Re vie w

Women, anxiety and mood: a

review of nomenclature,
comorbidity and epidemiology
Jeanne Leventhal Alexander†, Lorraine Dennerstein, Krista Kotz and
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Gregg Richardson
Women experience a high prevalence of mood and anxiety disorders, and comorbidity of
mood and anxiety disorders is highly prevalent. Both mood and anxiety disorders disturb
sleep, attention and, thereby, cognitive function. They result in a variety of somatic
complaints. The mood disorder continuum includes minor depression, dysthymia, major
depression and bipolar disorder. Chronobiological disorders, such as seasonal affective
disorder as well as premenstrual dysphoric disorder, occur in some women, with comorbid
seasonal affective disorder and premenstrual dysphoric disorder in just under half of these
individuals [1]. Early life experience, heritability, gender, other psychiatric illness, stress and
trauma all interact dynamically in the development of mood and anxiety disorders. The
For personal use only.

epidemiology, nomenclature and clinical diagnostic issues of these illnesses in midlife

woman are reviewed.

Expert Rev. Neurotherapeutics 7(11), S45–S58 (2007)

Materials & methods

Studies were retrieved using both Cochrane and PubMed searches. A literature search review
was performed to identify randomized controlled trials, some of which were also double-
blind, evidence-based review articles and meta-analyses, as well as evidence-based guidelines
relevant to the topics and symptoms reviewed. Reference lists from these articles were also
examined. As is standard, studies that used methodology consistent with evidence-based
medicine were used. Given the current limits of some areas of research, we also included less
reliable evidence when higher levels were not available. The limitations of these studies and
their application to clinical treatment are indicated.

†
Author for correspondence
Kaiser Permanente Northern
California, Psychiatry Women’s
Health Program, Oakland, CA;
Alexander Foundation for Women’s
Health, Nonprofit, Berkeley,
CA, USA
Tel.: +1 510 527 3010
Fax: +1 510 525 3189
jeanne@afwh.org
KEYWORDS
anxiety, bipolar disorder,
depression, dysthymic disorder,
epidemiology, major depressive
disorder, menopause,
perimenopause, premenstrual
dysthymic disorder, seasonal
affective disorder
Depression is the leading cause of health-
related disability according to the WHO [2,3].
It is common and can be quite serious in
nature [4,5]. Women carry a greater burden of
affective and anxiety disorders than men [6],
with the lifetime prevalence of depression in
women at approximately 21% compared with
13% in men [6]. Dysthymia also has a greater
prevalence in women (8%) than in men (5%)
and in mental-health settings represents 36%
[7] of outpatients [8]. A total of 75% of patients
with dysthymic disorder (DD) have exacerba-
tions that meet criteria for major depressive
disorder (MDD) [9] and in a recent study by
Klein et al. (2006), 95% of DD patients suf-
fered a major depressive disorder in their life-
times [10] . Depression with anxiety symptoms
is quite common and is in fact seen more
often than depression alone [11]. Data from
both the National Comorbidity Survey and
the Epidemiologic Catchment Survey show
that although rates of pure depression are
similar between women and men, women are
twice as likely to experience depression with
anxious and somatic symptoms [12,13]. Life-
time prevalence of anxiety disorders is two-
to three-times greater in women than in
men [14,15]. In an analysis of the USA National

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 Alexander, Dennerstein, Kotz & Richardson
Comorbidity Survey, Kessler et al. (2003) found that 72% of
respondents with lifetime MDD additionally met criteria for
one other DSM-IV disorder, with 59% meeting criteria for
anxiety disorder [16]. Impact on day-to-day functioning and
work productivity is significant and the economic cost of
depression has been underestimated [17]. Anxiety disorders have
also been found to affect work negatively, through absenteeism
and to reduce health-related quality of life [18].
Generalized anxiety with or without an accompanying
mood disorder
Anxiety of a pathological nature may be secondary to a more
severe psychiatric disorder (e.g., psychosis), substance abuse,
mood disorder and/or a physical illness (e.g., hyper-
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thyroidism). Anxiety disorders are second only to substance
abuse as the most prevalent psychiatric disorders in the USA,
with a lifetime prevalence of 5% [19]. While anxiety disorders
affect 30.5% of women, they affect only 19.2% of men. ‘Anxi-
ety disorders’ refers to a variety of conditions, including obses-
sive–compulsive disorder, panic disorder, social phobia, post-
traumatic stress disorder and generalized anxiety disorder
(GAD). One in three people are at risk of developing one of
these disorders sometime in their lifetime [20]. For GAD, onset
is most often before the age of 25 years, the course is chronic
and the risk factors include a family history of GAD, stress and
For personal use only.
trauma [19]. For the purposes of this review, we will only
address GAD.
In a 12-year follow-up longitudinal study of the stability of
an anxiety disorder diagnosis [21], it was found that 28% of
patients who had at some point received a diagnosis of GAD
were later diagnosed with DD or MDD. Comorbidity with
major depression is common, with the presence of GAD rais-
ing the risk of subsequent development of depression [22]. Het-
tema et al. (2006), in a population-based sample of 8068 adult
twins, found that prior GAD and stressful life events both
increase the risk of developing depression. Interestingly, they
also found this to be truer in males despite the higher depres-
sive risk in females [23] . Individuals with a depressive disorder
and GAD are more disabled than individuals with either
alone [24]. For those individuals with GAD or with MDD
comorbid with GAD, many will present for care with somatic
complaints as their sole focus and will not perceive anxiety as
their primary problem [24].
Individuals express anxiety in a variety of ways and may or
may not identify their worries as excessive. They may or may
not be distressed by constant worry or be impaired in their
occupational and personal functioning. Those suffering from
GAD report that their worries are persistent, intrusive and
affect their functioning. They also commonly complain
about mood problems, difficulty concentrating, sleep distur-
bances and fatigue. GAD is often chronic, but symptoms may
wax and wane during the patient’s lifetime. Anxiety interferes
with attention and certain aspects of cognitive function. It
can also worsen the cognitive function of an individual with
any other etiology for lowered cognitive function, that is,
S46
attention-deficit/hyperactivity disorder, sleep deprivation or mild
head trauma. This will be addressed in more depth in the subse-
quent article in this clinical series, ‘Role of psychiatric comorbidity
on cognitive function during and after the menopausal transition’.
Typical clinical presentations for individuals with anxiety
disorders will vary according to their insight into the psycho-
logical aspects of those disorders and whether their pre-
dominant symptoms are somatic or psychological. In BOX 1,
these clinical points are summarized. The reader is referred to
the Appendices for a GAD case ecample.
Box 1. Diagnosis and clinical points for generalized
anxiety disorder.
• Second only to substance abuse as the most prevalent
disorder in the USA [19]
• Onset prior to 25 years of age, chronic course [18]
• Risk factors include family history of generalized anxiety
disorder (GAD), stress and trauma [18]
• GAD significantly increases the risk of subsequent
depression [22]
• Comorbidity of GAD and major depressive disorder (MDD) is
common [23], with 75% developing a major depressive
episode in their lives [19]
• Individuals with comorbidity of GAD and MDD are more
disabled [24]
• GAD patients report persistent and intrusive worries that
affect their function and quality of life [24]
• Fatigue is a common complaint for a GAD patient
• Some GAD patients present with somatic symptoms only
and do not perceive their somatic symptoms as part of an
anxiety disorder
• Patients who have GAD experience excessive anxiety and
worry for more days than not for at least 6 months and have
difficulty controlling that worry, suffer associated physical
and psychological symptoms, all this causes significant
distress or impairment
• Diagnosis requires excessive anxiety and worry
(apprehensive expectation) occurring more days than not for
at least 6 months and at least six GAD symptoms from
DSM-IV [24]:
– Restlessness or feeling keyed up or on edge
– Being easily fatigued
– Difficulty concentrating or mind going blank
– Irritability
– Muscle tension
– Sleep disturbance (difficulty falling or staying asleep or
restless unsatisfying sleep)
Used with permission, ©www.afwh.org (2007).
Expert Rev. Neurotherapeutics 7(11), (2007)

Mood disorders continuum
Depressed mood can vary from depressive mood symptoms to a
MDD. This continuum of mood states; their long-term conse-
quences for quality of life, morbidity and functioning; and the
likelihood of progression to MDD have been of increasing
interest to psychiatric researchers.
Minor depression/depressive spectrum disorders
The prevalence of depressive spectrum disorders (DSDs) has
been estimated to be in the range of 10–24% of the general
population [25,26]. A DSD has been defined as the persistence of
depressive mood symptoms for at least 2 weeks that are not suf-
ficient to meet criteria for a DD or MDD [27]. DSD is consid-
ered inclusive of other terms that have been historically used to
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refer to subthreshold forms of mood disorders, terms such as
‘minor depression’ or ‘subsyndromal depression’. DSDs are part
of a continuum of mood disorders, influence quality of life and
may have ramifications for long-term risk for development or
recurrence of major depression [28]. Most individuals with DSDs
do not go on to develop major depression, but DSDs have been
found to be a significant risk factor for such a progression [29].
Other risk factors include family psychiatric history and chronic
illness [29,30]. DSDs appear to lead to functional impairment
similar to that seen with other mood disorders [31,32]. The reader
is referred to Rowe et al. (2006), for an in-depth current review
For personal use only.
of this topic [27]. In BOX 2, aspects of the minor depression or
depressive spectrum disorders are summarized.
Dysthymic disorder
DD is a form of chronic low-grade depression that is character-
ized by depressed mood for at least 2 years and the presence of
two or more of the symptoms listed in BOX 3. It is a chronic ill-
ness and was found, by Klein et al. (2006) in their longitudinal
study, to have an excellent recovery rate of 74%. However, a
relapse rate of 71% was also noted, with most relapses occur-
ring within 3 years of recovery [10]. Furthermore, many of the
patients displayed DSD symptoms or subthreshold depression
during their recovery periods. Historically, it has been consid-
ered a milder disorder than MDD, but recent studies on remis-
sion and chronicity have called this into question. Klein et al.
(2006) concluded that DD is in many ways a more serious con-
dition than a nonchronic major depressive episode, with DD
patients symptomatic 60% of the time (prospectively); patients
with nonchronic MDD are symptomatic only 21% of the
time [10].
DD is diagnosed when the mood problems do not fit either a
chronic mixed anxiety-depressive disorder (MAD) or a MAD
that is not in remission. A patient with DD may have experi-
enced a previous major depressive episode, but DSM-IV crite-
ria require that the disorder has been in remission for at least
2 months prior to this new diagnosis. When a DD is diag-
nosed, it is possible to have a superimposed MDD and in this
situation the patient receives both diagnoses. This of course
requires the presence of dysthymia for 2 years prior to the
superimposed MDD. The differential diagnosis always includes
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Women, anxiety and mood
Box 2. Summary of clinical points for minor
depression/depressive spectrum disorder.
• Persistence of depressive mood symptoms for at least
2 weeks but does not meet criteria for dysthymic disorder or
major depressive disorder [27]
• Common: 10–24% of the population [25]
• Most individuals do not go on to develop major
depression [29]
• Depressive spectrum disorders have been found to be a
significant risk factor for progression to major depression [28]
• Functional impairment in day-to-day life similar to that of
other mood disorders [29,30]
Used with permission, ©www.afwh.org (2007).
ruling out the physiological effects of substances, such as drug
or alcohol abuse, a medical problem, such as hypothyroidism,
and some other more serious psychiatric disorder, such as bipo-
lar illness or psychosis. The reader is referred to the Appendices
for a typical case example of this disorder.
Major depressive disorder
MDD as described in BOX 4 is characterized by more than five
symptoms from the list and is considered a serious form of
depression. It is the most common form of depression that is
comorbid with a GAD. A total of three-quarters of GAD
patients will develop an episode of major depression [19]. The
point prevalence (the measure of a condition in a population at
a given point in time) of major depression has been found to be
in the range of 4–14.8% with a range of 8.8–16% for depres-
sive symptoms [33]. Valenstein et al. (2001) point out that
patients who suffer from MDD miss an average of 4.8 work
days/3 months and have decreased work capacity for 11.5 more
days/3 months [33]. For MDD, the risk of a subsequent recur-
rence of depression further increases with each episode, with
one episode of depression conferring a 50% risk of a second
episode, a second conferring a 70% risk for a third and a third
Box 3. Diagnosis and clinical points for
dysthymic disorder.
• Chronic low-grade depression or depressed mood for at least
2 years, for most of the day, more days than not and two
symptoms from the following: poor appetite or overeating,
insomnia or hypersomnia, low energy or fatigue, low
self-esteem, poor concentration or difficulty making
decisions and feelings of hopelessness
• Chronic illness with excellent recovery rate (74%) [10]
• Relapse rate of 71%, majority within 3 years of recovery [10]
Used with permission, ©www.afwh.org (2007).
S47
 Alexander, Dennerstein, Kotz & Richardson

Box 4. Diagnosis and clinical points for major depressive disorder.

• Most common form of depression and the most serious

• Leading cause of disability in 2004 [48]
• Heritability higher in women (42%) than in men (29%) [45]
• Risk of recurrence increases with each episode, one episode increasing the risk of the second by 50%, two episodes by 70% for a
third and three episodes by 90% for a fourth [16,34]
• Association of stress or other risk factors with the new depressive episode decreases with each subsequent episode [35,36]
• Diagnosed by Diagnostic and Statistical Manual of Mental Disorders-IV criteria of ≥5 of the following symptoms in a 2-week
period [48] :
– ↓ interest, pleasure and mood (one of these symptoms is necessary for a diagnosis)
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– ↑ or ↓ sleep
– ↑ guilt, feelings of worthlessness and guilty preoccupations
– ↓ energy, ↑ tiredness and fatigue
– ↓ concentration and ability to think/make decisions/problem solve
– ↑ or ↓ appetite and ↑ or ↓ weight
– slowed speech or body movements, reduced speech volume or increased agitation or pacing
– suicide preoccupation with death or suicidal ideation
Used with permission, ©www.afwh.org (2007).
For personal use only.

conferring a 90% risk for a fourth [16,34]. As the illness
progresses and the patient suffers recurrent episodes, the
association of life stressors or other contemporaneous risk
factors with each episode decreases [35]. This association and
change were found to be highest for those without genetic
risk of major depression and less so for those with genetic risk
by Kendler et al. (2001). A kindling hypothesis has been pro-
posed, such that a patient may reach a point that he or she
experiences depressive episodes with no contemporaneous
stressors, similar to those patients who have a high genetic
risk and suffer recurrent depression with minimal contempo-
raneous stress [35] . Corruble et al. (2006) found, in their
recent cross-sectional survey of 13,377 treated patients with
unipolar depression, that there is a linear reduction of aver-
age life events observed prior to an episode of depression in
relation to increased frequency of past depressive
episodes [36]. This relationship remained even when the varia-
bles of age, gender and severity were examined. Genetic pre-
disposition to risk of depression has been associated with spe-
cific gene polymorphisms, notably the serotonin transporter
(5-HTT) gene and brain-derived neurotrophic factor
(BDNF) gene. Individuals who have the s allele of the
5-HTTLPR polymorphism have been found to have an
increased risk of depression with stressful life events
(SLE) [37]. BDNF gene has been found to have a single nucle-
otide polymorphism at nucleotide 196 (G/A). Individuals
with this nucleotide polymorphism have been found to have
reduced BDNF activity [38]. The combination of poly-
morphisms of BDNF, 5-HTTLPR and maltreatment/SLE
were shown to increase risk of depression in children [39] and
recently have also conferred increased risk in the adult popu-
lation [40]. The 5-HTTLPR s allele polymorphism may
impact ‘emotional responsivity’ to stress and thereby increase
the risk for the development of anxiety or depression conse-
quent to maltreatment or SLE in childhood [41] . Unipolar
depression appears to be rising in prevalence, moving from
the fourth to the leading cause of disability from 1990 [42] to
2004 [43].
Ohayon and Schatzberg in their recent editorial (2006)
commented that depression affects 20 million Americans and
nearly 19 million Europeans (European Union) and that
these rates appear to be increasing [44]. Kendler et al. (2006)
studied lifetime major depression in 42,161 twins, including
15,493 pairs from the National Swedish Twin Registry. The
heritability of major depression was found to be higher in
women (42%) than in men (29%) [45]. Thus, there appears to
be a dynamic interaction of heritability, gender, other psychiat-
ric illness, stress and trauma in the development of major
depression. The reasons for the observation of an increase in
depression worldwide are a topic of much research and have
not as yet been fully elucidated. The reader is referred to the
Appendices for a typical case example of this disorder.
Premenstrual dysphoric disorder
Premenstrual syndrome (PMS) affects 20–40% of women [46–48],
with the more severe form, premenstrual dysphoric disorder
(PMDD), having a 12-month prevalence rate of 3–8% of
women [49]. PMS and premenstrual dysphoria are characterized
by somatic and emotional symptoms with a luteal onset, and
remission in the follicular phase. PMDD is more severe, less

S48 Expert Rev. Neurotherapeutics 7(11), (2007)

 Women, anxiety and mood

prevalent and mood symptoms predominate; functional

impairment is always present and severe in some [50]. Menses- Box 5. Premenstrual dysphoric disorder.
related dysphoric symptoms are not uniformly reported, with
some women experiencing but denying them [43]. Women have • Core symptoms
been observed to fail to report menses-related symptom cyclic- • Depressed mood
ity, despite observed rates of 20–40% when these women were
• Moodiness
followed prospectively [47,48,51]. Richards et al. (2006) proposed
that this cyclicity may be a source of distress that these women • Anxiety and edginess
are not aware of [51]. • Anger or irritability
During the perimenopausal transition the follicular phase
shortens and PMS–PMDD symptoms may therefore appear Other symptoms
to extend for greater portions of the month [51]. By contrast, • Fatigue
due to anovulatory cycles, the overall frequency of symptoms
• Insomnia/hypersomnia
may actually decrease [51]. The reader is referred to a recent
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expert guideline review of the diagnosis and treatment of • Difficulty concentrating

PMS and PMDD by Steiner et al. (2006) [49]. • Appetite change/cravings
Up to 60% of women with premenstrual dysphoria have
• Decreased interest in usual activities
suffered or will suffer an episode of major depression [52–56].
The probability of a woman with lifelong PMDD suffering a • Feeling overwhelmed/out of control
major depressive episode is high, as is the probability of her • Physical symptoms (headache, breast tenderness and/or
having had such an episode prior to middle age [51]. swelling, bloating and joint/muscle pain, etc.)
An excellent prospective measure of PMDD, the daily
record of severity of problems (DRSP), developed by Dr Jean Diagnosis
Endicott, is in the public domain. It can be downloaded as a • More than five symptoms and at least one core symptom
pdf [101]. Diagnosis and clinical points for premenstrual dys-
For personal use only.

• Occur during last week of luteal phase

phoric disorder are summarized in BOX 5 and BOX 6, respec-
tively. The reader is referred to the Appendices for a typical • Relieved within a few days of starting menses; does not recur
case example of this disorder. during week following menses
• Interferes with work, school or usual activities
Seasonal affective disorder
• Not an exacerbation of another disorder
Seasonal affective disorder (SAD) is a subtype of mood dis-
order that occurs in the fall or winter, or in individuals with • Criteria confirmed by prospective daily ratings during at least
indoor occupations with little outdoor exposure. It meets crite- two consecutive symptomatic cycles
ria for a major depressive episode but is characterized by the Data from [57]. Used with permission, ©www.afwh.org (2007).
seasonality of its occurrence [59]. The most common symptoms
for SAD are summarized in BOX 7 [60]. In USA and Canadian
epidemiological studies, between 0.4 and 2.7% of the popula-
Box 6. Clinical points for premenstrual
tion were believed to have the disorder [61–63]. Bright light
dysphoric disorder.
exposure has been found to be as effective as antidepressant
medication [64]. There is a high comorbidity between SAD and
premenstrual dysphoria. In one study, 46% of women diag- • Premenstrual syndrome affects 20–40% of women [46–48]
nosed with SAD during the winter also had diagnoses of • somatic and emotional symptoms with luteal onset and
PMDD during the summer [1]. A typical case example for SAD resolution in follicular phase
is listed in the Appendices.
• Premenstrual dysphoric disorder impacts 3–8% of
Bipolar disorder
women [49]
The prevalence of bipolar disorder I and II in the USA has – mood symptoms predominate
been estimated at 3.4% [65]. Many patients with bipolar dis-
– functional impairment is always present and severe in
order are incorrectly diagnosed with unipolar depression or
some [50]
are not diagnosed at all for many years [66], in part due to
most patients’ lack of insight into their manic symptoms [67]. • Major depressive disorder: up to 60% of women with
A delay in diagnosis has been associated with a less positive premenstrual dysphoric disorder will develop a major
course and poorer outcome [68]. Some studies have shown that depressive episode [52–56]
the use of antidepressants in the absence of mood stabilizers Used with permission, ©www.afwh.org (2007).
(lithium or anticonvulsants) may result in increased cycling

www.future-drugs.com S49
 Alexander, Dennerstein, Kotz & Richardson
between manic and depressed states or to mixed states in a
portion of the bipolar patient population [69,70]. Substance
use, GAD and attention-deficit/hyperactivity disorder [71] are
common comorbidities [72,73]. Screening tests can be used in
primary care to rule out bipolarity but generally these lack
sufficient specificity and sensitivity for diagnostic certainty;
the skilled clinician does a better job of recognizing the
bipolar patient [67]. Important diagnostic validators discussed
by Phelps and Ghaemi (2006) [67], as well as by Perlis et al.
(2006) [74], are described in BOX 8. Beyond accurate diagnosis,
patients who are in treatment for bipolar disorder have spe-
cial issues in terms of pharmacokinetics during hormone
treatment (discussed later in the article ‘Treatment of vasomo-
tor symptoms in the menopausal transition and postmenopau-
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB Kiel on 11/06/14
sally: psychiatric comorbidity’. Diagnostic validators for bipo-
lar 1 and 2 in primary care are summarized in BOX 8. The
reader is referred to the Appendices for a typical case example
of this disorder.
Expert commentary
Mood problems are highly prevalent in women throughout
life, with significant comorbidity among different mood
diagnoses. Anxiety disorders and specifically GAD are com-
mon problems among women and increase a woman’s risk
for a depressive disorder. Chronobiological mood problems,
For personal use only.
such as PMDD, dramatically increase a woman’s risk of
developing a mood disorder in her lifetime. A woman with
SAD has just under a 50% chance of also developing
PMDD. Complicating this picture is the difficulty clinicians
experience in making a diagnosis of either an anxiety disor-
der or a mood disorder in the clinical setting. Both can be
characterized by somatic symptoms that neither the patient
nor the clinician may recognize as symptoms of an underly-
ing mood or anxiety disorder. The difficulties in achieving
Box 7. Clinical points for seasonal
affective disorder.
• Occurs in fall or winter or in individuals with
indoor occupations
• Prevalence is 0.4–2.7% of the population
• High comorbidity between seasonal affective disorder and
premenstrual dysphoric disorder
• Common symptoms include:
– depressed mood
– profound lack of energy
– hypersomnia
– hyperphagia
– carbohydrate craving
– weight gain
Used with permission, ©www.afwh.org (2007).
S50
diagnosis, and then treatment to remission, complicate cur-
rent efforts in medicine to treat these disorders. There is a
subpopulation of menopausal women who have a significant
risk of having one of the previously mentioned conditions
who are undiagnosed, diagnosed but subtherapeutically
treated or diagnosed and treated in the past with incomplete
remission. Teasing out the role of these illnesses in sympto-
matic menopausal women is often very challenging. An
awareness of these illnesses and the problems with their diag-
nosis and treatment is critical to the differential diagnosis
and treatment of the symptomatic menopausal woman. Anx-
iety and mood disorders impact day-to-day functioning and
quality of life, so failure to treat these disorders has signifi-
cant impact on patient morbidity in general. Mood dis-
orders, from symptoms of low mood to MDD to mood dis-
orders with bipolarity, are as important to recognize and treat
in midlife as in any other period of life [58].
Acknowledgements
The authors are thankful to the medical editors, Alison
Briton, Pam Johnson and Joan Cleeve, for their help with
this multiarticle, complex clinical review series that has
undergone many rewrites; to Lucy Tipton, Commissioning
Editor, Elisa Manzotti, Editorial Director, and Karen Row-
land, Head of Production, Future Science Group, for their
enduring efforts on behalf of this supplement; and to Expert
Review of Neurotherapeutics, the Future Science Group, for
generously agreeing to publish the entire series open access
with educational release of copyright. Dr Alexander is grate-
ful to Robin Dea, MD, Regional Director, Mental Health
Services of Northern California Kaiser Permanente, and
Chair, Chiefs of Psychiatry, for her support for this project
and for it’s adaptation for use in the delivery of care to
patients in Northern California Kaiser Permanente Psychia-
try’s (KPNC) ‘Psychiatry Model of Care Program’, as well as
outreach to other Kaiser Permanente Regions around the
USA; to Leventhal/Kline Management Inc. (LKMI) and its
principals, Harald Leventhal and Benita Kline, a nonprofit
management firm that has provided financial management,
accounting, administrative, tax and compliance services to
the Alexander Foundation for Women's Health (AFWH)
since its inception (www.philanthropicadvisor.com); and to
Johanna Lackner, MSW, MPH, of the Collaborative Medical
Education Institute (CMEI) for her invaluable help with the
continuing medical education aspects of the supplement. Dr
Alexander wishes to express her deepest appreciation to Lor-
raine Dennerstein, MD, without whom this work would not
have been possible. We wish to dedicate this supplement to
Dr Dennerstein, who retires from her university full-time
position after an illustrious and respected career in meno-
pause research, women’s health and psychiatry. Her research
has greatly influenced this field of women’s health and was
central to the successful completion and publication of this
ambitious review series on the psychiatrically comorbid
patient experiencing a symptomatic menopause.
Expert Rev. Neurotherapeutics 7(11), (2007)
 Women, anxiety and mood

Box 8. Diagnostic validators for bipolar disorder I and II in primary care [74].

• Assessment of hypomanic and manic symptoms

• Family history of bipolar disorder
• Course of illness
– early age of onset
– highly recurrent but brief depressive episodes
– atypical symptoms: hypersomnia, leaden anergy, psychotic depression and postpartum onset
– fears were more common than in MAD
• Antidepressant treatment response: mania, tolerance and nonresponse
• Inquiry into past ‘overactivity’ rather than mania
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• Prevalence in the USA is estimated at 3.4% [58]

– many incorrectly diagnosed or not diagnosed at all for many years [66,67]
Used with permission, ©www.afwh.org (2007).

Disclosure ACCME’s updated standards for commercial support. For a com-

Jeanne Leventhal Alexander, MD, Krista Kotz, PhD, MPH and
Gregg Richardson, PhD, MPH have no relevant financial rela-
tionships. Lorraine Dennerstein has received grants and/or
research support from Organon and Wyeth, is a consultant to
Boehringer-Ingelheim; and is a consultant to Procter & Gamble
For personal use only.
plete discussion of ACCME philosophies for accredited provid-
ers, standards for commercial support, as well as “Ask ACCME”,
please go to www.accme.org/index.cfm/fa/faq.home/Faq.cfm.
Content and views

and Bayer Schering.
Funding information
The support for the writing and content of the overall clinical
reviews as well as for this article as part of the clinical reviews
came from the authors’ respective institutions, the authors indi-
vidually and from individual private financial donations to the
AFWH, a 501(c)-3 nonprofit organization. Dr Alexander
donates her time to the AFWH and has not received any remu-
neration for this effort from the foundation. We are thankful to
the Lilly Pharmaceutical Grant Office for their educational grant
to AFWH in support of Dr Krista Kotz, PhD, MPH, in 2005; of
the medical editors, Pam Johnson, Alison Briton, and Joan
Cleeve. Continuing medical education credits for the entirety of
the clinical review series were supported by individual private
financial donations to AFWH, by the Lilly educational grant,
and the generosity of CMEI. Both AFWH and CMEI follow the
The content and views presented in this activity are those of the fac-
ulty/authors and do not reflect those of their institutions and affilia-
tions in the USA, the Alexander Foundation for Women’s Health,
Berkeley, California; Kaiser Permanente Northern California, the
Psychiatry Women’s Health Program, Psychiatry Model of Care Pro-
gram, the Family Violence Prevention Program, the Division of
Research, and the Behavioral Medicine and Psychiatry Departments
of the Oakland Medical Center, Oakland, California; in Australia,
the Office for Gender and Health, Department of Psychiatry, Uni-
versity of Melbourne, Melbourne, Victoria; and the Department of
Occupational Medicine, San Diego, California; and/or any of the
other institutional/academic/employment affiliations of the authors
respectively nor the CME providing organizations or funding sources
for this supplement, the Collaborative Medical Education Institute,
the American Academy of Family Practice, the Lilly Grant Bureau
and the private contributors to the Alexander Foundation for
Women’s Health, a USA 501(c)-3 nonprofit organization.

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Website
101 Facts for Health. Premenstrual dysphoric
disorder (2007)
www.PMDD.factsforhealth.org
Affiliations
• Jeanne Leventhal Alexander, MD, FABPN,
FRCPC, FAPA, FACPsych
Director, Kaiser Permanente Northern
California, Psychiatry Women’s Health Program,
Oakland, CA;
Alexander Foundation for Women’s Health,
Nonprofit, Berkeley, CA, USA
Tel.: +1 510 527 3010
Fax: +1 510 525 3189
jeanne@afwh.org
• Lorraine Dennerstein, AO, MBBS, PhD, DPM,
FRANZCP
Professor and Director, University of Melbourne,
Office for Gender and Health, Department of
Psychiatry, Victoria, Melbourne, Australia
ldenn@unimelb.edu.au
• Krista Kotz, PhD, MPH
Program Director, Kaiser Permanente Northern
California, Family Violence Prevention
Program, Oakland, CA;
Kotz Health Policy Consulting, Orinda,
CA, USA
krista.kotz@kp.org
• Gregg Richardson, PhD
Kaiser Permanente Northern California,
Clinical Neuropsychology, Department of
Behavioral Medicine, Oakland, CA, USA
Gregg.A.Richardson@kp.org
S53
 Alexander, Dennerstein, Kotz & Richardson

Appendices
• Appendix 1. Anxiety disorder case examples.
• Appendix 2. Depressive spectrum disorder case example.
• Appendix 3. Dysthymic disorder case example.
• Appendix 4. Major depressive disorder case example.
• Appendix 5. Premenstrual dysphoric disorder case example.
• Appendix 6. Seasonal affective disorder case example.
• CME post-test and method of participation.

Appendix 1. Anxiety disorder case examples.

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Case I
A 45-year-old patient presents to her clinician reporting that she is having more and more trouble with feeling tense in her body,
keyed up, on edge, unable to relax and not being able to stop her mind from dwelling on her current worries. Upon questioning she
reveals that she has always been ‘sensitive and easily made nervous’, that the family is a ‘nervous family,’ but that she had not had
much trouble controlling these symptoms until now. Lately, she finds that exercising and distracting herself simply does not stop her
from thinking the same thoughts over and over again, or from having unpleasant physical feelings and difficulty falling and staying
asleep. This has been going on for about 8 months, waxing and waning, sometimes getting better, sometimes worse. The overall
problem, she states, is that she is less able to function in her daily tasks. She says her mood drops in response to all the worries but
that if she can stop worrying she feels okay. She thinks her current situation is a magnification of what she has felt all her life but
“way worse” and feels this is the result of having teenage children facing a number of small but real challenges. She thinks her
For personal use only.

situation is manageable, as is theirs, but cannot seem to calm down. She has no history of drug or alcohol abuse. She has never had a
depressive episode, hypomania or psychosis and has no first-degree relative with bipolar illness. Her thyroid is normal, she has no hot
flashes and does not suffer from sleep apnea.

Treatment
The patient has generalized anxiety disorder (GAD). She would benefit from cognitive behavioral therapy (CBT) for anxiety if this were
available to her. She may need antidepressant treatment for her current exacerbation of GAD but she should try the CBT first and then,
if it is not helpful or not completely helpful, adjunctive antidepressant treatment could be offered. Use of calming medications, such
as benzodiazepines, could be offered but not instead of psychotherapy and/or antidepressant treatments. The benefits of different
forms of talk therapy will also be discussed in the article in this supplement entitled ‘Collaborative depression care, screening,
diagnosis and specificity of depression treatments in the primary care setting’, as there are several types of CBT, as well as other
nonsomatic therapies, that may also be helpful in this situation.

Case 2
Same case as above but the patient reports that she seems to always feel a bit low with some chronic sleep problems and low self-
esteem. When she was in the midst of a divorce years ago, she was diagnosed with depression and treated with an antidepressant, she
thinks fluoxetine. It greatly helped and resolved her depression as well as her anxiety. She stopped the medication after 9 months at
the recommendation of her psychiatrist, felt euthymic, but did suffer a return of low-grade anxiety symptoms. She thought these
were tolerable so she did not accept the offer of either continued psychotherapy or a resumption of fluoxetine. She now feels she has
the same symptoms as when she was last treated and wishes to go back on fluoxetine. She has no history of hypomania, psychosis,
drug or alcohol abuse and has no first-degree relative with bipolar illness. Her thyroid is normal and she does not suffer from hot
flashes or sleep apnea.

Treatment
This patient likely suffered an incompletely remitted GAD after treatment of her first episode of GAD and major depressive disorder
(MDD) and has now again developed full GAD and MDD. She should resume fluoxetine and psychotherapy.
Used with permission, ©www.afwh.org (2007).

S54 Expert Rev. Neurotherapeutics 7(11), (2007)

 Women, anxiety and mood

Appendix 2. Depressive spectrum disorder case example.

A 45-year-old woman presents to her clinician complaining of feeling low at times, for periods of a week to a few weeks, with
symptoms waxing and waning. When she feels low she does not focus or function as well in her daily routine and job. She says,
however, that the low feeling does not disturb her sleep, comes and goes, never worsens beyond what she has described and that she
“pretty much” has no other symptoms. She denies ever feeling unusually high or full of energy (r/o hypomania) nor does she ever have
problems with anxiety. She recalls one time in her early 20s when she felt depressed, didn’t sleep well and felt slowed down. This
lasted approximately 4 months and was in response to the death of her grandmother. She has watched her menstrual cycle for a
while, checking the calendar and decided her complaints have nothing to do with her cycle. She also read about seasonal affective
disorder in a woman’s magazine and says she has had this off and on since her 30s. She asks her clinician if there is anything that can
be done for this feeling. She has no history of hypomania, psychosis, drug or alcohol abuse and has no first-degree relative with
bipolar illness. Her thyroid is normal. She has no hot flashes or sleep apnea.
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Treatment
The patient appears to have a minor depression, her symptoms not meeting criteria for dysthymia or major depressive disorder.
Treatment would depend on what the patient is open to. An exploration of how she responds to stress, whether she has stressors at
the time of her low moods and whether or not she is open to psychotherapy would be helpful. Also, discuss whether or not she is
open to antidepressant medications. Psychotherapy would be the first-line treatment for her.
Used with permission, ©www.afwh.org (2007).

Appendix 3. Dysthymic disorder case example.

For personal use only.

A 39-year-old woman comes to her clinician and complains that she has been feeling tired and ‘out of it’ for almost 2 years. She
suffered stress on the job approximately 4 years ago but this resolved approximately 3 years ago. She had experienced a similar
feeling for about a year in college when she was overloaded with work and also pregnant with her first child. Her mother pitched in
and helped her baby after his birth and her stress decreased after some changes in her college schedule in addition to more help from
her husband, who was also a student at the time. She says she is gaining weight and has had an increased appetite. This is unusual, as
she does not usually gain weight. She says the biggest problem is that, “I don’t seem to be able to make any decisions, like I am
paralyzed. This is not like me. I am usually fairly decisive. Otherwise, I feel like my usual self. I don’t have any great stress right now. In
fact, life is good”. She has no history of hypomania, psychosis, drug or alcohol abuse, and no first-degree relative with bipolar illness.
Her thyroid is normal. She has no hot flashes and does not have sleep apnea.

Treatment
For this case, psychotherapy could be offered and if not completely effective could then be combined with antidepressant treatment.
If she had more symptoms than the two (low energy/fatigue, poor decision making), then a diagnosis of major depressive disorder
would have to be considered.
Used with permission, ©www.afwh.org (2007).

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 Alexander, Dennerstein, Kotz & Richardson

Appendix 4. Major depressive disorder case example.

A 52-year-old woman comes to her clinician and complains of 2 months of difficulty falling asleep and waking up at 5 am. She says
she cannot get negative thoughts out of her head. She keeps feeling that she is a lousy mother, wife and employee. In fact, she says
that her concentration is so poor that her work performance is seriously down. She worries about making a mistake and her mind
wanders off onto negative thoughts. She points out that this is uncharacteristic for her (“I am usually the optimist in the crowd, but
now I feel hopeless all the time”). She has stopped socializing as she does not feel comfortable and is even withdrawing from friends.
She ‘sheepishly’ admits to feelings of not wanting to live but says that these are just thoughts, that she has no plan. The fact that she
is thinking like this alarmed her and she decided to consult her clinician. She has no history of hypomania, psychosis, drug or alcohol
abuse, and has no first-degree relative with bipolar illness. Her thyroid is normal. She has no hot flashes and no apparent sleep apnea.

Treatment
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This lady is suffering an episode of depression. It is serious due to the suicidal ideation, but with no plan she could probably be treated
as an outpatient. She would benefit from both psychotherapy and medications.
Used with permssion, ©www.afwh.org (2007).

Appendix 5. Premenstrual dysphoric disorder case example.

A 34-year-old patient presents to her clinician complaining of difficulty functioning prior to her menstrual cycle but says this does
not occur each time. She has crying ‘jags’ and is impossible to be around as “I am so irritable”. “I eat too much and I feel heavy, with
bloating in my breasts and abdomen. It has been getting progressively worse over these last few years. My partner said I need to do
something, as I am just about impossible to live with the week before my period. I started to follow it on a calendar as I didn’t quite
For personal use only.

believe him and he was right. Not every month, but when I have it the symptoms seem to all occur between 7 and 3 days before my
period and usually get better within a day of my bleed”.

Treatment
The clinician should ask her to track her mood using a daily record of severity of problems so that she can be sure the reported
symptoms are not premenstrual exacerbation of an underlying mood or anxiety disorder. The clinician should also ask about mood
and anxiety at other times of the month. With prospective confirmation of at least 2 consecutive months and a severity that would
justify treatment, the clinician could offer a serotonergic antidepressant, to be taken for either the whole month or just the week
before her period. Other treatments are beyond the scope of this review. The reader is referred to Steiner et al. (2006) [49].
Used with permission, ©www.afwh.org (2007).

Appendix 6. Seasonal affective disorder case example.

Ms Smith presents to her clinician fatigued and with a 5-pound weight gain. She says that she does not remember having problems
like this until she moved to Alaska. The last three winters she seemed to start sinking beginning in the fall, and by the holidays was
depressed, lethargic, craving sweets and feeling worthless. She asks her clinician if it has anything to do with the weather and what
she would recommend.
Treatment
The clinician discusses other symptoms, establishes no other mood or anxiety disorders, and no problems in the summer. She then
discusses seasonal affective disorder with the patient and her different options including ‘light box treatment’ and/or
antidepressants [59].
Used with permission, ©www.afwh.org (2007).

S56 Expert Rev. Neurotherapeutics 7(11), (2007)

 Women, anxiety and mood

CME post-test and instructions to receive credit.

Release date: 1st November 2007

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2 unit ACCME, and AAFP CMA PRA category 2 credits™ or CEU
2h
US$5/ACCME unit or US$10/2 units
Go to www.afwh.org for a complete description of credit available or to the CME section of this
supplement

To obtain credit and take the CME post test

Read this article, then link to www.afwh.org, click on CME, then click on the journal article for which you wish to take the CME post-test. If
you have accessed the journal article online as HTML, you can link from the ‘CME’ notation to the post-test at the www.afwh.org site. If you
are reading these articles in paper format or as a PDF, then go to www.afwh.org and click on CME, then scroll to the article and click on
post-test. To receive the maximum number of American Academy of Family Practice CMA PRA category 1 credits™ or CEU for this article you
should read the review article, complete the online post-test and fill out the confidential online CME/CE registration and the activity
evaluation forms. Please be advised that CME/CE certificates require a 70% or greater score on the post-test. With successful completion of
the post-test, your CME/CE certificate will be issued to you by email. There will be a processing fee of $5/CME or CEU unit. AFWH and CMEI
privacy and confidentiality policies comply with the Accreditation Council for Continuing Medical Education (ACCME). All ACCME policies may
be found at: http://www.accme.org/incoming/pol_12_internet.pdf. CMEI has the highest level of security for online transactions and has
security measures in place to protect the loss, misuse and alteration of the information under their control. CMEI uses Secure Socket Layer
(SSL) to digitally encrypt information as it is transferred from an activity participant’s computer to CMEI
For personal use only.

CME/CEU online post-test (www.afwh.org)

Select an answer for each question. You must achieve a test score of 70% or greater to earn credit
1. Which of the following statements are correct? (a, a & c, c)
a. Approximately 75% of patients with dysthymic disorder have exacerbations that meet criteria for major depressive disorder
b. Approximately 25% of patients with dysthymic disorder have exacerbations that meet criteria for major depressive disorder
c. One study found that 95% of dysthymic disorder patients suffered a major depressive disorder in their lifetime
2. Which of the following statements are correct? (a, b, c)
a. Lifetime prevalence of anxiety disorders is two- to three-times greater in women than in men
b. Lifetime prevalence of anxiety disorders is four- to five-times greater in women than in men
c. Lifetime prevalence of anxiety disorders is one- to two-times greater in women than in men
3. Which of the following are considered to be negative effects of anxiety disorders? (a, a & c, a & d, all)
a. Absenteeism
b. Reduced health-related quality of life
c. Decreased day-to-day work productivity
d. High economic cost to the workplace, family, society and healthcare system
4. A depressive spectrum disorder (DSD) is characterized by which of the following? (a, a & c, all)
a. A persistence of depressive mood symptoms for at least 2 weeks that are not sufficient to meet criteria for a dysthymic disorder or major
depressive disorder
b. Most individuals with DSDs do not go on to develop major depression
c. DSDs have been found to be a significant risk factor for progression to major depression
d. DSDs appear to lead to functional impairment similar to that seen with other mood disorders

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 Alexander, Dennerstein, Kotz & Richardson

CME post-test and instructions to receive credit. (cont.)

5. Which of the following statements about dysthymic disorder are true? (a, a & c, all)
a. Dysthymic disorder is a form of chronic low-grade depression that is characterized by depressed mood for at least 2 years
b. It was found in one longitudinal study to have a recovery rate of 74%
c. Dysthymic disorder is in many ways a more serious condition than a nonchronic major depressive episode
d. Dysthymic disorder patients are symptomatic 60% of the time (prospectively)
e. Nonchronic major depressive disorder patients are symptomatic only 21% of the time
6. Which of the following describe the effect of major depression on functioning? (a, a & b, all)
a. Patients who suffer from major depressive disorder miss an average of 4.8 work days/3 months
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b. Have decreased work capacity for 11.5 more days/3 months

c. Have decreased concentration and are less engaged in day to day tasks

7. Premenstrual dysphoric disorder is characterized by which of the following? (a & c, abc, all)
a. 12-month prevalence rate of 3–8% of women
b. All women have premenstrual syndrome
c. The probability of a woman with lifelong premenstrual dysphoric disorder suffering a major depressive episode is high
d. Premenstrual syndrome is synonymous with premenstrual dysphoric disorder
For personal use only.

8. The most common symptoms of seasonal affective disorder are? (abc, a–d, all)
a. Depressed mood
b. Profound lack of energy
c. Hypersomnia and hyperphagia
d. Carbohydrate craving and weight gain
e. Difficulty sleeping
9. Which of the following represent the prevalence of bipolar I and II in the USA? (a, b, c)
a. 3.4%
b. 7%
c. 10%

S58 Expert Rev. Neurotherapeutics 7(11), (2007)