O A P L

OX F O R D A M E R I C A N P S YC H I AT RY L I B R A RY

Major Depressive
Disorder
O A P L
OXF OR D AM ER I C AN P S YC H I AT RY L I BR ARY

Major
Depressive
Disorder
Stephen M. Strakowski, MD
Erik B. Nelson, MD

1
1
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Library of Congress Cataloging-in-Publication Data

Strakowski, Stephen M., author.
Major depressive disorder / Stephen Strakowski, Erik Nelson.
p. ; cm.
Includes bibliographical references.
ISBN 978–0–9–02068–5 (alk. paper)
I.  Nelson, Erik, 964– author.  II.  Title. 
[DNLM: .  Depressive Disorder—Handbooks.  WM 34]
RC537
66.85'27—dc23
204047696

9 8 7 6 5 4 3 2 
Printed in the United States of America
on acid-free paper
 Contents

. Introduction  
2. Making a Diagnosis of Depression  5
3. Epidemiology of Depressive Disorders  5
4. Illness Comorbidity and Co-occurrence
with Depressive Disorders  23
5. Neurophysiology of Depressive Disorders  3
6. Genetics of Depression  43
7. Psychopharmacology and Other Biological
Therapies in the Management of Depression  49
8. Psychotherapy and Related Techniques  69
9. A Programmatic Approach to Treatment  75
0. Managing Special Populations  87

Appendix: Example Mood Chart   99

Index  0
Dr.  Strakowski would like to dedicate this book to his family, for their
unwavering support, and to his patients who serve as a constant inspiration.

Dr. Nelson would like to dedicate this book to his mother, whose struggle
with depression has not prevented her from being a wonderful teacher, wife,
and parent.
Chapter 

Introduction
Depressive disorders, often referred to as “clinical depression,” include
major depression, dysthymia, and other related conditions that have
plagued humanity throughout history. Unfortunately, this epidemic has often
been nearly invisible; affected people have typically been stigmatized and
ostracized, so they suffered in silence rather than seeking help. For much
of human history, “help” was quite barbaric, ranging from blood-letting to
witch burning, both of which managed to decrease the rates of depression
by eliminating the sufferer! In the past few years, stigma surrounding depres-
sion has dramatically decreased as a number of well-known individuals pub-
licly acknowledged personal experiences with depression. Newscaster Mike
Wallace (Sixty Minutes) was one of the first to use his own experiences with
depression and suicidality, coupled with his celebrity, to raise awareness of
this often mysterious malady. In his book Darkness Visible, the noted author

1
(of Sophie’s Choice) William Styron provides a heart-wrenching and gripping
attempt to describe the indescribable—the depth, darkness, and despair of
his experience with major depression. Actress Brooke Shields wrote of her
struggles with postpartum depression in Down Came the Rain, only to be pub-
licly criticized by fellow actor Tom Cruise, who expressed the depth of igno-
rance and stigma still maintained by the uninformed when faced with mental
illness. Ms. Shields’s courageous response to this criticism opened doors for
other women to seek help for postpartum depression. Terry Bradshaw, one
of the best quarterbacks in NFL history, taught us that depression attacks
even the toughest among us. Tipper Gore, Amanda Beard, Halle Berry,
J. K. Rowling, Jim Carrey, Ashley Judd, David Letterman, and many others
joined the battle against depression by discussing their own experiences; in
doing so, they demonstrated that depression cuts across social boundaries
with impunity. These brave celebrities put a public face on depression and
encouraged acceptance of it as a medical illness. However, the apparent
sudden increasing frequency of these announcements gives the misleading
impression that depression is somehow new or fashionable. Nothing could
be further from the truth.
The history of depression dates back millennia to the beginning of recorded
human history. Descriptions of depression appear in Ancient Egyptian papyri
as well as the Indian Mahabharata. As early as 400 bc, Hippocrates declared
that, rather than being of magical or spiritual origin, mental disorders arose
from imbalance among the various humors that comprised human health,
namely blood, phlegm, yellow bile, and black bile. Specifically, depression,
called “melancholia,” was believed to result from an excess of black bile
(melancholia translates literally as “black bile”). The great physician Galen
Major Depressive Disorder supported this humoral view of depression so that it persisted, more or less
intact, for nearly 500 years.–3 In the nineteenth century, European psychia-
trists began to delineate among different mental disorders, culminating in the
early twentieth-century work of Emil Kraepelin, who distinguished dementia
praecox from manic-depressive illness, the latter of which included both uni-
polar and bipolar depressive disorders. Indeed, the unipolar/bipolar distinc-
tion did not prevail until 957, when Leonhard proposed that the occurrence
of mania (bipolar disorder) defined a separate illness from one involving only
recurrent (unipolar) depressive episodes. With this long track record, then, it
should be no surprise that a number of famous individuals throughout history
recorded their struggles with depression (Table .).
As the stigma surrounding depression steadily diminishes, it becomes
increasingly obvious how troublesome it is. Epidemiological studies sug-
gest that at least 5% of individuals suffer from depression at some point
in their lives, with 5% in any given year; consequently, depression is one
of the most common medical conditions affecting humankind.4–6 Rates of
depression in medical settings are even higher as depression is comorbid
in more than half of people suffering from major neurological, psychiat-
ric, and other medical conditions. Although women experience depres-
sion more commonly then men, depression strikes across gender, race,
age, and class boundaries. By the year 2020, depression is expected to be
the leading cause of disability worldwide and, with suicide occurring in up
2

to 7–8% of depressed individuals; it is also one of the leading causes of

premature mortality. Although depression represents a major (if not the
major) current public health problem, less than half of affected individuals
receive evidence-based treatment.
Despite the prevalence and importance of depression, its causes are
not well understood. Many people who experience depression appear to
inherit a genetic risk, although environmental effects, especially stress and

Table .  Historical Figures Suffering From

Probable Depression
Individual Role When
Lived
Winston Churchill UK Prime 874–965
Minister
Charles Darwin Naturalist 809–882
Francisco Goya Painter 746–828
Ernest Hemingway Writer 899–96
William James Psychologist 842–90
Meriwhether Lewis Explorer 774–809
Abraham Lincoln US President 809–865
Isaac Newton Physicist 642–727
Friedrich Nietzsche Philosopher 844–900
Mark Twain Humorist/Author 836–90
Walt Whitman Poet 89–892
the occurrence of other illnesses, appear to significantly contribute to the

Introduction
onset of depression. Moreover, the specific genes that impart increased risk
for depression have not yet been identified. In fact, depression is so com-
mon in certain neurological, medical, and psychiatric conditions, we won-
dered whether it represents a nonspecific response to brain insult or injury.7
Contrary to this suggestion, however, there are individuals who develop

Chapter 
depression in the absence of any clear precipitants. Regardless, the end result
is a condition in which the healthy neural mechanisms that maintain emotional
homeostasis in the brain become disrupted. Nonetheless, as the neurobiol-
ogy of depression is clarified, treatment advances will hopefully move from
reliance on strictly empirical and often serendipitous treatment findings to
more targeted approaches.
It is truly unfortunate that most people suffering from depression do not
receive evidence-based treatment in a timely manner, since both medical
and psychological interventions significantly improve symptoms, function,
and outcome. In part, the sheer volume of depression stresses psychiatric,
medical, and therapeutic care delivery systems, so that many affected indi-
viduals simply land in the wrong clinic at the wrong time. Moreover, despite
advances, because society continues to stigmatize and minimize depres-
sive symptoms, people are often reluctant to seek help or to discuss their
concerns with caregivers. Indeed, the cognitive dissonance and negativity
that accompany depression leave many sufferers with the (false) a priori

3
assumption that “nothing will help me.” Also, as noted, depression often
occurs within the context of other medical and psychiatric conditions, so
sometimes it gets lost in the treatment of the other illness. Consequently,
effective treatment of depression can be challenging, particularly if it fails to
respond to the first intervention. Indeed, in these instances, successful treat-
ment is programmatic, incorporating sophisticated psychopharmacology,
evidence-based therapies, lifestyle modifications, and general good health
practices.
With these considerations in mind, in this Oxford American Psychiatry
Library (OAPL) volume, we review practical and succinct descriptions of
depression and its management in order to provide a quick reference for
the busy practitioner. This volume may also be useful for nonmedical people
suffering from depression and their families, as well as medical or psychol-
ogy students who are trying to better understand these common conditions.
A major focus of this volume will be to provide a programmatic approach to
the management of depression in order to develop systematically the best
treatment, as opposed to the common situation in which people receive
inadequate treatment that changes prematurely and too frequently, leading
to submaximal outcomes. Ultimately, the goal of this volume is to improve
the lives of people suffering from depression and to bring hope to them and
their loved ones.
[Authors’ Note: In this book we use the term “depression” (singular form)
to represent multiple conditions that perhaps more correctly would be called
“depressive disorders” (plural form). We made this choice because the sin-
gular form is more common in the vernacular; however, when distinctions
among depression subtypes are relevant, we use the plural form.]
Major Depressive Disorder References
. Davison K. Historical aspects of mood disorders. Psychiatry 2008; 8:47–5.
2. Paykel ES. Basic concepts of depression. Dialogues Clin Neurosci 2008;
0:270–289.
3. Goodwin FK, Jamison KR. Chapter  :  Conceptualizing manic-depressive
illness:  the bipolar-unipolar distinction and the development of the
manic-depressive spectrum. In: Manic-Depressive Illness: Bipolar Disorders and
Recurrent Depression. New York: Oxford University Press, 2007.
4. Weissman MM, Bruce ML, Leaf PJ, Florio LP, Holzer C. Affective disorders.
In: Robins LN, Regier DA, eds., Psychiatric Disorders in America: The Epidemiologic
Catchment Area Study, pp. 53–80. New York: Free Press, 99.
5. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S,
Wittchen H-U, Kendler KS. Lifetime and 2-month prevalence of DSM-III-R
psychiatric disorders in the United States. Arch Gen Psychiatry 994; 5:8–9.
6. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity and comor-
bidity of 2-month DSM-IV disorders in the National Comorbidity Survey
Replication. Arch Gen Psychiatry 2005; 62:67–627.
7. Strakowski SM, Adler CM, DelBello MP. Is depression simply a nonspecific
response to brain injury? Curr Psychiatry Rep 203; 5:386–294.
4
Chapter 2

Making a Diagnosis of
Depression

2..  Brief Historical Overview

As noted in Chapter , depression has accompanied humanity throughout its
history. Descriptions of depressive-like conditions are found in the ancient
Egyptian Ebers papyrus (ca. 500 bc), the Indian Ramayana and Mahabharata
(ca. 4th–5th century bc), and the Biblical Old Testament (perhaps as old as ca.
000 bc). The ancient Greeks considered depression (called “melancholia”)
a medical condition that arose from an imbalance of humeral constituents,
namely an excess of “black bile”; indeed, “melancholia” translates as “black
bile.” Hippocrates (ca. 400 bc) described melancholia as prolonged despon-

5
dency, loss of appetite, insomnia, and agitation. Aretaeus of Cappadocia
linked melancholia to suicide. These ancient descriptions are reminiscent of
the same symptoms used today to diagnose major depression.
The black bile hypothesis of melancholia persisted through the Middle
Ages, although it was unfortunately at times linked to the sin of “sloth,” and
so was attributed to demons or immorality to be remedied by forced manual
labor, beatings, or even witch burnings. With the Renaissance, some scholars
challenged the spiritual basis of melancholia, perhaps culminating in Richard
Burton’s The Anatomy of Melancholia (62 ad). Burton was a clergyman who
returned to the humoral (as opposed to moral) theory of melancholia, and
suggested it could be remedied by healthy diet, sleep, meaningful work, and
intellectual pursuits. Although he typically attributed the humoral imbalance
to specific causes, such as poor diet, he recognized that melancholia also
occurred de novo. As the focus of medicine shifted to hemodynamic theories
of disease in the eighteenth century, melancholia was increasingly considered
a physiological condition. With increasingly indiscriminate definitions of mel-
ancholia, the term “depression” began to be used by the late 800s, with
melancholia reserved for a subtype with psychosis.
In the late nineteenth and early twentieth century, Emil Kraepelin dra-
matically influenced psychiatry by separating manic-depressive insanity
from dementia praecox, based primarily on course of illness. Specifically,
manic-depressive insanity exhibited improvement between episodes,
whereas dementia praecox was unrelenting and deteriorating; the latter
became the basis for our current conceptualization of schizophrenia. This
distinction placed depression firmly into a single category with all other mood
disorders. Kraepelin’s conceptualization of affective illness was viewed as too
Major Depressive Disorder broad by many psychiatrists, however, leading Leonhard in 957 to coin the
term “bipolar disorder” in order to distinguish individuals who experienced
mania and depression (i.e., two poles) from those with only recurrent major
depression (i.e., one pole, or “unipolar” depression). Several landmark stud-
ies and the relative specificity of lithium for the treatment of bipolar disorder
reinforced this classification.2 Given that specific causes of depression remain
uncertain, the current diagnostic systems3,4 are based on empirical data
that have identified commonly co-occurring symptoms historically linked to
depression. Consequently, diagnoses of major depression and related condi-
tions rely on clinical assessment of these symptoms, more or less devoid of
hypotheses regarding underlying etiology. As discussed in Chapter , multiple
potential causes have been identified, suggesting that depression represents a
nonspecific response to a variety of brain insults.5 Nonetheless, for diagnostic
purposes, depression is defined as a collection of commonly co-occurring
symptoms, that is, a syndrome.

2.2.  Symptoms and Diagnosis of

Major Depression
Major depression, then, is defined by the co-occurrence of several specific
symptoms that are listed in Box 2.; these symptoms serve as the basis for
6

the two most widely used criteria sets, namely the American Psychiatric
Association’s Diagnostic and Statistical Manual of Mental Disorders (5th edi-
tion; DSM-5) and the International Classification of Diseases (0th revision;
ICD-0 [with ICD- currently under development and likely remaining

Box 2.  Symptoms of Major Depression

• Persistent sadness or low mood,2,3
• Anhedonia—loss of interest in pleasurable experiences,2
• Fatigue or low energy2
• Feelings of worthlessness or low self-confidence3
• Excessive guilt or self-blame
• Change in appetite and weight3
• Psychomotor agitation or retardation
• Anxiety and nervousness
• Disturbed sleep—insomnia or hypersomnia3
• Impaired concentration or indecisiveness3
• Somatic complaints (e.g., back pain, headache)
• Hopelessness3
• Suicidal thoughts or behavior

Considered a core symptom in DSM-5.
2
Considered a core symptom in ICD-0.
3
Included as DSM-5 criteria for dysthymia.
largely similar]). A diagnosis of depression requires at least four (ICD-0) or

Making a Diagnosis of Depression

five (DSM-5) of the symptoms from Box 2., including at least two of the core
symptoms. Moreover, these symptoms must represent a change in a person’s
typical behavior and must be relatively persistent nearly every day for at least
2 weeks (DSM-5) to  month (ICD-0). Symptoms must also cause functional
impairment in order to warrant a diagnosis of major depression.
Despite its name, perhaps the most defining and relatively specific symp-
tom of major depression is anhedonia, that is, the loss of the ability to
experience pleasure or a disinterest in pleasurable activities that a person
would normally enjoy. In many circumstances, depressed individuals do not
acknowledge feeling sad or down, but do express a loss of interest in hob-
bies, relationships, or other life pursuits. As part of the clinical assessment
of major depression, identifying these life pursuits and tracking them over
time helps to define the course of illness and recovery. One common and
relatively easily tracked expression of anhedonia in adults is a decrease in sex

Chapter 2
drive; clinicians often fail to inquire about sexual activity, potentially ignoring
an important clinical clue. As noted in Box 2., anhedonia is a core symptom
of major depression.
Another core symptom of depression is low or dysphoric mood, namely
persistent despondency and sadness. In adolescents, irritability often accom-
panies or substitutes for low mood during a depressive episode. Alternatively,
depressed individuals may report reactive dysphoria in which minor problems

7
lead to excessive negative emotional responses. Low mood is expressed in
many ways, depending on culture and sex, and men tend to be less likely to
describe these feelings than women.
The final core symptom is low energy or fatigue (Box 2.). Accompanying
low energy is often the cognitive experience of a loss of motivation, so that
even simple tasks, like showering, seem insurmountable to someone who
is depressed. These three core symptoms—anhedonia, low mood, and low
energy—commonly co-occur and in many ways define depression in and of
themselves. However, as noted, current criteria sets require one or more
additional symptoms from Box 2..
These additional symptoms reflect disturbances in neurovegetative
functions, behavior, and cognition. Sleep and appetite can be increased
or decreased. Weight loss accompanies appetite loss in some individuals.
Psychomotor changes range from retardation, in which movement and
thinking are slowed, to anxious agitation and restlessness. Anxiety and ner-
vousness occur in many depressed individuals such that the intersection
between anxiety and depressive disorders can be complex (see Chapter ),
and an anxious subtype of depression is recognized. Cognitive symptoms
include loss of self-esteem and thoughts of low self-worth and hopelessness.
During depression, individuals become self-accusatory, taking responsibil-
ity for negative circumstances in situations in which they had no impact or
control. Concentration difficulties occur and are sometimes misinterpreted
as memory loss as people fail to store information due to inattention. In
older patients, this symptom can be difficult to distinguish from early demen-
tia, although complicating this interpretation is that memory loss in depres-
sion may be a sign of incipient dementia in the elderly. Somatic complaints
Major Depressive Disorder are common during depression and typically include nonspecific pain syn-
dromes. Psychosis (hallucinations and delusions) and catatonia may occur
during a severe depressive episode. Delusions in depression often involve
themes of guilt, persecution or loss as part of the overall negative cognitive
presentation.
The most concerning behavioral expression of depression is suicidality.
Suicide represents a terrible permanent solution for a temporary and treat-
able problem. People with major depression have a high rate of suicide, with
a lifetime risk of perhaps 8%; depressed men are 5–7 times more likely to
commit suicide than women, although women make more attempts. People
who are untreated have up to a 5 times higher risk of suicide than those who
receive care. Hopelessness also increases the risk for suicide.

Key Point: Major depression is a syndrome characterized by persistent

anhedonia, low or dysphoric mood, low energy or fatigue, and a num-
ber of other neurovegetative and cognitive symptoms.

2.3.  Subtypes of Major Depression

Different combinations of the various symptoms that occur during a major
depressive episode define a few subtypes. Identifying subtypes may help to
8

guide treatment decisions (discussed briefly here, but in detail in Chapters 7

and 0).
2.3.. Anxious Depression
As noted, anxiety is common during major depression, affecting up to 80%
of people during an episode.6 Many of these individuals will concurrently
meet criteria for major depression and an anxiety disorder (e.g., generalized
anxiety or panic disorder). High levels of anxiety are associated with poorer
treatment response and increased risk of suicide. Anxious depression may be
more common in women than men.
2.3.2. Melancholic Depression
The term “melancholic depression” dates to ancient Greece, but in cur-
rent nomenclature refers to a specific presentation that includes severe
anhedonia, mood nonreactivity to life events, late insomnia (early morn-
ing awakening), marked loss of appetite, and psychomotor symptoms.
Melancholic depression is associated with greater likelihood of excessive
hypothalamic-pituitary-adrenal (HPA) axis activity and may be more respon-
sive to antidepressants (perhaps particularly tricyclic antidepressants) and
electroconvulsive therapy (ECT) than non-melancholic depression.7
2.3.3. Atypical Depression
Atypical depression is somewhat the converse of melancholic depression.
Namely, it involves hypersomnia instead of insomnia, weight gain instead of
weight loss, psychomotor “leaden paralysis” rather than agitation, excessive
rejection sensitivity in interpersonal relationships, and mood reactivity such
that people can be “cheered up” with positive events. Some studies suggest

Making a Diagnosis of Depression

that atypical depression may be linked to bipolar disorder, although this rela-
tionship is not definitive.2 It may also be more common in women, begin ear-
lier in life, and have a more chronic course than other types of depression.
Atypical depression may be less treatment responsive than other subtypes of
depression.
2.3.4. Psychotic Depression
Psychosis (that is, hallucinations and delusions) occurs in up to 5% of depres-
sive episodes, or about 0.6% of the population.8 In some individuals, these
symptoms can be difficult to identify, as responses to questions may be too
guarded or sparse to elicit delusional concerns. Delusions can be mood con-
gruent (i.e., themes of loss, sadness, or persecution) or incongruent (i.e.,
themes of grandiosity or physical impossibility). Mood-incongruent psychosis
may be less treatment responsive or may herald the onset of a primary psy-

Chapter 2
chotic disorder (e.g., schizophrenia) in young people or dementia in older
people. The presence of psychosis requires a combination of antidepressants
and antipsychotics, as neither medication by itself is particularly helpful. ECT
often is a first-line choice as well. The role of psychotherapy is limited.
Although relatively unusual now in Western culture, catatonia appears to
be more common in psychotic depression or bipolar mania than schizophre-
nia. Catatonia can be life-threatening, so warrants aggressive intervention.

9
ECT is often the treatment of choice in these cases, and benzodiazepines may
also acutely relieve symptoms.
2.3.5. Postpartum Depression
The perinatal period is characterized by a number of significant hormonal,
social, and physical changes that underlie an increased risk of depression. Up
to 6% of women experience a major depressive episode within the first
3 months after childbirth, and many develop symptoms even before deliv-
ery. In this period, major depression may be overlooked due to so-called
“excuses” for symptoms that include sleep deprivation, a change in social
roles, and physical changes associated with nursing and delivery; clinically it
is important to maintain a high index of suspicion for new depression post-
partum, particularly in high risk groups that include women with bipolar dis-
order, prior postpartum depression, recurrent prior depressive episodes, or
personality disorders. Indeed, the stresses from the so-called “excuses” may
increase the risk of depression.
2.3.6. Seasonal Affective Disorder
Certain individuals experience regular onset of depression during specific
times of the year. The more common pattern is the onset of depression
in the fall or early winter, with resolution in the spring. However, summer
depression also occurs in some individuals. People with bipolar disorder or
a history of recurrent depression are at higher risk of developing seasonal
patterns. Seasonal affective disorder is more common in higher latitudes. It
may respond to light therapy, preferentially compared with other depressive
subtypes.
Major Depressive Disorder 2.3.7. Treatment-Resistant Depression
Treatment-resistant depression has been variably defined, but typically refers
to cases in which symptoms do not improve with at least two adequate anti-
depressant trials from different medication classes. Although not formally
defined in DSM-5, it is common in clinical practice. Treatment-resistant
depression is common, affecting perhaps one-third to one-half of depressed
individuals. It has been associated with bipolar disorder, although is not lim-
ited to that condition. Approaches to treatment-resistant depression are pro-
vided in Chapter 7.
2.3.8. Severity Measures
Major depression is classified as mild, moderate, or severe, based on the
number of symptoms and level of functional impairment. Mild cases exhibit
a number of symptoms that just meets threshold with minimal functional
impairment. Severe cases meet all or nearly all of the symptoms, experience
psychosis, or demonstrate marked functional limitations. Moderate depres-
sion lies between these two extremes. Scores from rating scales are some-
times used to quantify severity.

Key Point: A number of subtypes of major depression exist, based

largely on the severity and combination of various symptoms.
These subtypes exhibit some differences in prognosis and treatment
10

response.

2.4.  Other Depressive Disorders

2.4.. Dysthymia
Dysthymia is now called “Persistent Depressive Disorder” in DSM-5, which is
descriptive since it is a condition in which depressive symptoms continue for
more than 2 years ( year in youth) and are largely unremitting, other than for
brief periods (2 months maximum). The definition in ICD-0 is similar. The
intent of these definitions is to identify cases of persistent depressed mood
accompanied by other symptoms from Box 2. that do not always meet cri-
teria for a full major depressive episode. Unlike major depression, anhedo-
nia is less characteristic of dysthymia. However, major depressive episodes
may occur during the course of dysthymia, a condition sometimes referred to
as “double depression.” Although currently classified as a mood disorder, at
times in the past dysthymia was considered a disorder of personality or tem-
perament, highlighting its persistent nature. Dysthymia tends to begin relatively
early in life and persist for years, if not a lifetime; it can be difficult to treat.
2.4.2. Disruptive Mood Dysregulation Disorder
“Disruptive Mood Dysregulation Disorder” (DSMDD) is a new diagnosis
in DSM-5 that may be included in ICD- as well.9 The key characteristics
are persistent irritable or low mood, accompanied by relatively frequent
and severe temper outbursts beginning in childhood. Criteria for DSMDD
were largely developed by a research group at the National Institute of

Making a Diagnosis of Depression

Mental Health (NIMH).9 This group was working with a group of irritable
children who were commonly referred with a diagnosis of bipolar disorder,
but lacked evidence of clear manic or hypomanic episodes. Family history
and outcome data suggested that these children suffered from a condition
associated with later developing depression rather than mania (i.e., bipolar
disorder). Although DSMDD appears to be relatively common, occurring in
up to 5% of children, controversy around the diagnosis continues, given its
recent addition to the psychiatric lexicon. Consequently, DSMDD should be
diagnosed only after other more commonly recognized conditions, such as
bipolar disorder, major depression, attention deficit hyperactivity disorder
(ADHD), oppositional defiant disorder, intermittent explosive disorder, or
autism, are ruled out.
2.4.3. Premenstrual Dysphoric Disorder

Chapter 2
“Premenstrual Dysphoric Disorder” is also a relatively new diagnosis,
although it arises from a long-standing history of behavioral and neuroveg-
etative symptoms that accompany menses that are popularly referred to as
premenstrual syndrome. Premenstrual Dysphoric Disorder includes affective
lability, commonly with periods of both depression and irritability, accompa-
nied by other typical depressive symptoms (Box 2.) and frequently physi-
cal agitation. The symptoms occur predictably during or a few days before

11
menses, every month or nearly so, and typically resolve within a few days.
Although discomfort with menses is nearly universal, Premenstrual Dysphoric
Disorder appears to affect perhaps up to 8% of premenopausal women and
exists across cultures.0
2.4.4. Secondary Depression
Major depression may be the singularly most common form of medical
comorbidity, as it occurs with brain insult or injury and many other stress-
ors and medical events. This co-occurrence is discussed in more detail in
Chapter 4.

2.5.  The Affective Spectrum

Some clinicians and scientists have advocated for the notion of an affective
spectrum that extends from minor depressive symptoms (e.g., dysthymia)
through recurrent depressive episodes that progress with the addition of
increasing manic symptoms (e.g., cyclothymia) through full hypomania (bipo-
lar II disorder) and mania (bipolar I disorder).2 Additionally, a number of
other conditions are sometimes added to the spectrum, such as anxiety disor-
ders, eating disorders, and some types of personality disorders. The rationale
for including these somewhat disparate conditions is that they not only com-
monly overlap with major depression, but also respond to antidepressants.
Unfortunately, this overlap may more accurately reflect the nonspecificity of
both the causes of depression and the effects of antidepressant medications,
Major Depressive Disorder rather than a spectrum per se. Nonetheless, the affective spectrum may have
heuristic value for research.

Key Point: The concept of an affective spectrum defined by various

combinations and severity of affective and other behavioral symptoms
is insufficiently developed to guide clinical decision making at this time.

2.6.  Course and Patterns of Illness of

Major Depression
Major depression can begin at any time across the life span, although it is
relatively uncommon prior to puberty. In the United States, the peak onset of
recurrent major depression is in the late teens or early twenties, but onsets
at other ages are not uncommon. Once initiated, without treatment a major
depressive episode typically lasts many weeks or months. Twenty percent
of individuals will continue to experience symptoms more than a year after
onset;3 some of these will develop persistent symptoms consistent with a
diagnosis of dysthymia that may continue for years and even to the end of
life. Treatment can dramatically decrease the duration and severity of symp-
toms in 3–8 weeks in perhaps one-half to two-thirds of individuals. Estimates
suggest that after a single episode of depression, 50% of individuals will, at
12

some point, experience at least one more episode; after a second episode,
the likelihood of recurrence increases to 80%. Although early episodes are
often associated with a precipitating stressor, this link decreases with each
recurrence. Consequently, over time the strongest predictor of future epi-
sodes is a history of past recurrences. Individuals with underlying psychiatric
(e.g., bipolar disorder) and medical (e.g., heart disease) conditions known
to increase risk for depression are also at higher risk of recurrence. Onset
of depression in childhood or adolescence predicts a likely course of recur-
rent depressive episodes later in life, as does significant childhood stress or
loss. The likelihood of recurrence steadily decreases as the time since the
last episode increases; hence, after two episodes, most treatment guidelines
recommend ongoing antidepressant treatment or therapy for prevention.
Depression, then, is a common, lifelong, recurrent illness.

2.7.  Differential Diagnosis of

Major Depression
2.7.. Bipolar Disorder
Depressive symptoms that occur in the course of bipolar disorder are not
unique, but look like any other case of depression. As noted, there may be
higher rates of atypical depression in bipolar individuals, but this occurrence is
not frequent enough to be diagnostic. Indeed, a diagnosis of bipolar disorder
requires the occurrence of either mania or hypomania, which differentiates it
from unipolar depression.
2.7.2. Schizophrenia or Schizoaffective Disorder

Making a Diagnosis of Depression

Depressive symptoms and episodes commonly occur in schizophrenic disor-
ders. Conversely, a small percentage of people with major depression also
experience psychosis, the defining symptoms of schizophrenia. Schizophrenia
and schizoaffective disorders are distinguished from psychotic depression
by the persistence of psychosis for a significant period of time (at least 2–4
weeks) prior to and beyond the depressive episode(s).
2.7.3. Sadness/Grief
The experience of bereavement following a loss can include symptoms like
those in Box 2.. Sadness following negative life events similarly is part of the
human condition and can be accompanied by the other symptoms of Box 2..
Depressive symptoms that do not meet full criteria for major depression and
that follow a stressor are sometimes referred to as an Adjustment Disorder.
The primary differentiator between “normal” sadness or grief and depression

Chapter 2
is that, in the former, the symptoms () follow a clear precipitant that would
make others sad in a similar situation; (2) typically resolve spontaneously;
and (3) most importantly, do not significantly impair psychosocial function.
However, stress and loss can precipitate a depressive episode, so monitoring
psychosocial function following a negative life event may permit early detec-
tion of a new depressive episode.

13
2.7.4. Drug/Alcohol Use Disorders
Chronic drug or alcohol use is commonly associated with low mood, anhedo-
nia, and most of the other symptoms in Box 2.. Alcohol abuse, in particular,
is known to be associated with, and to cause, high rates of depression. A pri-
mary depressive disorder can be differentiated from depression secondary
to substance abuse by occurrence of affective symptoms during periods of
sobriety and onset of affective symptoms prior to onset of substance abuse
in the former, or rapid resolution of affective symptoms following detoxifica-
tion in the latter.
2.7.5. Other Neurological and Medical Illnesses
As noted, depression is a common, nonspecific response to nearly any con-
dition that impacts brain function. Medical causes can occur anytime in life,
although they become more likely as individuals move into their fifties and
sixties. A first onset of a depressive episode after age 50, and especially after
age 60, warrants a careful medical evaluation to rule out conditions like those
discussed in Chapter 4.

References
 . Davison K. Historical aspects of mood disorders. Psychiatry 2008; 8:47–5.
2. Strakowski SM. Making a diagnosis of bipolar disorder. Chapter 2 in Bipolar
Disorder:  OAPL Library. New  York, NY:  Oxford University Press, 204,
pp. 5–6.
3. American Psychiatry Association. Diagnostic and Statistical Manual of Mental
Disorders (5th edition). Washington, DC: American Psychiatric Press, 203.
Major Depressive Disorder 4. World Health Organization. ICD-0 Classifications of Mental and Behavioural
Disorder: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health
Organization, 992.
5. Strakowski SM, Adler CM, Delbello MP. Is depression simply a nonspecific
response to brain injury? Curr Psychiatry Rep 203; 5:386–396.
6. Schuch JJ, Roest AM, Nolen WA, Penninx BW, de Jonge P. Gender differences
in major depressive disorder: results from the Netherlands study of depres-
sion and anxiety. J Affect Disord 204; 56:56–63.
7. Moussaoui D, Agoub M, Khoubila A. How should melancholia be incorpo-
rated in ICD-. World Psychiatry 202; (suppl. ):69–72.
8. Chakrabarti S. Psychotic and catatonic presentations in bipolar and depressive
disorders. World Psychiatry 202; (suppl. ):59–64.
9. Leibenluft E, Uher R, Rutter M. Disruptive mood dysregulation with dysphoria
disorder: a proposal for ICD-. World Psychiatry. 202; (suppl. ):77–8.
0. Figueira ML, Videira Dias V. Postpartum depression and premenstrual dys-
phoric disorder:  options for ICD-. World Psychiatry 202; (suppl.
):73–76.
14
Chapter 3

Epidemiology of
Depressive Disorders

3..  Population Prevalence and Incidence

Major depressive disorders are exceptionally common, perhaps the most
common medical conditions affecting humanity that are not associated with
aging or a self-limited virus. Although the specific prevalence of depressive
disorders varies somewhat across studies, nonetheless, based upon sev-
eral large US epidemiological investigations, the lifetime prevalence rate of
depression converges around 0–5%, with an annual rate of 3–5% (Table
3.).–4 European and other cross-national studies show similar rates of
depression in their populations (Table 3.).5 Several factors likely contrib-

15
15
ute to the variability observed among studies and populations. First, most
of these studies used different diagnostic criteria and ascertainment meth-
ods, thereby leading to different thresholds across individuals about the pres-
ence or absence of depression. Related to this factor, different cultures and
demographic groups likely express the symptoms of depression in different
ways, leading to variable validity and sensitivity of any specific criteria set or
ascertainment method. Third, depression is highly comorbid with a variety of
other medical and psychiatric conditions; consequently, depending upon how
these co-occurring and secondary cases were managed within various study
methods, and depending on differences in rates of these other conditions
across samples, the apparent rate of depression would change. With these
considerations in mind, coupled with the association of depression through-
out the course of humankind, perhaps the most parsimonious conclusion
is that depression is similarly common across humanity, although perhaps
somewhat variable in how it is expressed.

Key Point: Major depression is among the most common conditions

affecting humankind with rates up to 5% of the population; it is simi-
larly common across nations and cultures.

3.2.  Subgroups and Other Factors

3.2.. Sex
Depressive disorders are more common in women than men. Relatively
consistently across studies, women appear to be .5 to 2 times more
Major Depressive Disorder Table 3.  Prevalence (%) of Major Depression and Dysthymia
in Epidemiological Studies
Study Major Depression Dysthymia
Lifetime 2-month Lifetime 2-month
ECA, 980 4.9 2.7 3.2 —
NCS, 994 7. 0.3 6.4 2.5
NCS-R, 2005 — 6.7 — .5
CNCG, 996 9.6* 3.0+ — —
ECA = Epidemiologic Catchment Area study; NCS = National Comorbidity Survey;2
NCS-R = National Comorbidity Survey-Revised;3 CNCG = Cross-National Collaborative
Group.4
*Mean calculated across 9 countries. +Mean calculated across 7 countries.

likely to develop a depressive disorder. Although the specific reasons for

this sex-linked increased risk are not known, almost certainly some of the
variance is due to risks associated with the peripartum period, menarche,
menopause, and menstruation (i.e., premenstrual dysphoric disorder) that
are unique to women. In addition, since most cultures are more tolerant of
women expressing emotions than of men doing so, it is likely that depression
is under-recognized in the latter. Regardless, depression is common in both
sexes, so it should not be considered a uniquely female condition.
16

Key Point: Women are more likely than men to develop depression;

nonetheless, it is very common in both.

3.2.2. Age
Risk for depressive disorders extends across the life span, although is rela-
tively rare prior to puberty. When depression occurs in childhood or early
adolescence, it is often associated with later progression to (commonly)
bipolar disorder, (less commonly) schizophrenia, or (perhaps) other psychi-
atric conditions. The mean age at onset of depression is in the mid- to late
20s, with the largest peak of new cases occurring in the mid-20s to mid-30s.
Smaller peaks of increased rates of new onset depression are also seen in the
mid-teens and mid-50s.
The Epidemiologic Catchment Area (ECA) study observed that older age
groups demonstrated a relatively lower lifetime prevalence rate of depres-
sion than the younger cohorts, which is inconsistent with the notion that pop-
ulation rates of depression should accumulate with age. These findings raised
the question of whether depression is becoming more prevalent over time,
that is, increasing rates with each generation, which is called the “birth cohort
effect.” Later findings from the National Comorbidity Survey supported this
suggestion.2 However, there are other alternatives. Since depression can only
be diagnosed with clinical interviews, these findings might reflect generational
differences in awareness of or willingness to acknowledge behavioral symp-
toms. There is little doubt that stigma against mental illness has declined with
each generation over the past century, so these changes might impact how
people report behavioral conditions. Moreover, depression is associated with

Epidemiology of Depressive Disorders

increased risk of premature mortality (see Section 3.3), so that people with
depression may become under-represented in elderly samples. Finally, since
depression has been recognized and common since the dawn of civilization,
it would seem that if there was a history of birth cohort effects, then rates
of depression would be even higher than they are now, having accumulated
over the millennia of human history. Although some posit that the stresses
or experiences of modern life predispose people to depression, this sug-
gestion is inconsistent with the steady increase in human rights, health, and
opportunities, and the associated decreased level of stress simply to survive,
relative to centuries past. Indeed, claims that urban living increases the risk of
depression have not been substantiated by research. Currently, then, these
age-cohort effects are poorly understood. Regardless, depression can begin
at any time in life with no age group immune.

Key Point: Depressive disorders can begin at any time in life.

Chapter 3
3.2.3. Race/Ethnicity
As noted previously, depressive disorders are common across a wide range
of countries and cultures. Consequently, there are few racial and ethnic dif-
ferences. Within the United States, studies have been mixed as to whether

17
African Americans have somewhat lower rates of affective disorders in gen-
eral, and depressive disorders specifically, than other ethnic groups. Typically,
however, once other demographic differences are controlled, rates of
depression appear to be similar among US racial and ethnic groups.
In contrast to epidemiologic studies, for decades investigators have
reported that individuals of African descent in the United States and western
Europe are clinically diagnosed with schizophrenia at higher rates than whites,
with corresponding lower rates of affective disorders. African Americans
with mood disorders are up to 9 times more likely to be misdiagnosed with
schizophrenia than otherwise similar white individuals in clinical (as opposed
to research) settings. Similar differences are observed in Afro-Caribbeans in
the United Kingdom. Recent studies suggest that these diagnostic differences
result from clinicians overemphasizing psychotic symptoms while minimizing
affective symptoms in people of African descent, leading to misidentifica-
tion of mood disorders as schizophrenia. The use of structured interviews,
which forces a more systematic approach to diagnosis, seems to improve
this problem, although it does not eliminate it entirely. Clinicians of differ-
ent ethnic and racial backgrounds from their patients must also be aware of
differences in the way symptoms are described, that is, cultural differences
in “idioms of distress.” These studies remind clinicians to be sensitive to dif-
ferences in symptom expression among multicultural groups when assigning
a diagnosis.5–7

Key Point:  Depression is similarly common among ethnic groups,

although African Americans with affective disorders are at high risk for
being misdiagnosed with schizophrenia.
Major Depressive Disorder 3.2.4. Socioeconomic Status
In general, depressive disorders are minimally associated with socioeconomic
status, occurring similarly across income and educational levels. One pos-
sible exception to this statement is that the poorest and least educated may
have a slight increased risk of depression.2 However, as discussed in Section
3.3., depression negatively impacts work and psychosocial function, so the
directionality of this relationship is unclear, that is, whether poverty “causes”
depression or depression “causes” poverty. Regardless, the additional risk is
modest.

Key Point: Depressive disorders are similarly common across socio-

economic strata.

3.3.  Burden of Disease

3.3.. Morbidity and Disability
Although a depressive episode can be a singular event in a person’s life,
depressive disorders commonly progress into recurrent and even chronic
lifelong conditions. Moreover, as noted in Chapter 2, once a depressive
episode occurs, 50% of individuals develop subsequent episodes, and after
18

two episodes, the risk of yet another increases to 80%. Symptoms can per-
sist for many weeks, months, or even years in some individuals. Depressive
symptoms negatively impact psychosocial function, leading to impairments
across life domains including relationships, work, health, and even recreation.
Long-term follow-up studies suggest that depressive symptoms, even when
they no longer meet full syndrome criteria, are associated with impaired work
performance in more than 50% of affected individuals, including 20% who
are not able to work at all.8,9 Depression worsens the course of many major
medical conditions, including diabetes, heart disease, cancer, and stroke (see
Chapter 4). Consequently, major depression is recognized as one of the top
five leading causes of disability; specifically, a study from the Harvard School
of Public Health predicts that by the year 2020, depression will be the leading
cause of disability worldwide.0 Each year, more is spent on medical care for
depressive disorders than all cancers combined. Moreover, depression is
typically the leading cause of missed days at work. Consequently, the societal
costs of depressive disorders are staggering: between direct expenses for
medical care and indirect costs related to lost productivity, the United States
spends $00 billion annually on depression. These financial costs pale in com-
parison to the human toll in the lives of people affected by depression and
their friends and family.

Key Point: Depression is a leading medical cause of disability world-

wide, and is associated with lost productivity at work, impairments
in relationships, decline in general health, and loss of life enjoyment.
3.3.2. Mortality and Suicide

Epidemiology of Depressive Disorders

Depressive disorders are associated with premature death at virtually every
age. Suicide is a major component of this risk and is a common consequence
of depressive disorders. Up to 8% of individuals with depression commit sui-
cide; this percentage increases to 20% in the absence of treatment. Rates
of attempted suicide are approximately twice as high as completed suicides;
although women make more attempts, men are more likely to kill themselves,
primarily due to choosing more violent means of death. Finally, suicidal ide-
ation occurs in up to half of depressed individuals.
Several factors have been associated with an increased risk of suicide in
the course of depression. In particular, the presence of drug and alcohol
abuse, inadequate treatment, co-occurring anxiety disorders, and hopeless-
ness increase the risk of suicide. Chronic or recurrent depressive symptoms
increase the risk of suicide, as does the presence of other chronic medical or
psychiatric disorders. Suicide rates typically increase with age. The strongest
predictor of suicide is a history of previous suicide attempts. Nonetheless,

Chapter 3
preventing suicide remains difficult. Although risk factors may be useful to
predict the behavior of groups, they are often difficult to apply to a specific
individual at a specific time. The treatment of suicidal individuals with depres-
sion is discussed in more detail in Chapter 0.
In addition to its association with suicide, depression also appears to increase
the risk of all-cause mortality.2 Namely, depression is associated with higher

19
rates of many medical problems, including cardiovascular and cerebrovascular
disease and cancer. Moreover, depression is a common comorbidity across
many major medical illnesses, and it is typically associated with poorer general
outcomes and increased risk of premature death (see Chapter 4). Some of
these effects may be due to depressed individuals having higher rates than the
general population of cigarette use and drug and alcohol abuse, behaviors that
are known to increase the risk of cancer and cardio- and cerebrovascular dis-
eases. In fact, cigarette use may also independently increase the risk of suicide.
There is a complex relationship between heart disease and depression in
which the combination of conditions worsens the outcomes of both. For
example, in the Framingham heart study, although depression was not asso-
ciated with specific cardiac events per se, its presence increased the risk of
all-cause mortality in individuals with cardiovascular disease.3 Although the
specific mechanisms of these interactions between depression and heart dis-
ease are not known, several hypotheses have been proposed and are listed in
Box 3.. Similar findings have been observed following stroke.2
Through potentially a variety of associations and mechanisms, then,
depressive disorders increase morbidity and mortality. Because depression is
so common, it therefore is one of the world’s leading public health problems,
so effective treatment of depression becomes critical (see Chapter 9).

Key Point: Individuals with depressive disorders have higher mortal-

ity rates than their peers from the general population, and suicide is
a major contributor to this increased risk. Depression is one of the
world’s major public health problems.
Major Depressive Disorder
Box 3.  Proposed Links Between Depression and
Cardiovascular Mortality
Stress-diathesis hypothesis
Increased activity of HPA axis in depression leads to
. chronic adrenaline release;
2. sustained blood pressure elevation;
3. damage to coronary arteries and heart disease.

Autonomic dysregulation
Sympathetic/parasympathetic imbalance of depression leads to
. reduced heart rate variability;
2. inability of heart to respond to demands;
3. increased rates of arrhythmias & sudden death.

Platelet aggregation
Depression is associated with serotonin abnormalities that
. alter platelet aggregation properties;
2. increase clot formation in coronary arteries;
3. increase risk of CAD and sudden death.
20

HPA = hypothalamic-pituitary-adrenal, CAD = coronary artery disease.

Adapted from Seymour & Benning2

References
. Weissman MM, Bruce ML, Leaf PJ, Florio LP, Holzer C. Affective disorders.
In: Robins LN, Regier DA, eds., Psychiatric Disorders in America: The Epidemiologic
Catchment Area Study, pp. 53–80. New York: Free Press, 99.
2. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S,
Wittchen HU, Kendler KS. Lifetime and 2-month prevalence of DSM-III-R psy-
chiatric disorders in the United States. Results from the National Comorbidity
Survey. Arch Gen Psychiatry 994; 5:8–9.
3. Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova
M, Kessler RC. Lifetime and 2-month prevalence of bipolar spectrum disor-
der in the National Comorbidity Survey replication. Arch Gen Psychiatry 2007;
64(5):543–552.
4. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu H-G,
Joyce PR, Karam EG, Lee C-K, Lellouch J, Lepine J-P, Newman SC, Rubio-Stipec
M, Wells E, Wickramaratne PJ, Wittchen H-U, Yeh E-K. Cross-national epide-
miology of major depression and bipolar disorder. JAMA 996; 276:293–299.
5. Strakowski SM. Chapter 3: Epidemiology. In: Bipolar Disorder. Oxford American
Psychiatry Library. New York: Oxford University Press, 204. [Note: Segments
of section 3.2.2. are taken directly from this previous publication with permis-
sion of the author and the publisher.]
6. Strakowski SM, Keck PE Jr., Arnold LM, Collins J, Wilson R, Fleck DE, Corey
KB, Amicone J, Adebimpe VR. Ethnicity and diagnosis in patients with affective
psychoses. J Clin Psychiatry 2003; 64:747–754.
 7. Gara MA, Vega WA, Arndt S, Escamilla M, Fleck DE, Lawson WB, Lesser I,

Epidemiology of Depressive Disorders

Neighbors HW, Wilson DR, Arnold LM, Strakowski SM. Influence of patient
race and ethnicity on clinical assessment in patients with affective disorders.
Arch Gen Psychiatry 202; 69:593–600.
8. Judd LL, Schettler PJ, Solomon DA, Maser JD, Coryell W, Endicott J, Akiskal
HS. Psychosocial disability and work role function compared across the
long-term course of bipolar I, bipolar II and unipolar major depressive disor-
ders. J Affect Disord 2008; 08:49–58.
9. Judd LL, Akiskal HS, Zeller PJ, Paulus M, Leon AC, Maser JD, Endicott J, Coryell
W, Kunovac JL, Mueller TI, Rice JP, Keller MB. Psychosocial disability during the
long-term course of unipolar major depressive disorder. Arch Gen Psychiatry
2000; 57:375–380.
0. Murray CJ, Lopez AD. The Global Burden of Disease:  A  Comprehensive
Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors
in 990 and Projected to 2020. Cambridge, MA: Harvard School of Public
Health, 996.
. National Network of Depression Centers. “The Facts.” http://www.nndc.
org/the-facts.

Chapter 3
2. Seymour J, Benning TB. Depression, cardiac mortality and all-cause mortality.
Adv Psychiatr Treatment 2009; 5:07–3.
3. Wulsin LR, Evans JC, Vasan RS, Murabito JM, Kelly-Hayes M, Benjamin EJ.
Depressive symptoms, coronary heart disease, and overall mortality in the
Framingham Heart Study. Psychosom Med 2005; 67:697–702.

21
Chapter 4

Illness Comorbidity and

Co-occurrence with
Depressive Disorders

4..  What Is Comorbidity?

In medical parlance, “comorbidity” refers to the concurrent presence of two
or more distinct medical conditions. For example, if someone with coronary
artery disease develops streptococcal pharyngitis, since these two illnesses
are etiologically unrelated, they are distinct and therefore are comorbid. It
is expected that people with any one illness will develop second unrelated
illnesses at essentially the base population rate. When this expectation is vio-

23
23
lated, it suggests that the conditions share risks. In contrast, if an individual
with diabetes experiences renal failure, since these conditions share an under-
lying vascular pathology, rates of each are expected to occur at higher than
population base rates. Although this latter situation is often called comorbid-
ity, technically that is a misuse of the term, with “co-occurrence” being more
accurate. Therefore, the term “co-occurrence” is often preferred.
Because the specific etiologies of depressive disorders are both variable
and largely unknown, defining comorbidity is relatively difficult, although sec-
ondary illnesses occurring at population base rates that are unrelated to the
central nervous system (e.g., again, streptococcal pharyngitis) likely meet the
strict definition. Individuals with depression are not protected from illnesses
that affect the general population. However, individuals with depression also
exhibit elevated rates of a number of conditions that suggest common eti-
ologies or risk factors. Alternatively, depression may be the most common
co-occurring “secondary” illness in medicine, with increased rates in a wide
variety of psychiatric, neurologic, and medical conditions.2 In this chapter we
will discuss some of these reciprocal relationships.

Key Point: Depressive disorders are commonly complicated by other

psychiatric and medical conditions and, conversely, frequently compli-
cate the courses of other illnesses.
Major Depressive Disorder 4.2.  Co-occurrence of Depression and Other
Psychiatric Conditions
Major depression occurs commonly with other psychiatric disorders.
Whether depression is viewed as a consequence (secondary) or cause
(primary) of another illness depends on which condition is used to define a
particular case. In fact, determining whether depression is “primary” or “sec-
ondary” is often difficult, so this definition is typically based on which condi-
tion began first or which is more severe. In many instances, it is not possible
to retrospectively make this determination; moreover, this categorization is
based upon an assumption of causality, that is, that one condition produces
the other, when perhaps it is more likely that these syndromes share com-
mon risk factors leading to the expression of both. Indeed, the individual
symptoms of many psychiatric syndromes are nonspecific, almost guaran-
teeing overlap among the various disorders defined in DSM-5 or ICD-0.2
That said, when cases are specifically defined by a psychiatric disorder other
than depression, elevated rates of depression occur almost universally (see
Table 4.), supporting suggestions that the syndrome of depression is par-
ticularly nonspecific.2 Conversely, when depression is used to define cases
(i.e., depression is primary), elevated rates of other conditions are some-
what limited and include anxiety, substance use and impulse control disorders
24

(Table 4.2).
Table 4. lists rates of depression in several common psychiatric conditions
that were derived from best estimates of variable rates across publications
(see Strakowski et al.2 for details). A similar “best estimate” approach was used
to create Table 4.2. As illustrated in Table 4., co-occurring major depression
is common in virtually every major psychiatric illness with increased risks of

Table 4.  Lifetime Prevalence of Co-occurring Major

Depression in Common Psychiatric Disorders
Condition Lifetime Prevalence of
Depression
Bipolar I disorder 90%
Schizophrenia 50%
Obsessive compulsive disorder 30%
Panic disorder 50%
Generalized anxiety disorder 67%
PTSD 37%
ADHD 25%
Alcohol use disorders 40%
Drug use disorders 40%
Personality disorders 23%
PTSD = post-traumatic stress disorder; ADHD = attention deficit hyperactivity disorder;
PD = personality disorder.
Adapted from: Strakowski SM, Adler CM, DelBello MP. Is depression simply a non-specific
response to brain injury? Curr Psychiatry Rep 203; 5:386–393.
 Illness Comorbidity and Co-occurrence
Table 4.2  Psychiatric Conditions Co-occurring with
Primary Depression
Condition Lifetime Prevalence in
Primary Depression
Any anxiety disorder 60%
   GAD 50%
   Social phobia 30%
   PTSD 20%
Impulse control disorder 30%
Personality disorder 40%
Alcohol use disorder 7%
Drug use disorder 8%
GAD = generalized anxiety disorder; PTSD = post-traumatic stress disorder.
See references 3–7.

2 to 5 times (or greater) compared to the general population base rate of

Chapter 4
0–5% (Chapter 3). As noted by Strakowski et al.,2 it is actually rather dif-
ficult to identify a psychiatric disorder in which an increased risk of depres-
sion is absent. Consequently, it appears that any psychiatric illness increases
the risk for developing major depression. When depression develops dur-

25
ing the course of another psychiatric illness, this co-occurrence is associated
with earlier age at onset and poorer outcomes that include decreased rates
of recovery, increased rates of suicide, and worse psychosocial function.2
Moreover, multiple co-occurring illnesses (i.e., 2 or greater) are common.3
Conversely, the co-occurrence of anxiety, substance use, and impulse control
disorders in the course of depression similarly worsens outcomes. Several of
these common co-occurrences warrant additional comment.
4.2.. Bipolar Disorder
Bipolar I disorder is defined by the occurrence of mania. However, in up to
90% of individuals, major depressive episodes also occur; in fact, the depres-
sive symptoms dominate the long-term course of illness and morbidity asso-
ciated with bipolar disorder. Bipolar II disorder requires the occurrence of
depression by definition, so there is a 00% overlap.
4.2.2. Anxiety Disorders
Anxiety disorders are exceptionally common in people with “primary” depres-
sive disorders, occurring in up to 60% of individuals, and depression even
more commonly develops during the course of primary anxiety disorders. In
particular, there is a very strong relationship between major depression and
generalized anxiety disorder (GAD), specifically, such that co-occurrence is
the rule rather than exception. For example, in a New Zealand birth cohort
study,4 037 individuals were followed for up to 32 years; 2% developed
co-occurring GAD and major depression by adulthood. Among those who
developed depression, half also experienced GAD; in those with GAD, more
than 70% developed depression. Individuals who developed both conditions
were essentially equally as likely to have either one develop first. Similarly,
Major Depressive Disorder depression commonly co-occurs with social phobia, obsessive-compulsive
disorder (OCD), panic disorder, and post-traumatic stress disorder (PTSD),
suggesting shared mechanisms underlying anxiety and depressive disorders
(see Chapters 5 and 6).
4.2.3. Substance Use Disorders
Drug and alcohol abuse are elevated during the course of major depression,
occurring at perhaps twice the rates of the general population. Conversely,
rates of depression in primary drug- and alcohol-dependent individuals are
elevated up to 4 times the general population rates. Most individuals who
abuse alcohol will develop depressive symptoms, with many of those pro-
gressing to a major depressive episode or dysthymia. This co-occurrence can
be lethal, as the combination of depression and substance abuse significantly
increases the risk for suicide over either condition alone.
4.2.4. Personality Disorders
Up to 40% of individuals with personality disorders experience major depres-
sion. Although studies will report this co-occurrence with either condition
as the “primary” illness, since personality disorders are defined as lifelong,
in general they are probably the primary condition. However, some posit
that chronic affective symptoms may lead to the development of a personal-
ity disorder that was not present prior to the depressive illness. Regardless,
26

among the personality disorders, the Cluster C group, especially avoidant

personality disorder, appears to carry the highest risk, although depression
is also common in the course of borderline personality disorder and other
Cluster B conditions.5 The presence of a personality disorder is associated
with decreased treatment response of depression.
4.2.5. Dysthymia (Persistent Depressive Disorder)
Current diagnostic criteria sets permit the concurrent diagnosis of both
major depression and dysthymia, distinguished primarily by the relative chro-
nicity of the symptoms (i.e., dysthymia is more chronic; see Chapter 2). This
co-occurrence is common and has been referred to as “double depression.”
It is associated with poor treatment response.

Key Point: The course of depression is complicated by anxiety, sub-

stance use, and impulse control disorders. Conversely, co-occurring
depression is ubiquitous in other psychiatric conditions.

4.3.  Co-occurrence of Depression and Other

Neurological and Medical Illnesses
In addition to co-occurring in most, if not all, psychiatric conditions, depres-
sive disorders are also commonly part of the course of neurological illnesses.
As illustrated in Table 4.3, rates of depression are elevated 2 to 5 times higher
in most common neurologic conditions, such as stroke, epilepsy, migraine,
and dementia, as up to half of individuals are affected.2 In fact, coupled with
 Illness Comorbidity and Co-occurrence
Table 4.3  Lifetime Prevalence of Co-occurring Major
Depression in Common Non-Psychiatric Neurologic Conditions
Condition Lifetime Prevalence of
Depression
Stroke 30%
Epilepsy 35%
Parkinson’s disease 40%
Alzheimer’s disease 50%
Multiple sclerosis 50%
Migraine 47%
Adapted from: Strakowski SM, Adler CM, DelBello MP. Is depression simply a non-specific
response to brain injury? Curr Psychiatry Rep 203; 5:386–393.

the findings in psychiatric disorders, this co-occurrence is so common as to

suggest that depression can be a consequence of any condition that impacts
brain function. As with psychiatric conditions, depression worsens the course

Chapter 4
of illness of neurological conditions and is associated with treatment failure
and poor functional recovery.
The risk for increased depression associated with medical illness is not lim-
ited to conditions that directly impact brain function. For example, as listed in
Table 4.4, rates of depression are elevated across a wide variety of medical

27
conditions including, for example, coronary artery disease, cancer, autoim-
mune disorders, metabolic disorders, and chronic pulmonary and renal dis-
ease.2 The specific mechanisms underlying these associations are not known;
although the occurrence of stress from chronic illness has been proposed
as one common link, the risk appears to be greater in illnesses that impact
brain function, as evidenced by comparing Table 4.4 with Tables 4. and 4.3.
Importantly, although rates of depression are elevated in these various medi-
cal, neurological, and psychiatric conditions, co-occurrence is not 00%, so
that it is likely there are additional underlying shared genetic or neurobio-
logical risks leading to depression. Conversely, causes of depression may also
increase the risk of other medical conditions. These possibilities are discussed

Table 4.4  Lifetime Prevalence of Co-occurring Major

Depression in Common Non-Psychiatric Medical Conditions
Condition Lifetime Prevalence of
Depression
Cardiovascular disease 35%
COPD 40%
Chronic renal disease 30%
Cancer 30%
Diabetes 33%
COPD = chronic obstructive pulmonary disease.
Adapted from: Strakowski SM, Adler CM, DelBello MP. Is depression simply a non-specific
response to brain injury? Curr Psychiatry Rep 203; 5:386–393.
Major Depressive Disorder in Chapters 5 and 6. Several of these medical conditions warrant additional
comment.
4.3.. Dementia
In older individuals, particularly in those with no prior history, the develop-
ment of a new depressive episode may be the first indication of an evolving
dementing illness (e.g., Alzheimer’s disease). In particular, the presence of
significant cognitive impairment during the depressive episode, or a strong
family history of dementia, should initiate a high index of suspicion for the
possibility of dementia. However, depression in old age is common, indepen-
dent of dementia, so it should not be assumed to be the latter. Moreover,
depression causes cognitive impairments, especially decrements in concen-
tration, that may be misinterpreted as dementia in older patients, sometimes
termed “pseudodementia.” Conversely, depression may also develop during
the course of dementia and may contribute to worsening cognitive symp-
toms; again, in this circumstance a high index of suspicion of the combina-
tion is warranted, and careful neuropsychological evaluation is necessary in
order to make maximally effective treatment decisions. Finally, there is some
evidence, albeit less strong, that recurrent major depression earlier in life
increases the risk of developing dementia in senescence.
4.3.2. Parkinson’s Disease
28

As with dementia, a new onset of a depressive episode in older age might

herald the onset of Parkinson’s disease, particularly in the presence of the
other neurological symptoms. Likewise, depression commonly occurs during
the course of Parkinson’s disease and can be easily missed as a contributor to
sudden failure to respond to treatment or make psychosocial progress. Again,
a high index of suspicion for this co-occurrence is warranted.
4.3.3. Cardiovascular Disease
There is now a vast medical literature bidirectionally linking depressive and
cardiovascular disorders. Heart disease is more common in people with
depression and is associated with developing depression. Outcomes in
people with both are typically worse than either condition alone. Several
hypothesized mechanisms underlying the associations between cardiac
mortality and depression have been proposed that include increased
hypothalamic-pituitary-adrenal (HPA) axis reactivity, autonomic dysregula-
tion, and platelet aggregation abnormalities due to serotonin dysregulation;
these are outlined in Chapter 3 (Box 3.) but none has been firmly estab-
lished or has produced novel treatment interventions as yet. As with the
other medical conditions in Table 4.4, failure of an individual with cardiovas-
cular illness to predictably progress with treatment warrants a careful review
for depression.

Key Point: Rates of depression are elevated in a wide variety of medical

illnesses, but particularly those that affect the brain. A high index of
suspicion for co-occurring depression should be maintained in these
illnesses, particularly when treatment is less effective than expected.
 4.4.  Depression Is Nonspecific

Illness Comorbidity and Co-occurrence

As suggested throughout this chapter, depression occurs within the context
of a wide variety of medical, psychiatric, and neurological conditions. It is
a particularly common secondary illness in any condition that impacts brain
function. Together, these findings suggest that depression represents a non-
specific response to brain injury or insult, expressed through a shared neu-
robiological final pathway, but arising from a wide variety of causes.2 Possible
models for these neurobiological pathways and etiologies are discussed in
Chapters 5 and 6. Importantly, one implication of this possibility is that the
putative underlying cause may need to be first identified and managed in
order to maximize treatment outcomes for people suffering from depression.
This consideration is discussed additionally in Chapters 7–0.

Key Point: Depression occurs commonly in the context of any condi-

tion that impacts brain function, suggesting that, in many cases, it is a
nonspecific response to brain insult or injury.

Chapter 4
References

29
. Strakowski SM. Chapter 4: Illness comorbidity and co-occurrence in bipo-
lar disorder. In:  Bipolar Disorder. Oxford American Psychiatry Library.
New York: Oxford University Press, 204.
2. Strakowski SM, Adler CM, DelBello MP. Is depression simply a non-specific
response to brain injury? Curr Psychiatry Rep 203; 5:386–393.
3. Rush AJ, Zimmerman M, Wisniewski SR, Fava M, Hollon SD, Warden D,
Biggs MM, Shores-Wilson K, Shelton RC, Luther JF, Thomas B, Trivedi MH.
Comorbid psychiatric disorders in depressed outpatients: demographic and
clinical features. J Aff Disord 2005; 87:43–55.
4. Moffit TE, Harrington H, Caspi A, Kim-Cohen J, Goldberg D, Gregory AM,
Poulton R. Depression and generalized anxiety disorder:  cumulative and
sequential comorbidity in a birth cohort followed prospectively to age 32 years.
Arch Gen Psychiatry 2007; 64:65–660.
5. Mantere O, Melartin TK, Suominen K, Rytsala HJ, Valtonen HM, Arvilommi P,
Leppamaki S, Isometsa ET. Differences in Axis I and II comorbidity between
bipolar I and II disorders and major depressive disorder. J Clin Psychiatry 2006;
67:584–593.
6. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ,
Walters EE, Wang PS. The epidemiology of major depressive disorder: Results
from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;
289:3095–305.
7. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, Goodwin
FK. Comorbidity of mental disorders with alcohol and other drug abuse.
Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 990;
264:25–258.
Chapter 5

Neurophysiology of
Depressive Disorders

5..  Clinical Considerations for Models of the

Neurophysiology of Depression
As discussed in Chapters 2 and 4, depression is a heterogeneous condition
with a wide range of symptoms that commonly occur within the context of
other psychiatric and medical illnesses. Consequently, it appears that multiple
etiologies lead to the common “end-state” syndrome we call major depres-
sion. As we discuss the neurobiology of depression, then, we will primarily
focus on the features of this “end-state,” rather than the various co-occurring
syndromes that are beyond the scope of this handbook. With these thoughts

31
31
in mind, neurobiological models of depression must consider the following:
() a wide range of cognitive, affective, and neurovegetative symptoms and
signs; (2) a significant risk for recurrence after a first episode; (3) respon-
siveness to antidepressants; (4) a lifelong risk period; and (5) the assump-
tion of multiple and diverse precipitants. These clinical considerations suggest
that neurophysiological models of depression must describe a dysfunction
of mood and cognitive brain systems that are susceptible to interruption at
various points along pathways, and that have a genetic basis, at least in part
(reviewed clinically in Chapter 2).

5.2.  Depression Arises from Abnormalities in

Emotional and Cognitive Brain Networks
5.2.. Emotional Brain Networks and Depression
Based upon this brief review, the expression of depression almost cer-
tainly includes abnormalities in mood regulation and associated cognitive
processes.,2 Like most complex human behaviors, emotional states are con-
trolled by networks originating in the prefrontal cortex (Figure 5.).,2 The
prefrontal cortex is heterogeneous, composed of multiple histologically dis-
tinct regions that share a common general functional architecture. Namely,
each prefrontal area maps to specific regions of striatum then pallidum then
thalamus before connecting back to the originating prefrontal area to form
iterative brain networks with both feedback and feed-forward properties.
The various structures that comprise these networks receive sensory and
other processed information from throughout the brain—information that
Major Depressive Disorder
Dorsolateral Striatum
prefrontal cortex Nucleus accumbens

Globus pallidus

Anterior cingulate
Thalamus

Orbitofrontal
(ventral) prefrontal
cortex

Amygdala

Figure 5.  Schematic of key areas involved in the expression of depression

(adapted from Strakowski).

is integrated within prefrontal cortex. From a comparative evolutionary per-

32

spective, with increasing complexity of the prefrontal cortex, animal species

demonstrate increasingly nuanced variations of primitive “fight/flight” and
reward-seeking behaviors—behaviors driven by amygdala and ventral stria-
tum, respectively, which are perceived by humans as emotions.
Humans are distinguished from other animals by relatively excessive pre-
frontal development that supports the complex emotional-social behaviors
characterizing our species. Two prefrontal networks specifically modulate
human emotional function, and, like most prefrontal networks, follow the
previously reviewed pattern of organization. The ventrolateral prefrontal
network manages external emotional cues, such as correctly interpreting
facial expressions in others.,2 The ventromedial prefrontal network pro-
cesses internally referenced emotional states, that is, how we “feel.”,2 These
networks are illustrated in Figures 5.2 and 5.3.
Cognitive networks are similarly organized, but they originate in dorsal pre-
frontal areas (Figure 5.3). However, because they are reciprocally connected
to emotional (ventral) networks via the anterior cingulate, when emotional
prefrontal systems are activated, dorsal (cognitive) networks are deactivated.
It is this deactivation that may underlie the cognitive symptoms of depression.
Conversely, when cognitive networks are activated, they decrease emotional
network activity. This latter situation may be the neurobiological basis for suc-
cessful psychotherapy. Knowledge of these networks, then, forms a context
for functional neuroanatomic models of depression.

Key Point: Human emotional behavior is supported by ventral prefron-

tal cortical iterative networks that are reciprocally connected to dorsal
(cognitive) networks.
 of Depressive Disorders
External Emotional Control Internal Emotional Control

Thalamus Thalamus

G. pallidus G. pallidus
Amygdala

Ventromedial Nucleus
striatum accumbens

Chapter 5 Neurophysiology
Ventrolateral Ventromedial
PFC PFC/OFC
(BA 10, 47) (BA 11)
Anterior
temporal cortex Rostral
(BA 38, 20) insula

Anterior cingulate Subgenual cingulate

(BA 24, 32) (BA 25)

Cognition (Dorsal PFC)

33
Figure 5.2  Schematic of the proposed ventrolateral and ventromedial prefrontal
networks underlying human emotional brain networks (adapted from Strakowski,2).

5.2.2. Prefrontal Cortical Regions Are Dysfunctional

in Depression
Research consistently demonstrates that dysfunction of or disruption within
the prefrontal cortical networks contributes to the expression of depres-
sion. In particular, imaging studies find that the ventromedial prefrontal
cortex, which modulates internal mood states, as noted in Figure 5.2., is
over-activated in depression.3 Injuries localized to this brain region may actu-
ally eliminate depressive symptoms. The ventromedial prefrontal cortex is
heavily connected to the amygdala (see Section 5.2.3). It also heavily projects
to hypothalamic nuclei; these nuclei control the autonomic nervous system
and likely are the effector regions that create the physical sensations of emo-
tions (i.e., “feelings”).
Conversely, dorsolateral, and perhaps ventrolateral, prefrontal regions are
commonly under-activated in imaging studies of depression, and injuries to
these brain areas increase the risk of developing depression.3 The dorsolateral
prefrontal cortex is responsible for cognitive activities such as working mem-
ory, attention, and executive functions (e.g., planning and problem-solving).
This brain area is strongly connected to the hippocampus, which also sub-
serves memory and is abnormal in depression (see Section 5.2.5). As noted,
the dorsolateral prefrontal cortex is reciprocally connected to ventral (emo-
tional) prefrontal regions, so a decrease in dorsolateral prefrontal activation
may “release” excessive activation in the ventral prefrontal cortex. Indeed,
the opposite activation abnormalities noted between dorsolateral and
Major Depressive Disorder
Cognitive Control Emotional Control

Thalamus Thalamus

G. pallidus G. pallidus

Hippocampus Amygdala

Dorsal Ventral
striatum striatum/NA

Dorsolateral Ventrolateral/
PFC medial PFC
(BA 45) (BA10,11,47)

Anterior cingulate
(BA 24,32)
(Reciprocal connection)
34

Figure 5.3  Schematic of relationship between a cognitive (dorsal) and emotional

(ventral) brain networks. The latter are consolidated from Figure 5.2, simplified for this
diagram.

ventromedial prefrontal areas in depression suggest an imbalance between

cognitive and emotional brain networks such that extreme negative mood
states are associated with attentional and memory impairments (i.e., the
symptoms of depression). Of note, effective treatment corrects many of
these prefrontal abnormalities.
This reciprocal connection between prefrontal areas appears to occur within
the anterior cingulate. The cingulate is an integrative structure that manages
conflicting stimuli; its most anterior and ventral parts (i.e., subgenual cingulate)
are primarily responsive to emotional cues with increasing (non-emotional)
cognitive modulation as one moves dorsally and posteriorly (see Figure 5.).
The subgenual cingulate has been shown to be smaller and to have abnor-
mal metabolic activity in depressed subjects compared with healthy subjects.
Abnormalities in other areas of the anterior cingulate are also observed in imag-
ing studies of people with depression performing a variety of cognitive tasks.

5.2.3. In Depression, the Amygdala Is Overly Negative

As noted, the amygdala is responsible for “fight or flight” behavioral responses
to threats. It can be conceptualized as sending emotional signals (anger and
fear, respectively) as part of those responses. In humans, ventral prefrontal
networks nuance this response to contribute to the wide range of human
emotional states that characterize our species and that have gone awry in
depression (e.g., guilt, frustration, irritability, embarrassment). Imaging studies
suggest that during depression the amygdala is overly responsive to negative

of Depressive Disorders
emotional cues and, conversely, demonstrates blunted activation to positive
cues.4 Consequently, these findings suggest that, during depression, the amyg-
dala is sensitized toward negative emotional experiences. Successful antide-
pressant treatment appears to correct this amygdala bias.
5.2.4. Connections among Prefrontal Regions and
Amygdala Are Disrupted in Depression
As noted, in humans our excessively developed prefrontal cortex nuances
our emotional behaviors and experiences. In depression, this nuance is lost. In
part, this loss may reflect the specific regional abnormalities noted—that is, an

Chapter 5 Neurophysiology
overly activated emotional brain (i.e., ventral prefrontal cortex and amygdala)
with a hypo-responsive cognitive correction (i.e., dorsolateral prefrontal cor-
tex). However, depression does not simply localize to specific brain regions,
but instead appears to result from a more extensive network failure—a fail-
ure of the integrative processes of the prefrontal cortical circuits. Consistent
with this suggestion, a number of recent imaging studies report that during
depression, functional connections among the various brain regions of the
networks illustrated in Figures 5.2 and 5.3 appear to be lost, particularly those
between amygdala and prefrontal areas.4 Although the actual physical con-
nections among neurons are intact, the functionality of these connections fails.
Moreover, these studies suggest that disruptions anywhere in these networks

35
may increase the risk for depression. For example, in late-onset depression
in the elderly, abnormalities in white matter (i.e., the “connections”) occur
throughout these networks, consistent with this observation. With treat-
ment, as with the other abnormalities, functional connectivity improves.

5.2.5. The Hippocampus Is Smaller in Depression

A final common neuroimaging finding in depression is decreased hippocam-
pal volume. This finding appears to be associated primarily with recurrent or
chronic illness and may represent a consequence of a more severe course
of illness.4 The hippocampus is critical for memory functions, which are dis-
rupted in depression, as noted. The hippocampus is also closely integrated
into amygdala such that the two structures work together to consolidate
emotional memories and social behaviors. However, decreased hippocampal
volumes are also associated with chronic stress; stress is a common precipi-
tant for depression (Section 5.6), so that hippocampal volume findings may
simply reflect stress directly, rather than depression per se.

5.2.6. Functional Neuroanatomy of Depression: Summary

Taken together, neuroimaging research, coupled with studies of brain inju-
ries, suggests that the symptoms of depression arise from a loss of dorsal
and ventral prefrontal modulation of each other, the amygdala, and other
brain regions; that is, depression arises from a functional failure within these
prefrontal systems. Evidence that treatments modulate these abnormalities
provides validity of the model. Moreover, given the multiple components of
these networks, it is relatively straightforward to imagine disruptions from a
variety of causes impacting their function, consistent with a syndrome arising
Major Depressive Disorder from multiple etiologies. Some of these abnormalities may exist in individuals
at genetic risk for depression (see Chapter 6), consistent with an underlying
vulnerability in some families, but they also may occur de novo (e.g., with a
stroke). This model, then, provides a substrate to consider molecular and
other underlying causes of depression.

Key Point: The functional neuroanatomy of depression is characterized

by dysfunction of prefrontal cortical brain networks that modulate
human emotional and cognitive behaviors.

5.3.  Neurotransmitter Hypotheses

of Depression
5.3.. Monoamines: Serotonin and Norepinephrine
For decades, investigators hypothesized that mood disorders result from
dysfunctional monoamine neurotransmission, namely abnormalities in sero-
tonin and norepinephrine function and metabolism. These hypotheses arose
primarily from the neurochemical effects of antidepressants that typically
increase the availability of synaptic serotonin and, in some instances, nor-
epinephrine. Although monoamines originate in a limited number of specific
36

brainstem nuclei, they are widely distributed throughout the prefrontal net-
works described previously (Figures 5., 5.2, and 5.3).
Serotonergic abnormalities have been observed in studies of depressive
disorders for decades, driven in large part, as noted, by the observation
that most antidepressants alter aspects of serotonergic neurotransmission
(see Chapter 7). Some of the more common findings supporting the role of
serotonergic neurotransmission abnormalities in depression include the fol-
lowing: reduced serotonin metabolites (namely 5-hydroxyindoleacetic acid;
5-HIAA) in the cerebrospinal fluid of depressed and especially suicidal indi-
viduals; precipitation of depression with tryptophan depletion in individuals
with histories of depression (tryptophan is a metabolic precursor of sero-
tonin); abnormalities in serotonin transporter (5-HTT) function; and reduced
concentration of 5-HTA serotonin receptors.,4,5 Of note, 5-HTA receptors
are widely distributed throughout the prefrontal cortex as well as the amyg-
dala, hippocampus, and hypothalamic nuclei.4 The concentrations of these
receptors are decreased in imaging and postmortem studies in depressed
persons compared with healthy individuals. Similarly, imaging studies report
regionally specific abnormalities in 5-HTT function in these prefrontal net-
works, although there are inconsistencies in these reports. Animal models
of depression also demonstrate down-regulation of 5-HTA receptors and
abnormalities in 5-HTT function in brain structures homologous to those of
the human prefrontal networks that underlie the expression of emotions.4
Moreover, metabolism of the 5-HTA receptor and 5-HTT is regulated by
genes that have been, albeit inconsistently, associated with familial depression
(Chapter 6); these genes likely confer a risk for developing depression that
does not occur until other processes further disrupt the relevant prefrontal
networks,4,6 Nonetheless, together these findings and others suggest that

of Depressive Disorders
dysfunctional serotonergic neurotransmission within the previously reviewed
prefrontal networks almost certainly contributes to the expression of depres-
sion in many cases.
Similarly, effective antidepressants often decrease norepinephrine turn-
over in addition to having direct noradrenergic effects, and studies have
frequently observed abnormal noradrenergic neurotransmission in major
depression. Findings suggesting noradrenergic abnormalities in depression
include the following: elevated excretion of norepinephrine and its metabo-
lites in depressed individuals compared with healthy subjects; blunted growth
hormone response to α2-noradrenergic agonists (perhaps due to receptor

Chapter 5 Neurophysiology
down-regulation from elevated norepinephrine levels); precipitation of depres-
sive symptoms with norepinephrine depletion (using α-methylparatyrosine);
and links between depression and genes that affect norepinephrine
metabolism or the norepinephrine transporter (see Chapter 6). ,5,6
As with serotonin, norepinephrine receptors are widely distributed through-
out emotional and cognitive brain networks, so that abnormalities within this
neurotransmitter system will impact the function of these networks. Of note,
the noradrenergic and serotonergic systems are not independent, so a “pri-
mary” abnormality in one will almost certainly lead to “secondary” abnor-
malities in the other.
Finally, the third monoamine, dopamine, is commonly linked to psychiat-

37
ric disorders, although any role in depression is very ill-defined. Buproprion,
an effective antidepressant, may work through dopaminergic mechanisms,
although this possibility remains unclear. As noted in Chapter 4, Parkinson’s
disease, which is characterized by a specific lesion in dopamine neurotrans-
mission of the substantia nigra, has very high rates of co-occurring depres-
sion. Moreover, stimulants increase dopamine in the synapse, and may play
a secondary role in some antidepressant treatment regimens. Nonetheless,
dopaminergic abnormalities have not been identified consistently as underly-
ing major depression in general.
5.3.2. Glutamate and GABA
Glutamate is the predominant excitatory neurotransmitter in the brain,
particularly in prefrontal cortex; indeed, glutamate neurotransmission
occupies up to 85% of all of the brain’s synapses.7 Gamma-aminobutyric
acid (GABA) is the brain’s primary inhibitory neurotransmitter and is
present in most of the remaining synapses, so the function of emotional
and cognitive brain networks ultimately arises from a balance between
these two neurotransmitter systems, with monoamines serving a modu-
latory role.5–7 Magnetic resonance spectroscopy (MRS) studies find that
glutamate levels are decreased in prefrontal brain regions in depres-
sion. Moreover, abnormal GABA and glutamate levels in plasma, cere-
brospinal fluid, and postmortem studies have been noted in depression.7
Antidepressants across multiple drug classes alter glutamate receptor
responses, and chronic antidepressant administration reduces the presyn-
aptic release of glutamate; the time course of this effect is more consistent
with the therapeutic antidepressant response (which takes weeks) than the
Major Depressive Disorder immediate effects these drugs have on serotonin receptors and reuptake
(which occur in hours).7
Nonetheless, to date, no direct glutamate-specific antidepressant has been
successfully developed. However, recent studies report that pre-anesthetic
doses of ketamine, a glutamate N-methyl-D-aspartate (NMDA)–receptor
antagonist, may produce a rapid antidepressant response (within hours; see
Chapter 7). Additional research is needed to validate this novel treatment,
and doing so could shift the focus of antidepressant drug development from
the monoamine to glutamate systems.

Key Point: Depression is associated with metabolic and genetic abnor-

malities as well as dysfunction of several major neurotransmitters,
including serotonin, norepinephrine, glutamate and GABA. These
neurotransmitters are intimately involved in the function of prefrontal
brain networks that modulate mood and cognition.

5.4.  The Hypothalamic-Pituitary-

Adrenal Axis
Perhaps one of the first observations from biomedical studies of depres-
sion is that the hypothalamic-pituitary-adrenal (HPA) axis is dysfunctional.
38

The HPA axis controls the release of corticosteroids, which prepare our
bodies to manage acute stressful situations. The HPA axis originates in the
hypothalamic paraventricular nucleus that secretes corticotrophin-releasing
hormone (CRH) and vasopressin into the anterior pituitary gland. The ante-
rior pituitary then releases adrenocorticotropic hormone (ACTH), which
stimulates the adrenal gland to release corticosteroids, especially cortisol.
Rising cortisol levels provide negative feedback to the pituitary and hypo-
thalamus, decreasing additional CRH and ACTH release, thereby controlling
the overall stress response process (Figure 5.4). As noted previously, the
hypothalamus is heavily innervated by amygdala and prefrontal emotional
networks. In the short term, an increase in corticosteroids increases glu-
cose availability and adjusts energy management to allow a rapid survival
response, while suppressing a number of bodily functions that are not critical
for acute survival (e.g., digestion). Chronic stress disrupts this well-regulated
axis (see Section 5.6).
Studies in depression show abnormalities throughout the HPA axis,
typically consistent with a hyperactive or hyper-reactive (sensitized)
stress response system. Perhaps the first observation was that depressed
individuals fail to decrease cortisol release in response to administration
of dexamethasone. Failure to respond to dexamethasone is particularly
common in individuals with melancholic depression (see Chapter 2),
although this test is used clinically in the diagnosis of Cushing’s disease
(which has very high rates of co-occurring depression). Other abnormali-
ties observed within the HPA axis in depression include elevated plasma
 of Depressive Disorders
Hypothalamus (negative)
(paraventricular
nucleus)

CRH

Anterior (negative)

Chapter 5 Neurophysiology
pituitary

ACTH

Adrenal
cortex

39
Cortisol

Acute stress (“alarm”) response

Figure 5.4  The hypothalamic-pituitary adrenal (HPA) axis, illustrating the release of

corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH),
and cortisol.

cortisol concentrations, decreased corticosteroid function, and elevated

cerebrospinal CRH levels.8 CRH acts not only within the HPA axis, since
CRH receptors are located throughout the brain and, especially, in the
amygdala and prefrontal cortex. The HPA axis response may be blunted
in atypical depression. Consequently, abnormalities in CRH metabolism
and function may disrupt the emotional and cognitive networks previously
discussed. As discussed in Section 5.6, the HPA axis plays a central role in
linking stress and depression.

Key Point: Depression is associated with abnormalities within the HPA

axis, the body’s primary stress response system.
Major Depressive Disorder 5.5.  The Inflammatory Response
and Depression
Recent studies report associations between increased activation of the
immune system and depression. In particular, elevated levels of cyto-
kines, small proteins involved in immune cell signaling, have been observed
in depression.8 The specific cytokines involved are secreted by macro-
phages and typically modulate a pro-inflammatory response; these include
interleukin- (IL-), interleukin-6 (IL-6), and tumor necrosis factor-alpha
(TNF-α).8 Elevated levels of these proteins induce a “sickness behavior”
(familiar to everyone who has experienced a viral illness) that creates many
of the symptoms and signs of depression. Pro-inflammatory cytokine levels
are increased in a wide variety of chronic diseases, including stroke, some
cancers, heart disease, and renal failure, all of which have elevated levels of
depression. Moreover, interferon-α, used for the treatment of hepatitis C, is
associated with depression as a side effect nearly half of the time it is admin-
istered. Antidepressants may normalize levels of cytokines.8 Elevated levels
of pro-inflammatory cytokines impact HPA axis function, alter monoamine
and glutamate neurotransmission, and impair neuroplasticity processes in the
brain. However, the results of studies of cytokines are not always consis-
tent, so that the specific link between inflammation, the immune system, and
40

depression is still somewhat elusive.

Key Point:  Depression has been linked to the pro-inflammatory

response mediated by elevated levels of cytokines.

5.6.  Stress: A Common Pathway?

The strong association between stressful life events and the onset of depres-
sion is widely recognized; this association is observed both at the first epi-
sode and with recurrences. More recently, investigators have found that
even individual symptoms of depression may be linked to specific types of
acute stress, thereby expanding and refining this association.9 Animal mod-
els used to identify potential antidepressants are typically based upon mod-
els of chronic stress, leading some to propose that antidepressants may be
better thought of as “anti-stress-ants.”0 Chronic stress leads to decreased
dendritic growth in the hippocampus and amygdala. This impact of stress
on neurogenesis likely occurs through impaired expression of key growth
factors, such as BDNF (brain-derived neurotropic factor), coupled with
stress-induced local increases in glutamate that may precipitate neuronal
and glial loss.4, Effects of stress on neurogenesis are particularly important
in childhood brain development, and, indeed, major life events in youth are
one of the stronger predictors of later life depression. Stress also impacts
serotonergic neurotransmission: increased stress-induced cortisol release
decreases 5-HTT receptor binding.4,8 Hypothalamic 5-HTA receptors impact
CRH release within the HPA axis as well.8 Again through elevated release of
glucocorticoids, stress impacts glutamatergic neurotransmission by increasing

of Depressive Disorders
the release of glutamate from neurons, altering the responsiveness of glu-
tamate receptors, slowing the removal of glutamate from the synapse, and
altering the glial glutamate/glutamine cycle.7 Together, these effects alter
extracellular glutamate, which may become excitotoxic when elevated in
specific local regions, leading to injury or death of neurons and glia, thereby
disrupting the structure and function of the emotional and cognitive networks
that manage emotional behavior. Although acute stress increases HPA axis
activity and suppresses the immune response, chronic stress leads to changes
in the sensitivity of glucocorticoid receptors, resulting in increased cytokine
production. As noted in Chapter 4, depression is associated with a wide vari-

Chapter 5 Neurophysiology
ety of medical and psychiatric illnesses, all of which contribute significant life
stress. Consequently, acute or chronic stress from these conditions may be
the common shared etiologic mechanism leading to depression; however, ill-
nesses that affect the brain appear to have higher risk, beyond simply the
stress of being ill.0 Moreover, through effects mediated by the HPA axis,
stress may be a common etiology for many depressive episodes, but not all
episodes follow stressful life events.

Key Point:  Depression commonly follows stressful life events, and

stress impacts the networks that control human emotion and cogni-
tion through multiple mechanisms. Stress, then, may be a common

41
etiologic factor in many cases of depression.

5.7.  Summary of the Neurophysiology

of Depression
Depressi ve disorders appear to arise from disruption of
prefrontal-striatal-pallidal-thalamic brain networks that manage emotion and
cognition. These disruptions may result from multiple causes that include
abnormalities in brain development and neuroplasticity, abnormal function of
monaminergic or glutamatergic neurotransmission, dysfunction of the HPA
axis, or an excessive pro-inflammatory immune response. Underlying all of
these potential models of depression are genetic risk factors (Chapter 6) and
the potential impact of stressful life events. These varied risks for depression
are consistent with the observations stated at the beginning of this chapter,
that depression is associated with: () a wide range of cognitive, affective,
and neurovegetative symptoms and signs; (2) a significant risk for recurrence
after a first episode; (3) responsiveness to antidepressant therapies; (4) a life-
long risk period; and (5) the assumption of multiple and diverse precipitants.
Consequently, within a given individual, it is likely that one or more of these
diverse factors contribute to the development of a specific depressive epi-
sode. As we better understand the contributions of each of these potential
factors, it is hoped that treatments for depression can be individualized to
directly impact the underlying causes and elicit a more predictable and effec-
tive response.
Major Depressive Disorder References
. Strakowski SM. Chapter 5: Neurophysiology of bipolar disorder. In: Bipolar
Disorder, pp. 33–46. Oxford American Psychiatry Library. New York: Oxford
University Press, 204.
2. Strakowski SM. Chapter 3: Integration and consolidation: a neurophysiologi-
cal model of bipolar disorder. In: The Bipolar Brain: Integrating Neuroimaging
and Genetics. New York: Oxford University Press, 202.
3. Koenigs M, Grafman J. The functional neuroanatomy of depression: distinct
roles for ventromedial and dorsolateral prefrontal cortex. Beh Brain Res 2009;
20:239–243.
4. Savitz JB, Drevets WC. Imaging phenotypes of major depressive disor-
ders: genetic correlates. Neuroscience 2009; 84:300–330.
5. Goodwin FK, Jamison KR. Chapter 4: Neurobiology. In: Manic-depressive ill-
ness. New York: Oxford University Press, 2007.
6. Flint J, Kendler KS. The genetics of major depression. Neuron 204;
8:484–503.
7. Sanacora G, Treccani G, Popoli M. Toward a glutamate hypothesis of depres-
sion: an emerging frontier of neuropsychopharmacology for mood disorders.
Neuropharmacology 202; 62:63–77.
8. Roy A, Campbell MK. A unifying framework for depression:  bridging the
major biological and psycosocial theories through stress. Clin Invest Med 203;
36:E70–E90.
42

9. Cramer AO, Borsboom D, Aggen SH, Kendler KS. The pathoplasticity of dys-
phoric episodes: differential impact of stressful life events on the pattern of
depressive symptom inter-correlations. Psychol Med 202; 42:957–965.
0. Strakowski SM, Adler CM, DelBello. Is depression simply a nonspecific
response to brain injury? Curr Psychiatry Rep 203; 5:386–396.
. Ota KI, Duman RS. Environmental and pharmacological modulations of cel-
lular plasticity:  role in the pathophysiology and treatment of depression.
Neurobio Dis 203; 57:28–37.
Chapter 6

Genetics of Depression

6..  Depression Runs in Families

As noted throughout previous chapters of this book, the syndrome of
depression is a heterogeneous construct with a wide variety of medical and
psychiatric co-occurrences and potential causes. Consequently, the heritabil-
ity of some causes of depression (e.g., bipolar disorder) has been recognized
for centuries. However, studies from the early twentieth century suggested
that the syndrome of depression itself is heritable. Indeed, review of these
family and epidemiological studies suggests that the first-degree relatives of
someone who experiences depression are approximately 3 times more likely
to develop depression themselves than the general population.,2 Specifically,
in one recent review and analysis of available data, the risk of depression in a

43
43
first-degree family member of a depressed proband was approximately 2%,
compared to a base rate of 7% in the general population in that study.3
However, simply because depression is more common in a particular fam-
ily does not necessarily mean that it is a genetic illness, since families typically
share a common environment as well, which could be the causative agent. In
order to clarify the specific genetic risk, or heritability, of a condition, typically
two types of studies are performed: adoption and twin studies. Unfortunately,
there is a dearth of high-quality adoption studies of depression, so that cal-
culations of the heritability of major depression are based upon a handful of
twin studies (see Table 6.).,2 Twin studies compare the rates of an illness,
in this case depression, in monozygotic twins, who have 00% of their genes
in common, to dizygotic twins, who share only 50% of their genes, like any
other siblings. Differences in concordance rates of depression between the
two types of twins (i.e., rates in which both twins in a set are affected) can
then be used to calculate a relative genetic risk for the condition. This relative
risk is called the Holzinger heritability index (H2), and is calculated as

H2 = (Monozygoticconcordance – dizygoticconcordance) /
(100 – dizygoticconcordance)
Results of higher-quality twin studies of depression suggest a concordance
rate of depression in monozygotic twins of 30–50%, whereas in dizygotic
twins concordance is typically 20–30%. In their meta-analysis, then, Sullivan
and colleagues calculated a heritability index of 37% for major depression.2
In other words, 37% of the risk of developing depression was strictly a result
of inherited genes, whereas over 60% of the risk was related to specific
Major Depressive Disorder Table 6.  Concordance Rates (%) of Depression in Monozygotic
and Dyzogotic Twins: Example Studies
Study Monozygotic Dyzygotic
Male Female Male Female
Beirut et al.a 34 50 30 37
Kendler et al.b 40 67 33 32
Kendler & Prescottc 4 47 34 43
McGuffin et al.d 46 46 5 22
Adapted from Sullivan et al.2
Table references:
a
Beirut LJ et al. Arch Gen Psychiatry 999; 50:85–94.
b
Kendler KS et al. Behav Genet 995; 25:27–232.
c
Kendler KS, Prescott CA. Arch Gen Psychiatry 999; 56:39–44.
d
McGuffin P et al. Arch Gen Psychiatry 996; 53:29–36.

environmental experiences of the affected individual, with minimal effects

from the general shared environment. Notably, the relative heritability of
depression varies between the sexes, as it tends to be higher in women by
about 0 percentage points. Although this level of genetic risk is substantial, to
put it in the context of other psychiatric disorders, the heritability of bipolar
disorder is 85%, schizophrenia 8%, Alzheimer’s disease 75%, anorexia ner-
44

vosa 60%, and alcohol dependence 56%.4 Anxiety disorders (panic disorder,
generalized anxiety disorder) have relatively low rates of heritability, similar
to depression (i.e., 30–40%). This relatively low heritability in depression and
the commonly co-occurring anxiety disorders suggests that relatively modest
genetic risks, combined with environmental events (especially stress), lead to
the development of depressive and anxious syndromes. Genetic effects may
be sex-linked in that they have greater impact in women. Unfortunately, when
genetic effects occur, the specific modes of inheritance of major depression
remain unclear and likely vary among different families, and even among men
and women within a family. It is likely that this variability reflects multiple
genes, each with relatively minimal risk, which combine to lead to depression
in some individuals.
Complicating the heritability of depression is its common co-occurrence
with a wide variety of medical and psychiatric conditions that themselves
carry risk for depression and are themselves heritable, including bipolar I dis-
order, obsessive-compulsive disorder (OCD), Parkinson’s disease, migraine,
post-traumatic stress disorder, and personality disorders.4 It appears, in fact,
that rates of major depression are increased in family members of probands
with a wide variety of neurological and psychiatric conditions, whenever
these associations are studied.

Key Point: Depression runs modestly in families, with just under 40%

of the risk for developing this illness due to genetics. The remaining
risk reflects environmental factors. However, some causes of depres-
sion (e.g., bipolar disorder) are much more heritable, complicating this
consideration.
 6.2.  Genetics of Depression

Genetics of Depression
The last two decades saw an explosion in methods to study the human
genome, producing a steady increase in identifying genes that contribute to
the development of human disease and behavioral conditions. Despite its
relatively low heritability, major depression has been a focus of this research.
6.2.. Linkage Studies
Linkage studies are designed to measure differences in DNA markers on
chromosomes (called “loci”) to determine whether specific loci are associ-
ated with specific illnesses within families. In humans, chromosomes exist in

Chapter 6
pairs, with one set of chromosomes (i.e., half of the total complement of
genes) inherited from each parent.5 Consequently, each gene is represented
in duplicate, and one member of each gene pair is called an allele. During
gamete formation, pairs of chromosomes separate in order to provide only
one allele from each parent so that, when combined during fertilization, a full
complement of genes is inherited. In the process of gamete formation as the
chromosomes are separated (meiosis), genes “cross over” from one chro-
mosome to another, thereby providing mixed combinations of genes.5 This
recombination of genes is not random; genes farther apart are more likely to
cross over (recombine) than genes that are close together.5 The latter, then,
are considered “linked,” so that these copies of alleles are typically inherited

45
together. It is this variability in recombination, based on distances between
genes, that forms the basis of linkage studies. Linkages are then measured
using a logarithm of the odds of linkage, or LOD score. These associations
are logarithmic, so that an LOD score of .0 means that linkage is 0 times
more likely than non-linkage. Depending on the size of the study, a meaningful
LOD score can be variably defined, although it is typically greater than 3.0.5
A number of linkage studies have been performed in major depression.
In general, despite several studies with large families, there has been rela-
tively minimal confluence of results since the confidence intervals around any
particular linkage have tended to be broad and difficult to replicate. Despite
these difficulties, Flint and Kendler examined linkage studies to date and con-
cluded that there may be a “true signal” for genetic link to depression on
single loci on chromosomes 2, 3, and , and two sites on chromosome 5.
Moreover, some of these studies suggested sex-linked effects, consistent with
the family study results noted earlier. It is not clear to what specific gene
products these markers are related, however.
6.2.2. Genome-Wide Association Studies
Although linkage studies define potential chromosomal markers associated
with major depression, they do not define specific genes. One approach for
addressing this methodological shortcoming is through association studies.
The most comprehensive set of methods, called genome-wide association
studies (GWAS), were introduced in the past decade with advances in DNA
chip technology, in which millions of single nucleotide polymorphisms (SNP)
are evaluated in large samples simultaneously.5 SNPs are small areas of DNA
that show variability across human subjects in an otherwise relatively highly
Major Depressive Disorder conserved DNA. GWAS permits examination of virtually every gene in
the genome, with the primary limitation being the statistical interpretation
of thousands of data points.5 Consequently, to be effective, study samples
must be very large (e.g., in the tens of thousands).5 These methods have been
applied to the study of major depression, although no consistent or replicable
finding has been reported, unfortunately.,4
6.2.3. Candidate Genes
An alternative association approach uses results from GWAS, linkage studies,
or the proposed neurobiology of major depression to identify “candidate”
genes, which are then tested for association with major depression. A com-
mon design for these types of studies is to identify a proband with major
depression and the two parents, called a trio, and then to study multiple
trios to determine the association of depression with the candidate gene. As
reported by Flint and Kendler, several candidate genes potentially underlying
the expression of major depression have been identified from these methods,
although replication has typically been difficult. Nonetheless, significant asso-
ciations between major depression and a small number of candidate genes
reported in two or more meta-analyses or in single meta-analyses in the
absence of negative reports may provide some clues to the genetic contribu-
tions in depression. These candidate genes are as follows.
46

Serotonin-linked polymorphic region (5HTTLPR). This polymorphic region is

located in the serotonin transporter gene (SLC6A4), located on chromo-
some 7. The serotonin transporter transfers serotonin out of the syn-
aptic clef back into the presynaptic neuron. Selective serotonin reuptake
inhibitor (SSRI) antidepressants bind to the serotonin receptor, and spe-
cific alleles in this region may modify depressive response to stressful life
events.6
Serotonin A receptor (HTRA). This gene codes for the most widely distrib-
uted serotonin receptor, located throughout prefrontal networks that
modulate emotional responses in animal models and humans. It is localized
on chromosome 5. As noted, serotonin neurotransmission contributes
significantly to neurophysiological models of depression (see Chapter 5).
Methylenetetrahydrofolate reductase (MTHFR). The MTHFR gene on chromo-
some  codes for an enzyme that converts 5,0-methylenetetrahydrofolate
to 5-methyltetrahydrofolate, a critical step in the pathway toward forming
methionine. S-adenosyl-L-methionine has been studied as a putative “natu-
ral” antidepressant with mixed, although primarily negative, results.
Dopamine D4 receptor (DRD4). This gene is located on chromosome  and
codes the D4 dopamine receptor. This receptor is distributed throughout
the prefrontal cortex, amygdala, and hippocampus, regions relevant to the
control of emotion (see Chapter 5). However, it has typically been identi-
fied as playing a role in the expression of psychiatric illnesses other than
depression (e.g., schizophrenia or ADHD).
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3). The
GNB3 gene codes for the beta subunit of a G-protein that is part of the
cell-signaling pathway between membrane receptors and effector proteins
 in the cell body. It is located on chromosome 2. Its potential role in

Genetics of Depression
depression is not clear, but could be related to post-receptor cell-signaling
abnormalities.
Unfortunately, despite these leads, the absence of directly corresponding
findings from GWAS and linkage studies, coupled with the modest genetic
impact on the risk of major depression in general, raises doubts as to whether
any of these genes are clinically meaningful in large groups of depressed
individuals.–4 Most investigators currently believe that major depression
results from small contributions from multiple genes interacting with envi-
ronmental events, rather than a specific large genetic effect. As genetic tech-

Chapter 6
nologies advance, it may be possible to identify stronger links among gene
combinations with various subtypes of major depression.

Key Point: Genetic methods have identified a few promising candidate

genes associated with major depression, although failure to similarly
identify these in GWAS and linkage studies raises questions about
their validity.

6.3.  Summary and Relevance for Genetic

Counseling in Major Depression

47
From our review in this chapter, it is clear that genetics are only a portion
of the risk for depression, with individual environmental events often con-
tributing more risk. Moreover, it is therefore unlikely that a specific “depres-
sion gene” or combination of genes will be identified any time soon, if ever.
Similarly, then, a genetic test for depression is not likely to appear in the near
future. Nonetheless, family history information provides some ability to pre-
dict relative risk of developing depression, as outlined in Table 6.2.
As illustrated in Table 6.2, the risk to an individual for developing depres-
sion increases with increasing genetic closeness to the depressed proband.
However, once removed from first-degree relatives, the risk quickly trends
toward population levels. Moreover, given the virtual lifelong risk for depres-
sion and the strong effect of environment, these figures are at best rough
guidelines, and cases of depression in the complete absence of any family
history are common. As noted earlier, however, as genetic methods improve,
perhaps they will inform decisions on relative risk or treatment response to
better individualize the management of this common condition.

Table 6.2  Relative Familial Risks for Major Depression

Situation Risk
General population 7–5%
Sibling with depression 20–30%
Parent with depression 20–30%
Identical twin with depression 30–50%
Major Depressive Disorder Key Point: Family history provides some information to counsel genetic
risk for depression within an individual, although it is less informative
for depression than for psychiatric and medical disorders with stron-
ger heritability.

References
 . Flint J, Kendler KS. The genetics of major depression. Neuron 204; 8:484–503.
2. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depres-
sion: review and meta-analysis. Am J Psychiatry 2000; 57:552–562.
3. Goodwin FK, Jamison KR. Chapter 3: Genetics. In: Manic-Depressive Illness.
New York: Oxford University Press 2007.
3. Bienvenu OJ, Davydow DS, Kendler KS. Psychiatric ‘diseases’ versus behavioral
disorders and degree of genetic influence. Psychol Med 20; 4:33–40.
4. Strakowski SM, Adler CM, DelBello. Is depression simply a nonspecific response
to brain injury? Curr Psychiatry Rep 203; 5:386–396.
5. Strakowski SM. Chapter 6. Genetics of bipolar disorder. In: Bipolar Disorder,
pp. 47–54. Oxford American Psychiatry Library. New York: Oxford University
Press, 204;. [Note: Segments of the current chapter have been reproduced
from this reference with permission of the author and the publisher.]
6. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill
48

J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: mod-

eration by a polymorphism in the 5-HTT gene. Science 2003; 30:386–389.
Chapter 7

Psychopharmacology and Other

Biological Therapies in the
Management of Depression

7..  Introduction and Overview of

Biological Therapies
As noted throughout previous chapters in this book, major depression is a
complex disorder that is variable in its presentation and is associated with
numerous other medical and psychiatric conditions. Consequently, at times
the treatment of depression can be challenging, particularly in individuals with
complex comorbidity or treatment resistance. However, by understanding

49
49
how to optimize the use of available treatments, clinicians can help most
people with depression to recover and lead successful and productive lives.
Optimal treatment of major depression typically involves combining medical
and psychological interventions that are supported by clinical evidence. In this
chapter, we review the use of medical (“biological”) treatments for major
depression. In Chapter 8 we discuss psychotherapies shown to be effective
when used alone or in combination with biological therapies. In Chapter 9,
we take a broader look at the management of depression by considering pro-
grammatic approaches to treating patients suffering from this distressing con-
dition. Finally, in Chapter 0, we discuss managing a few special populations in
which treatment considerations can be more complex.
Prior to the development of antidepressant medications, there were
few viable options for the biological treatment of depression. Early meth-
ods attempted to harness the antidepressant effects of provoked seizures,
including insulin-induced hypoglycemia, pentylenetetrazol-induced seizures,
and electroconvulsive therapy (ECT). Of these, only ECT has endured as
an established treatment for depression (see section 7.7.). In the 950s,
the serendipitous discoveries of monoamine oxidase inhibitors (MAOIs)
and tricyclic antidepressants (TCAs) launched the modern antidepressant
era. These agents, as well as newer classes of antidepressants, produce
their effects by altering the neurotransmission of the monoamines serotonin
and norepinephrine (see Chapter 5, section 5.3.). Research supports the
idea that changes in monoamine activity in the central nervous system are
a necessary component of the mechanism of action of all currently avail-
able antidepressants drugs. However, in the past two decades it has become
increasingly clear that simply modifying monoamine levels or receptor activity
Major Depressive Disorder is, by itself, not sufficient to produce clinical effects. Recent preclinical and
clinical research supports the concept that modulation of monoaminergic sys-
tems produces the “downstream” effect of inducing neuroplasticity in impor-
tant brain regions involved in mood regulation. Moreover, these neuroplastic
effects appear to be integral to the therapeutic mechanism of antidepressants.
Of note, these changes occur approximately 2–4 weeks after antidepressant
therapy is initiated, which mirrors the typical onset of the clinical response.
The various classes of antidepressants have become the mainstay of bio-
logical therapy for major depression. Improved tolerability associated with
the newer antidepressants, particularly the serotonin reuptake inhibitors,
has contributed to the widespread use of these drugs. In general, antide-
pressants produce clinically significant benefits (e.g., 50% reduction in symp-
toms) in approximately 60% of individuals treated in controlled clinical trials,
although rates of full remission with a single antidepressant trial are signifi-
cantly lower (~30–40%), particularly in “real world” settings in which people
with co-occurring medical and psychiatric illnesses or a history of treatment
resistance are included. Experts recommend continuing antidepressants for
at least 6–2 months after full remission of a depressive episode in order
to decrease the chance of relapse, consistent with data from several out-
come studies. Moreover, people with recurrent depressive episodes typically
require long-term maintenance therapy to reduce the risk of future episodes.
It is therefore important to minimize the level of overall side effects that
50

people experience with antidepressant therapy, which may interfere with

adherence in long-term treatment programs. Indeed, low rates of adherence
in intermediate and long-term treatment of antidepressants is often cited as
a barrier to the successful management of depression. Despite a dearth of
rigorously controlled data to support their effectiveness as long-term mainte-
nance treatments, antidepressants also have a role in the prevention of future
episodes in people with the recurrent forms of the illness.

Key Point:  Antidepressants are the primary biological therapy for

depression; they are used both to manage acute episodes and to pre-
vent recurrence over the longer term.

7.2.  Choosing an Antidepressant

Studies suggest that the various classes of antidepressants are essentially
equal in their ability to reduce depressive symptoms. Table 7. lists medi-
cations currently approved in the United States for the treatment of major
depression. All antidepressants have a delay in therapeutic response of 2–4
weeks from the initiation of treatment, and a full response (i.e., remission)
may take as long as 8–2 weeks. Given similar effectiveness among medica-
tions, the choice of which antidepressant to use as first-line treatment is typi-
cally based on the relative safety, tolerability, and ease of use of each drug.
Consideration is also given to co-occurring psychiatric and other medical
conditions that may be affected by a particular antidepressant. For example,
 Chapter 7 Psychopharmacology & Biological Therapies
Table 7.  Generic (and Trade) Names and Dose Ranges
for FDA-Approved Antidepressants
Medication Dose Range
Tricyclic antidepressants (TCAs)
Imipramine (Tofranil) 00–300 mg
Nortriptyline (Pamelor) 75–50 mg
Desipramine (Norpramin) 00–300 mg
Monoamine oxidase inhibitors (MAOIs)
Tranylcypromine (Parnate) 30–60 mg
Phenelzine (Nardil) 60–90 mg
Selegeline—transdermal (Emsam) 6–2 mg/24 hours
Serotonin reuptake inhibitors (SSRIs)
Fluoxetine (Prozac) 20–60 mg
Paroxetine (Paxil) 20–60 mg
Sertraline (Zoloft) 50–200 mg
Citalopram (Celexa) 20–40 mg
Escitalopram (Lexapro) 0–20 mg
Serotonin norepinephrine-reuptake inhibitors (SNRIs)
Venlafaxine (Effexor) 50–375 mg
Duloxetine (Cymbalta) 60–20 mg

51
Desvenlafaxine (Pristiq) 50 mg
Levomilnacipran (Fetzima) 40–20 mg
Other antidepressants
Bupropion (Wellbutrin) 300–450 mg
Mirtazapine (Remeron) 30–45 mg
Vilazodone (Viibryd) 40 mg
Vortioxetine (Brintellix) 5–20 mg

tricyclic antidepressants (TCAs) would be a poor choice for first-line treat-

ment in someone with a history of cardiac arrhythmia, as TCAs can adversely
affect cardiac conduction. Selective serotonin reuptake inhibitors (SSRIs)
are often preferred in people with co-occurring obsessive-compulsive dis-
order, as they are first-line treatments for this condition as well. In certain
cases, the choice of an antidepressant may be tailored to benefit particular
symptoms that the person is experiencing. For instance, in someone with
severe insomnia, a sedating antidepressant may provide immediate relief for
this symptom prior to the onset of significant effects on mood.
Considerable research has been conducted to identify treatment bio-
markers that would predict which antidepressant is most likely to produce
a response in a specific individual. Some candidate approaches include quan-
titative electroencephalogram (EEG), genetic testing of functional polymor-
phisms that predict response, and functional neuroimaging techniques. To
date, none of these has yet been demonstrated to be predictive enough to
warrant routine application in typical clinical settings.
Major Depressive Disorder 7.2.. First-Line Treatments
As mentioned, the choice of antidepressant is initially based on tolerability, as
there is no clear distinction in effectiveness among the classes of antidepres-
sants. SSRIs are considered first-line agents for treating an acute episode of
depression based on tolerability, relative safety in overdose, and less potential
for negative impact on co-occurring medical conditions. These medications
are also relatively easy to prescribe and manage clinically. Although some
studies suggest a greater chance of reaching full remission with dual reuptake
inhibitors such as serotonin-norepinephrine reuptake inhibitors (SNRIs), the
latter agents may be less well tolerated than the relatively pure SSRIs.
7.2.2. Second-Line Treatments
Although it is a common practice to switch to a different class of antide-
pressants when a person fails to respond adequately to an SSRI, switching
to a second SSRI is also a reasonable option. When switching to a different
class, recommended second-line agents include SNRIs, bupropion, and mir-
tazapine. Due to its lack of adverse impact on sexual functioning, bupropion
should be given special consideration when sexual side effects contributed to
the decision to discontinue previous treatment. Many clinicians view these
medications (SNRIs, bupropion, and mirtazapine) as first-line treatments as
well, given their levels of efficacy and generally good tolerability. In particular,
bupropion tends to be well tolerated, perhaps as much or more so compared
52

with SSRIs, so it is a reasonable first choice for many individuals.

7.2.3. Third-Line Treatments
TCAs and MAOIs are typically reserved as third-line therapies for major
depression due to their decreased tolerability and increased potential for tox-
icity. However, certain subtypes of depression may have a more favorable
response to these agents than the newer drugs, so that special consideration
should be given to their use in certain clinical situations (as will be discussed
subsequently in this chapter). Typically, TCAs are selected prior to MAOIs
due to potentially dangerous food and drug interactions that may occur with
the latter.

Key Point: There are a number of effective antidepressants available,

none of which has consistently shown superior efficacy to the oth-
ers. Consequently, prescribing often relies on differences in side-effect
profiles and managing co-occurring conditions.

7.3.  Specific Antidepressants

7.3.. Monoamine Oxidase Inhibitors
MAOIs were discovered serendipitously in the 950s when isoniazid was
found to have mood-enhancing properties in patients treated for tuberculosis.
The antidepressant effects of MAOIs are mediated by irreversible inhibition
of monoamine oxidase A (MAO-A), an enzyme that degrades monoamine
neurotransmitters in the central nervous system (CNS). Inhibition of MAO-A
increases concentrations of norepinephrine (NE), dopamine (DA), and sero-

Chapter 7 Psychopharmacology & Biological Therapies

tonin (5HT) in the neuronal synapse, which is thought to produce downstream
effects in cellular function that lead to the reduction of depressive symptoms.
The only reversible MAOI, moclobemide, is available in Canada and the
United Kingdom, but is not approved by the FDA for use in the United States;
it has a lower incidence of dietary interactions than other MAOIs. MAOIs
are classified as either hydrazine derivatives (phenelzine, isocarbozazide) or
non-hydrazines (tranylcypromine, selegeline), with the non-hydrazines caus-
ing less sedation and risk of hepatotoxicity. Selegeline, which is predominantly
an MAO-B inhibitor at serum concentrations obtained with oral administra-
tion, has been approved as a patch for transdermal delivery. With the higher
serum concentrations obtained through transdermal administration, selege-
line also inhibits MAO-A, which produces greater antidepressant effects.
Selegeline has fewer side effects than other MAOIs, and dietary restrictions
are not required at the lowest effective dose.
Results from numerous placebo-controlled trials demonstrate the effec-
tiveness of MAOIs for the treatment of major depression. Several studies
report that MAOIs are more effective than TCAs in depression with atypical
features (also called anergic depression; see Chapter 2). Moreover, MAOIs
are effective in some people who fail to respond to treatment with a TCA.
Conversely, MAOIs may be less effective than TCAs in individuals with severe
depression or melancholic features.

53
Despite their demonstrated benefits for depression, the use of MAOIs has
diminished dramatically over the past few decades due to troublesome side
effects and the improved tolerability of newer drugs. Common MAOI side
effects include dizziness, headache, dry mouth, insomnia (greater with tran-
ylcypromine), sedation (greater with phenelzine), constipation, blurry vision,
nausea, cognitive effects, and orthostasis. More concerning are severe and
potentially lethal reactions that may occur with MAOIs due to drug and dietary
interactions. Specifically, eating foods that contain high concentrations of the
vasopressor tyramine while taking an MAOI may produce a hypertensive crisis
that consists of elevated blood pressure, occipital headache, palpitations, sweat-
ing, nausea and vomiting, chills, stiff neck, fever, and dilated pupils. In extreme
cases, hypertensive crisis can cause stroke or even death. Consequently, peo-
ple who are prescribed MAOIs must follow a diet restricting consumption of
foods high in tyramine (see Table 7.2). In addition, a hypertensive crisis may
result from an interaction of MAOIs with indirect sympathomimetic drugs such
as pseudoephedrine, a common ingredient of over-the-counter cold prepara-
tions. Finally, combining MAOIs with SSRIs or other drugs with serotonergic
properties, such as certain opioid analgesics, may result in a severe and poten-
tially fatal form of serotonin syndrome (see section 7.3.3).
7.3.2. Tricyclic Antidepressants
TCAs were the most widely prescribed antidepressants prior to the approval
of fluoxetine in 987, although their use was limited by poor tolerability and
significant toxicity. Imipramine, the first TCA to be approved, was devel-
oped as an antipsychotic until it was found to have more potent antidepres-
sant effects (and actually minimal or no antipsychotic efficacy). The primary
Major Depressive Disorder
Table 7.2  MAOI Dietary Restrictions
Food Category Food Item
Dairy Aged or fermented cheese
Meats Air dried, aged, or fermented meats
Spoiled or improperly stored meats, poultry, fish, or
animal livers
Pickled herring
Fruits Banana peel
Vegetables Fava beans
Beverages All tap or unpasteurized beers (including non-alcoholic)
Soy Tofu, soy sauce
Other Concentrated yeast extract
Sauerkraut
Excessive caffeine
Excessive chocolate
OTC supplements containing tyramine
Adapted from EMSAM (selegiline patch) [package insert]. Napa, CA: Dey Pharma LP, 200.
Nardil (phenelzine sulfate) [package insert]. New York: Pfizer, Inc., 20.

mechanism of action of TCAs is the inhibition of norepinephrine reuptake

54

into presynaptic neurons, which results in increased availability of this neu-

rotransmitter in neural synapses. However, all TCAs block the reuptake of
serotonin to some degree as well. TCAs are classified as secondary (e.g.,
desipramine, nortriptyline) or tertiary amines (e.g., amitriptyline, imipra-
mine). Tertiary amines have greater serotonin reuptake inhibition, as well as
greater antihistaminic and anticholinergic effects, than secondary amines, and
they undergo demethylation to form secondary amine metabolites in vivo. All
TCAs are known to block α adrenergic receptors, histamine type  recep-
tors, and cholinergic receptors to some degree, which produces many of
the side effects caused by these drugs. Because tertiary amines have greater
affinity for these receptors, they are associated with greater side effects than
secondary amines.
Results from numerous placebo-controlled studies support the effective-
ness of TCAs in major depressive disorder. TCAs may be more effective
than SSRIs in depression with melancholic features, and TCAs with greater
serotonin reuptake inhibition have been shown to be more effective for indi-
viduals requiring inpatient treatment (i.e., for more severe cases). As men-
tioned previously, TCAs appear to be less effective than MAOIs in atypical
depression.
The biggest drawbacks to TCAs are the abundant and sometimes seri-
ous side effects associated with their use. Common side effects include those
mediated by anticholinergic activity, such as dry mouth, blurred vision, and
constipation. In the elderly, anticholinergic effects may precipitate more seri-
ous problems, such as urinary retention, tachycardia, exacerbation of narrow
angle glaucoma, or delirium. TCAs also have direct effects on cardiac conduc-
tion that may cause arrhythmias in overdose, or even at therapeutic levels in
individuals who are predisposed. Higher plasma levels may cause CNS toxic-

Chapter 7 Psychopharmacology & Biological Therapies

ity in the form of seizures, delirium, and coma. In overdose, fatalities due
to cardiac or neurological complications are not uncommon and may even
be delayed many hours after the event. Moreover, interactions with agents
that inhibit the cytochrome P450-2D6 hepatic isoenzyme may cause higher
plasma levels of TCAs than expected, putting patients at risk of toxicity, even
with doses in the typical therapeutic range.

Key Point: MAOIs and TCAs are effective antidepressants, but their

use has declined since newer antidepressants are better tolerated.
Nevertheless, both classes of medication have roles in the treat-
ment of some depression subtypes or following failure to respond to
newer drugs.

7.3.3. Serotonin Reuptake Inhibitors

During the last 30 years, selective SSRIs have become the most commonly
prescribed antidepressants due to improved tolerability and ease of use, and
therefore are considered first-line agents for treatment of depression. The
primary mechanism of action of these drugs is inhibition of the serotonin
reuptake transporter, which increases the concentration of serotonin in the
neural synapse. All SSRIs have significantly greater effects on serotonin trans-

55
porters than norepinephrine or dopamine transporters, which distinguish
them from TCAs. They also have little affinity for alpha adrenergic, histaminic,
or cholinergic receptors, which explains their relatively low rates of sedation,
hypotension, dry mouth, or tachycardia compared to TCAs or MAOIs.
Although medications classified as SSRIs share a common primary mecha-
nism of action, there are subtle differences among them that are clinically
relevant in some cases. Citalopram and escitalopram are the most selective
agents with regard to serotonin transporter blockade, while paroxetine pro-
duces the most potent serotonin reuptake inhibition. It also has a relatively
short half-life and no active metabolites, which explains why people are more
likely to experience serotonin withdrawal symptoms (see below) after abrupt
discontinuation of paroxetine compared to other SSRIs. Paroxetine also
has slightly more norepinephrine reuptake inhibition than the other SSRIs,
which may become modestly clinically significant at higher doses. Sertraline
produces mild inhibition of the dopamine reuptake transporter, although the
clinical significance of this effect is unclear. The active metabolite of fluox-
etine, norfluoxetine, has a half-life of up to 6 days, greatly reducing the risk
of withdrawal symptoms with fluoxetine, even after abrupt discontinuation.
Although most studies do not indicate clinically significant differences in effec-
tiveness among the SSRIs, a recent meta-analysis suggests slight advantages
when using sertraline or escitalopram.2 The advantages found with these
agents extended to comparisons with other new-generation, non-SSRI anti-
depressants and were based on data that considered both therapeutic ben-
efits and acceptability of the drugs.
As previously mentioned, there is some debate about whether SSRIs
are as effective as TCAs in severe or melancholic depression. Conversely,
Major Depressive Disorder there are reports that SSRIs are superior to TCAs in depression with
atypical features, dysthymia, or bipolar depression. Evidence suggests
that TCAs are more effective in men, while women may be more likely
to respond to SSRIs. Despite the potential advantages of TCAs in these
situations, tolerability nonetheless becomes the deciding factor in specific
individuals, since no drug is effective when not taken. As with TCAs, there
is evidence that SSRIs are superior to placebo during the maintenance
phase of treatment.
In general, SSRIs have a broad dosage range across which they are effective
and well-tolerated. Most individuals tolerate starting therapy in the therapeu-
tic dose range without need for titration. However, people who are more
sensitive to SSRI side effects may require gradual titration to a therapeutic
dose. It is important to note that many individuals require increases beyond
the minimal therapeutic dose in order to obtain an optimal response from
these drugs. Moreover, some individuals tolerate doses of SSRIs beyond the
upper end of the approved dose range and appear to require treatment with
higher doses in order to achieve full remission of symptoms. However, when
considering extending the dose range, it is important to note that citalopram
doses above 40 mg have been linked to prolongation of the QTc interval
on electrocardiogram (ECG), which can be associated with a serious cardiac
arrhythmia called torsades de pointe.
SSRIs are much more tolerable than TCAs and therefore demonstrate
56

lower treatment dropout rates. This distinction is mainly due to their rela-
tive lack of activity at cholinergic, histaminic, and adrenergic receptors. SSRI
side effects are primarily caused by the enhancement of serotonin activity
at post-synaptic serotonergic receptors, which also produces their thera-
peutic effects. They are relatively safe in overdose, although fatalities due
to cardiotoxicity have been reported with overdoses of citalopram and
escitalopram.
Common side effects include gastrointestinal disturbance (nausea, diar-
rhea, gastroesophageal reflux), CNS activation (insomnia, anxiety/agitation),
and sexual side effects (most commonly decreased libido, delayed orgasm/
ejaculation). Gastrointestinal disturbance and CNS activation are dose related
and tend to diminish within a few days in most patients.
Sexual dysfunction, which occurs in 30–60% of patients, is usually persis-
tent and is a common reason for discontinuation. It is important for clinicians
to advise individuals about this risk and to inquire about it during the course
of treatment; otherwise, the person may simply stop the medication and
disappear from treatment. Specific “antidotes” for sexual side effects have
been used with some success, particularly treatment with phosphodiesterase
inhibitors such as sildenafil, or the addition of bupropion. In some individu-
als, a brief drug holiday (e.g., over a weekend) may help as well, especially
with shorter acting drugs, although this holiday may elicit antidepressant with-
drawal symptoms. Weight gain and affective blunting are less frequent, yet
bothersome side effects.
Recent epidemiologic studies link long-term SRI treatment to a slight
increased risk of certain medical conditions, including gastrointestinal bleeding
(estimated 2 x risk), bone density loss, and cataracts. A slight increased risk of

Chapter 7 Psychopharmacology & Biological Therapies

other types of abnormal bleeding has also been reported, including increased
post-surgical bleeding and potentially elevated risk of cerebral hemorrhage.
Hyponatremia, a rare complication of SSRIs, is more common in the elderly
and can be life-threatening if not detected and addressed.
A withdrawal phenomenon known as SSRI discontinuation syndrome is
commonly seen with rapid reductions in SSRI dosage. This syndrome typically
occurs within 2 days of dose reduction or cessation of therapy and is char-
acterized by dizziness, nausea, fatigue, chills, paresthesias, visual disturbance,
insomnia, anxiety, and irritability. Due to the nature of these symptoms, peo-
ple often believe they are experiencing a flu-like infection or a recurrence of
their depressive illness. Although not medically serious, the symptoms can be
extremely uncomfortable and may last up to 2 weeks. Among SSRIs, parox-
etine is associated with higher rates of the discontinuation syndrome due to
its short half-life and lack of active metabolites (the SNRI venlafaxine is also
associated with significant withdrawal symptoms). To avoid discontinuation
symptoms, SSRIs should be tapered gradually, particularly when patients are
on higher doses. In rare cases, it is necessary to switch to a longer half-life
drug such as fluoxetine and taper it to avoid more serious withdrawal.
Serotonin syndrome is a serious, potentially fatal condition that may occur
during SSRI or SNRI therapy. It is caused by over-stimulation of serotonin
receptors and most commonly occurs when more than one serotonergic

57
drug is administered simultaneously. Symptoms include tremor, diaphoresis,
rigidity, myoclonus, and autonomic dysregulation, which may progress to
hyperthermia, rhabdomyolysis, coma, and death. Fatalities due to serotonin
syndrome have mostly occurred with the combination of serotonergic drugs
and an MAOI, although two fatalities have been reported in individuals taking
oxcarbazepine in combination with a serotonin reuptake inhibitor. Due to the
risk of serotonin syndrome, the combination of an MAOI and a serotonin
reuptake inhibitor is contraindicated. Caution should also be used when com-
bining serotonin reuptake inhibitors with other serotonergic agents.

Key Point:  SSRIs are widely prescribed, tolerable, and safe, so are
first-line interventions for most cases of depression.

7.3.4. Serotonin-Norepinephrine Reuptake Inhibitors

The serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of
second-generation antidepressants whose mechanism of action includes inhi-
bition of both serotonin and norepinephrine reuptake. This dual reuptake
inhibition is similar to the mechanism of action of TCAs, although SNRIs lack
specific activity at histaminic, cholinergic, and adrenergic receptors and there-
fore have different side effect and safety profiles from TCAs. The first three
SNRIs approved—venlafaxine, duloxetine, and desvenlafaxine—are predom-
inantly serotonergic at lower doses, with increased effects on norepinephrine
at higher doses. Levomilnacipran, however, has greater noradrenergic than
serotonergic effects.
Major Depressive Disorder The effectiveness of SNRIs in depression has been established in numer-
ous placebo-controlled trials. Studies report a more rapid onset of action
(–2 weeks) and greater chance of achieving full remission of depression with
SNRIs compared to SSRIs. In comparison with SSRIs, SNRIs appear to have
lower discontinuation rates due to lack of efficacy, but higher discontinuation
rates due to adverse events, so that the classes of drug have similar effec-
tiveness. In addition, data suggest that SNRIs are particularly helpful for pain
symptoms that often accompany depressive episodes.
Side effects caused by SNRIs include those related to serotonin that are
associated with SSRIs, such as gastrointestinal disturbance (nausea, diarrhea,
gastroesophageal reflux), CNS activation (insomnia, anxiety/agitation) and
sexual dysfunction. As a result of noradrenergic stimulation, SNRIs may also
increase heart rate and blood pressure, which may result in clinically signifi-
cant tachycardia or hypertension in some people. Duloxetine has been asso-
ciated with increased hepatic transaminases that are clinically significant in
approximately –2% of treated individuals. SNRIs may also cause serotonin
syndrome, as previously described for SSRIs.
7.3.5. Bupropion
Bupropion was approved for the treatment of major depression in 985. The
drug was withdrawn from the market in 986 after it was blamed for causing
seizures in a number of individuals, primarily with bulimia; it was reintroduced
58

in 989 with a decrease in the allowed maximum daily dose to 450 mg. The
effectiveness of bupropion in the acute treatment of depressive episodes has
been demonstrated in several placebo-controlled trials. Moreover, it has been
shown to be as effective as fluoxetine in mild to moderate depression and
equivalent to TCAs in severely depressed hospitalized individuals. Due to its
mild stimulant-like effects, bupropion is particularly beneficial to people with
anergic/atypical depression or depression with comorbid attention deficit
hyperactivity disorder (ADHD). Often referred to as an “atypical antidepres-
sant,” bupropion’s precise mechanism of action is unknown, although there
is some consensus that it involves both norepinephrine reuptake inhibition
and, to some degree, enhancement of dopaminergic function, with little to no
effect on serotonergic neurotransmission.
Typical side effects of bupropion are consistent with its activating prop-
erties and include anxiety/agitation, tremor, insomnia, and mild increases in
blood pressure. Despite the new maximum daily dosing, bupropion is still con-
traindicated in people with a history of seizures or traumatic brain injury, and
those with current symptoms of bulimia or anorexia. Although one extended
release formulation of bupropion is safe to use in a single daily dose, even at
the maximum of 450 mg, other approved formulations of bupropion must
be given in divided doses to avoid an increase in seizure risk. Compared with
serotonin-acting antidepressants, bupropion has low rates of sexual dysfunc-
tion and is actually used as an antidote for sexual side effects of SSRIs due to
its propensity to enhance sexual functioning. Given its efficacy and tolerabil-
ity, bupropion is often used as a first-line antidepressant. Moreover, it is also
approved as a treatment to assist with smoking cessation.
7.3.6. Mirtazapine

Chapter 7 Psychopharmacology & Biological Therapies

Mirtazapine is another “atypical antidepressant” that was approved in the
United States in 996. Owing to its mixed effects on monoamine recep-
tors, it is sometimes referred to as a “noradrenergic and specific seroto-
nergic antidepressant” (NaSSA). Specifically, mirtazapine is an antagonist of
alpha-2 autoreceptors, as well as an antagonist of alpha-2 heteroreceptors
located on serotonergic neurons. The former enhances CNS norepineph-
rine release, while the latter increases the release of serotonin. Moreover,
mirtazapine specifically blocks serotonin 5-HT2 and 5-HT3 receptors in the
CNS, which potentiates antidepressant effects and may reduce gastrointes-
tinal and sexual side effects caused by the drug’s enhancement of serotonin
release. Mirtazapine also has potent antihistaminic effects, but little activity at
cholinergic receptors.
Clinical trials demonstrate the effectiveness of mirtazapine in people with
depression, with relatively equivalent efficacy to TCAs, even in individuals
with severe depression. One advantage of mirtazapine is that it may provide
early improvement of insomnia and anxiety. Moreover, evidence suggests a
faster onset of action of antidepressant effects with mirtazapine, compared
with SSRIs, which is independent of its effects on insomnia.
Common side effects with mirtazapine include sedation, dry mouth,
increased appetite, and weight gain; the latter is often a concern that lim-
its mirtazapine’s use in clinical practice. Noradrenergic effects increase with

59
higher doses, which in some patients may result in decreased sedation and
appetite-stimulating effects. Liver enzymes are increased with mirtazap-
ine treatment in approximately 2% of treated individuals, and rare cases of
severe neutropenia and agranulocytosis have been reported.

7.3.7. Other Serotonergic Antidepressants

Vilazodone is a combined serotonin reuptake inhibitor and partial serotonin-a
receptor agonist that was approved for the treatment of depression in the
United States in 20. Although it is too early to determine whether the dual
action of vilazodone confers advantages over SSRIs, evidence suggests that it
may have a relatively earlier onset of action and reduced sexual side effects.
The most commonly observed adverse events are diarrhea, nausea, vomiting,
and insomnia. Vortioxetine, approved in the United States in 203, has been
termed a “serotonin modulator” because of its multiple effects on serotoner-
gic neurotransmission. Specifically, it acts as a serotonin reuptake inhibitor,
5-HTa receptor agonist, 5-HTb receptor partial agonist, 5-HT3a receptor
antagonist, and 5-HT7 receptor antagonist. Preclinical studies suggest that this
combined effect on serotonin receptors results in increases in norepinephrine
and dopamine transmission, which may mediate improvements in executive
function and learning reported in clinical and preclinical studies with this drug.
Vortioxetine appears to be associated with low rates of weight gain and som-
nolence, while reports regarding sexual side effects have been mixed. The
most common side effects are nausea, vomiting, dizziness, headache, and
constipation.
Major Depressive Disorder Key Point: SNRIs, bupropion, and mirtazapine are commonly used,
although less than SSRIs. They are all effective antidepressants, con-
sidered first-line treatments by many reasonable clinicians. Roles
for the new and novel serotonergic antidepressants vilazadone and
vortioxetine in treatment algorithms for depression remain to be
clarified.

7.4.  Treatment-Resistant Depression

Despite substantial improvements in the treatment of depression in the past
50 years, it is an unfortunate fact that only about 30% of affected individu-
als achieve full remission of symptoms during their first antidepressant trial.
Moreover, only two-thirds of depressed people experience a 50% reduction
of symptoms, leaving 30–40% who do not attain significant improvement with
a first antidepressant treatment. Individuals who do not adequately respond to
antidepressants are said to exhibit “treatment resistance.” Most researchers
define “treatment resistance” as a demonstrated lack of response to two or
more antidepressant trials of adequate dose and duration. This threshold for
treatment-resistant depression is supported by the results of the STAR*D algo-
rithm study, which found a drop in remission rates from approximately 30% for
each of the first two antidepressant trials to 5% or less with subsequent trials.3
60

7.4.. Therapeutic Strategies for

Treatment-Resistant Depression
There are several approaches to consider when an adequate trial of an anti-
depressant fails to result in complete remission of symptoms. Initially, ensure
that the dose of the current antidepressant has been optimized, that is,
increased to the point that either no further benefit is seen, or the maxi-
mum tolerated or highest safe dose is reached. For certain antidepressants,
such as SSRIs, the fully effective dose is often higher than the minimum dose
within the therapeutic range. When treatment response is not complete after
optimizing a single antidepressant, the clinician must choose between switch-
ing to a new medication or adding a second agent to boost the response to
the initial antidepressant. There are no clear guidelines regarding this choice,
but it makes empirical sense to switch antidepressants when there has been
little or no response or when side effects are creating a significant burden,
and to augment the current antidepressant when the person has attained a
significant but incomplete response. In cases of more severe treatment resis-
tance, one may consider combination or augmentation strategies, even if the
response to the first antidepressant has been minimal. Another option to
consider at any point at which response to treatment is inadequate is starting
an evidence-based psychotherapy that specifically targets depressive symp-
toms. These therapies are discussed in Chapter 8.
7.4.2. Switching Antidepressants
In cases in which the practitioner chooses to switch antidepressants after
an initial failed trial, there are few data to guide the choice of the next
antidepressant. Although many clinicians choose to switch to an antide-

Chapter 7 Psychopharmacology & Biological Therapies

pressant in a different therapeutic class, switching to a second SSRI is also
reasonably effective. This decision will typically be driven by side effect
considerations, as well as the various symptom combinations targeted for
improvement.
7.4.3. Augmentation or Combination Therapy
Evidence supports the effectiveness of adding a second antidepressant
(typically referred to as combination therapy) or a non-antidepressant agent
known to enhance antidepressant effects to an antidepressant monotherapy
(termed “augmentation”). Regarding the latter, two atypical antipsychotics,
aripiprazole and quetiapine, are FDA-approved as add-on treatments in peo-
ple who do not reach full remission with an antidepressant, and olanzapine is
approved in combination with fluoxetine for treatment-resistant depression.
Evidence also supports benefits with the addition of lithium, thyroid hor-
mone, l-methylfolate, buspirone, omega-3 fatty acids, s-adenosylmethionine
(SAMe), and psychostimulants to an antidepressant. See Table 7.3 for com-
mon augmentation strategies.
Although commonly used, there are currently no antidepressant combina-
tions that are approved by the FDA. Clinical trials support benefits from the
addition of bupropion to an SSRI or SNRI. This combination is popular in
part because bupropion may reduce residual fatigue or sexual side effects, in

61
addition to enhancing the antidepressant effect of the initial drug; moreover,
bupropion tends to be well tolerated. Other antidepressant combinations
that have been studied and that show some promise in treatment-resistant
depression include the addition of TCAs to ongoing SSRI therapy and mir-
tazapine added to an SSRI or SNRI.

Key Point: When depressed individuals fail to adequately respond to an

antidepressant, switching from or augmenting the current treatment
must be considered. Switching often involves using a new class of anti-
depressant and is preferred when there is limited response to the first
treatment. Augmentation by adding another antidepressant, lithium,
or other medication is preferred when there is a partial response.

7.4.4. Ketamine for Treatment-Resistant Depression

Although not currently FDA-approved for the treatment of depression, stud-
ies demonstrate that the anesthetic and psychotomimetic drug ketamine pro-
duces rapid antidepressant effects in some people with treatment-resistant
depression. After a single intravenous dose of ketamine, a robust reduction
in depressive symptoms is typically seen within hours, with effects lasting a
week or longer in some individuals. Ketamine is a glutamate NMDA receptor
antagonist that appears to have rapid effects on cortical networks that are
often dysregulated in a depressive episode. Moreover, ketamine appears to
increase levels of brain-derived neurotrophic factor (BDNF) and other neuro-
trophic factors that have been linked to neuroplastic changes that occur dur-
ing antidepressant treatment.4 Despite these promising findings, uncertainty
Major Depressive Disorder
Table 7.3  Common Medications Used to Augment
Antidepressants in Treatment-Resistant Depression
Medication Range (daily dose, Comments
mg)
Lithium Serum conc. 0.6–.0 Consider in recurrent illness as
maintenance benefits reported; only
drug shown to reduce suicidality
Thyroid hormone 25–50 micrograms ~50% respond in 2–3 weeks in trials;
(T3) may work better in women
Buspirone 30–60 mg Add to SSRI; 30% remission rate
in STAR*D study; may work by
enhancing serotonin release
L-methylfolate 5 mg Add to SSRI; approved as medical
food for people with depression and
low folate levels
Psychostimulants Depends on agent Useful in people with fatigue or
hypersomnia; no placebo-controlled
studies
Omega-3 –2 gms/day; Controlled trials with mixed results,
EPA:DHA ratio 2: but well tolerated
Atypical antipsychotics
Quetiapine 50–300 mg FDA-approved for augmentation of
antidepressants; may be an effective
62

monotherapy as well
Aripiprazole 5–5 mg Partial dopamine agonist;
FDA-approved for augmentation
Olanzapine 6–8 mg Approved as formulation combined
with fluoxetine 50 mg for people who
have failed two AD trials

exists regarding the sustainability of ketamine’s antidepressant effects, and the

potential for psychosis and dissociative side effects raises concerns about the
safety of longer-term use as well.

7.5.  Complementary and

Alternative Treatments
In recent years, a number of naturally occurring substances have been proposed
as potential non-pharmaceutical treatments for depression. For many of these
agents, there are insufficient data from controlled trials to support their effective-
ness in major depression. However, there is evidence to support some comple-
mentary and alternative therapies. For example, l-methylfolate is FDA-approved
as a medical food for people with low folate levels and inadequate response to
an antidepressant. This naturally occurring derivative of folic acid is thought to
enhance the effects of SSRIs by promoting production of serotonin through its
role as a methyl donor during serotonin synthesis. Results from two

Chapter 7 Psychopharmacology & Biological Therapies

placebo-controlled trials of adjunctive l-methylfolate have been published to date.
Pooled data from these studies show a significant benefit with l-methylfolate 5 mg
compared to placebo when added to ongoing SSRI therapy.
Hypericum, the active ingredient in St. John’s wort, has been extensively
studied as an antidepressant agent. Although meta-analyses suggested that
treatment with hypericum is superior to placebo, results vary significantly
among studies, with larger trials demonstrating a less robust effect than
smaller trials.5 Moreover, different preparations of hypericum have been
studied, making it harder to generalize from existing reports. Hypericum is
known to enhance activity of the P450 3A4 hepatic pathway, which raises
concerns about significant drug interactions with its use.
Omega-3 fatty acids, either as monotherapy or as an adjunct to antide-
pressants, have been reported to have antidepressant properties. However,
results from placebo-controlled trials are mixed, with only a portion of studies
showing greater benefits with omega-3 compared to placebo. Preparations
with a higher concentration of EPA as opposed to DHA are more likely
to show an antidepressant effect in clinical trials. Recent meta-analyses of
omega-3 effects in depression also yield conflicting results, with one study
supporting an effect greater than placebo, and another finding only a minimal
effect that was negligible after adjusting for possible publication biases.6,7

63
Key Point: Although “nutraceutical” treatments for depression often
receive significant press, to date, controlled studies of these interven-
tions have yielded mixed results. However, in some instances, augmen-
tation with l-methylfolate or omega-3 fatty acids may be warranted.

7.6.  Light Therapy

A significant body of literature supports the concept that bright light therapy,
generally administered through a light-box device, is an effective treatment
for major depression. Although this treatment is typically reserved for people
with a seasonal pattern of depressive episodes characterized by depression
during winter months, studies also support the use of light therapy as an
augmentation strategy when there is an inadequate response to antidepres-
sants. Light therapy helps to normalize circadian rhythm disturbances associ-
ated with depression, and its mechanism of action is thought to be related
to effects on melatonin function and serotonin activity. Treatment typically
involves indirect optic stimulation with full-spectrum non-ultraviolet light at
an intensity of 0,000 lux for 20–30 minutes per day. It may be most effec-
tive when administered at either the beginning or end of the day as a way to
extend the day, from a light exposure perspective. The most significant risks
of light therapy include the potential for retinal damage and the induction of
hypomania or mania in bipolar depression.
Major Depressive Disorder 7.7.  Neurostimulation Techniques
In the past few years, electroconvulsive therapy (ECT) has been joined by
vagus nerve stimulation and transcranial magnetic stimulation as neuro-
stimulation or neuromodulation techniques that are FDA-approved for
treatment-resistant depression.
7.7.. Electroconvulsive Therapy
ECT, which has been in use since 937, is considered to be the most effective
treatment for acute episodes of depression, as well as for treatment-resistant
depression. Generally, ECT is reserved for severe refractory depression,
depression associated with elevated risk of harm (e.g., a highly suicidal indi-
vidual), and depression with psychotic features. It is estimated that ECT has a
clinically significant effect in 60–85% of cases, including approximately 50% of
medication non-responders. Moreover, ECT is equally as effective in severe
or psychotic depression as it is in less severe, non-psychotic cases. ECT’s
mechanism of action is not known, but research suggests several possibilities,
including the modulation of monoamine and other neurotransmitter systems,
alteration of neuroendocrine processes, increases in neurotrophic factors
that promote neurogenesis, and anticonvulsant effects that alter the activity of
brain regions involved in mood regulation. The most significant adverse event
caused by ECT is cognitive impairment, with the most common symptoms
64

being anterograde memory and autobiographical memory disturbance, which

generally resolves between  and 6 months after treatment is completed.
This side effect may be less pronounced following unilateral, as opposed to
bilateral, ECT. A recent meta-analysis of studies using objective measures of
cognition showed no evidence of impairment compared to baseline 2 weeks
after ECT. However, there are case reports of people experiencing persistent
memory deficits following ECT, and this perception contributes to the stigma
against using ECT, despite its considerable efficacy and tolerability.
ECT is typically administered three times per week for a total of 6–2
treatments, although specific “dosing” studies are scarce. The therapeutic
component is a generalized seizure, produced using an electrical stimulus
to the scalp. Electrodes are placed either bilaterally or unilaterally; bilateral
placement is more effective, while unilateral placement produces less cog-
nitive side effects as noted. Memory deficits also appear to be less with
brief-pulse type of electrical stimulus, lower stimulus intensity, and twice ver-
sus thrice per week treatment.
One significant drawback of ECT in treatment-resistant depression is that
there is commonly a high rate of relapse after the course of ECT is com-
pleted. Antidepressants are often ineffective in preventing relapse after suc-
cessful ECT in these cases, which is not particularly surprising since typically
these same individuals were unresponsive to medications in the first place.
Nonetheless, combination treatment with nortriptyline and lithium may yield
better results than other medication interventions. Although there is a paucity
of data from controlled trials, continuing ECT sessions at a lower frequency
after the initial series of treatments, known as continuation or maintenance
ECT, is an option when there has been a favorable response to an initial

Chapter 7 Psychopharmacology & Biological Therapies

course of ECT.
7.7.2. Vagal Nerve Stimulation
Vagal nerve stimulation (VNS), the second neurostimulation technique devel-
oped for the treatment of major depression, is FDA-approved for use in
those who have failed to respond to at least four previous medication tri-
als. VNS involves an electrical stimulator that is implanted in the upper chest
with a lead that connects to the afferent branch of the vagus nerve. A mild
electrical impulse is generated for about 30 seconds every 5 minutes. The
stimulated vagus afferents then transmit a signal to key limbic and cortical
brain regions involved in mood regulation, including the raphe nucleus, locus
coeruleus, orbitofrontal, parieto-occipital, and temporal cortex, hypothala-
mus, and amygdala. Despite FDA approval, the only study comparing VNS
to sham stimulation did not show a significant benefit with VNS stimulation
after 0 weeks of treatment. FDA approval was granted based on a 2-month
follow-up study that demonstrated greater improvement in subjects treated
with VNS added to ongoing antidepressant therapy, compared to a group of
subjects who received treatment as usual with antidepressants alone (5% vs.
4% remission rate, respectively). Side effects with VNS include hoarseness
when the stimulator is active (since the vagal nerve also contributes to vocal
fold control) and occasional problems with swallowing or breathing.

65
7.7.3. Transcranial Magnetic Stimulation
Transcranial magnetic stimulation (TMS) is a technique that uses a magnetic
field rather than an electrical impulse to alter neuronal activity. To this end,
an electromagnetic coil is placed against the scalp overlying the dorsolateral
prefrontal cortex (DLPFC). Typically, high-frequency stimulation to the left
DLPFC, and, more recently, low-frequency stimulation of the right DLPFC
have been used. The stimulation is typically administered five times per week
for 5–6 weeks. The DLPFC shares connections with other brain regions
linked to the pathogenesis of depression such as the anterior cingulate, and
modulation of activity in these regions may be a possible mechanism for the
antidepressant effects of TMS. Meta-analyses of TMS trials showed remis-
sion rates of 9% using left-sided high-frequency stimulation8 and 35% with
low-frequency treatment to the right DLPFC.9 Response rates for sham TMS
were 5% and 0%, respectively, in these studies. Side effects are generally
minimal and include headache, dizziness, and scalp irritation, although sei-
zures may occur in a very small number of individuals.
7.7.4. Deep Brain Stimulation
Deep brain stimulation (DBS) procedures, similar to those approved for
Parkinson’s disease and severe obsessive-compulsive disorder, are cur-
rently being investigated as a neurostimulation technique for severe
treatment-resistant depression. This method uses an implanted device that
intermittently stimulates neurons, which can either increase or decrease neu-
ronal firing rates in the surrounding region depending on the frequency of
stimulation. Two implantation sites have been primarily studied so far: the
Major Depressive Disorder ventral capsule/ventral tegmentum and the subgenual cingulate gyrus. A
recent meta-analysis of studies conducted using the subgenual cingulate site
showed an average 2-month remission rate of 26% in chronic and severely
treatment-resistant depression. Although there is less evidence for the ventral
capsule site, preliminary data suggest that DBS implantation in this region may
also be effective.

Key Point: Neurostimulation techniques are effective for depression,

although they are typically used only in cases of treatment resistance.
ECT may be the most effective antidepressant available, but its use is
limited by stigma and misperceptions.

7.8. Conclusion
Over the past six decades, a number of new biological therapies were
developed for the treatment of major depression. These interventions have
greatly expanded treatment options and improved the quality of life and
overall health of many people who suffer from this recurrent and often dis-
abling disorder. Improvements in tolerability made these treatments safer and
more palatable, especially when long-term maintenance therapy is indicated.
Despite these improvements, a significant percentage of people with depres-
66

sion do not receive adequate benefit with current treatments, or experience

side effects that negatively impact their quality of life. Hopefully, research will
yield new treatments that are effective for these individuals, as well as bio-
markers that predict which treatment is most effective for a particular person.

References
. Duric V, Duman RS. Depression and treatment response: dynamic interplay of
signaling pathways and altered neural processes. Cell Mol Life Sci CMLS 203;
70:39–53.
2. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptabil-
ity of 2 new-generation antidepressants: a multiple-treatments meta-analysis.
Lancet 2009; 373:746–758.
3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes
in depressed outpatients requiring one or several treatment steps: a STAR*D
report. Am J Psychiatry 2006; 63:905–97.
4. Caddy C, Giaroli G, White TP, Shergill SS, Tracy DK. Ketamine as the proto-
type glutamatergic antidepressant: pharmacodynamic actions, and a systematic
review and meta-analysis of efficacy. Ther Adv Psychopharmacol 204; 4:75–99.
5. Shelton RC. St John’s wort (Hypericum perforatum) in major depression. J Clin
Psychiatry 2009; 70 Suppl 5:23–27.
6. Bloch MH, Hannestad J. Omega-3 fatty acids for the treatment of depres-
sion: systematic review and meta-analysis. Mol Psychiatry 202; 7:272–282.
7. Grosso G, Pajak A, Marventano S, et al. Role of omega-3 fatty acids in the treat-
ment of depressive disorders: a comprehensive meta-analysis of randomized
clinical trials. PloS One 204; 9:e96905.
 8. Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remis-

Chapter 7 Psychopharmacology & Biological Therapies

sion and drop-out rates following high-frequency repetitive transcranial mag-
netic stimulation (TMS) for treating major depression: a systematic review and
meta-analysis of randomized, double-blind and sham-controlled trials. Psychol
Med 204; 44:225–239.
9. Berlim MT, Van den Eynde F, Jeff Daskalakis Z. Clinically meaningful efficacy
and acceptability of low-frequency repetitive transcranial magnetic stimulation
(TMS) for treating primary major depression: a meta-analysis of randomized,
double-blind and sham-controlled trials. Neuropsychopharmacol Off Publ Am Coll
Neuropsychopharmacol 203; 38:543–55.

67
Chapter 8

Psychotherapy and
Related Techniques

8.. Introduction
Although effective pharmacologic management is essential in the treatment of
major depression for many people, it is often not sufficient to maximize out-
comes. In particular, research demonstrates that functional impairment per-
sists even after remission of symptoms, often for weeks or months. Although
medications contribute to functional recovery by decreasing depressive symp-
toms, the presence of residual symptoms, a relatively common occurrence,
is associated with higher levels of ongoing functional impairment. Additional
interventions such as psychotherapy are, therefore, often needed to help

69
69
people fully recover from an episode of depression. In addition, research
evidence suggests that combining certain types of psychotherapy with anti-
depressant medication improves outcomes from acute depressive episodes,
including cases of treatment-resistant depression, thereby minimizing the
effect of residual symptoms on psychosocial functioning. Furthermore, in
patients with mild to moderate depression, some modes of psychotherapy,
such as cognitive behavioral therapy (CBT) and interpersonal therapy (IPT),
are considered first-line treatment alternatives to antidepressants.
Depressive episodes often create significant psychosocial consequences,
damaging interpersonal relationships, job performance, finances, and
self-esteem of affected individuals. Medications cannot address these issues
directly. Moreover, for people whose depression was precipitated by trauma
or loss, or for whom childhood trauma or neglect is a major predisposing
factor, psychotherapy is an essential part of helping them cope with these life
events and minimizing the impact they have on recovery from depression.
Consequently, a comprehensive treatment of depression typically requires
use of evidenced-based psychotherapy.

Key Point: Although medications are often useful and even necessary

to manage depression, a number of psychotherapies have developed
an evidence base suggesting significant utility of these interventions
in depression. Psychotherapies are critical for managing the negative
psychosocial consequences of depression.
Major Depressive Disorder 8.2.  Cognitive Behavioral Therapy
Cognitive behavioral therapies (CBT) are the most well-established
evidence-based psychotherapeutic treatments practiced in mental health
care. Originally developed by Aaron Beck, cognitive therapy is based upon
the premise that depression arises from negative automatic thoughts that
are an individual’s default response, setting him or her up for a vicious cycle
of negative thoughts, followed by corresponding negative behavior and
expectations, leading to additional negative thoughts and emotions that ulti-
mately result in impaired function and depressive symptoms (Figure 8.). 2
Cognitive therapy is designed to identify and modify these automatic
negative thoughts to break the cycle. Behavioral therapy is an extension
of this cognitive approach in which modifications based upon correcting
negative behaviors are implemented to further disrupt this vicious cycle.3
Mindfulness-based cognitive therapy is a recent variant that includes medi-
tation techniques that help people to learn to relate differently to negative
thoughts, feelings, and bodily sensations in ways that reduce rumination or
automatic self-defeating cognitions, as well as providing improved stress
management.
The reciprocal connections observed between emotional and cognitive
parts of the prefrontal cortex, as discussed in Chapter 5, provide neurobio-
logical support for this basic premise that cognitive interventions can be used
70

to modify behavior. CBT is effective in the treatment of depression, as well

as many conditions that co-occur with depression, such as anxiety disorders,
addictions, eating disorders, post-traumatic stress disorder (PTSD), and
obsessive-compulsive disorder (OCD). In many of these conditions, specific
manuals were developed and validated in clinical trials to specifically direct the
course of treatment. CBT can be used both for the short-term management

NEGATIVE THINKING

Hopelessness
Self-defeating behavior
Anxiety

Helplessness

STRESS

Insomnia

Figure 8.  The vicious cycle of negative thinking (Strakowski3).

 Psychotherapy and Related Techniques
Box 8.  Uses of CBT in Depression
. Managing acute depression
2. Relapse prevention
3. Stress reduction
4. Interpersonal interactions
5. Medication adherence
6. Comorbidities
–Anxiety and anxiety disorders
–Alcohol and drug abuse
–PTSD
–OCD
–ADHD
–Eating disorders
–Smoking

Chapter 8
of acute symptoms and over the longer term to improve specific areas of
function (Box 8.).3
CBT has been extensively studied in major depression and, in general,
results of those studies suggest that CBT enhances recovery from mild to

71
moderate depressive episodes. Response to CBT is generally equivalent to
medications. CBT is also useful as an adjunct to pharmacotherapy in severe
nonpsychotic depression and in partial responders to antidepressant treat-
ment. Moreover, studies support the use of CBT alone or in combination
with medications for maintenance treatment of depression; the combination
approach decreases the risk of recurrence more effectively than either treat-
ment alone. Studies also suggest that CBT may be effective as an adjunct to
pharmacotherapy for treatment-resistant depression.4
Specifically, CBT can be applied to improve medication adherence, manage
inter-episode affective symptoms, and improve stress management by modi-
fying maladaptive coping strategies. Combined, these effects contribute to
long-term functional improvement. Indeed, improvement from CBT appears
to accumulate over time, presumably as individuals internalize more adaptive
thoughts and behavioral patterns. Moreover, when effectively administered,
the additional cost of CBT is offset by savings that result from needing addi-
tional components of care (e.g., fewer medications and hospitalizations). On
balance, then, CBT is recommended for many, if not most, individuals with
major depressive disorder.

Key Point: Cognitive behavioral therapy (CBT) is the most established

psychotherapy for treating depression. It has a rich evidence base and
is effective as monotherapy for many cases of depression.
Major Depressive Disorder 8.3.  Interpersonal Therapy
Interpersonal therapy (IPT) has a long history of application in psychiatry,
particularly in the management of depression. It is based upon the prem-
ise that maladaptive social interactions are connected with both stress and
depressive symptoms, so it therefore focuses on improving these interactions
within the context of current relationships, rather than focusing on past life
experiences as is done in classic psychodynamic psychotherapy. No assump-
tions about causality are made in this work. This approach has significant face
validity based on evidence that depression may negatively affect social rela-
tionships, and that higher levels of stress related to interpersonal conflicts or
lack of social support have a negative effect on the outcome and course of
major depressive illness.
IPT has been commonly studied for the treatment of depression. These
studies support benefits with IPT for acute depressive episodes and relapse
prevention. However, some studies report greater benefit with pharmaco-
therapy compared with IPT. In fact, a recent meta-analysis of IPT studies in
depression found no difference between IPT and other psychotherapies, and
a slight advantage of pharmacotherapy over IPT for acute depressive epi-
sodes.5 This analysis reported increased benefit with the combination of IPT
and medication, compared with pharmacotherapy alone in maintenance ther-
apy, that is, to prevent relapse, but not for the acute treatment of depression.
72

8.4.  Other Psychotherapies

Several other psychotherapies may be considered in the treatment of depres-
sion. Dialetical behavioral therapy (DBT) is a manualized, modified CBT
specifically designed to manage the suicidality, self-destructive behavior, and
emotional dysregulation of individuals with borderline personality disorder.
DBT manages these behaviors by validating the associated thoughts and
feelings while moving individuals toward more adaptive responses to them.
Although DBT has amassed a large database supporting its utility in border-
line personality disorder, it has not been extensively studied in major depres-
sion. However, DBT may be indicated in individuals suffering from depression
when borderline personality traits are present.
Behavioral activation is the term used to describe a collection of tech-
niques generally considered to be a form of supportive therapy that also
includes several elements of CBT. The main goal of behavioral activation is
to facilitate the person’s engagement in activities that improve mood or other
depressive symptoms, or that are essential to the person’s overall functioning.
Commonly used behavioral activation strategies include decreasing avoidant
behaviors (e.g., social withdrawal), reducing a person’s identification with
“being depressed” when this reinforces depressive symptoms, and using con-
tingency management to reinforce desired behaviors.
Psychodynamic psychotherapy has a long history in psychiatry, originally
evolving from psychoanalytic roots. Psychodynamic psychotherapy works
from an assumption that maladaptive behaviors are manifestations of
subconscious drives and wishes, often based upon unhealthy upbringing.3

Psychotherapy and Related Techniques

Some versions of psychodynamic psychotherapy, including strict, time-limited
formats, have been demonstrated to be effective for depression. However,
there is currently insufficient evidence to support using classic psychoanalytic
techniques, such as dream interpretation or free association techniques, to
specifically treat the symptoms of major depression.

8.5.  Supportive Psychotherapy

Perhaps the most commonly applied therapy in clinical practice is a mixture of
education, encouragement, acute problem-solving, and aspects drawn from
the previously discussed therapies, which is referred to in combination as sup-
portive psychotherapy. Supportive psychotherapy originally developed as a
way to treat people who are not considered appropriate candidates for psy-
chodynamic or psychoanalytic psychotherapy. Supportive therapy is inherently
pragmatic and rarely structured, and it can be delivered within the confines

Chapter 8
of even short medication visits. Goals of supportive psychotherapy include
improvements in illness self-management, coping skills, problem-solving abil-
ity, stress management, and regulation of negative emotions.
In research designed to investigate the effectiveness of psychotherapy in
depression, supportive therapy is often used as a control condition to struc-

73
tured therapies. Although in some studies it performs similarly, on balance
structured psychotherapies are superior to primarily supportive interven-
tions, although clinicians trained to deliver these treatments are frequently not
available, so supportive therapy often becomes the default. Consequently, we
recommend that clinicians learn one or more structured psychotherapies so
that they can integrate key elements of structured therapy into a supportive
therapy model to provide a more consistent therapeutic structure if time or
resource constraints preclude providing the better structured interventions.

Key Point: In addition to CBT, interpersonal therapy has a growing

database suggesting that it is effective for managing mild to moderate
depression and as an adjunct to medication. Other psychotherapeutic
interventions may also have a role in managing depression.

8.6.  Lifestyle Management

A number of lifestyle factors have been proposed as mutable contributors
to stress and potentially depression. For example, improving diet, ensuring
adequate sleep, promoting exercise, and limiting exposure to toxins such as
tobacco and alcohol are all cost-effective interventions that improve over-
all mental well-being and presumably lower the risk for depression. Direct
benefits of regular, moderate levels of exercise have been examined in
depression with mixed results, with larger studies finding minimal benefits
of exercise over control conditions.6 Regardless of direct findings on depres-
sion, healthy diet, exercise, and sleep patterns provide substantial health
Major Depressive Disorder benefits so belong in the management of mental health conditions, including
depression.3

8.7.  Traditional Therapies

Acupuncture has been a staple of non-Western medicine for millennia.
Consequently, there have been recent efforts to determine its efficacy in
depression; to date, there is inadequate evidence to recommend this treat-
ment. A variety of yoga therapies have been studied in depression and other
psychiatric disorders; yoga techniques are common mainstays for anxiety and
stress management, so there is some face validity in using yoga to manage
depression. However, a recent meta-analysis of 2 controlled trials of yoga
in people with high levels of depressive symptoms (three studies included
people with a major depressive disorder) found minimal to moderate benefits
at best.7 The authors cautioned that the generalizability of these results was
limited by the short-term nature of the studies, small numbers of trials, and
considerable heterogeneity in the types of yoga that were used.

8.8. Conclusions
74

Psychotherapies, particularly CBT and interpersonal psychotherapy, play key

roles in the treatment of depression. Psychotherapies complement psycho-
pharmacology to maximize behavioral outcomes and function, and may also
be appropriate monotherapy in mild to moderate cases. A state-of-the-art
programmatic approach to the management of depression therefore requires
the integration of psychotherapy and sophisticated psychopharmacology to
maximize treatment benefit and outcome.

References
. Gelenberg AJ, Freeman MP, Markowitz JC, et  al. Practice Guideline for the
Treatment of Patients with Major Depressive Disorder. Washington, DC: American
Psychiatric Association, 200.
2. Beck AT. Cognitive Therapy of Depression. New York: Guilford Press; 979.
3. Strakowski SM. Psychotherapy and complementary treatments. In:  Bipolar
Disorder, p.  76. Oxford American Psychiatry Library. New  York:  Oxford
University Press, 204.
4. Rupke SJ, Blecke D, Renfrow M. Cognitive therapy for depression. Am Fam
Physician 2006; 73():83–86.
5. Cuijpers P, Geraedts AS, van Oppen P, Andersson G, Markowitz JC, van Straten
A. Interpersonal psychotherapy for depression: a meta-analysis. Am J Psychiatry
20; 68(6):58–592.
6. Cooney GM, Dwan K, Greig CA, et  al. Exercise for depression. Cochrane
Database Syst Rev 203; 9:CD004366.
7. Cramer H, Lauche R, Langhorst J, Dobos G. Yoga for depression: a systematic
review and meta-analysis. Depress Anxiety 203; 30():068–083.
Chapter 9

A Programmatic Approach
to Treatment

9.. Introduction
As noted throughout this handbook, depression is a heterogeneous condi-
tion arising both idiopathically and within the context of other medical and
psychiatric disorders. It typically results from a complex interplay of environ-
mental and inherited risks. This complexity requires thoughtful treatment that
integrates different management approaches to maximally benefit depressed
individuals. Chapters 7 and 8 provide overviews of pharmacologic and psy-
chotherapeutic interventions, but these interventions are only components
of a programmatic approach to treatment. In this chapter, we develop an

75
75
integrated programmatic approach to guide treatment planning for people
with depression. Importantly, depression is so common that there simply are
not enough psychiatrists available to manage it; consequently, these guide-
lines are presented with a broad range of physicians (especially primary care)
and other mental health professionals in mind, since they will provide most
depression care.

9.2.  Pulling It All Together: The Program

Like other complex medical illnesses, optimal management of depression
often requires more than simply prescribing a medication and sending peo-
ple out to fend for themselves, hoping for the best. Behavioral symptoms
can be mystifying and, by definition, cause marked psychosocial impairment.
Many causes of depression are themselves complex psychiatric (e.g., bipo-
lar disorder) or medical (e.g., multiple sclerosis) illnesses that also require
systematic treatment programs. Functional recovery is often slow, typically
trailing symptom remission by weeks or months, and is interrupted with every
recurrence or relapse. Despite these challenges, most people who develop
depression can expect to lead healthy lives, particularly with the right treat-
ment program. These programs have multiple components that we will now
pull together (Box 9.).
9.2.. Comprehensive Clinical Assessments
Major depression is a clinical diagnosis (like all psychiatric and many other
medical conditions); there are no blood tests or MRI scans to establish its
presence. Consequently, a comprehensive clinical assessment is the most
Major Depressive Disorder
Box 9.  Components of a Programmatic Treatment Plan
for Depression
A. Comprehensive clinical assessments
B. Ongoing safety evaluations
C. Clearly defined and shared treatment goals
D. Agreed-upon treatment plan to meet goals
E. A good support network
F. Mood charting
G. Efficient, predictable, and standardized follow-up appointments that
. Review the mood chart
2. Assess suicidal and other dangerous behaviors
3. Evaluate change in co-occurring conditions and stress
4. Review treatment adherence and side effects
5. Review and support general health measures
6. Review drug and alcohol use, including smoking
7. Review psychosocial function
8. Provide evidence-based treatment that is demonstrating
improvement
9. Make treatment changes deliberately and systematically
0. Answer questions and provide education.
76

Adapted from Strakowski.

important first step toward managing it. Because depression is often associ-
ated with other psychiatric and medical illnesses, it is paramount to recognize
these, as well as recent contributing stressors, since the optimal management
of a particular individual will vary based upon these factors.
To this end, we recommend that each clinician develop a semi-structured
approach toward an initial evaluation of someone presenting with depres-
sion to ensure that a full psychiatric, medical, and psychosocial formulation
is obtained. For the psychiatric assessment, there are several instruments
available, such as the Structured Clinical Interview for DSM-5 (SCID),2
Schedule for Affective Disorders and Schizophrenia for School Age Children
(K-SADS),3 or the Diagnostic Interview for Genetics Studies (DIGS).4 These
interviews provide structure for obtaining consistent and comprehensive clin-
ical information from each individual and can be performed by nonphysicians.
However, they are time-consuming. Alternatively, in lieu of such an instru-
ment (although one might argue that these interviews represent the highest
level of care), clinicians should emulate the approach of the interview, namely
following a specific process each and every time to guard against overlooking
symptoms and co-occurring psychiatric conditions.
In addition to a comprehensive diagnostic assessment, another essential
element of successfully managing depression is monitoring key symptoms
during treatment to assess the effectiveness of the approach. Consequently,
as part of the ongoing assessment, clinicians must identify which symptoms of
depression are present, as well as the relative severity of these symptoms at
the initial evaluation. These symptoms then become “targets” that the clini-

Programmatic Approach to Treatment

cian explores at each visit to determine whether the treatment regimen is
working.
One approach to assess the severity of depressive symptoms is to use
clinical rating scales that provide a numeric value, based on the number and
intensity of symptoms present. Such rating scales improve the tracking of
treatment response by providing consistency to measures of symptoms from
one visit to the next. Moreover, conducting symptom ratings helps identify
early improvement not easily detected by more global questioning, which is
useful when determining whether to continue an antidepressant or to switch
to a new agent. Similarly, when a treatment is established as having some
benefit, rating scales are helpful for identifying residual symptoms that may
otherwise go undetected, thereby guiding the clinician to consider additional
approaches to optimize the treatment regimen in order to maximize qual-
ity of life and decrease the chance of recurrence. Examples of commonly
used and validated rating scales include self-rating scales such as the Beck
Depression Inventory and Zung Self-Rating Depression Scale, or scales that

Chapter 9 A
are completed as part of a clinician-conducted interview such as the Hamilton
Depression Rating Scale (HDRS),5 Montgomery-Ǻsberg Depression Rating
Scale (MADRS),6 and Quick Inventory of Depressive Symptomatology
(QIDS).7 These scales can usually be completed quickly in the context
of a typical office appointment, and they are widely available on-line (e.g.,

77
Zung at http://www.psy-world.com/zung_sds.htm; QIDS at http://www.
ids-qids.org/; MADRS at http://www.psy-world.com/madrs.htm; HDRS
at http://healthnet.umassmed.edu/mhealth/HAMD.pdf ). Rating scales for
co-occurring psychiatric conditions are available as well, and these may be
incorporated as part of the ongoing assessment of treatment response.
To complement the psychiatric assessment, a thorough medical review of
systems (ROS) and medical history are warranted. Many electronic medical
records now include an ROS to remind and guide clinicians to cover a broad
set of medical symptoms and signs. The ROS, coupled with a review of cur-
rent and past medications, can identify possible co-occurring medical illnesses
that must be considered in the course of treatment. These two components
of the assessment (medical and psychiatric) are part of any good clinical prac-
tice, but are often performed incompletely with psychiatric patients, espe-
cially in primary care settings.
A third piece that is somewhat unique to the assessment of psychiatric
conditions in general and depression specifically is an evaluation of recent
stressors. As noted, in many instances, depression represents a response to
a stressful life event. Consequently, management of the event or response to
the event may be a major part of optimizing treatment. Major life events span
a variety of circumstances, but often involve loss of relationships (divorce,
death), loss of physical integrity (cancer, stroke), or loss of independence
(being fired). Again, useful checklists that can be completed quickly before
or within the context of an office visit are available on the Internet (e.g., the
Holmes and Rahe Stress scale at http://www.mindtools.com/pages/article/
newTCS_82.htm). These guidelines provide a framework for discussion to
assist with evaluation of stressors.
Major Depressive Disorder Finally, obtaining a psychiatric and medical family history is a critical part of
the evaluation of depression, to define potential genetic contributions as well
as to identify other familial conditions that may be contributing to the depres-
sive episode. Indeed, at times, a depressive episode may be the first presenting
syndrome for another evolving condition, such as bipolar disorder, Parkinson’s
disease, or Alzheimer’s disease. Unfortunately, because families often do not
discuss mental illnesses, these reports may be unreliable or spotty.
At the conclusion of this evaluation, the presence or absence of depres-
sion, based upon clinical criteria, will be clearly established, the contribution
of additional psychiatric and medical conditions will be identified, and the
context of recent life events will be defined. With this information, then, an
optimal treatment plan can be developed. Importantly, most depressed indi-
viduals’ goals will be focused on returning to their typical level of function,
rather than simply resolving symptoms. Consequently, in order to identify
realistic functional goals, assessments are necessary of prior ability to form
relationships, employment history, educational achievement, and recreational
and other activities.
Obviously, a comprehensive evaluation can be time- and labor-intensive.
Consequently, diagnostic evaluations do not end after the first meeting. New
information will arise during the course of treatment, and new medical and
psychiatric conditions may develop as well. Because of the nuances and mul-
tiple potential contributions to any specific depressive episode in any specific
78

individual, if treatment is not working as expected, the first assumption to

challenge is that the diagnostic assessment was complete.

Key Point: Depression is a clinical diagnosis often complicated by other

conditions and stressors. A comprehensive evaluation is necessary to
develop an effective treatment plan.

9.2.2. Ongoing Safety Evaluations

At times, the major challenge in managing depression is keeping affected indi-
viduals alive, since suicide is unfortunately a common consequence of this
condition. Managing suicidality is discussed in detail in Chapter 0. Briefly, it
requires a careful assessment of potential risks in a given individual at a spe-
cific time, and then determining whether more restrictive care, including hos-
pitalization, is required to keep the individual safe. Additionally, as noted in
Chapter 2, up to 5% of depressed individuals develop psychotic symptoms.
Thought disorder or delusional beliefs can impair reality testing to the point
that depressed individuals put themselves inadvertently into risky situations
that lead to exploitation, injury, or death. Less commonly, depression may
contribute to impulsive violence. Typically, violence is much more common
in men than women, but can occur within the context of depression in either
sex. Whether violence is actually more common in depressed individuals than
the general population is not clear; in fact, it may be associated more so with
the underlying cause of depression (e.g., substance abuse or bipolar disor-
der), rather than the depression per se. As with suicide, a careful risk assess-
ment is necessary to determine the most appropriate level of care.
 Perhaps the greatest risk period for either suicidal or homicidal violence is

Programmatic Approach to Treatment

during treatment in cases in which energy levels improve before hopelessness
and negative cognition; consequently, it is imperative to schedule appoint-
ments during early phases of treatment to assess potential risk, particularly
in individuals with histories of violence or suicidality. In particular, this risk
may be higher for young adults and adolescents. The presence of psycho-
sis also increases the risk of violence, as does the presence of a number of
co-occurring psychiatric conditions and substance abuse. These evolving risks
are reminders that safety evaluations are not singular events, but are an ongo-
ing part of clinical care. As a general rule, when in doubt in the treatment of
someone in whom violence or suicide is a concern, err on the side of more
restrictive care (e.g., hospitalization versus outpatient management).
Additionally, co-occurring medical illnesses may become life-threatening,
and, in fact, depression typically worsens the course of many medical ill-
nesses. Studies suggest that individuals with mental illness receive substan-
dard medical care, so that psychiatrists or other mental health clinicians will
often, by necessity, assume a general medical role or help guide depressed

Chapter 9 A
individuals to better medical providers. Moreover, if a previously successful
treatment program suddenly begins to fail, an exacerbation or development
of a new medical illness may be contributing to the failure. New medical
illnesses occur as a consequence of aging, poor self-care associated with the
impairments of depression, and risks associated with treatment (e.g., obesity

79
secondary to medication-induced weight gain). Managing co-occurring condi-
tions is discussed in more detail in Chapter 0.

Key Point: Suicide and, less commonly, other violence are risks asso-
ciated with depression. Ongoing safety assessments are therefore
required in its management.

9.2.3. Clearly Defined and Shared Treatment Goals

Once a comprehensive assessment is completed and risks to safety have been
identified, this information must be translated into a treatment plan. As a first
step, the clinician should share the results of the evaluation with the depressed
individual (and family or friends participating in treatment decisions), and
together develop specific and realistic treatment goals. Unrealistic treatment
goals overstate outcomes and may lead to discouragement; understated goals
produce apathy and low expectations. As part of this process, clinicians must
take the time to understand how treatments work. For example, antidepres-
sants will produce side effects immediately (from acute neuronal receptor
effects), but treatment benefits trail by weeks and functional recovery by
months. A week on an antidepressant, or a couple of sessions of cognitive
behavioral therapy, is unlikely to lead to dramatic improvement. Moreover,
the course of recovery tends to not only be slower than any of us really
want, but also erratic. Typically, people with depression do not respond by
consistently feeling just a little better each day; rather, improvement involves
both forward and backward steps, with the forward steps ultimately winning
out, 3–8 weeks later.
Major Depressive Disorder Since managing depression often involves concurrent management of
stressors and co-occurring conditions, part of the process is to set goals
in each of these contributing areas. A  major part of this component of
goal-setting is for clinicians to educate the depressed individual with regard
to how depression arises from multiple sources, and how managing each of
these potential causes is necessary for maximal improvement. Goals should
integrate an understanding of evidence-based treatments and what the rela-
tive risks, benefits, and rates and timing of response are likely to be. These
goals ideally span not only symptom resolution, but a return to typical levels
of function. Of course, goal setting will vary based upon the nature of the
depressive illness; it will be much more comprehensive for individuals who
experience relatively frequent recurrences of severe depression compared
to those experiencing a first (and perhaps only) mild or moderate episode,
for example. In recurrent depression, goal setting will evolve over time as
people become more effective at managing their illness; like other aspects of
care, goal setting is an ongoing process, not a one-time event. Indeed, goal
setting in people with recurrent depression not only entails identifying goals
for recovery from the current episode, but also strategies to prevent future
episodes.
Finally, as part of this process, it must be decided how it will be determined
that a goal has been met (i.e., what the measurement is). Again, in the case
of a first mild depression, the measurement may simply be that “I feel like
80

my old self ” or that the MDRS score is back to zero. In recurrent, chronic,
or more severe cases, these assessments become more complex and may
involve measurements such as the number of days of missed work or the
average depression score over several weeks. To this end, mood charting is
helpful and is probably necessary in chronic, severe, or commonly recurrent
depression. Because of its importance, mood charting is discussed separately
in section 9.2.6. With shared goals and expectations regarding treatment,
the clinician and depressed individual will be working collaboratively toward
recovery.

Key Point: Thoughtful, realistic, and hopeful treatment goals are essen-

tial to guide treatment decisions and expectations. Managing expecta-
tions successfully can significantly improve treatment outcomes.

9.2.4. Agreed-Upon Treatment Plan to Meet Goals

Once goals are set, a treatment plan is developed. The first component is to
manage safety issues. Recognize and address risk factors that can be changed
(e.g., substance abuse; see Chapter 0 for more details). Work with the per-
son’s support system to demystify suicide, placing it within the context of risks
of a depressive illness, rather than a moral or social failing. Plan to discuss
suicide and other forms of violence as part of the ongoing assessment pro-
cess, keeping an open dialogue about this risk. It is not possible, in the end, to
accurately predict suicide; however, by managing the risks and guiding people
into the safest environment possible concordant with those risks, perhaps it
can be prevented.
 A next step is to address the various potential contributors to depression.

Programmatic Approach to Treatment

If a medical problem may be a component, find someone who can manage
it expertly. If life events are contributing, identify a therapist who can assist
with managing both the stress and the response to stress. Co-occurring
psychiatric illnesses require their own treatment plans that may or may not
share common components. For example, the treatment of depression
and co-occurring obsessive-compulsive disorder share key treatment com-
ponents (SSRI antidepressants plus cognitive behavioral therapy), whereas
depression in bipolar disorder requires different decisions (i.e., maximizing
mood stabilizers rather than relying on antidepressants). If substance abuse is
a problem, aggressively manage it (e.g., with 2-step programs); ongoing sub-
stance abuse can prevent or delay treatment response. A goal of managing
co-occurring syndromes and contributors to depression is to identify treat-
ments that provide dual purpose whenever possible, while addressing both
conditions always (see Chapter 0 for additional discussion).
With this in mind, the next step is to determine whether managing the
contributing element alone is likely to resolve the depressive episode. If the

Chapter 9 A
depression is mild and the link with another medical, psychiatric, or substance
abuse condition is clear, then it is medically reasonable to first manage the
underlying potential cause to see if the depression improves spontaneously.
However, because depressive symptoms are in and of themselves disabling, if
the symptoms are moderate or worse, or there is not relatively quick resolu-

81
tion with treatment of the potential underlying cause (say, within  month),
then aggressively treating the depression itself is warranted.
Once this decision is made, there are three typical options: () treat with
an antidepressant alone; (2) treat with an evidence-based psychotherapy
alone; or (3) combine medication and psychotherapy. The latter option has
been shown to be the most effective. However, this approach increases the
time committed to treatment, the cost of care, and, relative to therapy alone,
the risks of medication side effects. With everything else being equal, how-
ever, combination therapy is the best choice, particularly for moderate or
more severe depression. Psychotherapy or medication alone is similarly effec-
tive for mild to moderate levels of depression. The former may be preferred
when there is a clear, manageable life-event precipitant, whereas the latter
may be better in the absence of such. In either case, the depressed individ-
ual’s preference will often guide this decision. An important component of
the treatment plan is to ensure that the treatment chosen will meet the goals
previously set. For example, if “better stress management” is a goal, simply
prescribing medication will not meet that goal and may lead to treatment dis-
satisfaction and non-adherence.
Regardless, a major reason for treatment failure is that once a treatment is
agreed upon and a plan instituted, it is not aggressive enough. An occasional
therapy session or inadequate dose of medication will fail. As noted previ-
ously, acute depressive episodes and the slow process of recovery can be
both life-altering and life-threatening and therefore warrant aggressive man-
agement. If improvement is not evident by 3–4 weeks or not fairly robust
by 6 weeks, then changes are indicated. In people receiving either medica-
tion or therapy alone, the best next step is to add the missing element. If
Major Depressive Disorder this combination is already in place or does not produce benefit within a few
weeks after being implemented, then alternative therapy or medication should
be considered. Regular appointments, no less frequent than every 2 weeks,
are recommended until treatment response is clearly established (often by
week 6, but perhaps as late as 8–2 weeks for full symptom remission).
When making changes in treatment, the clinician should develop with
the depressed individual a menu and flow chart for the next intervention.
Whenever possible, it is best to try to make one treatment change at a time
in order to gauge the impact of that change; however, in severely ill individu-
als, this approach may not be possible or will be delayed until the individual
is more stable. In these instances, once stabilized, critical review of the value
of each treatment needs to occur. When adding an additional medication,
remember that there are a few studies of combination therapy involving two
drugs, but virtually none with three or more. If someone continues to have
significant symptoms on three medications, then the medications are prob-
ably not offering benefit and require reassessment and change. A mantra we
keep in mind is “we want to prescribe as much medication as needed but
as little as possible.” Particularly with recurrent depression, and in any case
of treatment-resistant depression, deliberate, systematic treatment changes
represent the best approach, with a constant eye toward identifying contrib-
uting factors that may have been previously missed.
A major goal for any treatment plan is to actually follow the plan;
82

non-adherence is another leading cause of treatment failure. Consequently,

working collaboratively to achieve adherence must be a treatment goal.
Factors contributing to non-adherence are multiple and include poor insight
into illness, lack of education regarding treatment, insufficient support to
manage treatment plans, overly complex treatment, and a variety of cultural
factors (e.g., the meaning of medication to different individuals). One step
toward managing treatment non-adherence is to develop a treatment envi-
ronment so that non-adherence will be reported and addressed nonjudgmen-
tally. Mood charting (see section 9.2.6) provides a method for monitoring
treatment adherence in which it can be somewhat impersonally recorded
onto a chart, rather than having to face someone directly and admit it.
Second, a well-developed educational program demonstrating the impact
of not following treatment, repeated over time, may bring some individu-
als toward better adherence. Again, mood charting can be useful to demon-
strate symptom emergence after not taking medication for several days, for
example. Third, a well-designed treatment program will integrate treatment
adherence into the program, teaching individuals how to place treatment
adherence into the larger context of successful, healthy living. Finally, most
people stop taking medications if side effects outweigh benefits. In other
words, side effects that are tolerable when the depression is at its worst may
become intolerable with symptom improvement, leading to treatment dis-
continuation. Consequently, side effects must be assessed over time, even
after clinical improvement occurs. For example, medication-induced sexual
dysfunction is rarely reported spontaneously, and perhaps may not be an
issue when symptoms are severe, but with improvement it becomes a con-
cern and, if not directly assessed, is a common reason for stopping treatment.
 Key Point: A treatment plan should address safety and contributing fac-

Programmatic Approach to Treatment

tors. The first treatment decision involves determining whether to only
manage the underlying precipitant or to treat the depression itself. It
must be then determined whether psychotherapy alone, medication
alone, or the combination is the best choice. Combination treatment
is more effective, but the decision must balance costs, side-effect risks,
and overall treatment goals.

9.2.5. A Good Support Network

Most individuals with depression arrive at treatment for the first time with
psychosocial support, namely family and friends. Major depression, particu-
larly if it becomes chronic or recurrent, can devastate relationships, however,
so enlisting these important individuals in the person’s care as soon as pos-
sible creates a more effective support system. Friends and family members
can be enlisted to help individuals with recurrent depression identify early
warning symptoms to prevent episodes, manage psychosocial consequences

Chapter 9 A
of depressive episodes and symptoms, and aid with treatment adherence.
A central component to building this support structure is regular education
for these family and friends about the nature, course, and treatment response
of depression in order to help set expectations and guide decision-making.
Depression is a mystifying and disabling condition that causes many affected

83
individuals and their families to feel isolated. Support groups combat these
feelings by bringing together individuals with common experiences in order
to create a network of consumers of psychiatric and mental health services,
and to develop best personal practices to manage the disability of depression.
Because depression is so common, most communities have existing support
groups. Often the best of these are linked to large national organizations that
have a strong alliance with modern mental health care. The National Alliance
for the Mentally Ill (NAMI)8 and the Depression and Bipolar Support Alliance
(DBSA)9 are two national groups that are strong advocates for people suf-
fering from major mood disorders and their families. Based on their national
structure and size, these groups have a range of helpful resources. Clinicians
are encouraged to become familiar with these and other organizations in their
area to direct individuals with depression.

Key Point: Depression is often both mystifying and disabling. A good

support system improves the likelihood of treatment response and
recovery.

9.2.6. Mood Charting

As noted, recovery from depression is erratic and slow. Consequently,
at any given time, symptoms may be worse than the day before, even if
the person is recovering. In people with a history of recurrent episodes,
depression may return despite good treatment. Moreover, since even
evidence-based treatment relies on a certain amount of trial and error,
identifying the treatment that is most effective for improving symptoms
Major Depressive Disorder and preventing future episodes requires deliberate symptom monitoring.
Unfortunately, in the absence of specific approaches toward making these
assessments, both clinicians and depressed individuals rely on how the per-
son feels at the time of appointments, rather than recognizing the course
of the illness throughout the entire previous interval; this approach can
be misleading, as life events near the time of appointments (both positive
and negative) or even random symptom fluctuations can alter presenta-
tion in the short term that may be misattributed to treatment failure or
success. For these reasons, daily mood charting is highly recommended.
Even a simple record of mood symptoms or other individualized mea-
sures of treatment success (e.g., hours worked) help to develop a pro-
cess for monitoring treatment response over time. Ideally, the mood
chart should record graphically to allow easy viewing and interpretation.
Moreover, charting can be individualized to include potential precipitants
and triggers, such as hours of sleep, alcohol use, medication adherence, or
stressful life events. Then, during appointments, weeks and even months
of recordings can be reviewed to better identify the long-term effects of
various treatment interventions. An example mood chart is provided in
the Appendix. Additionally, the technological (and especially smart phone)
explosion has produced computer and phone programs and applications
that can serve this same purpose (e.g, http://www.dbsalliance.org/site/
PageServer?pagename=wellness_tracker). The key is to find a means of
84

mood charting that is easy to complete, will be consistently used, and can
be shared with the treating clinician.

Key Point: Depression is managed through trial-and-error treatment

assignment and a typically erratic treatment response; consequently,
mood charting is critical to determine the effectiveness of treatment
interventions.

9.2.7. Efficient, Predictable, and Standardized

Follow-Up Appointments
In order to manage the many components of treating depression, appoint-
ments should follow a standardized approach that we operationalized into 0
steps; these steps can be completed in a typical appointment (see Box 9.).
. To begin, review the mood chart and other symptom ratings to
identify changes over time. Mood charts should be brought to every
appointment until recovery is achieved.
2. Assess suicidal and other dangerous behaviors as indicated.
3. Evaluate changes in co-occurring medical and psychiatric conditions
and other factors (e.g., stress). Use rating scales or other approaches
to ensure systematic assessment. Complete an ROS to identify new
medical or psychiatric conditions and to develop treatment plans
accordingly.
4. Review adherence to treatment and emerging side effects.
Non-adherence to treatment is a primary cause of treatment failure
 and unaddressed side effects a common contribution. Address sexual

Programmatic Approach to Treatment

dysfunction effects of SSRIs, if prescribed.
5. Review and support general health measures—for example, regular
sleep and exercise. In particular, these often improve anxiety that
accompanies depression.
6. Review drug and alcohol use, including smoking. Develop cessation
plans. Note that smoking both increases anxiety and imparts an inde-
pendent risk of suicide.
7. Review psychosocial function and whether functional goals are
being met.
8. Provide evidence-based treatment that is demonstrating improve-
ment. Note that therapy and medication may be delivered by separate
providers, so these steps should be accordingly distributed. In these
instances, the clinicians should work together closely to ensure that
they are providing consistent recommendations.
9. Plan treatment changes, ideally one at a time. Make changes delib-
erately and systematically and monitor the impact of changes with

Chapter 9 A
mood charting.
0. Answer questions and provide education.
Many of these steps can be managed by clinician extenders (e.g., medical
assistants) or self-report instruments to help manage time more efficiently. By

85
providing systematic predictable care, clinicians can guide depressed individu-
als to their best outcomes.

Key Point: Due to its complexity, depression requires a deliberate sys-

tematic treatment program to maximize outcomes. Correspondingly,
appointments should be standardized and predictable.

References
. Strakowski SM. Chapter 9: A programmatic approach to treatment. In: Bipolar
Disorder, pp. 85–94. Oxford American Psychiatry Library. New York: Oxford
University Press, 204. [Note: Segments of the current chapter have been
reproduced from this reference with permission of the author and the
publisher.]

Example Diagnostic Interviews

2. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview
for DSM-IV Axis I  Disorders, Patient Edition (SCID-I/P). Biometrics Research
Department. New York: New York State Psychiatric Institute, 995.
3. Geller B, Zimerman B, Williams M, Frazier J. Washington University
in St. Louis Kiddie and Young Adult Schedule for Affective Disorders and
Schizophrenia (WASH-U-KSADS). St. Louis: Washington University School of
Medicine, 996.
4. Diagnostic Interview for Genetic Studies v. 4.0. Rockville, MD: National Institute of
Mental Health, 2004.
Major Depressive Disorder Example Symptom Rating Scale
5. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to
change. Br J Psychiatry 979; 34:382–389.
6. Hamilton M. A rating scale for depression. Journal of Neurol, Neurosurg Psychiatr
960; 23:56–62.
7. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz
JC, Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB. The
6-item Quick Inventory of Depressive Symptomatology (QIDS) Clinician
Rating (QIDS-C) and Self-Report (QIDS-SR): A psychometric evaluation in
patients with chronic major depression. Biological Psychiatry 2003; 54:573–583.

Support Group Links
8 . National Alliance on Mental Illness (NAMI): www.nami.org
9. Depression and Bipolar Support Alliance (DBSA): www.dbsalliance.org
86
Chapter 0

Managing Special Populations

0..  Pediatric Depression

As discussed in Chapter 3, depression strikes across all age groups; conse-
quently, it affects children and adolescents. Diagnosing depression in youth,
in general, follows the same clinical criteria as in adults, with some excep-
tions. Depressed children and adolescents often present with irritability as
the primary mood symptom, and agitation occurs more commonly than in
adults as well. Pediatric depression is associated with fewer changes in neu-
rovegetative functions, namely sleep and appetite, than in adults, although
depression can be a cause for a child to fall off the expected growth curve.
Withdrawal from peers, especially in adolescents, may be more common
than in adults. Both children and adolescents express suicidal thoughts and

87
87
commit suicide; in fact, there is a peak in suicide rates in young adult and late
adolescent males, which then decline for a few years before steadily rising
throughout the rest of adulthood. The differential diagnosis for depression in
youth is similar to that of adults, excluding diseases of aging, of course (see
Chapter 2). Stressful life events, particularly those that damage relationships
with family and peers, may be more commonly related to depression in this
age group, whereas medical causes are less so. Family history information
can be critical for managing depression in younger individuals, as the depres-
sive episode may be the first evidence of another evolving psychiatric illness,
such as bipolar disorder, schizophrenia, personality disorders, drug and alco-
hol abuse, or post-traumatic stress disorder (PTSD) arising from physical or
sexual abuse. Depression before puberty, especially when accompanied with
psychosis and psychomotor slowing, represents a high risk for later develop-
ing bipolar disorder, particularly when there is a family history of the latter
illness. Although the treatment of pediatric depression is similar in approach
to that of adults, it cannot be assumed to be the same. There are relatively
fewer US FDA-approved antidepressants for youth, and the evidence base
for psychotherapies is also much weaker.
At this time, the only medications that are FDA approved specifically for
the treatment of depression in individuals younger than 8 years old are
fluoxetine and escitalopram. Depressed youth may be more sensitive than
adults to many of the side effects of antidepressants. In particular, weight gain
is more problematic; consequently, attention to height and weight percen-
tiles in individual growth curves must be followed carefully, and general health
measures (diet and exercise) are important to implement. Conversely, young
people metabolize drugs faster than adults so that relatively higher doses
Major Depressive Disorder (after adjusting for body weight) may be necessary; importantly, as children
age, dose adjustments are expected.
In 2004 the FDA released a black box warning for serotonin reuptake
inhibitor (SRI) antidepressants that children and adolescents receiving these
drugs may experience an increased risk of developing suicidal behaviors; this
warning was extended to young adults up to age 25 years in 2006. The FDA
based this warning on a review of 2,200 children and adolescents receiv-
ing SRIs in clinical trials in which increased reports of suicidal thoughts were
noted in those getting medicine (4%) compared to placebo (2%). However,
no actual suicides occurred in these studies. More recently, Bridge and col-
leagues reviewed nearly 0  years of antidepressant studies in youth and
concluded that the risks of not receiving medication exceeded that of being
treated. That said, there may be a subset of youth who become agitated on
SRI antidepressants, and some of these may have yet undiagnosed bipolar
disorder, so are at risks for mixed states; both of these situations increase
the risk of suicidality. In total, although careful monitoring of youth on these
medications, especially during the first 4 weeks, is advised, treatment with an
antidepressant generally appears to be a better choice than no treatment for
depression in youth when balancing the potential benefits and risks.
Psychotherapies offer alternatives without the specific risks associated with
SRI antidepressants. However, specific psychotherapies have been relatively
infrequently studied in youth with depression, and the results of these studies
88

often provide mixed evidence of efficacy. Perhaps the best studied psycho-
therapy in children and adolescents is cognitive behavioral therapy (CBT).
CBT is well established as an effective antidepressant intervention in adults;
in children and adolescents it also appears to have efficacy, although stud-
ies are less consistent.2,3 Similarly, the combination of an antidepressant plus
CBT may be more effective than either alone in youth, although, again, some
studies have not found this benefit.4 Regardless, at this point in time, CBT
plus antidepressant medications both appear to be first-line interventions for
children and adolescents with depression, while considering the caveats men-
tioned here. Since stressful life events are often associated with depression
in youth, helping to alleviate stressful environments may serve a particularly
important role in the treatment of children and adolescents.

Key Point: Pediatric depression is similar to that in adults, although

symptom differences are observed. Treatment is less well defined and
so may require somewhat different strategies compared with adults in
order to achieve maximal outcomes.

0.2.  Late-Life Depression

Depression occurs commonly in late life. Older adults are exposed frequently
to common depression precipitants, including higher rates of major medi-
cal illnesses, increasing loss of family and friends, and stress from diminish-
ing capabilities and independence. However, depression is not an expected
or “normal” part of late adulthood, so it should not be minimized as such.
The point prevalence of depression in the elderly approaches 5% with up

Managing Special Populations

to a 5–20% lifetime prevalence; perhaps half of these cases occur for the
first time after age 65 years.5 Compared with younger adults, underlying
co-occurring medical illnesses are much more likely to be contributing fac-
tors; risk of suicide increases with age as well. Otherwise, diagnostic and
course of illness considerations are similar across the adult age span.
In many cases, late-life depression is simply a recurrence of illness that first
occurred at a much younger age. In any case, a new episode of depression
may represent a worsening or new medical condition, so a careful medical
examination in this age group is particularly important. Common illnesses
associated with depression were reviewed in Chapter 4.
Treatment of depression in older adults is complicated by several fac-
tors. First, there are few clinical studies in this age group, so that neither

Chapter 0
efficacy nor tolerability of standard antidepressants or psychotherapies is
well defined. Second, the more commonly co-occurring medical illnesses
in late-life depression may alter antidepressant disposition and metabolism.
Finally, psychotherapies have rarely been studied with particular attention to
the needs and concerns of older adults. Nonetheless, several guidelines can
be followed.6
With aging, drug metabolism decreases. Consequently, medication doses
that are safe and tolerable in midlife become intolerable and potentially toxic
with aging. When starting a new antidepressant in late life, we recommend

89
beginning at one-half to one-third of the standard adult dose and then titrat-
ing upward more slowly than in younger adults, monitoring carefully for
tolerability while assessing efficacy. At the first sign of agitation or cognitive
symptoms suggestive of delirium (e.g., confusion), re-evaluate all medica-
tions that are being prescribed, even if they have been taken for years, as
metabolism may have changed. ECT or TMS may be preferable in this age
group compared with younger individuals, as they might be better tolerated
and safer than medications. Otherwise, medication choices are largely guided
by the same decision processes as in younger adults. Finally, psychothera-
pies must incorporate the stresses of later life, including decreased ability to
sleep, declining physical health, and loss of spouse, partners, and friends. In
older individuals, following a systematic, deliberate approach, as described in
Chapter 9, is perhaps even more important than in younger individuals, with
a focus on minimizing the number of medications prescribed for all conditions
to prevent complications from side effects and drug-drug interactions.6

Key Point: Managing depression in late life requires increased attention

to co-occurring medical problems as well as changes in drug distribu-
tion and metabolism.

0.3.  Depression and Pregnancy

Managing depression during pregnancy is relatively complex. Pregnancy (espe-
cially childbirth) is a high-risk period for developing a first depressive episode
or experiencing a recurrence in women with a prior history of depression.
Major Depressive Disorder Estimates suggest that up to 20% of women will experience depression during
pregnancy. In particular, women with a previous postpartum depression or
bipolar disorder are at very high risk for a new depressive episode. Most of the
commonly prescribed antidepressants are not thought to be teratogenic, but
unfortunately, limited data make it difficult to accurately assign specific risks;
moreover, longer-term risks on the developing child after birth are unknown.
Table 0. lists the pregnancy classification of commonly prescribed antide-
pressants. Recently, paroxetine was downgraded to FDA pregnancy class D
due to reports of increased risk of cardiac defects with fetal exposure. All of
the SRI antidepressants impart a risk of withdrawal symptoms in the baby at
birth following third trimester exposure. Conversely, depression during preg-
nancy is associated with increased rates of low birth weight and premature
delivery. Postpartum depression risks mother-child bonding and infant failure
to thrive. Consequently, when considering antidepressants during pregnancy,
typically the risk-benefit analysis becomes one of weighing unknown risks

Table 0.  US FDA Pregnancy Classifications for Commonly

Prescribed Antidepressants
Medication Classification
Tricyclic antidepressants (TCAs)
Imipramine (Tofranil) C
90

Nortriptyline (Pamelor) D
Desipramine (Norpramin) N
Monoamine oxidase inhibitors (MAOIs)
Tranylcypromine (Parnate) N
Phenelzine (Nardil) C
Selegeline—transdermal (Emsam) C
Serotonin reuptake inhibitors (SSRIs)
Fluoxetine (Prozac) C
Paroxetine (Paxil) D
Sertraline (Zoloft) C
Citalopram (Celexa) C
Escitalopram (Lexapro) C
Serotonin norepinephrine-reuptake inhibitors (SNRIs)
Venlafaxine (Effexor) C
Duloxetine (Cymbalta) C
Desvenlafaxine (Pristiq) C
Levomilnacipran (Fetzima) C
Other antidepressants
Bupropion (Wellbutrin) C
Mirtazapine (Remeron) C
Vilazodone (Viibryd) C
Vortioxetine (Brintellix) C
The FDA classifies drug safety in pregnancy using the following categories: A = controlled studies
show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out; D = positive
evidence of risk; N = not assigned.
from antidepressants against both known and unknown risks of depressive

Managing Special Populations

episodes (Table 0.).6
Given the uncertain risks of antidepressants for a developing fetus and
future human, in general, it is preferred to minimize in utero exposure when-
ever possible. In the case of a planned pregnancy, if a woman is on an anti-
depressant and has recovered, then tapering medications prior to attempting
conception is probably the best choice. An exception to this suggestion is
the case of women who have severe depressive recurrences; in these cases,
known risks of depression that is likely to recur may take priority over the
unknown risks of continuing medication. In the case of an unplanned preg-
nancy in which the woman is on an antidepressant, again, if she has recov-
ered, tapering and discontinuing the antidepressant is probably preferred.
However, in this latter case, note that medication teratogenic effects primar-

Chapter 0
ily occur during the first trimester, so these types of risks are decreased if the
decision to discontinue treatment occurs after that time. Again, the risks on
long-term development after the child is born are unclear.
If a woman is currently depressed and pregnant or wanting to become
pregnant, given the recognized negative effects of depression on pregnancy,
it is probably preferable to maintain or initiate treatment. In mild to moder-
ate cases, CBT or another evidence-based psychotherapy is the first-line
choice. If a woman is unwilling to participate in therapy or if symptoms are
severe, treatment with one of the class C antidepressants previously noted

91
is indicated. Regardless, if medications are discontinued, psychotherapy and
general health measures should be increased. Omega-3 fatty acid therapy
may provide benefit for depression and also for the developing infant, so
should be considered (we recommend its use in most cases). Omega-3 fatty
acids may increase the risk of bleeding, so discontinuation a few weeks prior
to the expected delivery date is probably prudent. ECT or TMS are gener-
ally safe during pregnancy and offer alternatives, particularly ECT for severe
or psychotic acute episodes. Given the high risk of relapse at delivery in
women with a prior history of postpartum depression, standard treatment
should be reinitiated during the final month of pregnancy, if possible. In all
cases, care must be coordinated among the pregnant woman, her obstetri-
cian, and her psychiatrist, with ongoing assessments and discussion of the
relative risks of stopping or remaining on treatment.6 The final decision will
be based on balancing the best information possible about the relative risks
of treatment versus the risks of depression.

Key Point: Managing pregnancy in depression is complex, requiring

careful risk versus benefit calculations of whether or not to remain
on medications. The decisions require coordinated discussions among
the pregnant woman, her obstetrician, and her psychiatrist.

0.4.  Managing Suicidal Individuals

Suicide is a tragic and all too common consequence of depression. Up to 8%
of people with depression commit suicide, which is approximately 5 times
Major Depressive Disorder higher than the general population. Fortunately, with increasing treatment
availability and awareness, this rate may now be decreasing.7 Nonetheless,
suicide remains a significant concern in the management of depression.
There are several steps that clinicians can take to decrease the risk of
suicide in people with depression. First, suicide assessment should become
a routine part of appointments, particularly during periods of high risk.
Discussing suicide does not increase the risk of suicide; in fact, this simple
intervention likely diminishes the risk. Many individuals are ambivalent about
suicide, so talking about these thoughts with an empathic clinician may help
the individual move forward to better solutions.6 Similarly, clinicians can assist
family members so that they, too, are comfortable with these discussions and
can participate in a nonjudgmental, supportive, and problem-solving manner.
A second component of managing suicide is to recognize risk factors
(see Box 0.). Some of these, such as family or personal history of sui-
cide attempts, cannot be modified, but nonetheless provide a context for
risk assessment. Others, such as substance use or the presence of anxiety
or psychotic symptoms, can be addressed through changes in treatment or
lifestyle. Within these risks are inflection points such as hospitalization or the
occurrence of major life stressors (e.g., divorce or loss) that indicate a need
for increased vigilance for suicidal behavior. Moreover, there are protective
factors that can be enhanced, including social support and improvement of
92

Box 0.  Suicide Risk and Protective Factors

Risk Factors
Prior suicide attempts
Family history of suicide
Suicidal ideation
Hopelessness
Drug/alcohol abuse
Anxiety/panic attacks
Psychosis
Personality disorder
Recent loss/major life stressor
Medical illness

Protective Factors
Supportive family/children at home
Strong religious beliefs
Strong social support
Future oriented
Good coping skills
Ongoing mental health care
Limited access to highly lethal methods of suicide (e.g., guns)
Adapted from Hawton3 and Strakowski.6
coping skills (Box 0.). Finally, limiting access to more lethal means of sui-

Managing Special Populations

cide, such as firearms, is an important step to help lower the risk of com-
pleted suicide.
When an individual expresses suicidal thoughts, a careful assessment of
acute and chronic risk factors, inflection points, and the presence of protec-
tive factors is used to determine whether hospitalization is necessary. If hos-
pitalization is not needed, then developing clear outpatient contingency plans
for increasing suicidal thoughts will help both the depressed individual and his
or her family members manage these impulses. It is important to explain the
need to report any increase in suicidal ideation promptly to assess whether
hospitalization is required, while taking steps to decrease suicidal thoughts
before they are acted upon.
Over the long term, with chronic suicidal ideation in particular, treatment

Chapter 0
must be tailored to assist the person with depression in building more protec-
tive factors while minimizing risks; therapy can be targeted to manage suicidal
impulses and the underlying risk factors by developing alternative adaptive
behaviors. Regarding specific treatments, as mentioned in Chapter 7, lithium
decreases suicide risk in both unipolar and bipolar depression;8 consequently,
lithium augmentation may be a valuable treatment option in suicidal individu-
als. Due to risks associated with overdose, it may need to be prescribed in
small amounts when suicide risk is high. Dialectic behavioral therapy (DBT)
is also specifically designed to help manage chronic suicidality. Regardless,

93
suicide remains a complex behavior that is often impulsive and difficult to
predict. By approaching the treatment of depression comprehensively, as
described in this book, it is hoped that the risk of this tragic outcome can be
ameliorated.
Despite the significant decrease in suicides in many countries, which
coincides with the increased use of antidepressant treatments over the last
30 years, there is evidence that in rare cases there is an increase in suicidal
thoughts or behavior after the initiation of an antidepressant. As mentioned
in section 0., this phenomenon occurs more frequently in adolescents and
young adults, with the rate estimated to be 4 and 5 cases, respectively, per
,000 people treated in these age groups. Greater caution is therefore war-
ranted in the first few weeks after an antidepressant is started in this age
group, with frequent clinical contact to monitor suicidal thoughts.

0.5.  Managing Co-occurring Conditions

As discussed in Chapter 4, depression is commonly comorbid with other psy-
chiatric and medical disorders. Consequently, managing depression requires
ongoing attention to these other conditions. The vast number of potential
combinations exceeds the scope of this book, so only general guidelines are
provided here.
0.5.. Substance Use Disorders
Evidence from the National Comorbidity Study suggests that the presence
of a depressive disorder doubles the risk of a substance use disorder.9
Major Depressive Disorder These conditions negatively impact the course of illness, and there-
fore must be addressed as part of the overall treatment of depression.
Historically, some self-help groups advocated against any medication use
in people recovering from drug or alcohol addictions, regardless of other
conditions; this stance is not tenable for most individuals with severe or
recurrent depression, since antidepressant medications are often essen-
tial for wellness. Conversely, some psychiatrists advocate not treating
depression until co-occurring substance abuse has remitted for a sig-
nificant period, based on the idea that the negative effects of substance
use on mood will block the benefits of antidepressant treatment. This
approach is not supported by evidence from clinical trials in individuals
with alcohol dependence and an independent depressive disorder (i.e.,
non-substance-induced), which demonstrates a clear benefit of antide-
pressants compared with placebo. In these studies, a correlation was typi-
cally seen between depressive symptom improvement and greater success
in maintaining abstinence as well. However, studies including individuals
with depression and co-occurring cocaine or opioid use disorders have
shown less clear benefits with antidepressant treatment. The strategy of
delaying antidepressant therapy also does not take into account evidence
that the presence of major depressive disorder complicates substance use
treatment such that relapse of substance use is significantly more likely.
Consequently, co-occurring depression and substance use disorders must
94

be managed concurrently.
Because there is currently minimal overlap in effective medications for
depression and substance use disorders, if drugs are used for the latter these
typically will need to be added to an effective antidepressant regimen. One
pharmacologic strategy for people with an alcohol use disorder and inde-
pendent major depressive disorder that is supported by empirical evidence
is the combination of the SSRI sertraline and naltrexone, the latter being
FDA approved for reducing alcohol relapse. Treatment with this combina-
tion appears to be more effective in reducing alcohol relapse and depressive
symptoms than either medication alone.0
There is significant overlap in cognitive/behavioral strategies used for
both depression and substance use, and attempts to integrate these CBT
approaches have shown promise. Regardless, standard approaches to drug
and alcohol abuse should be initiated as soon as possible in depressed indi-
viduals with these conditions.

Key Point:  The best overall approach for managing co-occurring

depression and substance use disorders is to aggressively identify the
best treatment regimen possible for depression while concurrently
initiating aggressive therapies for the substance use disorder. When
possible, integrated treatment for both conditions is preferable.

0.5.2. Co-occurring Psychiatric Conditions

In addition to substance use disorders, other psychiatric conditions com-
monly co-occur in depression (Chapter 4, see Table 4.2). In particular, anxiety
disorders occur in 60% of depressed individuals. Fortunately, treatments

Managing Special Populations

commonly used in the management of depression are also a central part
of managing anxiety disorders. Namely, antidepressants with serotonergic
effects are also typically effective anxiolytics, which includes most of the drugs
discussed in Chapter 7. Bupropion may be the most commonly used excep-
tion, although in people whose anxiety is completely secondary to depres-
sion, even bupropion may improve the anxiety. Additionally, evidence-based
psychotherapies, such as CBT, are effective for both depression and anxiety
disorders. Consequently, the combination of a serotonergically active antide-
pressant plus CBT is often sufficient to manage this common co-occurrence.
Personality disorders also commonly complicate depression and typically
require concurrent antidepressant treatment plus an evidence-based psy-
chotherapy. In particular, DBT in depressed individuals with borderline per-

Chapter 0
sonality disorder may be particularly effective for this combination. Finally,
depression is commonly a secondary consequence of other major psychiatric
conditions, such as bipolar disorder and schizophrenia, in which neither anti-
depressant therapy nor psychotherapy is the backbone treatment. In these
cases, maximizing the primary therapy (e.g., mood stabilizers in bipolar dis-
order, or antipsychotics in schizophrenia) is the first intervention. If doing so
fails to improve depressive symptoms, then the addition of an antidepressant
or depression-focused evidence-based psychotherapy is indicated. The best
treatment of co-occurring psychiatric conditions involves identifying effective

95
treatments that manage both conditions, well-designed psychotherapeutic
interventions to address the combined symptoms, ongoing assessments of
and attention to both conditions, and an integrated treatment plan and team.
Charting symptoms of both conditions to systematically identify effective
interventions becomes critical in these complex situations. Again, the general
principles of programmatic treatment described in Chapter 9 apply.

Key Point:  The best overall approach for managing co-occurring

depression and other psychiatric disorders is to first stabilize the pri-
mary illness and then manage the secondary condition, with an eye
toward integrated treatments whenever possible.

0.5.3. Co-occurring Medical Illnesses

Also as described in Chapter 4, individuals with depression suffer from higher
rates than the general population of many medical conditions and, conversely,
rates of depression are elevated in people with most major medical illnesses.
As previously discussed, it appears that any medical condition that impacts the
brain elevates rates of depression.2 There are two primary challenges when
managing medical comorbidities in depression. First, studies have shown that
people with mental illness receive substandard medical care in the community
as compared to people without mental illness. Although the specific reasons
for this bias are not clear, it is likely that primary and specialist medical provid-
ers attribute symptoms of medical illness to the psychiatric condition, thereby
discounting them. A second challenge is that primary care providers are
often unfamiliar or uncomfortable with psychotropic medications, and may
Major Depressive Disorder be reluctant to start standard medical therapies or are unaware of potential
drug-drug interactions that negatively impact the treatment of depression.6
However, since depression is so prevalent, in the end, primary care providers
manage most cases of depression since there are simply not enough psychia-
trists to meet the demand. Consequently, ongoing education for those clini-
cians (such as reading this book) is critical to tackle these challenges.
When faced with co-occurring medical illness and depression, there are
several guidelines to follow. First, evaluate the current medication list, as these
may be contributing to the development of depressive symptoms. Simplifying
a complex medication regimen may be all that is necessary to relieve depres-
sive symptoms. Next, be sure that the medical conditions are maximally
managed; again, a poorly or under-treated medical illness may bring with it a
higher risk of depression. Finally, if depressive symptoms persist after these
two steps, initiate treatment as described in Chapters 7–9 in this book. In indi-
viduals requiring complex pharmacological treatment for their medical condi-
tion, it is prudent to lean first toward evidence-based psychotherapy when
possible, at least in mild to moderate cases of depression. When adding an
antidepressant, also check for potential drug-drug interactions, to avoid toxic-
ity or loss of efficacy of the medical treatment. As with other co-occurrences,
aggressive management of all co-occurring conditions, while trying to mini-
mize the total drug burden and integrating treatment whenever possible, will
lead to the best outcomes of these complex cases.
96

Key Point: Managing medical illness in depression requires attention and

aggressive management of all conditions, while integrating therapy as
much as possible.

References
. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent
DA, MD. Clinical response and risk for reported suicidal ideation and suicide
attempts in pediatric antidepressant treatment: a meta-analysis of randomized
controlled trials. JAMA 2007; 297:683–696.
2. Arnberg A, Ost LG. CBT for children with depressive symptoms:  a
meta-analysis. Cogn Behav Ther 204; 43:275–288.
3. Klein JB, Jacobs RH, Reinecke MA. Cognitive-behavioral therapy for adolescent
depression: a meta-analytic investigation of changes in effect-size estimates.
J Am Acad Child Adolesc Psychiatry 2007; 46:403–43.
4. Ma D, Zhang Z, Zhang X, Li L. Comparative efficacy, acceptability, and safety
of medicinal, cognitive-behavioral therapy, and placebo treatments for acute
major depressive disorder in children and adolescents: a multiple-treatments
meta-analysis. Curr Med Res Opin 204; 30:97–995.
5. Fisk A, Loebach Wetherell J, Gatz M. Depression in older adults. Annu Rev Clin
Psychol 2009; 5:363–389.
6. Strakowski SM. Chapter 0: Managing special populations. In: Bipolar Disorder,
pp. 95–05. Oxford American Psychiatry Library. New York: Oxford University
Press, 204;. [Note: Segments of the current chapter have been reproduced
from this reference with permission of the author and the publisher].
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Managing Special Populations

terns of fluoxetine prescriptions and suicide rates in the United States. PLoS
Med 2006; 3(6):e90.
8. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of
suicide in mood disorders: updated systematic review and meta-analysis. BMJ
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9. Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC.
Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with
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0. Pettinati HM, Oslin DW, Kampman KM, et  al. A double-blind,

placebo-controlled trial combining sertraline and naltrexone for treat-
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. Hides L, Samet S, Lubman DI. Cognitive behaviour therapy (CBT) for the
treatment of co-occurring depression and substance use: current evidence
and directions for future research. Drug Alcohol Rev 200; 29(5):508–57.
2. Strakowski SM, Adler CM, DelBello MP. Is depression simply a non-specific
response to brain injury? Curr Psychiatry Rep 203; 5:386–393.
3. Hawton K, Casañas I, Comabella C, Haw C, Saunders K. Risk factors for sui-
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97
Appendix

Example Mood Chart

99
 100 appendix

Month: July
Day Measurement  2 3 4 5 6 7 8 9 0  2 3 4 5 6 7 8 9 20 2 22 23 24 25 26 27 28 29 30 3
Medications:
Fluoxetine 20 mg X X X X X X X X X X X X X X X X X X X X X X X X X X
CBT homework X X X X X X X X X X X X X X X X X X
Alcohol use, glasses 0   2  5 3 6 4 6 4 3 5 5  0 0 0 0 0 0 0  0 0  0 0 0 0 0
Sleep, hours 7 8 7 8 7 4 5 4 3 5 2 2 6 9 9  2 2 2 2 0 0 9 8 8 7 6 7 7 7 7
Mood:
Feeling well X X X X X X X
Mild depression X X X X X X X X X X X X X
Moderate depression X X X X X X X X X X X
Severe depression
Example of a mood chart identifying possible items to be measured. In this example, early improvement from starting fluoxetine was lost after missing doses and drinking too much. CBT was
added on day 7, but was not really engaged until day 9. With these treatments, symptoms improved. The changes here are exaggerated, especially temporally, for illustration purposes only
and should not be viewed as a typical course or treatment response.
This design is loosely based on the “Personal Calendar” available from the Depression and Bipolar Support Alliance (DBSA). The DBSA sells at a nominal cost a more detailed, 6-month
calendar/mood chart that is strongly recommended for any practice in which people with mood disorders receive care. DBSA can be contacted on their web site: www.DBSAlliance.org;
DBSA, 730 N. Franklin Street, Suite 50, Chicago, IL 6060-7224. (800) 826-3632.
 Index
ACTH. See
adrenocorticotropic
hormone
acupuncture, 74
adjustment disorder, 13
adolescents, 87, 93
adrenocorticotropic
hormone (ACTH),
38, 39f
affective spectrum, 11
African Americans, 17
age, 16–17, 87
alcohol disorders. See drug/
alcohol use disorders
alleles, 45
alternative
treatments, 62–63
amygdala, 32, 32f, 34–35,
34f, 38, 40, 46
Anatomy of Melancholia, The
(Burton), 5
anhedonia, 6b, 7, 8
anorexia, 58
anterior cingulate,
32, 32–33f
antidepressants
bupropion, 37, 51t, 58,
61, 91t, 95
choosing, 50–52
citalopram, 51t, 55,
56, 91t
desipramine, 51t, 91t
desvenlafaxine, 51t,
57, 91t
duloxetine, 51t, 57,
58, 91t
escitalopram, 51t, 55,
87, 91t
first-line treatments, 52
fluoxetine, 51t, 53, 55, 57,
58, 61, 87, 91t
generic and trade
names, 51t
imipramine, 51t, 53, 91t
levomilnacipran, 51t,
57, 91t
mirtazapine, 51t, 52,
59, 91t
monoamine oxidase
inhibitors, 49, 51t,
52–53, 91t
nortriptyline, 51t, 91t
paroxetine, 51t, 55,
90, 91t
phenelzine, 51t, 91t
during pregnancy,
90–92, 91t
second-line
treatments, 52
selegeline (transdermal),
51t, 53, 91t
serotonin norepinephrine-
reuptake inhibitors, 51t,
52, 57–58, 61, 91t
serotonin reuptake
inhibitors, 50, 51, 51t,
52, 54–58, 61, 88, 91t
sertraline, 51t, 55, 91t
side effects, 50, 87
switching, 60–61, 77
therapeutic
mechanism, 50
third-line
treatments, 52–55
tranylcypromine, 51t, 91t
treatment-resistant
depression and, 60–61
tricyclic, 49, 51, 51t, 52,
53–56, 58, 61, 91t
venlafaxine, 51t, 57, 91t
vilazodone, 51t, 59, 91t
vortioxetine, 51t, 59, 91t
anxiety
co-occurrence with
depression, 24–25t,
25–26, 95
heritability, 44
as subtype of
depression, 8
Aretaeus of Cappadocia, 5
aripiprazole, 61, 62t
association studies,
45–46, 47
atypical
antidepressants, 58, 59
atypical antipsychotics, 62t
atypical depression, 8–9
augmentation therapy, 61
autonomic
dysregulation, 20b
Beck, Aaron, 70
behavioral activation, 72
behavioral therapy, 70
behavior modification, 70
bereavement, 13
biological therapies, 49–66
overview, 49–50
See also antidepressants
bipolar disorder, 5, 56, 90
coining of term, 6
co-occurrence with
depression, 24t,
26, 81, 95
definition, 25
depression before
puberty and, 87
differential diagnosis, 2, 12
birth cohort effect, 16, 17
black bile hypothesis, 1, 5
borderline personality
disorder, 72, 95
Bradshaw, Terry, 1
brain, 3
Brintellix. See vortioxetine
bulimia, 58
bupropion, 37, 51t, 52, 58,
61, 91t, 95
Burton, Richard, 5
101
cardiovascular disease, 19,
20b, 27t, 28
catatonia, 9
CBT. See cognitive
behavioral therapy
Celexa. See citalopram
children, 87
chromosomes, 45, 46
chronic conditions, 18,
19, 27, 40
Churchill, Winston, 2t
cingulate, 34, 34f
citalopram, 51t, 55, 56, 91t
clinical depression. See
depression
cognitive behavioral therapy
(CBT), 69, 70–71, 71b,
72, 88, 91
cognitive brain
networks, 31–36
combination therapy, 61,
81, 82, 88
comorbidity, 15, 23, 93–96
complementary
treatments, 62–63
co-occurring conditions,
23–29, 81
anxiety, 24–25t,
25–26, 95
bipolar disorders, 24t,
26, 81, 95
managing, 93
medical, 3, 13, 15, 18,
26–28, 44, 77, 79,
89, 95–96
INDEX co-occurring conditions (Cont.)
psychiatric, 3, 13, 15,
24–25, 44, 95
schizophrenia, 24t, 95
substance use,
24–25t, 26, 94
corticosteroids, 38
corticotrophin-releasing
hormone (CRH), 38,
39, 39f
cortisol, 38–39, 39f, 40
CRH. See
corticotrophin-releasing
hormone
Cruise, Tom, 1
Cushing’s disease, 38
Cymbalta. See duloxetine
cytokines, 40, 41
Darkness Visible (Styron), 1
Darwin, Charles, 2t
DBS. See deep brain
stimulation
DBT. See dialectical
behavioral therapy
deep brain stimulation
(DBS), 65–66
delusion. See psychosis
102
dementia, 28
dementia praecox, 2, 5
depression
burden of disease, 18–19
causes of, 2–3, 6, 75
as common disorder,
2, 3, 15
co-occurring/comorbid
conditions, 23–29, 81
anxiety, 24–25t,
25–26, 95
bipolar, 24t, 26, 81, 95
managing, 93
medical, 3, 13, 15, 18,
26–28, 44, 77, 79,
89, 95–96
psychiatric, 3, 13, 15,
24–25, 44, 95
schizophrenia, 24t, 95
substance use,
24–25t, 26, 94
course and patterns of, 12
diagnosis of, 5–12
differential diagnosis of,
12–13, 87
epidemiology of
disorders, 15–20, 16t
population prevalence
and incidence, 15
subgroups, 15–17
famous people stricken
with, 1, 2, 2t
functional neuroanatomy
of, 35–36
history of, 1–2
mortality and, 2, 17, 19
neurophysiology of
disorders, 31–41
abnormalities in
emotional and
cognitive brain
networks, 31–36
clinical considerations
for models, 31
as nonspecific, 29
severity measures, 10
special populations, 87–96
stigma surrounding, 1,
2, 3, 16
subtypes, 8–10, 15
suicide and, 6b, 8, 19
symptoms of, 6–8, 6b, 18,
19, 76–77, 84
terminology of, 3, 5
See also antidepressants;
specific types and
treatments
desipramine, 51t, 91t
despondency. See sadness
desvenlafaxine, 51t, 57, 91t
dexamethasone, 38
Diagnostic and Statistical
Manual of Mental
Disorders, 6–7
dialectical behavioral therapy
(DBT), 72, 93, 95
disability, 18, 83
disruptive mood
dysregulation
disorder, 10–11
dopamine, 37, 53, 59
dopamine D4 receptor
(DRD4), 46
dorsal prefrontal areas, 32,
32f, 34f
dorsolateral regions, 33, 34f
double depression, 10
Down Came the Rain
(Shields), 1
DRD4. See dopamine D4
receptor
drug/alcohol use disorders,
19, 81, 85
co-occurrence
with depression,
24–25t, 26, 94
differential diagnosis, 13
duloxetine, 51t, 57, 58, 91t
dysphoric mood, 7
dysthymia. See persistent
depressive disorder
ECT. See electroconvulsive
therapy
Effexor. See venlafaxine
elderly. See old age
electroconvulsive therapy
(ECT), 49, 64–65, 92
emotional brain
networks, 3, 31–32,
32–34f, 35, 38
Emsam. See selegeline
(transdermal)
Epidemiologic Catchment
Area, 16
escitalopram, 51t, 55,
87, 91t
ethnicity, 17
evidence-based treatment,
69–70, 85, 91, 95
family history, 78, 87
Fetzima. See levomilnacipran
fight or flight
responses, 32, 34
fluoxetine, 51t, 53, 55, 57,
58, 61, 87, 91t
GABA. See
gamma-aminobutyric acid
Galen, 1–2
gamma-aminobutyric acid
(GABA), 37–38
gender, 15–16, 44
genetics, 43–48
candidate genes, 46–47
dopamine D4 receptor
(DRD4), 46
guanine
nucleotide-binding
protein (GNB3), 46
methyleneteta­
hydofolate
reductasae
(MTHFR), 46
serotonin 1A receptor
(HTR1A), 46
serotonin-linked
polymorphic region
(5HTTLPR), 46
couseling, 47
familial risks for
depression, 43–44, 47t
genome-wide
association studies,
45–46, 47
linkage studies, 45, 47
genome-wide association
studies (GWAS),
45–46, 47
glutamate, 37–38, 40, 41
GNB3. See guanine
nucleotide-binding
protein
goals, 76t, 79–80, 81, 85
Goya, Francisco, 2t
grief, 13
guanine nucleotide-binding
protein (GNB3), 46
GWAS. See genome-wide
association studies
hallucination. See psychosis
heart disease. See
cardiovascular disease
Hemingway, Ernest, 2t
heredity. See genetics
hippocampus, 33, 34f,
35, 40, 46
Hippocrates, 1, 5
Holzinger heritability
index, 43
HPA. See
hypothalamic-pituitary-
adrenal (HPA) axis
HTR1A. See serotonin 1A
receptor
hydrazines, 53
hypericum, 63
hypomania, 12
hypothalamic-pituitary-
adrenal (HPA) axis, 20b,
28, 38–41, 39f
hypothalamus, 38, 39f
imipramine, 51t, 53, 91t
immune system, 40
inflammatory response, 40
insomnia, 51
International Classification
of Diseases, 6–7
interpersonal therapy
(IPT), 69, 72
isoniazid, 52
James, William, 2t
ketamine, 38, 61–62
Kraepelin, Emil, 5
levomilnacipran, 51t, 57, 91t
Lewis, Meriwether, 2t
Lexapro. See escitalopram
lifestyle management, 73–74
light therapy, 63
Lincoln, Abraham, 2t
linkage studies, 45, 47
lithium, 6, 62t, 93
loci, 45
logarithm of the odds
(LOD) score, 45
low energy, 6b, 7
low mood, 7
mania, 12
manic-depressive illness. See
bipolar disorder
MAOIs. See monoamine
oxidase inhibitors
medical history, 78
medical illness, 13, 18,
26–28, 44, 77, 89, 95–96
melancholia, 1, 5, 8,
38, 54, 55
melatonin, 63
mental illness, 95–96
methionine, 46
methylenetetahydofolate
reductasae (MTHFR), 46
l-methylfolate, 62–63, 62t
mindfulness-based cognitive
therapy, 70
mirtazapine, 51t, 52, 59, 91t
moclobemide, 53
monoamine oxidase
inhibitors (MAOIs), 49,
51t, 52–53
dietary restrictions, 54t
during pregnancy, 91t
side effects, 53
monoamines, 36–37, 49
mood charting, 76t,
82, 83–84
mood-incongruent
psychosis, 9
morbidity, 18
mortality, 2, 17, 19, 20b
motivation, 7
MTHFR. See
methylenetetahydofolate
reductasae
naltrexone, 94
Nardil. See phenelzine
National Comorbidity
Survey, 16
negative behavior, 70, 70f
negative thinking, 70, 70f
neurogenesis, 40
neurological disorders,
13, 26–27
neurostimulation
techniques, 64–66
neurotransmitter
hypotheses, 36–38
glutamate and
GABA, 37–38
monoamines, 36–37
Newton, Isaac, 2t
Nietzsche, Friedrich, 2t
non-adherence to
treatment, 82, 84
norepinephrine, 36–37, 49,
53, 54, 57, 59
norfluoxetine, 55
Norpramin. See desipramine
nortriptyline, 51t, 91t
obsessive-compulsive
disorder, 24t, 51, 81
olanzapine, 61, 62t
old age, 28, 88–89
omega-3 fatty acids,
62t, 63, 92
oxcarbazepine, 57
Pamelor. See nortriptyline
Parkinson’s disease, 28, 37
Parnate. See
INDEX
tranylcypromine
paroxetine, 51t, 55, 90, 91t
Paxil. See paroxetine
pediatric depression, 87–88
persistent depressive
disorder, 1, 10, 12,
16t, 26, 56
personality disorders,
24–25t, 26, 95
phenelzine, 51t, 91t
platelet aggregation, 20b
postpartum depression,
1, 90, 92
prefrontal cortical regions,
31–35, 32–33f, 37, 38,
46, 65, 70
premenstrual dysphoric
disorder, 11, 16
Pristiq. See desvenlafaxine
programmatic approach,
3, 75–85
components of, 76t
comprehensive clinical
assessments,
75–78, 76t
evaluations, 76–78, 79
follow-up appointments,
103
76t, 84–85
monitoring of
symptoms, 76–77
mood charting, 76t,
82, 83–84
rating scales, 77, 84
safety evaluations,
78–79, 84
support network, 76t, 83
treatment goals,
76t, 79–80
treatment plans, 78, 79,
80–83, 84
Prozac. See fluoxetine
psychodynamic
psychotherapy, 72–73
psychosis, 9, 13
psychostimulants, 62t
psychotherapy, 69–74
behavioral activation, 72
cognitive behavioral
therapy, 69, 70–71,
71b, 72
dialectical behavioral
therapy, 72
evidence-based, 69–70
interpersonal, 69, 72
psychodynamic, 72–73
supportive, 73
in youth, 88
quetiapine, 61, 62t
race, 17
rating scales, 77, 84
INDEX Remeron. See mirtazapine
review of systems
(ROS), 77, 84
sadness, 6b, 13
St. John’s wort, 63
schizoaffective disorder, 13
schizophrenia, 5
African Americans and, 17
co-occurrence with
depression, 24t, 95
differential diagnosis, 13
seasonal affective disorder, 9
secondary depression, 11
selegeline (transdermal),
51t, 53, 91t
serotonin, 20b, 36–37, 49,
53, 54, 62–63
serotonin 1A receptor
(HTR1A), 46
serotonin-linked
polymorphic region
(5HTTLPR), 46
serotonin
norepinephrine-reuptake
inhibitors (SNRIs), 51t,
52, 57–58, 61, 91t
serotonin reuptake
104
inhibitors (SSRIs), 50, 51,
51t, 52, 54, 55–57, 58, 61,
88, 91t
serotonin syndrome, 57
sertraline, 51t, 55, 91t, 94
sex drive, 7
sexual function, 52,
56, 58, 82
Shields, Brooke, 1
5HTTLPR. See
serotonin-linked
polymorphic region
“sickness behavior,” 40
sloth, 5
SNRIs. See serotonin
norepinephrine-reuptake
inhibitors
socioeconomic status, 18
special populations, 87–96
late-life, 28, 88–89
pediatric, 87–88
pregnant, 89–92
suicidal, 92–93
SSRI discontinuation
syndrome, 57
SSRIs. See serotonin
reuptake inhibitors
stress, 35, 40–41, 70f, 77, 81
stress-diathesis
hypthothesis, 20b
Styron, William, 1
subgenual cingulate, 34
substance use disorders.
See drug/alcohol use
disorders
suicide
in later life, 89
melancholia and, 5
protective factors, 90b
risk factors, 19, 79,
90b, 92–93
safety evaluations, 78–79
thoughts of and
depression, 6b, 8, 19
in young people,
87, 88, 93
supportive
psychotherapy, 73
support network, 76t, 83
TCAs. See tricyclic
antidepressants
tertiary amines, 54
thyroid hormone, 62t
TMS. See transcranial
magnetic stimulation
Tofranil. See imipramine
torsades de pointe, 56
transcranial magnetic
stimulation (TMS), 65, 92
tranylcypromine, 51t, 91t
treatment goals, 76t, 79–80
treatment plans, 78, 79,
80–83, 84
treatment-resistant
depression, 10, 60–62
augmentation or
combination therapy
for, 61
electroconvulsive therapy
for, 64
ketamine for, 61–62
light therapy for, 63
medications to augment
antidepressants
for, 62t
neurostimulation
techniques, 64–66
psychotherapy and, 69
switching
antidepressants, 60–61
therapeutic strategies
for, 60
tricyclic antidepressants
(TCAs), 49, 51, 51t, 52,
53–56, 58, 61, 91t
Twain, Mark, 2t
twin studies, 43, 44t
tyramine, 53
unipolar disorder, 2, 6, 12
vagal nerve stimulation, 65
venlafaxine, 51t, 57, 91t
ventrolateral prefrontal
network, 32–33, 33–34f
ventromedial
prefrontal network,
32–34, 33–34f
vilazodone, 51t, 59, 91t
Vilbryd. See vilazodone
violence, 78–79
vortioxetine, 51t, 59, 91t
Wallace, Mike, 1
Wellbutrin. See bupropion
Whitman, Walt, 2t
women, 15–16, 44
yoga, 74
youth, 87–88, 93
Zoloft. See sertraline