the second study, 58% of patients with OCD and a coexisting
depression (n = 68) met lifetime criteria for bipolar disorder [235]. Data
from the ECA study also provides support for an increased lifetime risk of
OCD in bipolar subjects [236].
Serotonin dysregulation has long been considered the primary neuro-
biological abnormality mediating OCD symptom development [237].
Much of this assumption has been based on the consistent finding that
antidepressants with potent serotonin-reuptake inhibiting (SRI) effects

have preferential efficacy in the treatment of OCD [238,239]. Moreover,
antidepressants with nonselective serotonergic or primary noradrenergic
actions appear to lack efficacy in OCD. Various pharmacological challenge
paradigms conducted in OCD patients have also failed to detect evidence of
altered noradrenergic function compared with control subjects. In contrast,
challenge studies conducted with serotonergic (5-HT) probes have revealed
evidence of altered behavioral or neuroendocrine responses in OCD patients
compared with control subjects [238,240–242]. Yet, though most of the
results from 5-HT pharmacological probes have detected evidence of altered
5-HT function in OCD, the neuroendocrine or behavioral abnormalities
identified have been highly variable and inconsistent across the various
studies [240,243]. The neurobiological studies coupled with the finding that
a substantial minority of OCD patients fail to benefit from SRI therapy has
led to increasing interest in pathophysiological mechanisms beyond
serotonergic systems. The growing support for the efficacy of dopamine
antagonists as adjuvant agents in the treatment of refractory OCD patients
has resulted in renewed interest in the role of dopaminergic dysfunction in
OCD [244,245]. In addition, the extensive preclinical literature implicating
neuropeptide influences on memory, stereotypic behaviors, and grooming
behaviors has also resulted in considerable focus on the potential role of
neuropeptide function in OCD [232]. Dopaminergic and neuropeptide
mechanisms may be particularly important in early onset OCD that is
associated with male gender and an elevated risk of comorbid tic disorder
[231].
Twin and family studies have provided evidence that OCD has
a significant genetic component [246,247]. Recent investigations using
genetic association techniques in OCD have focused on attractive candidate
genes in the serotonin (5-HT) and dopaminergic (D) pathways. OCD has
been associated with polymorphic variants of the D4 receptor in some
studies [248,249] but not in others [250,251]. Mixed results have also been
reported concerning the transmission of alleles associated with poly-
morphisms in the 5-HT1Dbeta receptor gene [251–253], the 5-HT2A
receptor gene [254], and the promoter region of the 5-HT transporter gene
(5-HTTLPR) [255]. OCD has also been associated with a polymorphism in
the coding region for the catachol-O-methyltransferase (COMT) gene [256]
and a polymorphism related to variations in MAO-A activity [257]. The
extensive range of findings concerning potential genetic markers in OCD
may well reflect our inability to differentiate biologically distinct subtypes
within OCD.
The SRIs (SSRI antidepressants and the TCA, clomipramine) remain the
cornerstone of the pharmacological treatment for OCD [239,258–263].
Although these medications effectively reduce OCD symptoms, the average
improvement is fairly modest (30–40%). There is a significant delay in the
onset of therapeutic effects in OCD, so the minimum duration of an SRI
trial is 10 to 12 weeks. Recommended SRI doses in OCD (fluoxetine: 60–80

mg/day; sertraline: 150–200 mg/day; fluvoxamine: 150–300 mg/day;
paroxetine: 40–60 mg/day; citalopram, 40–60 mg/day) are generally robust
compared with those commonly used for antidepressant treatment
[239,243]. Analysis of data from clomipramine multicenter trials revealed
that the presence of certain early side effects and a later age of onset for
OCD were the only factors at baseline that were strong predictors of
subsequent response to clomipramine [264,265]. A similar analysis of the
multicenter fluoxetine trials in OCD revealed that response rates and overall
improvement were greatest for patients with histories of remission, lack of
previous drug treatment, and more severe OCD [265,266]. Nonresponse to
either clomipramine or fluoxetine treatment has also been linked to the
presence of (a) concomitant schizotypal personality disorder; (b) prominent
compulsions; and (c) a longer illness length [267].
Despite the substantial risk for lifetime comorbid psychiatric disorders in
OCD, there is little information concerning the potential impact of
comorbid conditions on outcome and treatment response in OCD. Some
studies have linked the presence of depression in OCD with poorer
treatment response than OCD alone [268], but other investigations have
failed to demonstrate any significant association between comorbid mood
and anxiety disorders and treatment response or prognosis of OCD [269]. A
recent report suggested that patients with OCD and comorbid PTSD may
have a poorer response to behavioral or pharmacological treatment
interventions [270]. In addition, the presence of social anxiety disorder in
patients with OCD was associated with a poor response to SSRI
antidepressants in one report [271]. OCD patients with comorbid bipolar
disorder were more likely to have a poor outcome and to be receiving
multiple psychotropic medications than the OCD patients with unipolar
depression in the second study conducted by Perugi and colleagues [235].
There is also some evidence that patients with OCD and comorbid tic
disorder may have a more severe clinical course and a poorer treatment
response than patients with OCD alone [233,272,273]. Initial reports
suggested that OCD patients with comorbid chronic tic disorder were more
likely to benefit from a combined regimen of an SSRI antidepressant and
a neuroleptic augmentation than patients with OCD alone [274]. However,
in a subsequent double-blind placebo-controlled study of risperidone
addition in SSRI-refractory patients (n = 36), there was no evidence of
difference in treatment response rates between the OCD patients with
chronic tic disorder and those without tic disorder [244].
Women and OCD

In addition to the consistent finding that women have a greater lifetime
prevalence rate for OCD than men, a number of other gender differences
have been identified in OCD. Most evidence suggests that men (mean age,
20 years) have a significantly earlier onset of OCD than women (mean age,
25 years). Women are also much less likely than men to develop OCD
during childhood. Onset of OCD before the age of 10 is associated with
male gender, tic disorder, and a positive family history [272]. After
menarche, females begin to develop OCD at a much greater rate than
males; the robust increase in prevalence rates for OCD in females eventually
results in the previously mentioned overall increased prevalence rate for
OCD in women [11,209,275]. There is also some evidence that the course
of OCD may be more episodic and less severe in women [221,275].
Women with OCD may also have a more acute onset of OCD [275]. Al-
though women were more likely than men to report a stressful event in the
year preceding onset of OCD in one report [275], a more recent study did
not replicate this finding [276]. At the time of OCD onset, women are more
likely to endorse excessive worries related to aggression than men with
OCD.
Cleaning compulsions are particularly common in women with OCD
[229,277,278]. Several reports indicate that OCD in women is associated
with being married and having children [277,278]. In adolescents with OCD,
female gender is associated with compulsive rituals, whereas males are more
likely to endorse obsessive thoughts [279]. Gender differences have also
been identified in the comorbid conditions that occur in OCD. The lifetime
risk of depression is higher in women than in men with OCD [229]. Co-
morbid panic disorder is also more likely to occur in women with OCD,
whereas bipolar disorder is more common in men with OCD [277]. The
lifetime risk for anorexia nervosa and bulimia nervosa are also reported to
be significantly higher in women than in men with OCD in most studies (see
references [218,228,275,278]). However, in a study of 62 patients with OCD
(31 women and 31 men), Rubenstein and colleagues failed to detect a
significant gender difference in prevalence rates, despite finding sub-
stantial lifetime rates of anorexia nervosa (13% men versus 6.5% women)
and bulimia nervosa (3.2% men versus 6.5% women) in patients with
OCD [230].
Gender differences may also exist in response to serotonergic probes
during challenge studies conducted in patients with OCD. Women with
OCD administered the serotonergic probe fenfluramine have an attenuated
cortisol response compared with men with OCD and control subjects
[280]. Gender differences in responses to acute intravenous clomipramine
challenge in OCD have also been reported. After administration of clomipr-
amine as a serotonergic probe, men with OCD experienced acute exacerba-
tions in OCD symptoms, whereas women with OCD failed to demonstrate
any substantial change in OCD symptoms during the same study [281].
After 10 weeks of treatment with either clomipramine or fluvoxamine,
the women with OCD also exhibited a better anti-obsessional response.
The gender difference detected in anti-obsessional response was more pro-
nounced after clomipramine than fluvoxamine treatment [281]. These

findings provide support for the importance of serotonergic mechanisms
in OCD, especially in women. In addition, women with OCD appear to have
a higher lifetime risk of comorbid disorders linked to serotonin dysregu-
lation, including depression, panic disorder, PTSD, and eating disorders. In
contrast, male gender is associated with early onset OCD and comorbid tic
disorder [231,272], indicating that dopaminergic mechanisms may play an
important role in at least a subset of men with OCD.
Results from a number of studies have confirmed that OCD has a strong
genetic component, although the precise mechanism of inheritance remains
unclear. Polymorphic variants have been identified in two genes that
modulate monoamine metabolism: catachol-O-methyltransferase (COMT)
and monoamine-oxidase-A (MAO-A). Four genetic studies have reported
that polymorphic variations in the COMT gene occur more commonly than
expected in patients with OCD [256,282–284]. In addition, two of the studies
suggested that the association between OCD and variations in the COMT
gene were gender related, although one found a higher occurrence of the
genetic variation in women with OCD [256] and the other in men with OCD
[282]. A sexually dimorphic association has also been reported between
OCD and polymorphic variants related to MAO-A activity. Women with
OCD exhibited an excess of allele 1 polymorphism in the MAO-A gene
compared with control subjects [257,285]. An association between OCD and
an allele of the MAO-A gene that is linked to high MAO-A activity has also
been reported, especially in male OCD probands with comorbid depression
[282]. Although these findings require further replication, they suggest that
potential gender differences may exist in the genetic susceptibility for OCD.
Data derived from the multicenter, placebo-controlled OCD treatment trials
with clomipramine and fluoxetine, respectively, have been reexamined for
potential gender differences in treatment response in several reports.
However, no evidence of gender differences in medication response have
been identified in these analyses [264,266].
OCD and female reproductive cycle events

The marked increase in OCD prevalence after menarche, as well as
evidence suggesting a more acute onset and a more episodic course for
women with OCD, suggests that OCD may be substantially influenced by
the female reproductive cycle. Several reports have examined the potential
relationship between the menstrual cycle and OCD symptom severity.
Undergraduate women without demonstrable OCD are reported to engage
in more OCD-like behaviors, such as ‘‘excessive cleaning or cleaning of
things not usually cleaned’’ during the luteal phase than at any other time
during the menstrual cycle [286]. In women with OCD, the premenstrual
(late luteal) phase has been linked to acute OCD symptom exacerbations
[287,288]. In the largest study to date, the relationship between menstrual

cycle phase and OCD symptom severity was retrospectively examined in 57
women with OCD. Nearly half (42%) of the women reported premenstrual
worsening in their OCD symptoms, and a substantial number (21%) also
reported premenstrual dysphoria [288].
Several case series suggest that a substantial portion (13–36%) of women
with OCD report the onset of their illness during pregnancy or the
postpartum period [157,288–292]. A number of reports also indicate that
women with preexisting OCD will experience a worsening in symptomatol-
ogy during pregnancy [288–291,293]. Williams and colleagues have reported
the largest study to date (n = 57) concerning the course of OCD during
pregnancy, the postpartum period, and the premenstrual cycle [288]. Their
findings revealed that 69% of the women with preexisting OCD did not
experience a significant change in their symptoms during pregnancy. In the
remaining patients with OCD, 17% reported a significant worsening and
14% reported improvement in their OCD symptoms during pregnancy.
Pregnancy was associated with the onset of OCD in 13% of the patients.
Postpartum worsening in OCD symptoms occurred in 29% of the women
with preexisting OCD. Postpartum depression was even a more common
finding (37%) in the women with OCD [288]. A postpartum worsening in
OCD symptoms has been consistently reported across several studies with
estimates suggesting a 20% to 30% risk (see references [157,288,289,292]).
Miscarriage has also been identified as a substantial risk factor for the onset
or recurrence of OCD. In the largest report (n = 223) to date, the relative
risk of OCD was eight times greater than the control subjects in the 6
months following miscarriage [164]. These results provide strong evidence
that female reproductive hormone cycles substantially influence the oc-
currence, severity, course, and outcome in OCD. Although pregnancy is
not associated with substantial symptom change in most women with
preexisting OCD, the postpartum period is associated with an increased risk
of onset or exacerbation in OCD.
Posttraumatic stress disorder (PTSD)

Although many individuals are exposed to trauma, only one of four will
develop PTSD [10,294,295]. Population surveys have consistently demon-
strated a twofold greater lifetime prevalence rate for PTSD in women
(12.5%) than men (6.2%) [10,295]. Respondents meeting criteria for PTSD
in the ECA study had significantly greater job instability, family history of
psychiatric illness, parental poverty, child abuse, and separation or divorce
of parents before age 10 [22]. PTSD can occur at any age, but certain
traumatic events are associated with an especially high risk of subsequent
PTSD development. The most common cause of PTSD in men is combat
exposure. Women are most likely to develop PTSD as a consequence of
sexual assault, sexual molestation, or childhood physical abuse [295]. Foa

reported that 95% of rape victims and 75% of victims of nonsexual assaults
develop PTSD symptoms within 2 weeks of the traumatic event [296]. There
is also evidence that sudden unexpected death of a loved one may also
represent one of the most common causes of PTSD in the community [65].
Results from an epidemiological cohort study of victims trapped in
a ballroom fire (n = 127) suggests that multiple factors are likely to be
important in determining subsequent risk for PTSD. For example, an
increased risk of PTSD was associated with female gender, the number of
previous traumas, a past history of simple phobia, threatened death, trauma
exposure, hospitalization for trauma-induced injuries, and the presence of
burns. However, alcohol consumption and intoxication as well as a sense of
control during the trauma were associated with a reduced risk of PTSD.
These results confirm that the development of PTSD is determined by the
effects of factors that are preexisting (eg, gender) as well as factors that are
peritrauma (eg, alcohol consumption), and posttrauma (eg, trauma-related
injuries/hospitalization) exposure related. These results also suggest that
certain peritraumatic factors, such as sense of control, alcohol consumption,
and intoxication may prevent PTSD [297].
Although exposure to life-threatening traumatic events is fairly common,
a number of studies confirm that PTSD is poorly recognized in various
clinical settings. Unfortunately, delayed recognition of PTSD can have
catastrophic consequences. A diagnosis of PTSD is associated with marital,
occupational, and financial difficulties [298,299]. The work impairment
associated with PTSD is similar to that associated with major depression
[299]. A diagnosis of PTSD has also been linked to an increased risk of
chronic medical disorders, including bronchial asthma, hypertension, and
peptic ulcer [22]. Though a diagnosis of PTSD is associated with
disproportionate use of the health care system, few patients with PTSD
seek or receive mental health treatment [299]. This finding is particularly
troubling because PTSD has also been linked to a greater risk of psychiatric
comorbidity and elevated rates of suicide attempts [22]. Comorbid
psychiatric conditions are common in PTSD, with most estimates suggesting
a 70% to 80% lifetime risk. Mood and substance use disorders are
particularly common in PTSD (see references [10,68,295,296]). According to
the NCS, respondents meeting criteria for PTSD were twice as likely to have
comorbid alcohol and substance abuse as respondents without PTSD
[67,68,295]. For at least a third of sufferers, PTSD is a persistent condition
lasting many years [298]. Avoidance symptoms and social anxiety disorder
were reported to occur more frequently in chronic than in acute PTSD in the
ECA study [22].
Accumulating evidence suggests that intense psychological trauma can
cause long-standing alterations in the neurobiological response to stress.
Most evidence suggests that the pathophysiology of PTSD is multi-
factorial, but likely involves dysregulation of the glutamatergic, monoamine
neurotransmitter (noradrenergic and serotonergic), and neuroendocrine

pathways [300]. There is some evidence that the development of PTSD may
be facilitated by an atypical biological response in the immediate aftermath
of severe trauma exposure that may then predispose the individual to
develop sustained neurobiological abnormalities and a maladaptive psy-
chological state. PTSD has also been associated with brain structural as well
as functional abnormalities [299]. The development of PTSD may be
facilitated by an atypical biological response in the immediate aftermath of
a traumatic event, which in turn leads to a maladaptive psychological state
[301]. Cumulative evidence indicates that the SSRI antidepressants
constitute first-line pharmacotherapy for PTSD [302,303]. TCA and MAOI
antidepressants are also effective for PTSD and should be considered for
patients with PTSD who fail to respond to SSRI treatment [299,304]. The
SSRI antidepressants appear to have a broad spectrum of activity in PTSD.
Common PTSD symptoms, such as anxiety, insomnia, and an exaggerated
startle response, are reported to improve during SSRI treatment. Moreover,
SSRI treatment may also ameliorate PTSD symptoms, such as intrusive
trauma-related recollections, feelings of emotional numbing, and avoidance
behaviors [304]. Pharmacotherapy for PTSD should be initiated at a low
dose and maintained for at least 12 months before discontinuation is
considered [302].
Women and PTSD

The gender difference in prevalence rate for PTSD has been linked to
a differential rate of exposure to trauma. However, this assumption appears
to be incorrect. In a sample of over 1000 young adults, Breslau and col-
leagues found similar rates of exposure to traumatic events, but sub-
stantially more women than men met criteria for PTSD [67,68]. Potential
confounding factors, such as the increased prevalence of preexisting anxiety
or major depressive disorders in women, were examined but failed to
account for the observed gender difference noted in the prevalence of
PTSD. Instead, women appeared to have a markedly increased susceptibility
for PTSD development, especially if the trauma occurred before age 15 (see
references [10,64,66,67,295]). Results from the National Comorbidity
Survey also implicate multiple factors in the elevated risk of PTSD in
women [305]. However, there was substantial overlap between factors that
predicted an increased risk for trauma exposure and development of PTSD.
Once the overlapping risk factors are excluded, only one risk factor (history
of affective disorder) predicted PTSD in women, whereas two factors
(history of anxiety disorder and parental mental disorder) were associated
with an increased risk of PTSD in men [305]. These findings suggest that
most variables identified as predictive of PTSD are actually more indicative
of trauma exposure than PTSD.
Major depression and generalized anxiety disorder are common

comorbid disorders in PTSD regardless of gender, whereas coexisting
somatoform pain disorder is more common only in women with PTSD. The
presence of certain comorbid conditions may also increase the risk for
subsequent development of PTSD. Preexisting depression appears to convey
an increased risk for subsequent exposure to traumatic events as well as the
development of PTSD once trauma occurs [67,68]. The development of
conduct disorder may also increase the risk for PTSD, particularly in girls,
by exposing youth to situations in which they are traumatized [306]. Women
who are victims of sexual assault have an extremely high risk of subsequent
development of PTSD. For example, 3 months after the trauma, female rape
victims were found to be twice as likely as women victimized by nonsexual
crimes (48% versus 25%) to have PTSD [296]. Women may be particularly
susceptible to the long-term complications of abuse that occurs during
childhood. Women with histories of childhood abuse are reported to have
a level of functional impairment that is commensurate with that of women
with recent abuse [307]. Women victimized by domestic violence are more
likely to develop anxiety symptoms as well as PTSD, whereas male victims
of domestic violence are at greater risk of developing substance use
disorders. An elevated risk of depression and an increased number of
physical and psychological health problems have also been reported in
women exposed to ongoing domestic violence. This finding appears to be
independent of the severity of domestic violence or the presence of injuries
sustained. That is, women who sustain severe injuries do not appear more
likely to develop psychiatric symptoms or PTSD [58]. Though this finding
may seem counterintuitive, it likely reflects the importance of ‘‘perceived
threat’’ in the formation of PTSD. That is, a victim’s perception of danger
or possibility of death during an assault or exposure to trauma may be more
important subsequent risk for PTSD as compared with more objective or
realistic assessments of life-threatening events. These findings suggest that
sexual assault, childhood abuse, and individual assessment of threat during
the occurrence of trauma may represent the strongest predictors of
subsequent PTSD development in women. These findings suggest that
sexual assault and childhood sexual abuse represent significant risk factors
for the development of PTSD in women. They also confirm that childhood
abuse has particularly devastating complications that are likely to persist
into adulthood in women. Certain factors appear to substantially increase
the risk of development of PTSD and other complications in women. These
factors include (a) exposure to sexually related trauma or aggression; (b)
occurrence of abuse or severe trauma during childhood or before the age of
15; and (c) perception within the victim that the traumatic event is life-
threatening or that escape is unlikely.
Several recent studies have provided further information about the
potential relationship between traumas related to assault and PTSD in
women. A community survey conducted in the Detroit area found that the
twofold increase in PTSD in women was due primarily to their greater risk
of developing PTSD following assaultive violence in general. Women were
much more likely to experience avoidance and numbing symptoms in
response to assaultive violence than men [69]. Data from a community
survey conducted in Canada also reported that women were at a significantly
increased risk for PTSD following nonsexual assaultive violence (eg,
mugging) but not following nonassaultive trauma (eg, fire) [308]. Fullerton
and colleagues [309] examined the potential relationship between various
factors (previous trauma, PTSD, major depression, anxiety disorder besides
PTSD, passenger injury, and peritraumatic dissociation) and subsequent
occurrence of acute PTSD in women and men after a serious motor vehicle
accident (n = 121). Women did not differ from men in meeting the overall
reexperiencing criterion for a diagnosis of PTSD, but women were nearly
five times as likely to meet the overall avoidance/numbing criterion and
almost four times as likely to meet the overall arousal criterion for PTSD.
The gender differences noted in acute PTSD were not associated with
previous trauma, PTSD, peritraumatic dissociation, major depression, or
anxiety disorder not including PTSD or with passenger injury. However,
dissociative symptoms at the time of the accident were associated with
a significantly higher risk for acute PTSD in women than in men. Gender
differences in peritraumatic dissociation may help explain differences in risk
for PTSD and for some PTSD symptoms in women and men [309].
There have been few reports concerning the effects of combat-related
exposure on women. Although women are more likely to be diagnosed with
PTSD than men, male military veterans are diagnosed with PTSD at a much
greater rate than female military veterans. This finding is generally
attributed to higher rates of combat exposure in male than female veterans.
However, results from a recent study suggest that this may not be correct.
In a retrospective chart review of military veterans (n = 110), Pereira [310]
found that veterans exposed to higher levels of combat related stress were
more likely to have increased PTSD symptomatology. However, there was
no evidence of gender differences in the relationship demonstrated between
combat-related stress and PTSD. That is, male and female veterans exposed
to similar levels of combat-related stress were equally likely to have PTSD
symptoms. These results suggest that female veterans are underdiagnosed
with combat-related PTSD. Elevated rates of chronic medical illness may be
one of the many adverse consequences that arise from failing to identify and
diagnose PTSD in women military veterans. Kimerling and colleagues [310]
examined the relationship between traumatic exposure, specific PTSD
symptoms, and subsequent reports of health problems in female Vietnam
War-era veterans (n = 52). There was a significant relationship detected
between PTSD symptoms and reported health problems in the women with
previous trauma exposure. In particular, the presence of the PTSD symptom
cluster of hyperarousal was most strongly associated with increased health
complaints [311]. These results suggest that although women have a similar
risk for PTSD after combat-related trauma exposure, they are less likely to
receive a PTSD diagnosis than men. This may have particularly serious
implications because persistent PTSD symptoms, particularly hyperarousal,
may result in elevated rates of chronic health problems in female military
veterans.
Gender differences have also been identified in the biological alterations
associated with PTSD. An elevated norepinephrine-to-cortisol ratio has been
reported in men with PTSD, whereas women with PTSD have demonstrated
significantly elevated levels of urinary norepinephrine, epinephrine, dopa-
mine, and cortisol on a daily basis [312]. The HPA axis has strong, multilevel
inhibitory effects on the women reproductive hormones [313]. Because HPA
axis alterations are implicated in PTSD, the marked fluctuations in estrogen
and progesterone levels that characterize the women reproductive cycle may
have a significant impact on the course of PTSD. The relative hyper-
cortisolism that occurs during the third trimester of pregnancy is speculated
to cause a transient suppression of the adrenals during the postpartum
period [313]. This finding suggests that women with preexisting PTSD may
experience substantial changes in symptomatology during pregnancy or the
postpartum period. Unfortunately, little systematic information is available
concerning the potential impact of the reproductive cycle in women with
preexisting PTSD. Seng and colleagues (2001) [314] investigated the potential
relationship between PTSD and specific pregnancy complications using
Michigan Medicaid claims data from 1994 to 1996. Pregnancy complication
rates were compared in the women coded with a PTSD diagnosis (n = 2200)
and a comparison group of women who were not coded with any psychiatric
diagnoses. The women with PTSD were found to have significantly higher
odds ratios for ectopic pregnancy, spontaneous abortion, hyperemesis,
preterm contractions, and excessive fetal growth than the comparison group
of women. These results suggest that women with PTSD have an increased
risk for certain pregnancy complications. There is also evidence that women
who experience increased symptoms of psychosocial stress after exposure to
a natural disaster (flood) may also have a subsequent increased risk of
pregnancy loss and perinatal complications [315].
Multicenter, placebo-controlled trials of sertraline [316,317], fluoxetine
[318,319], and paroxetine [320], respectively, have demonstrated significant
efficacy in the treatment of OCD. However, there is some evidence of
a gender difference in treatment response in PTSD. In a small sample of
male combat veterans with severe, chronic PTSD (n = 12), patients given
fluoxetine did exhibit a greater response than those given a placebo [321].
There was also some suggestion of a potential gender difference in the
multicenter trials conducted in PTSD patients with sertraline in that women
appeared to have a significantly greater degree of PTSD symptom reduction
than men [316]. Sertraline [316] and fluoxetine [318], respectively, appeared
to have greater efficacy on symptoms of avoidance/numbing and
hyperarousal during the multicenter trials compared with the reexperiencing
cluster of PTSD symptoms. This differential effect on PTSD symptom

clusters may account for the gender effect detected during the trials. There
was no evidence of gender differences or differential response of PTSD
symptom clusters reported in the multicenter, placebo-controlled PTSD trial
of paroxetine [320]. Several studies conducted in PTSD suggest that
potential gender differences in response may exist, so further investigations
appear warranted.
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Anxiety Disorders in Women

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Psychiatr Clin N Am 26 (2003) 621–672

Anxiety disorders in women

Data obtained from large-scale epidemiological studies of psychiatric

E-mail address: [email protected]ﬂ.edu

the early onset and elevated occurrence of anxiety disorders in women

adverse consequences that arise from childhood abuse. Breslau and

Generalized anxiety disorder (GAD)

course (see references [71,73,79,83,84]). Remission rates appear to be low in

Women and GAD

of symptoms or diagnosis. The gender diﬀerence was continued in repeat

GAD and the female reproductive cycle

Panic disorder and agoraphobia

months [107]. At 1 year of follow-up, 40% of the panic patients in the

patients were considered to be receiving optimal pharmacological treatment;

Women and panic disorder

men to eschew transportation by bus and to avoid unfamiliar places when

Panic disorder and the female reproductive cycle

to demonstrate evidence of menstrual cycle phase (follicular versus luteal)

biological eﬀects may convey an anxiolytic action [156,158,159]. Proges-

of improvement (60–70%) in panic symptomatology. However, buspirone

panic disorder. However, the potential contribution of diﬀerential

Women and simple phobia

Social anxiety disorder (SAD)

appears to be the most common form of social anxiety disorder. Anxiety

may characterize a familial form of the disorder [189]. Similar ﬁndings

nonspeciﬁc risk factor for the development of an anxiety disorder in

A number of pharmacological treatments, including the MAOIs,

Women and social anxiety disorder

of comorbid psychiatric disorders than the men. Moreover, the women

Obsessive-compulsive disorder (OCD)

antidepressants with potent serotonin-reuptake inhibiting (SRI) eﬀects

trial is 10 to 12 weeks. Recommended SRI doses in OCD (ﬂuoxetine: 60–80

Women and OCD

nounced after clomipramine than ﬂuvoxamine treatment [281]. These

OCD and female reproductive cycle events

[287,288]. In the largest study to date, the relationship between menstrual

Posttraumatic stress disorder (PTSD)

sexual assault, sexual molestation, or childhood physical abuse [295]. Foa

neurotransmitter (noradrenergic and serotonergic), and neuroendocrine

Women and PTSD

Major depression and generalized anxiety disorder are common

cluster of PTSD symptoms. This diﬀerential eﬀect on PTSD symptom

[111] Weissman M, Klerman G, Markowitz J, Ouellette R. Suicidal ideation and suicide

[159] Shear M. Anxiety disorders in women: gender-related modulation of neurobiology and

[185] Schneier F, Heckelman L, Garﬁnkel R, et al. Functional impairment in social phobia.

[208] Yonkers K, Dyck I, Keller M. An eight-year longitudinal comparison of clinical course

[275] Bogetto F, Venturello S, Albert U, et al. Gender-related clinical diﬀerences in obsessive-

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