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Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff.
Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.433754. Printed
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Chapter 53. Treatment of Depression
CHANGES IN CONCEPTUALIZATION OF DEPRESSIVE DISORDERS
The past 20 years have seen a shift in the way psychiatrists conceptualize depressive disorders.
This evolution in our thinking has been stimulated by the results of epidemiological studies and of
long-term clinical follow-up studies, investigations of spectrum disorders, advances in biological
psychiatry, and results of large clinically focused national trials. In the past, major depressive
disorder was viewed as episodic and self-limited. However, longitudinal observations of patients
treated for major depressive disorder show that after recovery from an index episode of major
depression, patients remain symptomatic about 60% of the remainder of their lives with another
episode of major depression, minor depressive disorder, or subsyndromal symptoms of depression
(Judd et al. 1998a). Data from the National Institute of Mental Health (NIMH) Collaborative
Depression Study demonstrated that the recurrence rates of major depressive disorder are
extraordinarily high over time: 60% at 5 years of follow-up, 75% at 10 years, and 87% at 15 years
(Keller et al. 1982, 1984, 1992; Kupfer 1991).
Thus, the majority of people with major depressive disorder can be conceptualized as having a
chronic illness with a dynamic course. This view of depression as a chronic and frequently recurring
illness is a major paradigm shift. A second major shift in our thinking about major depressive
disorder has revolved around the tension between conceptualizing the “depressions” as several
discrete disorders (e.g., major depressive disorder, dysthymia, double depression, minor
depression) versus considering major depressive disorder as part of a spectrum of mood disorders.
In this schema, an individual may traverse over time between meeting criteria for major depressive
disorder and meeting criteria for euthymia, minor depression, or subsyndromal depressive
symptoms (Judd et al. 1998b; Maddux and Rapaport 2004).
Current epidemiological and clinical outcome data support the postulate that major depressive
disorder is part of a fluid spectrum of depressive disorders. The presence of depressive
symptoms—be they symptoms of subsyndromal depression or minor depression or residual
symptoms after partially successful treatment—carries significant risks for psychosocial disability,
increases the risk for chronicity, and is associated with greater medical comorbidity, greater health
care utilization, greater risk for recurrence, and greater risk for suicide (Akiskal et al. 1997; Judd
and Akiskal 2000; Rapaport et al. 2002; Wells et al. 1989). The results of preliminary clinical trials
suggest that both minor depressive disorder and subsyndromal depressive disorder are responsive
to treatment with either pharmacotherapy or focused brief psychotherapies (Maddux and Rapaport
2004; Rapaport et al. 2002). This paradigm shift has profound implications for how we
conceptualize the goals for treatment of major depressive disorder. In the past, the goals of
treatment were the acute amelioration of the most troublesome symptoms of major depressive
disorder: a 50% response on an objective measure of the severity of depression was defined as a
successful outcome. Now the goal of treatment for an episode of major depressive disorder is the
complete eradication of depressive symptoms. Asymptomatic status is defined as the elimination of
all signs and symptoms of depression and a return to normal functioning (Judd and Akiskal 2000;
Judd et al. 1998b).
Another significant advance that has modified our conceptualization of major depressive disorder
and its treatment is the NIMH-funded Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) study. This study is the largest and most authoritative investigation of the efficacy of anPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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evidence-based approach to the acute treatment of major depressive disorder. Results from the
STAR*D study (Trivedi et al. 2006d) indicate that only 28% of patients remit even with a
systematic, ratings-guided initial trial with a selective serotonin reuptake inhibitor (SSRI). The
majority of patients required a stepwise application of treatments with increasingly aggressive
augmentation or treatment-switching strategies to attain remission (Rush et al. 2006b). At
6-month naturalistic follow-up, the patients who remitted earlier in their course of treatment and
those with less resistant depression (i.e., those who remitted with level 1 or level 2 treatment [see
study description in the “Acute Treatment” section]) were less likely to have relapsed at follow-up.
This supports the idea that early successful treatment focused on remission gives the patient the
best opportunity for long-term success. Further large-scale studies are needed to inform not only
our continued understanding of acute therapy for depressive disorders but also our knowledge of
what strategies are most effective during the continuation and maintenance phases of therapy.
The development and refinement of imaging techniques, preclinical models, molecular genetic
techniques, and computational techniques are leading to a marked increase in our knowledge about
the biological underpinnings of depressive disorders. At this time, we have not been able to link our
phenotypic investigations of the course and prognosis of depressive disorders with specific
biological processes; however, our knowledge of the neuroanatomical circuits that are abnormal in
some patients with depressive disorders is rapidly expanding (Goldapple et al. 2004; Kennedy et al.
2001; Mayberg et al. 2000). This knowledge combined with fundamental advances in animal model
development, molecular biology, and whole-genome scanning techniques in genetics will markedly
alter our understanding of the biology of mood disorders in the future (Nemeroff and Vale 2005;
Perlis 2007).
In summary, major depressive disorder is a chronic illness with symptoms that fluctuate over a
continuum of severity. Even the mildest form of depression, subsyndromal depression, is associated
with both psychosocial morbidity and a risk for developing major depressive disorder (Beekman et
- 1997; Fergusson et al. 2005; Fogel et al. 2006; Hermens et al. 2004; Judd et al. 1994; Rieckmann
et al. 2006). The goal of treatment of all forms of depression needs to be the return to an
asymptomatic state of the patient’s prior “normal” functioning. Thus, the treatment of patients with
major depressive disorder requires aggressive and varied therapies that may need to continue for
years, if not indefinitely.
EPIDEMIOLOGY
Prevalence of Depressive Disorders
Major depressive disorder is one of the most common medical disorders affecting adults in the
world (Lopez and Murray 1998). In the United States the lifetime prevalence of major depression
for men is 9% and 17% for women (Hasin et al. 2005), while the lifetime prevalence of dysthymia
is 4% for men and 8% for women (Kessler et al. 1994). The lifetime prevalence of minor
depression is 10% for individuals between the ages of 15 and 54 years (Kessler et al. 1997). For
persons 65 years and older, the 1-month point prevalence of minor depression is 13%, which is
twice the prevalence of major depressive disorder for this age group (Judd and Akiskal 2002;
McCusker et al. 2005). The lifetime prevalence for subsyndromal depression is 11.8% for the
general population (Goldney et al. 2004; Judd et al. 1994).
Risk Factors for Depressive Disorders
Several risk factors seem to increase a person’s vulnerability to developing a depressive disorder.
The vulnerability factors for which the greatest preponderance of evidence exists suggesting that
they might increase the risk include female sex, age, a family history of a mood disorder, a history
of trauma, and comorbid medical and psychiatric conditions.
A significant body of evidence indicates that the sex of an individual is an important risk factor for
the development of depressive disorders. Prior to puberty the prevalence of depression is equal in
boys and girls. However, beginning with puberty, women demonstrate a twofold increase in the
prevalence of major depressive disorder (Weissman and Klerman 1977). This trend is seen across Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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countries and ethnic groups (Weissman et al. 1996). The difference in prevalence rates between
men and women is not easily understood. It has been postulated that the difference may in part be
explained by the role of changes in levels of -estradiol in the genesis of depression. Data suggest
that there may be specific periods of the life cycle when a woman may be at greater risk of
developing a mood disorder, such as during pregnancy and postpartum (Burt and Stein 2002; Joffe
et al. 2002). It has also been speculated that this difference in prevalence rates may reflect the
complex interplay between an intrinsic biological vulnerability, societal pressures, and a style of
coping that more readily seeks help.
Age is another risk factor in the development of depressive disorders; the onset of major depressive
disorder increases dramatically beginning in adolescence (12–16 years of age) and continuing
through the age of about 44 years (Hasin et al. 2005). The mean age at onset has been reported to
be 30 years, whereas the mean age at the start of treatment is 33.5 years of age, reflecting the
amount of time depression often goes undiagnosed or untreated. In elderly populations, risk factors
for depression are slightly different and include female sex, low socioeconomic status,
bereavement, prior depression, medical comorbidity, disability, cognitive deterioration, and
vascular disease (Helmer et al. 2004). The elderly are at risk for a “downward spiral” that can occur
when disability or cognitive impairment leads to depressive symptoms, depressive symptoms
increase disability, and so on. Depression in the elderly affects psychosocial function, health care
utilization, quality of life, work productivity, risk for suicide, and medical compliance and outcome.
A family history of psychiatric illness is among the most profound risk factors for the development
of an episode of major depressive disorder (Reinherz et al. 2003). No one gene has been clearly
identified as a cause of major depression, and it may be concluded that depressive disorders are
likely polygenetic in nature. This might further explain the heterogeneity of the disease and
treatment response. New research has demonstrated that genetics coupled with environmental
conditions may contribute to the development of depression. The work led by Caspi et al. (2003)
and verified by others (Cervilla et al. 2007; Kendler et al. 2005) indicates that depressive responses
to traumatic life events are modulated by genetic makeup. Individuals who carry two short alleles
at the serotonin transporter (5-HTT) gene are more likely to develop depression after a stressful
event than those with one or two long alleles. Other studies have found that genetic variants in the
dopamine transporter (Elovainio et al. 2007) or enzymes responsible for polyamine catabolism
(Sequeira et al. 2006) may be implicated as a risk factor for the development of depression.
Prolonged exposure to severe traumatic events in childhood has been linked to future depressive
episodes. Trauma such as sexual abuse or the loss of a parent that occurs at a critical
developmental period can result in permanent alteration of the hypothalamic-pituitary-adrenal
(HPA) axis. It is recognized that individuals with depression, particularly those exposed to early
trauma, have altered stress responses (Gillespie and Nemeroff 2005; Heim et al. 2000; Nemeroff
and Vale 2005). Some individuals with major depressive disorder have altered HPA axis activity
with elevated circulating levels of cortisol, hypersecretion of corticotropin-releasing hormone, and
adrenal hypertrophy, which normalize after resolution of depressive symptoms (Nemeroff and Vale
2005).
Other clinical and demographic variables have been linked to an increased risk of developing
depressive disorders. These include stressful life events such as the death of a loved one, divorce,
or job loss. Certain personality characteristics also may predispose an individual to develop a mood
disorder. Individuals who score higher on measures of neuroticism, interpersonal dependency, or
external locus of control may be vulnerable to stressful life events precipitating a major depressive
episode (Hirschfeld et al. 1983; Paykel et al. 1996). Investigations suggesting that certain cultural
groups may be at increased risk of a mood disorder (Native Americans) and that other cultural
groups may have greater inherent resilience (Asian and Hispanic groups) are an area of renewed
interest (Hasin et al. 2005). Further investigation of the role that intrinsic cultural differences may
play, not only in the presentation of major depressive disorder but also in the protection against
depressive symptoms, is warranted (Harris 2004).Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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Many medical illnesses are comorbid with major depressive disorder (Table 53–1). Cancer, acquired
immunodeficiency syndrome, respiratory disease, cardiovascular disease, Parkinson’s disease, and
stroke are associated with an increased risk for depression. An interesting bidirectional relationship
exists between depression and cardiovascular disease. For example, depression is a risk factor for a
future cerebrovascular accident, and stroke is a well-documented risk factor for depression.
Although there are little data on prevalence rates, an acute myocardial infarction is a risk factor for
depression. Some studies suggest that depression is common among cardiac patients, with
40%–50% of cardiac patients having mild, moderate, or major depressive symptoms and women
being more likely to be depressed than men (Drago et al. 2007). The presence of moderate or major
depression following myocardial infarction increases the risk for death by 3.5 times (Glassman and
Shapiro 1998). Depression is also associated with rehospitalization and mortality in patients with
heart failure.
TABLE 53–1. Medical conditions often comorbid with major depressive disorder
Infectious Metabolic Neurological General medical
Encephalitis Addison’s disease Brain tumor Alcohol or sedative withdrawal
Hepatitis Cushing’s disease Dementia, cortical Arthritis
HIV/AIDS Diabetes Dementia, subcortical Cancer
Influenza Hyponatremia Huntington’s disease Cardiovascular disease
Meningitis Nutritional deficiencies Migraine headaches Chronic pain syndromes
Mononucleosis Pituitary dysfunction Multiple sclerosis Cocaine or stimulant withdrawal
Pneumonia Renal disease Parkinson’s disease Connective tissue diseases
Postviral syndrome Thyroid disease Poststroke syndrome Fibromyalgia
Syphilis
Seizure disorders Heavy metal poisoning
Tuberculosis
Traumatic brain injury Irritable bowel syndrome
Urinary tract infection
Liver failure
Menopause
Myocardial infarction
Premenstrual syndrome
Pulmonary disease
Selenium toxicity
Sleep disturbance
Note. AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus.
Major depressive disorder is highly comorbid with other psychiatric disorders such as anxiety,
dementia, schizophrenia, and substance abuse. In primary care settings, more than 75% of patients
with diagnosed depression also present with an anxiety disorder (Olfson et al. 1997). Patients with
depression and anxiety have more chronic and severe illness, greater occupational and
psychosocial impairment, and, when the comorbidity is unrecognized, a greater rate of psychiatric
hospitalization and suicide attempts (Hirschfeld 2001). Fifty percent of schizophrenic patients have
comorbid depression. When present with schizophrenia, depression is an additional risk factor for
suicide and decreased social and performance status (Ginsberg et al. 2005). The rate of major
depressive disorder in Alzheimer’s disease patients is between 20% and 40%. Diagnosing
depression in Alzheimer’s disease may be complicated by the overlap between symptoms of
dementia and those of depression: loss of motivation, social withdrawal, isolation, and apathy are
common to both disorders. Persons with dementia may have difficulty verbalizing subjective
feelings such as sadness or hopelessness. Therefore, observable behavioral signs and symptomsPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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such as irritability, social withdrawal, worsened functional impairment, and agitation may be more
reliable indicators of the presence of a mood disorder in patients with Alzheimer’s disease. There
seems to be a complex relationship between depression and dementia: the presence of depression
may be a harbinger of dementia, and dementia seems to be a risk factor for depression (Potter and
Steffens 2007). Substance abuse is also highly comorbid with depressive disorders. Estimates of
the prevalence of depressive disorders in patients with alcohol dependence is 15%–67%; for
patients with cocaine addiction the prevalence is 33%–53%, and for patients with opiate
dependence the lifetime rate of affective disorders ranges from 16% to 75% (Nunes 2003).
Symptoms of substance withdrawal (cocaine, methamphetamine, alcohol) do overlap with
symptoms of depression, but the type and severity tend to be distinctly different (Rapaport et al.
1993).
In summary, the exploration of factors that influence vulnerability and resilience has been
complicated by the heterogeneity of depressive disorders. Despite this obstacle, it is clear that
certain moderating factors have been identified that increase the risk of developing a depressive
disorder. These include female sex, aging, family history, childhood trauma, certain personality
styles, stressful life events, and presence of other psychiatric and medical illnesses.
Disability and Costs Associated With Depressive Illnesses
Major depressive disorder is associated with significant disease burden, exceeding that of
cerebrovascular diseases and cancer. It is the leading cause of years lived with disability worldwide
for young adults (Lopez et al. 2006). Psychosocial disability progresses along a gradient parallel to
the increasing severity of depressive symptoms (Judd et al. 2000; Kessler et al. 1997). People with
subsyndromal depressive symptoms and depressive disorder have higher disability ratings for
social and role functioning than patients with hypertension, diabetes, arthritis, gastrointestinal
problems, or back problems (Rapaport et al. 2002). Depressed persons rate themselves as having
worse health and spend more days in bed than patients with many other chronic medical conditions
including arthritis, diabetes, and lung disease (Wells et al. 1989). Even patients with minimal
symptoms or subsyndromal depression have functional impairment more akin to that seen in
patients with major depression than in nondepressed control subjects (Beekman et al. 2002). Thus,
patients with depressive disorders have decreased income, productivity, physical functioning, and
health status and more days spent in bed than control populations (Judd et al. 1996; Maddux and
Rapaport 2004).
The costs associated with major depressive disorder are staggering. For individuals 18–65 years of
age, 85% of the cost of depressive disorders is due to lost productivity (Smit et al. 2006). It is
estimated that depressive disorders cost employers in the United States $44 billion in productivity
annually. Twenty percent of this financial burden is due to absenteeism, with 80% of this loss due
to presenteeism; that is, a worker is well enough to come to work but unable to perform the job
efficiently (Stewart et al. 2003). Thus, although individuals who are mildly depressed may appear
to be functional, subtle impairments in abilities have a significant impact on productivity.
Depressive disorders are also prevalent and incur significant societal costs in the elderly (Cuijpers
et al. 2004; Horowitz et al. 2005). In contradistinction to the costs in younger adults, the costs
associated with major depressive disorder and other forms of depression in the elderly are
primarily driven by increased health care utilization, medical disease burden, and mortality.
The greatest “cost” associated with depressive disorders is the increased likelihood that an
individual suffering from a depressive disorder will commit suicide. According to the Centers for
Disease Control and Prevention, suicide is the eleventh leading cause of death in the United States:
approximately 32,000 known suicides were identified in the 2005 census. In that year the overall
suicide rate was almost double the homicide rate in the United States (11.05 per 100,000 vs. 5.9
per 100,000). Suicide is the second leading cause of death for individuals between the ages of 25
and 34 years and the third leading cause of death for young people between the ages of 15 and 24
years. Eighty percent of people who commit suicide are male. Suicide is more common in white than
Hispanic or black individuals. Statistical risk factors for suicide include being male, being white,Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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being single, having been hospitalized for a suicide attempt or having any history of a previous
attempt, having a family history of suicide, and abusing substances. Women are more likely to
attempt suicide, whereas men are more likely to complete it. In fact, longitudinal 40-year data from
- Angst et al. (2002) suggested that the 17.7% of the Zurich community cohort of people with a
diagnosis of major depressive disorder committed suicide.
The elderly constitute a special at-risk group for successful completion of suicide. People older than
65 years constitute only 13% of the population and yet are responsible for 18% of all suicides: this
is the highest suicide rate for any age group. Risk factors for suicide among older individuals are
slightly different than the factors among younger individuals; for older individuals they include
social isolation, physical illness, divorced or widowed status, and male sex (U.S. Department of
Health and Human Services 2001). Older individuals who attempt suicide usually employ more
lethal means (guns, drug overdoses) than younger individuals do.
It is clear that early identification and vigorous treatment are essential to decrease the likelihood
that an individual with a depressive disorder who is suicidal will take his or her life (Clayton and
Auster 2008). Despite recent guidance from the U.S. Food and Drug Administration (FDA)
suggesting that suicidal thoughts and behavior among individuals younger than 25 years may
increase during the first 10 days after starting an antidepressant, and despite a recent report based
on the STAR*D database that found an association between two ionotropic glutamate receptor
genes (GRIA3 and GRIK2) and an increased risk of SSRI-induced suicidal thoughts, the vast
majority of data suggest that antidepressant medication decreases suicidal thoughts and lowers
rates of suicide completion (R. D. Gibbons et al. 2005; Henriksson and Isacsson 2006; Laje et al.
2007; Rich and Isacsson 1997; Søndergård et al. 2006). These observations are supported by the
longitudinal work of J. Angst et al. (2005), who found that treatment with antidepressants, lithium,
and clozapine reduced the number of suicides in their cohort. They observed that long-term
treatment, particularly combined treatment, was associated with reduced overall mortality over
40-year follow-up. Taken as a whole, these data suggest that suicidal ideation with intent and
planning must be considered a medical emergency that merits the same type of diligent care that a
physician would give to other emergent conditions like a myocardial infarction.
DEFINITION OF DEPRESSIVE ILLNESS
Beginning with DSM-III (American Psychiatric Association 1980), American psychiatry made the
transition to descriptive nosology. The hallmarks of DSM-IV (American Psychiatric Association
1994) nosology for depressive illness are the requirement that a constellation of signs or symptoms
be present for a minimum length of time and that they induce some type of measurable functional
impairment. For the diagnosis of major depressive episode, an individual must have experienced,
over a single 2-week period, one of two “gatekeeper” symptoms—feeling sad/”blue” or having
anhedonia—plus four additional symptoms. These symptoms must cause substantial functional
impairment or disability, cannot be due a concomitant medical or substance use disorder, and must
persist every day for a significant portion of the day. DSM-IV-TR (American Psychiatric Association
2000a) criteria for major depressive episode are presented in Table 53–2.
TABLE 53–2. DSM-IV-TR criteria for major depressive episode
- Five (or more) of the following symptoms have been present during the same 2-week period and represent
a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of
interest or pleasure.
Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent
delusions or hallucinations.
(1) depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels
sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can
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(2) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every
day (as indicated by either subjective account or observation made by others)
(3) significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight
in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make
expected weight gains.
(4) insomnia or hypersomnia nearly every day
(5) psychomotor agitation or retardation nearly every day (observable by others, not merely subjective
feelings of restlessness or being slowed down)
(6) fatigue or loss of energy nearly every day
(7) feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day
(not merely self-reproach or guilt about being sick)
(8) diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective
account or as observed by others)
(9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan,
or a suicide attempt or a specific plan for committing suicide
- The symptoms do not meet criteria for a mixed episode.
- The symptoms cause clinically significant distress or impairment in social, occupational, or other important
areas of functioning.
- The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a
medication) or a general medical condition (e.g., hypothyroidism).
- The symptoms are not better accounted for by bereavement (i.e., after the loss of a loved one, the
symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid
preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation).
DSM-IV-TR allows the clinician to categorize the severity of the depressive disorder as mild
(symptoms barely meet the threshold for diagnosing the disorder and are not associated with
significant impairment), moderate (symptoms and functional impairment are somewhere between
mild and severe), or severe (several symptoms in excess of those required to make the diagnosis
are present, and symptoms markedly impair the individual’s functioning). The current nosology
classifies psychotic depression as major depressive disorder, severe, with psychotic features, rather
than as a distinct entity. DSM-IV-TR also provides specifiers to characterize the current depressive
episode, the two most significant being “with melancholic features” and “with atypical features.”
DSM-IV-TR criteria for the melancholic features specifier and for dysthymic disorder are presented
in Tables 53–3 and 53–4, respectively.
TABLE 53–3. DSM-IV-TR criteria for melancholic features specifier
Specify if:
With melancholic features (can be applied to the current or most recent major depressive episode in
major depressive disorder and to a major depressive episode in bipolar I or bipolar II disorder only if it is the
most recent type of mood episode)
- Either of the following, occurring during the most severe period of the current episode:
(1) loss of pleasure in all, or almost all, activities
(2) lack of reactivity to usually pleasurable stimuli (does not feel much better, even temporarily, when
something good happens)
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(1) distinct quality of depressed mood (i.e., the depressed mood is experienced as distinctly different
from the kind of feeling experienced after the death of a loved one)
(2) depression regularly worse in the morning
(3) early morning awakening (at least 2 hours before usual time of awakening)
(4) marked psychomotor retardation or agitation
(5) significant anorexia or weight loss
(6) excessive or inappropriate guilt
TABLE 53–4. DSM-IV-TR criteria for 300.4 dysthymic disorder
- Depressed mood for most of the day, for more days than not, as indicated either by subjective account or
observation by others, for at least 2 years. Note: In children and adolescents, mood can be irritable and
duration must be at least 1 year.
- Presence, while depressed, of two (or more) of the following:
(1) poor appetite or overeating
(2) insomnia or hypersomnia
(3) low energy or fatigue
(4) low self-esteem
(5) poor concentration or difficulty making decisions
(6) feelings of hopelessness
- During the 2-year period (1 year for children or adolescents) of the disturbance, the person has never been
without the symptoms in criteria A and B for more than 2 months at a time.
- No major depressive episode has been present during the first 2 years of the disturbance (1 year for
children and adolescents); i.e., the disturbance is not better accounted for by chronic major depressive
disorder, or major depressive disorder, in partial remission.
Note: There may have been a previous major depressive episode provided there was a full remission (no
significant signs or symptoms for 2 months) before development of the dysthymic disorder. In addition, after
the initial 2 years (1 year in children or adolescents) of dysthymic disorder, there may be superimposed
episodes of major depressive disorder, in which case both diagnoses may be given when the criteria are met
for a major depressive episode.
- There has never been a manic episode, a mixed episode, or a hypomanic episode, and criteria have never
been met for cyclothymic disorder.
- The disturbance does not occur exclusively during the course of a chronic psychotic disorder, such as
schizophrenia or delusional disorder.
- The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a
medication) or a general medical condition (e.g., hypothyroidism).
- The symptoms cause clinically significant distress or impairment in social, occupational, or other important
areas of functioning.
Specify if:
Early onset: if onset is before age 21 years
Late onset: if onset is age 21 years or older
Specify (for most recent 2 years of dysthymic disorder):
With atypical features
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disorder and depressive disorder not otherwise specified. (The cardinal features of dysthymic
disorder are presented in Table 53–4.) In order to be classified as having dysthymic disorder, an
individual may not meet the threshold criteria for major depressive disorder during the first 2 years
of illness and cannot be better characterized as having major depressive disorder, chronic, or major
depressive disorder, in partial remission. Dysthymic disorder is thought to have an early and
insidious onset. Most patients who are seen in clinical settings seek treatment because of a major
depressive disorder that has become superimposed on dysthymia. These cases of double depression
tend to be challenging to treat and have a worse prognosis than uncomplicated major depression.
The category depressive disorder not otherwise specified has been used as a catchall for the
presence of signs and symptoms of depression that do not meet criteria for major depressive
disorder, dysthymia, or one of the adjustment disorders. Minor depressive disorder and
subsyndromal depressive disorder fall within the rubric of depressive disorder not otherwise
specified in DSM-IV-TR. More recent work has demonstrated that minor depressive disorder is
associated with significant disability, morbidity, and impairment (Howland et al. 2008; Judd and
Akiskal 2000; Judd et al. 1994; Rapaport and Judd 1998; Rapaport et al. 2002). In contradistinction
to major depressive disorder, minor depressive disorder is characterized mostly by affective and
cognitive symptoms such as sadness, loss of pleasure/enjoyment, irritable mood, anxious mood,
pessimism, difficulty concentrating, lack of involvement, and fatigue. This constellation of
symptoms has been demonstrated to be stable and persistent in individuals with minor depression
(Rapaport et al. 2002). The research criteria for minor depressive disorder in the appendix of
DSM-IV-TR exclude individuals who have had a prior episode of major depressive disorder.
However, research suggests that this is unnecessarily restrictive; subjects with and without a prior
history of major depressive disorder have identical demographic and clinical presentations, severity
of illness, and acute treatment response (Howland et al. 2008; Judd et al. 2004; Rapaport et al.
2002).
A number of different definitions of subsyndromal depressive disorder have been discussed in the
literature. For many investigators, subsyndromal depressive disorder is thought to be equivalent to
minor depressive disorder. However, Judd et al. (1994) suggested that subsyndromal depressive
disorder be defined as the presence of any of two or more associated symptoms of depression:
problems with sleep, appetite, concentration, or suicidal thinking without the presence of sadness
or anhedonia. Although there is no consensus about the diagnosis of subsyndromal depression at
this time, the presence of signs and symptoms associated with depression has negative prognostic
value. Such individuals are at greater risk of developing an episode of minor or major depressive
disorder within the next year (Judd et al. 1994, 1997).
In conclusion, the definitions of the syndromes that constitute the spectrum of unipolar mood
disorders will continue to evolve with our understanding of the neurobiology of what we call mood
disorders.
NEUROBIOLOGY OF DEPRESSION
Depressive disorders have many features that clearly indicate a complex neurobiological
component to the disease state. The discovery in the 1950s of antidepressant pharmacological
therapies provided the initial evidence of an underlying biochemical alteration in depressed
patients. Studies in genomics and imaging and the identification of neural pathways involved have
advanced our knowledge. As a result, several complementary but distinct lines of investigation into
the neurobiology of depression have begun to take hold.
Depression has for many years been predominantly hypothesized to be marked by a depletion of
monoamine neurotransmitters, specifically norepinephrine, serotonin, and dopamine. The
involvement of monoamines in mood alterations was first documented in the 1950s with the
observation that individuals treated with high doses of reserpine, an antihypertensive agent that
depletes the brain of monoamines, developed depression (Freis 1954). Later studies of monoamine
depletion were developed to investigate the direct effects of monoamines on mood. Because
monoamines are synthesized from essential amino acid precursors tryptophan (for serotonin) andPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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tyrosine (for norepinephrine and dopamine), a transient depletion can be achieved by ingesting a
tryptophan-free or tyrosine-free amino acid mixture. In healthy individuals, depressed mood has
been noted after tryptophan or tyrosine depletion in some studies, although more marked results
are found in subjects with a family history of mood disorders or in drug-free subjects in remission
from depression (Ruhe et al. 2007). Although depletion studies have never induced levels of clinical
depression in healthy individuals or increased depressive symptoms in clinically ill patients not
taking medication, what has been intriguing is that subjects with major depression who responded
to SSRIs relapsed after serotonin depletion (Delgado et al. 1990). These results suggest that
patients who are clinically ill with major depression have deficits in brain monoamine
concentrations and that these deficits play a modulatory role with other systems that have a more
direct role in the symptoms of depression.
As our understanding has grown about the mechanism of action of antidepressant therapies, more
attention has been given to the neurotransmitter systems involving glutamate and -aminobutyric
acid (GABA). Evidence for the role of these neurotransmitter systems in depression comes from
studies of therapies that have been shown to target the N-methyl-D-aspartate (NMDA) class of
glutamate receptors, specifically lamotrigine, ketamine, and amantadine (Pittenger et al. 2007),
and anticonvulsant therapies, which have a GABAergic route of action. Studies have demonstrated
alterations of these systems in subjects with depression. One postmortem gene expression study
demonstrated that the brains of suicide victims suffering from major depression had
downregulation of the spermidine/spermine N1-acetyltransferase (SSAT) gene, which was
subsequently linked to the presence of an allelic variant (Sequeira et al. 2006). SSAT is the
rate-limiting enzyme for the catabolism of polyamines, which in turn regulate the NMDA receptors.
Furthermore, a meta-analysis of the body of studies performed revealed that cerebrospinal fluid
levels of GABA in subjects with depression are significantly lower than levels in nondepressed
control subjects (Petty et al. 1993).
Depression is also marked by dysregulation of other important systems. External stressful stimuli
are known to be a major risk factor for a depressive episode, and depressed individuals are often
characterized with altered biological responses to stress. This is likely due to dysregulation and
overstimulation of the HPA axis (Gertsik and Poland 2004; Holsboer 1995). Early studies (Brown
and Shuey 1980; Carroll 1982; Coppen et al. 1983) found that in a large percentage of unmedicated
individuals with depression, secretion of the stress hormone cortisol is not suppressed after
dexamethasone administration, a condition known as dexamethasone nonsuppression.
Dexamethasone is a synthetic glucocorticoid and acts at the level of the anterior pituitary
corticotrophs to reduce the secretion of adrenocorticotropic hormone (ACTH), which in turn
decreases the production of cortisol in the adrenal cortex. Dexamethasone nonsuppression
therefore indicates impairments in the feedback mechanisms of the HPA axis. Correspondingly,
elevated levels of circulating cortisol have been reported in subjects with depression (J. L. Gibbons
and McHugh 1962; Rubin et al. 1987). This impairment of HPA axis regulation has been traced
upstream to dysregulation of corticotropin-releasing hormone (CRH), a hypothalamic hormone that
controls the release of ACTH (Holsboer 2000). Depressed individuals have higher CRH neuronal
activity (Raadsheer et al. 1994) and display a blunted ACTH and cortisol response to infusion of
synthetic CRH (Gispen-de Wied et al. 1993; Gold et al. 1986). This global hyperactivity of the stress
response in depressed individuals has been demonstrated to be a characteristic of the current
depressed state, because the remission of clinical symptoms induces a normalization of responses
to dexamethasone or CRH along with normalization of plasma cortisol levels (Amsterdam et al.
1988; Arana et al. 1985; Sachar et al. 1970). Dysregulation of the HPA axis activity and higher rates
of depression are more prominent in individuals exposed to childhood trauma or abuse (Bremne
and Vermetten 2001), suggesting that hyperactivity of the HPA axis during critical periods of brain
development leads to higher rates of depression later in life.
This cascade of alterations in the HPA axis, and subsequent increase in glucocorticoids, is thought
to be responsible for the structural and functional changes seen in the limbic structures of
depressed individuals. In vivo magnetic resonance imaging studies demonstrate hippocampalPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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shrinkage in depressed patients relative to healthy control subjects (Campbell et al. 2004; Videbech
and Ravnkilde 2004). Although the exact mechanism of this loss of hippocampal volume is
unknown, it is presumably through cell death, cell atrophy, and/or reduction in neurogenesis.
Successful antidepressant therapy has been shown to increase cellular proliferation (Duman 2004;
Warner-Schmidt and Duman 2006), and chronic stress induces the converse, giving further
credence to the neurobiological component of depression.
Taken together, these observed alterations in monoamines and other neurotransmitters, in the HPA
axis function, and in neuronal plasticity can be conceptualized as a state of depressive illnesses
rather than a trait of the illnesses. Given that successful clinical therapies often reverse these
trends, one has to ask, What is the underlying cause? It is clear that a familial predisposition to
depression is present, lending support to the idea of a genetic component to depression. Ongoing
research has failed to pinpoint a specific genetic anomaly, which is likely due to the heterogeneity
of the disorder and the additive role that environmental factors play in triggering depressive
episodes in individuals who may be genetically predisposed to depression. However, with the
advent of high-throughput technology, such as whole-genome sequencing and single nucleotide
polymorphism detection, specific genetic trends have been demonstrated.
Some very positive studies point to polymorphisms of the 5-HTT gene (Caspi et al. 2003; Kendler et
- 2005) that may modulate the sensitivity of individuals to stressful life events. Additional work
has implicated allelic polymorphisms in glucocorticoid receptors (Binder et al. 2004; Brouwer et al.
2006; van Rossum et al. 2006) and CRH receptors (Liu et al. 2007; Papiol et al. 2007). Most
interesting has been the discovery that there exist subpopulations of depressed individuals with
genetic anomalies in the 5-HTT gene who have a higher risk of developing adverse side effects to
SSRI treatment than individuals without those anomalies (Hu et al. 2007; Smits et al. 2007a). A
study was conducted to determine whether genetic prescreening for a variant in the 5-HTT gene to
identify which class of antidepressants would be best suited for each subject’s course of treatment
would lead to better treatment outcomes (Smits et al. 2007b). Positive results were minor,
however, and the costs involved suggest that the gains made were unsubstantial. One clear genetic
variation that has been demonstrated as clinically valuable is alteration in the gene for the
cytochrome P450 enzyme CYP2D6, a liver enzyme involved in drug metabolism. Individuals may
have normal, intermediate, or poor metabolism rates depending on whether they carry no alleles,
one allele, or two alleles. This trait has been seized on as a potential aid in properly dosing patients,
and the FDA has approved use of a test to aid physicians in genetic testing (Roche Pharmaceuticals
2008).
Other studies have begun to examine the contribution of the immune system and cytokines in major
depressive disorder, suggesting a new avenue for therapeutic alternatives. Cytokines are a
heterogeneous group of signaling and regulatory molecules produced by immunocompetent cells,
and generally are categorized as proinflammatory or anti-inflammatory. The proinflammatory
cytokines interferon alfa and interferon gamma have potent antiviral and immunomodulatory
properties and are used to treat various forms of cancer and hepatitis C (Adams et al. 1984;
Borgstrom et al. 1982; Meyers 1999). These cytokine therapies have been noted to be accompanied
by depressed behavioral effects that can be significantly reduced by pretreatment with paroxetine
(Capuron et al. 2002; Musselman et al. 2001), thus supporting the cytokine theory of depression.
Furthermore, individuals with depressive disorders have higher plasma concentrations of the
proinflammatory cytokines interleukin 1 (IL-1) and interleukin 6 (IL-6) than do nondepressed
individuals, and concentrations correlate with the severity of depressive symptoms (Maes 1995,
1999). Some studies have demonstrated that the immune system is in an activated state in subjects
with depressive disorders (Kling et al. 2007; Maes et al. 1995; Schiepers et al. 2005; Sluzewska et
- 1996). Although the precise role that cytokines play in depression is difficult to elucidate,
continued research in this direction is warranted.
As presented in greater detail in other chapters of this book (see Chapter 45, “Neurobiology of
Mood Disorders”), it is clear that our understanding of the biological underpinnings of depressive
disorders is rapidly increasing. In the future the combination of advances in molecular medicine,Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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imaging, and data analysis will begin to clarify the relationship between what currently appear to
be disparate biological findings.
EVALUATION OF DEPRESSION
Context
The setting of the psychiatric assessment is important in that it provides a context that defines the
focus of the encounter and therefore the content of the examination. For example, the assessment
of the depressed patient in the emergency room is very different from the assessment of the
depressed patient in the office, and that is very different from the assessment within a general
hospital setting. The assessment of a depressed person in the emergency room focuses on a rapid,
yet thoughtful, determination of safety and appropriate disposition—that is, does this person
require hospitalization or is treatment in a less restrictive environment more appropriate? To
expedite the determination of disposition in the emergency room, the evaluation focuses on issues
of safety, suicidal thinking, future orientation, stability of social supports, housing, and recent drug
and alcohol use. This assessment should also include a review of recent life events and potential
precipitating stressors. Collateral information from family, friends, and outside physicians is helpful
in determining the appropriate level of care.
In the office setting, it is possible to carry out a more traditional and complete initial examination.
This includes a detailed review of the patient’s signs and symptoms of depression, any comorbid
medical or psychiatric disorders, and the patient’s psychiatric history. A family history of psychiatric
illness is very important. The focus of the initial evaluation is on establishing rapport, determining a
working diagnosis, and developing an initial treatment plan.
In contrast, when a psychiatrist is acting as a consultant in a general hospital setting, the
assessment has a different focus. Because either the illness itself or a treatment intervention may
have provoked the episode requiring hospitalization, the consultant needs to carefully review the
current medical chart. The stress of the hospitalization, bereavement, delirium, or a head injury
may mimic a depressive disorder in an individual hospitalized in an acute care setting. Somatic
symptoms such as pain, constipation, insomnia, and nausea frequently stimulate angry behavior or
exacerbate a sense of helplessness in a patient. The amelioration of such somatic concerns may
decrease the intensity of depressive symptoms in the hospital setting. Thus, the goals of the
consultant in a general hospital setting are to determine a working diagnosis and intervention plan,
to communicate this to the primary care team, to facilitate its implementation, and to establish a
plan for follow-up after discharge.
Initial Evaluation and Differential Diagnosis
Although all psychiatrists have been trained in the appropriate approach to initial examination and
differential diagnosis, unfortunately many times patients are misdiagnosed because components of
the diagnostic assessment have been inadvertently omitted. It is important to remember that a
complete initial diagnostic assessment should include not only the history of the present illness but
also a complete assessment of current and past comorbid psychiatric conditions, a family medical
and psychiatric history, and a social and developmental history. Frequently, busy practitioners
forget to ask about early childhood trauma or sexual trauma. Performing a formal mental status
examination may be particularly important if one is assessing either an older person with a
depressive disorder or someone with significant medical comorbidities.
One needs to either contact the primary care physician or consider performing a medical history
and a physical examination for patients with a new onset of major depressive disorder. Many
medical conditions, medications, and substances (alcohol, benzodiazepines, barbiturates) can cause
depressive symptoms, as shown in Tables 53–1 and 53–5.
TABLE 53–5. Medications that may cause depressionPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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Acyclovir Clonidine Metoclopramide
Alcohol Cocaine (withdrawal) Metrizamide
Amantadine Contraceptives Metronidazole
methyldopa Corticosteroids NSAIDs
Amphetamines (withdrawal) Cycloserine Opiates
Anabolic steroids Dapsone Pentazocine
Anticonvulsants Digitalis Pergolide
Antihistamines Disopyramide Phenylpropanolamine
Antineoplastic agents Disulfiram Physostigmine
Antipsychotic medications Estrogens Prazosin
Baclofen Ethambutol Progestins, implanted
Barbiturates Fluoroquinolone antibiotics Reserpine
Benzodiazepines Guanethidine Statins
-adrenergic blockers Interferon alfa Sulfonamides
Bromocriptine Isotretinoin Thiazide diuretics
Calcium channel blockers Levodopa
Cimetidine Mefloquine
Note. NSAIDs = nonsteroidal anti-inflammatory drugs.
Rating Scales
One of the greatest challenges psychiatry and psychology have faced is quantifying the impact of
psychiatric illness and therapies on a patient’s life. Most practitioners do not establish baseline
levels of symptom severity and do not systematically measure the changes in symptoms caused by
their interventions. Some have worried that introducing scales to systematically assess symptom
severity would contaminate the therapeutic process; however, this postulate has fallen out of favor.
As the biology of depressive disorders is beginning to be elucidated and depressive disorders are
being recognized as syndromes related to brain dysfunction, it is imperative for practitioners to
employ a more rigorous approach to assessment and treatment. With “pay for performance”
standards coming to psychiatry in the near future, employing standardized assessments will place
the practitioner ahead of the curve in demonstrating the effectiveness of his or her treatment
interventions.
Objective measurement of signs and symptoms of depressive disorders facilitates a more rational
approach to treatment. These assessments provide accurate delineation of the severity of baseline
signs and symptoms of depression. Thus, as was done in the STAR*D study, the clinician can use
follow-up assessments to guide therapeutic decisions. Ratings also can be used as a tool to engage
patients in their therapy and as an ongoing component of psychoeducation about depressive
disorders.
The most commonly employed ratings (Table 53–6) evaluate the severity and frequency of specific
symptoms associated with depression. These items’ scores are usually summed into a composite
score that represents the overall severity of the syndrome. The rating scales can be divided into
two large groups: clinician-rated scales and self-report scales. For many years the field of
psychiatry has placed greater value on clinician-rated scales. Proponents of clinician-rated scales
suggest that they are more objective because the clinician is an unbiased observer, judging the
severity and frequency of the symptoms (Carroll et al. 1973). Some favor clinician-rated measures
because they allow the interviewer an opportunity to ask the patient follow-up questions and elicit
sufficient data to ensure the accuracy of an answer. However, such ratings are highly dependent onPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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the skill of the interviewer and the interviewer’s fidelity to the intent and structure of the
instrument. Proponents of patient-rated measures argue that a patient can provide a unique and
valuable perspective to the assessment of his or her illness. Critics have raised legitimate concerns
about self-reporting bias (Carroll et al. 1973); such bias could take the form of symptom
minimization or symptom exaggeration. Furthermore, the presence of a negative cognitive schema
might lead patients to minimize the extent of improvement that occurs early in therapy. Yet
self-report assessments can be an important tool to enhance self-monitoring as the patient begins
to “buy in” to therapy and adherence.
TABLE 53–6. Rating scales for symptoms of depression
Clinician-rated scales
Hamilton Rating Scale for Depression
Montgomery-Åsberg Depression Rating Scale
Inventory of Depressive Symptoms
Self-report scales
Zung Self-Rating Depression Scale
Beck Depression Inventory
Public Health Questionnaire–9
Quick Inventory of Depressive Symptoms–Self-Report
Rating scales for work and functioning
Endicott Work Productivity Scale
Work and Social Adjustment Scale
Sheehan Disability Scale
Rating scales for quality of life
Medical Outcome Survey
Quality of Life Enjoyment and Satisfaction Questionnaire
Quality of Well-Being Scale
Quality of Life in Depression Scale
Clinician-Rated Scales
Three clinician-rated scales are commonly used to assess the severity of major depressive disorder:
the Hamilton Rating Scale for Depression (Ham-D), the Montgomery-Åsberg Depression Rating
Scale (MADRS), and the Inventory of Depressive Symptoms (IDS). These are described below:
The initial Ham-D was a 17-item scale developed by Max Hamilton in the United Kingdom while he
worked with inpatients with primarily endogenous major depressive disorder (Hamilton 1960, 1967).
When the scale was first published, it was suggested that the interview would usually require 45–60
minutes to perform (Hamilton 1960). This scale became a mainstay of depression research, and a
variety of iterations emerged: 21-, 24-, 25-, 28-, and 31-item forms of the Ham-D (Ham-D-21,
Ham-D-24, etc.). Shorter forms of the original Ham-D have also been proposed that are thought to
measure the “core features” of depression, but these have not been widely accepted by clinicians. Other
attempts to refine the Ham-D have included the development of structured interviews. The most
popularly accepted form is the Structured Interview Guide for the Ham-D (SIGH-D; Williams 1988), but
that has recently been supplanted by the GRID-Ham-D, which systematically measures the severity and
frequency of symptoms (Tabuse et al. 2007). Thus, the Ham-D is a commonly used clinician-rated scale
with multiple refinements that has been frequently employed in research settings.
- The MADRS (Montgomery and Åsberg 1979) was developed to be sensitive to the potential benefits ofPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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pharmacological interventions. It is shorter than the standard Ham-D-17 and does not contain as many
items measuring somatic concerns or anxiety. Items are rated from 0 to 6, with two items not having
the benefit of a specific series of descriptors to anchor them to the rest of the scale. This is a reliable
and well-validated scale (Khan et al. 2004).
The IDS has both clinician-rated and self-report forms. The clinician-rated form has 30 items that are
rated 0–3. This scale includes cognitive signs and symptoms of depression as well as the DSM-IV
symptoms (Rush et al. 1986; Trivedi et al. 2004). It has been well validated. The IDS clinician-rated
scale also comes in an abbreviated form, the Quick Inventory of Depressive Symptoms (Rush et al.
2003). This version rates all of the DSM-IV signs and symptoms of depression from 0 to 3. It is well
validated and was one of the primary outcome measures in the STAR*D study (Rush et al. 2006a;
Trivedi et al. 2004).
Self-Report Scales
A wide array of self-report measures are available for patients and clinicians to consider:
One of the first measures developed was the Zung Self-Rating Depression Scale (Zung 1965). This
20-item scale, with ratings from 1 to 4, measures the severity of depressive symptoms. As is the case
with the Ham-D, the scale was developed prior to the advent of DSM-III, so some features of the scale
are not as closely aligned with our current nosology as the more recently developed self-report
measures (Guy 1976).
A second self-rating scale commonly employed, particularly in psychology, is the Beck Depression
Inventory (BDI; A. T. Beck and Beamesderfer 1974). The BDI is a byproduct of A. T. Beck’s descriptive,
theoretical, and treatment work investigating cognitions and depression. It is a well-validated and
commonly employed measure that focuses primarily on the more cognitive aspects of depression.
Another instrument, which has been gaining greater acceptance as a patient-rated measurement of
major depressive disorder, is the Public Health Questionnaire–9. This questionnaire consists of the first
nine items of the larger Public Health Questionnaire that was developed as an assessment tool for
studying primary care patients (Kroenke et al. 2001). The nine symptoms are 1) depressed mood, 2)
anhedonia, 3) appetite change, 4) sleep disturbance, 5) psychomotor change, 6) loss of energy, 7)
feelings of worthlessness/guilt, 8) diminished concentration, and 9) suicide.
Each item is scaled from absent (a score of 0) to present nearly every day (a score of 3). This
instrument is well validated and has been used to longitudinally follow the course of illness because it is
possible to assess the presence or absence of symptoms (Cannon et al. 2007; Kroenke et al. 2001).
However, this instrument does not directly measure the intensity of symptoms.
A fourth patient-rated measure that is widely used is the Quick Inventory of Depressive
Symptoms–Self-Report (QIDS-SR; Rush et al. 2003). This instrument correlates highly with the
clinician-rated version. It includes assessments of intensity and frequency and covers all the cardinal
signs and symptoms of major depressive disorder outlined in DSM-IV. This measure is easy for both
clinicians and patients to use (Trivedi et al. 2004).
Self-report measures of work and functioning
If one is to reconceptualize major depressive disorder, symptoms are only part of the syndrome.
Major depressive disorder impacts the individual’s physical health, ability to function, interactions
with significant others, interactions with family members, and quality of life. Thus, it is important to
quantify not only the severity of symptoms but also the impact of the syndrome on other aspects of
the patient’s life. There are three readily available self-report measures of work and functioning
that the clinician can ask the patient to complete:
One of the best-validated instruments is the Endicott Work Productivity Scale (Endicott and Nee 1997).
Although this has the advantage of being well validated and complete, it has the disadvantage of being
relatively time-consuming for the patient to use.
A second scale that has been validated, and that is very easy to use, is the Work and Social Adjustment
Scale (Mundt et al. 2002). It consists of five Likert scales that measure an individual’s perception of
work and social functioning.
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The Sheehan Disability Scale (Leon et al. 1992) is another simple and widely accepted approach to
assessing disability. This 3-item Likert scale measures dysfunction at work, in social settings, and with
family members. It is very easy to perform, is reliable, and has high patient acceptance.
Measurements of Quality of Life
Measurement of quality of life has been increasingly recognized as an important component for the
treatment of psychiatric illnesses. There are several widely used instruments that measure aspects
of quality of life, as described below:
The most widely accepted instrument, employed in both psychiatry and medicine in general, is the
Medical Outcome Survey. The versions most commonly used are the three Short Form (SF) instruments:
SF-36, SF-12, and SF-4 (Ware and Sherbourne 1992; Ware et al. 1996). The advantage of these scales
is that they are widely used, so there is a vast amount of data available validating them in a variety of
conditions. The disadvantage of the Medical Outcome Survey is that it is relatively insensitive to change
with symptom improvement. This is due to the scoring algorithm, which truncates the range of the scale.
The second instrument that has been commonly used in a variety of trials is the Quality of Life
Enjoyment and Satisfaction Questionnaire (Q-LES-Q). The Q-LES-Q is available in both a long form and a
one-page summary form, which is the most commonly used version of the questionnaire (Endicott et al.
1993; Rapaport et al. 2005). This scale has 14 items that are rated from 1 to 5 and summed to create a
total score. There are also two general items; one is general life satisfaction, and the other assesses
satisfaction with medication the patient is taking. The short form of the Q-LES-Q is well validated and
takes less than 5 minutes to complete.
An instrument that is available in both an interview form and a self-report form is the Quality of
Well-Being Scale (QWB) (Kaplan 1993; Kaplan and Anderson 1990). This scale has been developed and
validated across many medical and psychiatric conditions. The QWB allows one to get a measure of
quality-adjusted life-years. The intent of such a scale is to measure the impact of an illness or a number
of illnesses on an individual’s overall fitness.
An additional instrument that has been reported in the depression literature is the Quality of Life in
Depression Scale (Hunt and McKenna 1992). Although this is a well-validated instrument, it does not
allow one to generalize the impact of illness on quality-of-life dysfunction beyond major depressive
disorder.
A less formal but ecologically valid approach is to elicit from the patient the three symptoms or life
problems that are most debilitating for the patient at the time of initial assessment. These can be
symptoms or signs of depressive disorder, functional impairment, or problems affecting quality of life.
The patient is then asked to assess his or her symptoms/problems daily. In our practice at Cedars-Sinai
Medical Center, we have called this approach the most troubling symptoms model for monitoring care.
During the initial interview, the patient and therapist collaboratively identify and quantify life problems
related to the mood disorder on a Likert scale of 1–10. This approach has several strong points. First, if
the patient assesses his or her condition daily, it facilitates the engagement of the patient in therapy,
because the patient is monitoring problems that he or she has identified as significant. Second, it allows
the patient to know that the physician truly hears what the patient’s complaints and concerns are. This
enhances the therapeutic relationship and adherence to therapy. Third, this being a fine-grained
approach to assessing on a daily basis the severity of problems that the patient has identified, it allows
the patient and the clinician to discern subtle changes that frequently are missed when patients are
assessed weekly or less frequently. This approach facilitates rational discussion between the patient and
the clinician about the patient’s condition and, when necessary, the need to alter the treatment course.
This has proven to be a simple yet effective technique for monitoring both the severity of the illness and
the impact of the illness on the patient’s life.
In summary, it is clear that a systematic assessment of the signs and symptoms of an illness, as
well as the impact of the illness on other aspects of the patient’s life, is necessary to maximize the
opportunity for treatment gains. The use of either clinician-rated or self-report measures enables
physicians to objectively monitor the course of treatment and the benefits of interventions and is
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TREATMENT OPTIONS
The treatment of major depressive disorder is now commonly conceptualized to have three phases:
acute treatment, continuation treatment, and maintenance treatment (Frank et al. 1991b). The
overall goal of acute treatment is remission. Thus, during acute treatment the patient is vigorously
treated with pharmacotherapy, psychotherapy, or a combination of both until all symptoms of the
depressive disorder have been eliminated. It is thought that remission is associated with the
restoration, over time, of the individual’s quality of life and functioning. The consequences of not
achieving remission have been discussed previously in this chapter (see “Changes in
Conceptualization of Depressive Disorders” and “Disability and Costs Associated With Depressive
Illnesses”). They include an increased risk of treatment resistance (Judd et al. 1998b; Paykel et al.
1995), persistence of psychosocial dysfunction (Miller et al. 1998), an increased risk of morbidity
and mortality from medical illnesses (Murray and Lopez 1997), and an increased risk of suicide. The
focus of continuation treatment is to protect the patient against a relapse back into the current
episode of major depressive disorder. Studies have demonstrated clearly that if treatment is
discontinued after the acute phase, more than half of individuals will have a relapse of major
depressive disorder (Thase 1999). The goal of maintenance therapy is to prevent a recurrence or
new episode of major depressive disorder. Because major depressive disorder is a chronic and
recurrent illness for most individuals, full-dose maintenance therapy is essential in order to
minimize the risk for and the number of future episodes (Bump et al. 2001; Prien et al. 1984).
Antidepressant Medications
Under ideal circumstances, the choice of an antidepressant medication is a collaborative process
between the physician and the patient. Considerations that need to be weighed by the physician
and patient can be broadly grouped as patient preferences, pharmacodynamic concerns, and
pharmacokinetic concerns. Particularly in the age of direct-to-consumer advertising and the
Internet, many patients take an active approach to their pharmacotherapy. Patients either have
searched the Internet for information about treatment options for major depressive disorder or
have been influenced by the advertisements that they see on television. Thus, many patients come
to the initial appointment with their own biases and beliefs about what would be the best treatment
option. However, a variety of other patient-related variables may come into play when selecting an
antidepressant medication including side effects (especially sexual side effects, weight gain, and
insomnia), dietary restrictions, and ease of use (Table 53–7). Addressing these issues with the
patient is important to enhance adherence to therapy. Other patient-specific factors that need to be
taken into account are the patient’s prior history of response to a medication or a family history of
response to a certain class of medications. This may influence both the patient and the physician
regarding the choice of medication to treat the current depressive episode.
TABLE 53–7. Antidepressant medications
Type Drug (trade name) Daily dosing Pharmacology Side effects and other
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Type Drug (trade name) Daily dosing Pharmacology Side effects and other
concerns
Sertraline (Zoloft)
25–200 mg
Paroxetine (Paxil)
10–60 mg
Citalopram (Celexa)
10–60 mg
Escitalopram
(Lexapro)
5–20 mg
SNRI Venlafaxine (Effexor) 37.5–400 mg Inhibits reuptake of
5-HT and NE
Nausea, insomnia, sedation,
sexual dysfunction, sweating,
hypertension, discontinuation
syndrome
Duloxetine
(Cymbalta)
30–120 mg
MAOI Phenelzine (Nardil)
Tranylcypromine
(Parnate)
45–75 mg Irreversibly inhibits
MAO from breaking
down into NE, 5-HT,
and dopamine
Hypotension, weight gain,
sedation, dry mouth, sexual
dysfunction, dietary restrictions,
risk of hypertensive crisis,
life-threatening drug–drug
interactions
Selegiline (Emsam
[transdermal])
20, 30, or 40
mg
At recommended
doses, does not inhibit
gut MAO-A
Weight gain, sedation
Atypical Mirtazapine (Remeron) 15–45 mg Improves 5-HT and NE
tone: 2 presynaptic
blocker on NE and
5-HT neurons
Blocks 5-HT2A, 5-HT2C,
and 5-HT3
Blocks H1
Weight gain, sedation, abnormal
dreams, dry mouth, hypotension,
constipation, rare agranulocytosis
Bupropion (Wellbutrin) 75–450 mg in
three divided
doses (maximal
single dose, 150
- mg)
SR 200–450 mg
in two divided
doses
XL 150–450 mg
daily
Blocks reuptake of NE
Increases dopamine in
frontal cortex
Blocks dopamine
transporter pump
Agitation, restless insomnia,
weight loss, anorexia, sweating,
headache, tremor, hypertension,
rare seizures
Trazodone (Desyrel) 100–450 mg Blocks 5-HT2A
Blocks 5-HT reuptake
Orthostatic hypotension, nausea,
dry mouth, dizziness, rare
priapism, occasional sinus
bradycardia
Note. 5-HT = 5-hydroxytryptamine (serotonin); 5-HT2A = 5-HT type 2A receptor; H1 = histamine type 1
receptor; MAO = monoamine oxidase; MAO-A = monoamine oxidase isozyme A; MAOI = monoamine oxidase
inhibitor; NE = norepinephrine; SNRI = serotonin–norepinephrine reuptake inhibitor; SR = sustained release;
SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XL = extended release.
Although we have not been able to discern distinct biological subtypes, pharmacogenetics
(discussed in more detail below) has now developed to the point that it can inform our therapeutic
decisions. The specific pharmacodynamic properties of an agent certainly need to be taken intoPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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account when identifying the appropriate medication for an individual. Although the tricyclic
antidepressants and the monoamine oxidase inhibitors have a long history of proven efficacy, these
classes of agents have fallen out of favor because of their side-effect profiles. The majority of
commonly used antidepressants (see Table 53–7) work via one or more mechanisms: 1) inhibition
of serotonin reuptake, 2) inhibition of the reuptake of both serotonin and norepinephrine, 3)
stimulation of noradrenergic and dopaminergic activity, or 4) 2 antagonism of noradrenergic and
serotonergic neurons. Physicians now can use knowledge about the pharmacodynamics of agents to
influence a treatment choice. For example, a clinician is visited by a 50-year-old white male with
chronic, persistent depression. The patient is currently complaining of diarrhea and persistent
symptoms of depression despite medication with sertraline at a dosage of 200 mg/day. In taking
the patient’s history, the clinician learns that the patient has had persistent problems with diarrhea
and lack of treatment response with three other SSRIs and with both of the FDA-approved
serotonin–norepinephrine reuptake inhibitors. In this case, use of an agent like mirtazapine might
be preferable.
The pharmacokinetic profile of the agent is another variable that needs to be taken into account in
selecting an antidepressant medication. As would be expected, antidepressants differ in their
protein binding, rate and mechanism of elimination, half-life, lipophilicity, and effects on other
metabolic pathways. Therefore, it is important to carefully determine what other medications the
patient may be taking. Drug–drug interactions may increase blood levels of concomitant
medications, and at times those interactions can be unpleasant or even life-threatening.
In summary, the choice of initial antidepressant medication is ideally a collaborative
decision-making process between the patient and the physician. It requires an understanding of the
patient’s preferences, family history, prior treatment history, and current medical conditions; any
current medications he or she may be taking; the side-effect profile of the proposed agent; and the
pharmacokinetic and pharmacodynamic properties of the compound. Engagement of the patient in
this decision-making process is more likely to enhance adherence to the medication regimen.
Pharmacogenetics
There has been recent attention on the field of pharmacogenetics—the concept of tailoring drug
therapy to a patient’s genetic makeup (Perlis 2007). Currently, tests are available commercially to
screen for allelic variation in the CYP450 genes (Roche Diagnostics, Switzerland). These tests
purportedly would allow the physician to select an antidepressant dose based on some knowledge
of how the medication will be metabolized and possibly eliminated. This application has limitations
given that many other factors are involved in drug metabolism besides a patient’s genetic makeup,
such as smoking status, diet, concurrent treatment therapies, and other environmental and
physiological factors.
Other genetic variations that have been demonstrated to be associated with depression or response
to therapy include variation in the gene for SSAT—an enzyme responsible for the metabolism of
polyamines (Sequeira et al. 2006)—and genetic variation in CRH (Liu et al. 2007; Papiol et al. 2007)
or glucocorticoid receptors (Binder et al. 2004; Brouwer et al. 2006; van Rossum et al. 2006),
components of the stress response system. These variations may also prove useful in the future for
tailoring pharmacological treatments to individual patients.
Of all other genetic variations, the gene encoding 5 HTT (the serotonin transporter) has been the
most widely studied. Individuals who carry a specific polymorphic variation are genetically
vulnerable to developing depression when exposed to trauma early in life (Caspi et al. 2003;
Kendler et al. 2005). Testing for 5-HTT genetic variation has been used to identify which class of
antidepressants should be used to begin treatment (Smits et al. 2007b). In this study, results were
positive in that when genetic testing was used to predict the best type of antidepressant to
prescribe, 65% of the screened patients were in remission 6 weeks later, compared with 60% of
non–genetically screened patients. Future pretreatment genetic testing must be evaluated on a
wider scale and must also include a cost assessment. Nevertheless, other studies have
demonstrated that such pretreatment genetic screening for the 5-HTT variation may aid inPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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determining a patient’s vulnerability to side effects of pharmacological treatment (Hu et al. 2007;
Smits et al. 2007a).
Somatic Therapies
Five somatic therapies have been investigated to various degrees either as monotherapies or as
adjuvant therapies for treatment-resistant depression: electroconvulsive therapy (ECT), vagus
nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), deep brain
stimulation (DBS), and light therapy. ECT is the best studied of the somatic interventions. It is
clearly one of the treatments of choice for individuals with treatment-resistant depression.
Although the mechanism of action of ECT is still not well understood, it is a safe and efficacious
treatment. In repeated studies, ECT has been found to be more efficacious than placebo (sham ECT)
and more efficacious than pharmacotherapy for treatment-resistant patients. (For a review of ECT
data from the United Kingdom, see UK ECT Review Group 2003.)
VNS was initially developed for the treatment of epilepsy. In 2005 it was approved by the FDA for
use in treatment-resistant depression. The basis of this approval was a study in which patients with
resistant depression who received adjunctive VNS therapy demonstrated statistically significantly
greater improvement in both remission rates and response rates than comparably ill patients who
did not receive VNS therapy (George et al. 2005). One of the key findings to emerge from these
studies of VNS is that its effect may be cumulative and one may not see the full benefit of VNS
stimulation until 9–12 months after treatment is begun (Sackeim et al. 2007; Schlaepfer et al.
2008). The most common side effects of VNS therapy are a voice tremor, cough, dyspnea, and neck
soreness.
rTMS was first identified as a treatment for depression by a group of NIMH researchers (George et
- 1995). Since that time, several smaller studies have supported the finding that rTMS may be an
effective treatment for major depressive disorder (for reviews, see Couturier 2005; George et al
2007). The results of a recent 21-site study that compared rTMS with sham treatment over the left
dorsolateral prefrontal cortex indicated a response rate of 24.5% in the depressed group versus
15.1% in the control group (O’Reardon et al. 2007). These findings led to the recent FDA approval
of rTMS for the treatment of depression.
DBS is an FDA-approved treatment for severe, intractable Parkinson’s disease. It was used in a
small open-label study by Mayberg et al. (2005) in which six patients with intractable
treatment-resistant depression had electrodes implanted in the subgenual cingulate cortex. At
6-month follow-up, four of the six subjects were judged to be treatment responders.
Older literature suggested that phototherapy might be an effective augmentation therapy for
individuals with certain forms of depressive disorders (Kripke 1981; Lewy and Sack 1986). This has
been best studied in patients with seasonal affective disorder. Light therapy for 90 minutes per day
has been able to effectively treat, and also prevent the development of, depressive disorder (Even
et al. 2007; Westrin and Lam 2007). Light boxes are employed by some clinicians to augment
typical antidepressant responses.
In summary, at this time few somatic therapies have demonstrated efficacy for treatment-resistant
depression. Two approaches are FDA approved, ECT and VNS, and at least three other somatic
therapies show potential benefits. It is clear that more work needs to be done investigating somatic
options for patients with treatment-resistant depression.
Alternative Therapies
There is a panoply of alternative therapies that are being investigated both as monotherapies and
in conjunction with more traditional forms of psychotherapy or pharmacotherapy. The best
investigated alternative therapy is exercise. Evidence suggests that exercise performed a minimum
of three times a week, the equivalent of walking 2 miles at a pace of 20 minutes per mile or faster,
is associated with a significant decrease in symptoms of depression. Preliminary work studying the
acute effects of exercise as a monotherapy or as an augmentation strategy suggests that exercisePrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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causes a sustained decrease in depressive mood ratings (Antunes et al. 2005; Osei-Tutu and
Campagna 2005; Trivedi et al. 2006b, 2006c).
Data investigating the efficacy of massage therapy for the treatment of depressive disorders come
mostly from open studies. In these studies, massage seems to decrease measures of depression
and anxiety (Field et al. 1996). Yoga is an alternative therapy that has been investigated in small
studies contrasting yoga with both pharmacotherapy and ECT. In these small acute trials, yoga did
cause a significant decrease in measures of depression (Janakiramaiah et al. 2000; Pilkington et al.
2005) Acupuncture has not yet been demonstrated to have efficacy as an adjuvant therapy or as
monotherapy for major depressive disorder. Both a recent Cochrane analysis and recently published
results of a large sham-controlled study suggest that acupuncture may not be effective as a
treatment for depressive disorders (Allen et al. 2006; Smith and Hay 2005).
Several alternatives to traditional pharmacotherapy show promise. The best studied natural
products are St. John’s wort, S-adenosyl-L-methionine, and omega-3 fatty acids (Conklin et al.
2007; M. Fava et al. 2005; Mischoulon and Fava 2002; Murck et al. 2005; Stahl et al. 2008). At this
time, all three of these treatments show promise and are under investigation in large NIMH-funded
trials.
In summary, although there is burgeoning interest in the use of nontraditional somatic and
pharmacotherapeutic treatments for major depressive disorder, these therapies require
significantly more rigorous investigation.
Psychotherapy for Major Depressive Disorder
Just as our concept of major depressive disorder has evolved over the last few decades, so has our
understanding of the goals of treatment and the length of time required for effective treatment. As
recently as the 1980s and early 1990s, there was a schism between psychotherapists and
practitioners of pharmacotherapy. The field of psychiatry was caught in a miasma of arguments
where disciples argued about the relative merits of psychotherapy versus pharmacotherapy
(American Psychiatric Association 2000b; Elkin et al. 1989; Jacobson and Hollon 1996). Fortunately,
we have made a transition to focus on helping patients attain remission, maintain remission,
restore functioning, and enhance quality of life. Controlled studies have demonstrated that
psychotherapy, pharmacotherapy, and combined treatment all have a valuable role to play in
achieving these goals (Hollon et al. 2005; Keller et al. 2000; Otto et al. 2005).
At this time, practitioners and researchers involved in the study of psychotherapy for major
depressive disorder face a variety of issues. Some of the questions that are currently being
investigated, and for which we do not have definitive answers, are the following:
Are there certain patients who are more responsive to psychotherapy than others? If so, are there
certain patient characteristics that would predict whether an individual would be more responsive to
cognitive-behavioral therapy (CBT) than to some other evidence-based form of psychotherapy such as
interpersonal psychotherapy (IPT)?
What are the attributes of the people who are most likely to benefit from combined therapy?
If combined therapy is used, must both forms of therapy be continued after a response is achieved in
order to sustain the response?
Evidence-based psychotherapies require much greater participation by the patient, homework
assignments, and much more effort than pharmacotherapy. Thus, it is reasonable to ask, are patients
willing to accept psychotherapy?
Another challenge is, how can academic institutions successfully disseminate evidence-based
psychotherapies?
A related challenge is, how can one ensure that therapists are truly adherent to the key principles of
the therapy? It is clear that treatment success, to a significant extent, is based on the fidelity of the
practitioner to the model.
An ever-pressing issue is, will insurers and society adequately compensate individuals to perform these
time-intensive psychotherapies?Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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Cognitive-Behavioral Therapy
CBT comprises a constellation of interventions that target, to varying degrees, maladaptive or
critical thinking and behavioral patterns that are destructive, such as inactivity, avoidance, and
social withdrawal. A great deal of the initial theory and research validating cognitive therapy was
performed by Aaron Beck. He was the first to cogently develop and articulate a cognitive model of
depression, and he employed rigorous observational research techniques to study the efficacy of his
postulated interventions (A. T. Beck et al. 1979). Key to this model is the observation that
depressed individuals have negative mental self-representations of the world, themselves, and
their future. He postulated that these representations negatively biased information processing.
This led him to develop a short-term structured, collaborative, problem-focused, intervention that
involves teaching patients cognitive and behavioral skills to combat depression (A. T. Beck et al.
1979).
One of the key components of CBT is helping patients identify “automatic thoughts”—the negative,
depressogenic cognitions that pervade a depressed individual’s thinking. By monitoring and
recording these thoughts, patients can begin to get a sense of how their thoughts stimulate
unpleasant feelings, sensations, and maladaptive behaviors. This allows a patient to learn to
evaluate both the accuracy and the value of automatic thoughts and create an environment in
which he or she learns to empirically test the accuracy of these thoughts. In the process of doing
so, the patient begins to generate balanced and more adaptive cognitions (e.g., “There are many
things that I do well in my life”). An important aspect of the cognitive model of depression is the
presence of negative self-schemata, that is, feelings of being worthless or helpless (J. S. Beck
1995; Feldman 2007; Jacobson et al. 1996; Kuyken et al. 2007).
The second component of most forms of CBT is the development of behaviorally oriented
interventions to target specific symptoms and to enhance rewarding experiences. Interventions like
behavioral activation can be focused to eliminate target symptoms like inertia or social withdrawal.
Another type of behavioral intervention that is commonly employed in CBT is the teaching of
problem-solving skills. This entails the breaking down of tasks that feel overwhelming into smaller
discrete, manageable goals. An important component of problem-solving skills training is the
development of decision-making skills that help individuals formulate a model for weighing the
pros and cons of a situation (Feldman 2007; Kuyken et al. 2007).
A number of modifications of classical CBT for depression are currently being investigated and are
gaining significant attention. These include the use of behavioral activation as a stand-alone
intervention for depression and the development of therapies that promote psychological
well-being and that target cognitive reactivity (i.e., the tendency to respond to sad moods with
more negative thinking) (Dimidjian et al. 2006). Well-being therapy is based on a theoretical model
by Ryff (1989) that emphasizes the promotion of mental health and not merely the amelioration of
mental illness. Thus, patients engaged in this therapy become aware of periods of well-being and
challenge automatic thoughts and behaviors that interrupt such periods of pleasant emotions (G. A.
Fava 1999). Another form of CBT that has become increasingly popular incorporates
mindfulness-based interventions into CBT. It can be done either in individual settings or as part of
group CBT treatment. This goal of this mindfulness-based approach is to enable patients to become
“decentered” with regard to depressogenic thoughts and see them as mental events rather than as
accurate reflections of their reality or core aspects of themselves (Kabat-Zinn 1990; Segal et al.
2002). A third form of cognitively based psychotherapy that has gained acceptance in the research
community and increasing acceptance in the clinical community is the cognitive-behavioral analysis
system of psychotherapy (CBASP). This was initially designed as a treatment for chronic depression
that targets problematic interpersonal patterns and uses situational analysis to challenge
maladaptive thinking processes (McCullough 2000). One of the key differences between traditional
CBT and CBASP is the integration of concepts of transference reactions into the therapy itself
(Butler et al. 2006).
This has been an exciting decade of development for CBT. Both the theoretical framework andPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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practice of cognitively based therapies continue to be refined and modified by researchers. This
suggests that cognitive-behavioral psychotherapy will play an increasingly important role in the
treatment of depression.
Efficacy of CBT
The overwhelming majority of studies investigating the efficacy of CBT for major depressive
disorder are outpatient studies. (The few inpatient studies that have been performed usually
combined CBT with pharmacotherapy, and the results of these studies are equivocal [de Jong-Meyer
et al. 1996; Hautzinger et al. 1996; Miller et al. 1989a, 1989b].) Meta-analyses suggest that CBT
and medication are equally effective in the acute treatment of major depressive disorder (DeRubeis
et al. 1999). This is a change from the results of an earlier study, which indicated that CBT was as
efficacious as imipramine for treatment of mild and moderate depression but less efficacious for
severe forms of depressive disorder (Elkin et al. 1995). This perception was promulgated by the
initial analyses of the NIMH Treatment of Depression Collaborative Research Program. These
findings were influential in the American Psychiatric Association (2000b) practice guideline
recommendation that pharmacotherapy should be the first-line treatment for more severe
depression.
CBT with either pharmacotherapy or psychotherapy is also effective for the treatment of moderate
to severe depressive disorders, as demonstrated by DeRubeis et al. in a meta-analysis (DeRubeis et
- 1999) and an NIMH-funded clinical trial (DeRubeis et al. 2005). Behavioral activation therapy
also has been found to be comparable to medication for the treatment of moderate to severe
depression (Dimidjian et al. 2006). Data from one continuation study suggest that patients who
receive CBT are more likely to maintain their remission status (with no more than three booster
sessions of CBT during the 12-month continuation phase) than patients who responded to acute
treatment with medication followed by discontinuation of medication (Hollon et al. 2005). Of course
the flaw with many of the early studies is they did not follow the now commonly accepted tenet
that appropriate pharmacotherapy requires sustained pharmacotherapy beyond the acute treatment
period. Recent data from the NIMH-sponsored University of Pennsylvania–Vanderbilt
University–Rush University treatment collaborative show that 1-year relapse rates were equivalent
for individuals treated with CBT with up to three optional booster sessions and those maintained on
medication over 1 year of follow-up (Hollon et al. 2005).
The number of well-performed studies that have combined antidepressant treatments with CBT is
relatively limited. The studies performed to date suggest that there may be a slight advantage for
combined treatment over either treatment alone. One very thoughtful large multisite study
investigated the use of combined treatment consisting of nefazodone plus CBASP (a therapy for
chronic depression that also has elements of IPT) versus CBASP alone or nefazodone alone. In this
study, the effect sizes of combined treatment were significantly greater than the effect sizes of
either treatment alone (Keller et al. 2000). The size of this study allowed the authors to perform
additional analyses to examine whether specific factors might identify those patients best suited for
a specific therapy. Secondary analyses of this data set determined that patients with a history of
childhood trauma responded better to CBASP, either alone or in combination, than to monotherapy
with medication.
Several studies have used some form of CBT either to augment antidepressants’ effects or to
attempt to treat residual symptoms (G. A. Fava et al. 1997; McPherson et al. 2005; Nemeroff et al.
2003). In the STAR*D study, augmentation of citalopram monotherapy with CBT and augmentation
with pharmacological agents produced similar response rates; however, subjects receiving CBT
augmentation tended to respond more slowly than those receiving pharmacological augmentation
(Thase et al. 2007). CBT has also been used by investigators to treat residual symptoms of
depressive disorders (G. A. Fava et al. 2004; Paykel et al. 1999); these studies suggest that adding
CBT is more effective than continuing management with medication alone. Furthermore, follow-up
evaluation of patients suggests that CBT augmentation may decrease the rate of relapse over time.
In summary, the data suggest that CBT is an effective first-line treatment for individuals with majorPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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depressive disorder. Furthermore, CBT may have an important role in facilitating remission for
those who have residual symptoms of depression after adequate pharmacotherapy. Intriguing
preliminary data suggest that CBT may play a powerful role in decreasing the risk of a relapse or
recurrence of major depressive disorder. However, more research is needed.
Interpersonal Psychotherapy
IPT is a brief form of individual psychotherapy that focuses on one of four problem areas during
acute treatment: grief, role transitions, role disputes, and interpersonal deficits. Acute therapy is
tailored to the patient’s specific presenting problems. IPT has been demonstrated to be an
efficacious acute treatment both for outpatients and, more recently, for inpatients with major
depressive disorder (Frank et al. 1990, 1991a; Luty et al. 2007; Reynolds et al. 1999; Schramm et
- 2007). The majority of studies investigating IPT as a monotherapy have been performed with
outpatients. These studies demonstrated that IPT is an efficacious treatment for individuals with
recurrent depressive disorder, older individuals with depression, and women with major depressive
disorder (Frank et al. 1990, 1991a; Luty et al. 2007; Reynolds et al. 1999). A study of inpatients
with either major depressive disorder or bipolar II disorder (in the depressed phase of their illness)
reported that the combination of 5 weeks of intensive IPT plus medication was more efficacious
than medication and treatment as usual (Schramm et al. 2007). The group receiving combined
therapy with IPT was more likely to sustain response and remission at 3-month follow-up than
individuals in the medication management group without IPT. However, at 1-year follow-up, the
two groups had comparable relapse rates (Schramm et al. 2007).
Ellen Frank and colleagues have been responsible for some of the most thoughtful work
investigating the efficacy of IPT as a monotherapy, in combination with pharmacotherapy, and,
most recently, as a maintenance therapy. The focus of maintenance IPT is broader than the focus of
acute therapy because the goal is to prevent recurrence and to consolidate the gains made in
therapy by augmenting the competencies and strengths achieved during acute IPT. Thus, the focus
of maintenance IPT is to reinforce skills in coping with interpersonal life events in the four
traditionally identified problem areas (grief, role transitions, role disputes, and interpersonal
deficits). In a recent study designed to assess the treatment frequency necessary to prevent
relapse into depression, Frank et al. (2007) reported that monthly booster sessions were as
efficacious as twice-a-month booster sessions in preventing relapse for women who had been
responsive to acute IPT as a monotherapy. However, maintenance IPT monotherapy was not
efficacious as a relapse prevention technique for women who had initially required
pharmacotherapy combined with IPT to achieve remission.
In conclusion, the data are clear that both CBT and IPT can be efficacious as monotherapies for the
treatment of major depressive disorder. Growing data suggest that these psychotherapies may be
effective not only in the acute treatment of depression but also in the maintenance treatment of
depressive disorders. However, we are still not sure how to match the therapy to a specific patient.
There is some indication that patients with avoidant or more passive personality styles may be less
successfully treated with IPT than with CBT (Joyce et al. 2007). However, crucial issues limit the
effectiveness of both of these psychotherapies: patient acceptance (Thase et al. 2007; Wisniewski
et al. 2007), therapist training and fidelity to the techniques (Shaw et al. 1999), and public policy
that limits reimbursement. Until we have dealt with these challenges, the dissemination and
acceptance of evidence-based psychotherapies will be relatively limited.
TREATMENT APPROACHES
Acute Treatment
The goal of acute treatment of an individual with major depressive disorder is to identify a
medication or psychotherapy that is effective and treat the individual vigorously enough to help him
or her achieve remission. Recently, most of our understanding of acute treatment has been derived
from Phase II and Phase III industry-sponsored studies of antidepressants. Many of these
short-term studies were designed to differentiate an investigational compound from placebo. ThePrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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goal of these trials was not to achieve disease remission but rather to demonstrate that the
investigational compound was more efficacious than a placebo compound.
For many years, researchers have looked at the concept of response, defined as a 50% drop from
baseline ratings of depression, as an indicator of an appropriate acute treatment trial. In most of
these short-term studies, active treatment with psychotherapy, pharmacotherapy, or combined
treatment was associated with a 60%–70% rate of response. However, it is now believed that
remission rather than merely response is the appropriate goal for acute treatment (M. Fava et al.
2003). The majority of studies reporting remission rates have been short-term industry-sponsored
trials that involved garden-variety depressive disorders and showed that approximately one-third
of individuals achieve remission within 6–10 weeks of treatment. This finding was corroborated by
the recent reports from the STAR*D study (Rush et al. 2006b), which showed that approximately
36% of patients achieved remission (as defined by QIDS-SR) with aggressive and vigorous
treatment with citalopram.
The major question that has plagued the field of psychiatry has been what to do after an initial
treatment intervention is not successful in achieving remission. The STAR*D study is the first
large-scale investigation of mood disorders that has systematically attempted to answer this and
other key questions. Patients who did not respond to treatment with citalopram were offered the
option of allowing the physician to determine the next treatment, switching to another medication
or to CBT monotherapy, or augmenting citalopram with psychotherapy or CBT (Rush et al. 2004).
The majority of patients wanted to control their treatment course and elected to either switch
medications or join the augmentation group (Wisniewski et al. 2007). Patients who chose the
switch option were randomly assigned to receive either sustained-release bupropion, sertraline, or
extended-release venlafaxine. In this study, it did not matter whether a patient was switched to a
medication within the same class as the one that he or she was receiving previously (SSRIs) or to a
medication with a different mechanism of action: all response rates were approximately 30% (Rush
et al. 2006c).
In the medication arm of the augmentation group, individuals treated with citalopram had either
bupropion or buspirone used as the augmenting agent. Again, the remission rates were essentially
equivalent regardless of the agent used and were approximately 30% (Trivedi et al. 2006a). In the
next level of the treatment algorithm (level 3), patients who did not meet remission criteria, and
were willing to continue, again had the opportunity to switch medications, this time to either
mirtazapine or nortriptyline, or to augment citalopram with lithium or triiodothyronine. The
remission rates at this level ended up being approximately 13% no matter which treatment
strategy was chosen. Individuals who still did not meet remission criteria, and who were willing to
continue to participate in the study, were randomly assigned to receive either tranylcypromine or
mirtazapine plus extended-release venlafaxine (level 4). By this time, the study, which had initially
enrolled over 3,000 patients, had less than 100 patients in each arm of the trial. Remission rates for
patients participating in this fourth step of the trial were approximately 13%. Thus, for individuals
who were willing to participate through all four steps of the treatment algorithm used in the
STAR*D study, the overall accumulative rate was 67% (Rush et al. 2006b).
The STAR*D study represents a significant advance in our knowledge about the acute treatment of
major depressive disorder. Its strengths include the fact that it recruited subjects from both
primary care and specialty clinics who were seeking treatment for major depressive disorder.
Another strength of this study is the fact that there were few exclusion criteria, so this represented
a real clinical sample. An acknowledged challenge faced by the investigators was the fact that it
was not possible to truly perform a double-blind, placebo-controlled study. This study begins to
answer some very important questions. The results from the study suggest that a switch in
medication provides essentially the same remission rate as augmentation therapy. This has
important clinical implications for patients, particularly as more and more medications become
generic. A second important observation of this study is that a switch within a class of
antidepressants was as efficacious as a switch between classes of agents. For many individuals,
this seems counterintuitive; however, it may reflect the heterogeneity of depressive disorders orPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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the fact that medications, even within the same class, have subtle but possibly important
pharmacodynamic and pharmacokinetic differences. A third important finding in this study is that
as patients progressed further through the algorithm for treatment resistance, remission rates
declined. This suggests that we need a wider array of treatment options than those studied in the
STAR*D study to maximize the likelihood of remission.
Two interesting papers have come out as part of the second wave of STAR*D publications. The first
covers the part of the study that investigated the efficacy of CBT for patients who did not respond
initially to citalopram. Regardless of whether subjects switched to CBT alone or used it as an
augmentation strategy, approximately 30% of individuals attained remission. These individuals
generally took longer to reach remission than those who had opted for medication as either a
switch from or augmentation to citalopram (Thase et al. 2007).
The second recently published STAR*D paper reported 12-month follow-up data (Rush et al.
2006b). The three major findings were as follows:
Individuals who did not attain remission were very likely to relapse into an episode of major depressive
disorder within 6 months.
Even when individuals did achieve remission, two-thirds of those who met remission criteria acutely
experienced a significant exacerbation of symptoms over the next 6 months.
The patients most likely to have an exacerbation were those who required multiple treatment attempts
in order to reach remission (i.e., those entering levels 3 and 4 of the STAR*D algorithm).
The STAR*D study is a good first step toward the systematic approach of investigating treatment
options for patients who are nonresponsive to an initial antidepressant therapy. There are, of
course, many treatment options that were not selected to be part of this trial. They include
augmentation with dopamine agonists (amantadine, pergolide, ropinirole, and pramipexole),
psychostimulants (methylphenidate, dextroamphetamine, and modafinil), and natural products.
Most of these agents have been used primarily in small or uncontrolled studies. The largest body of
evidence suggesting efficacy is from studies with the atypical antipsychotic medications. A recent
meta-analysis of 10 randomized, double-blind, controlled trials demonstrated superior response
and remission rates for atypical antipsychotic medication augmentation of FDA-approved
antidepressants versus placebo augmentation (Papakostas et al. 2007). Aripiprazole has received
FDA approval as an augmenting agent in patients who do not respond to SSRI or
serotonin–norepinephrine reuptake inhibitor (SNRI) monotherapy. In general, more rigorous
large-scale studies of these atypical antipsychotic agents are warranted.
In conclusion, only 30% of clinical patients vigorously respond to the first treatment approach tried
during the acute phase of treatment. After an initial intervention has failed, it is important to
carefully reassess the patient. It is important to reconfirm the diagnosis of major depressive
disorder to assure oneself that all potential comorbidities have been identified and that one has
taken a careful trauma history. In particular, subsyndromal forms of posttraumatic stress disorder
and occult problems with alcohol and substance use disorders frequently confound the initial
treatment of an episode of depression. It is also important to ensure that the patient is truly
medically stable because neoplasms, vitamin deficiencies, and even certain infections and
dementing disorders may initially masquerade as a depressive disorder. Another important variable
to consider is the patient’s commitment to getting well. Is the patient truly compliant with the
proposed treatment measurement, be it psychotherapy or pharmacotherapy? When the physician is
assured that the course has not been complicated by any of the above-mentioned confounding
factors, it is reasonable to pursue an alternative approach to treatment. It is fortunate that with
recently published data from the STAR*D study, we now have a stronger foundation for selecting
second- and third-line treatment options for a patient whose depression is resistant to the initial
treatment approach.
Continuation Treatment
The understanding for the need for continuation treatment evolved out of the series of consensusPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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meetings sponsored by the MacArthur Foundation that were held to review the data about the
course and treatment options for major depressive disorder. These meetings led to a series of
papers suggesting that major depressive disorder is not a time-limited event for many people but
rather a chronic and continuous syndrome that requires more than acute treatment (Frank et al.
1991b; Kupfer 1991). The goals of the continuation treatment phase include the following:
- The prevention of relapse into an episode of major depressive disorder
- A consolidation of gains made during acute treatment in terms of symptom reduction
- The enhancement of quality of life and functioning of the patient
The need for continuation therapy has been documented in hundreds of trials investigating therapy
after acute treatment. Thase (1999) estimated that the risk of relapse is at least 50% when
pharmacotherapy is discontinued after acute treatment. Although there is no consensus about the
time required for continuation treatment, most investigators and clinicians consider between 4 and
9 months of treatment, at the same intensity used in acute treatment, to be a minimal length of
time for continuation therapy (Melfi et al. 1998).
Some interesting data suggest that combined therapy may facilitate continued remission;
specifically, the combination of psychotherapy and pharmacotherapy may be beneficial (G. A. Fava
et al. 1994). At this time, two studies have investigated the need to continue an augmentation
therapy that was initially beneficial. Rapaport et al. (2006) studied the value of continuation
therapy with risperidone added to antidepressant monotherapy for patients who were resistant to
monotherapy but who entered remission with augmentation therapy. In this study, the relapse
rates were identical for individuals randomly assigned to continue receiving antidepressants plus
augmentation therapy versus those who received antidepressants plus a placebo. Bauer et al.
(2000) investigated the value of continued lithium augmentation in patients with resistant
depression and reported that continuation therapy with lithium decreased the relapse rate more
than placebo augmentation.
Currently, we have more questions than answers about the best approach to treatment during the
continuation phase. We do not yet know the appropriate length of time for continuation treatment,
nor do we know what the best strategies are if a patient’s condition begins to worsen during
continuation treatment. However, it is clear that continuation treatment benefits patients by
protecting against recurrence of the initial episode of depression and by allowing a consolidation of
gains that impact not only symptom control but also quality of life and functioning.
Maintenance Treatment
A growing body of literature suggests that many individuals with major depressive disorder, a
chronic and recurrent illness, require maintenance treatment. At this time, we are unable to
biologically predict who will require maintenance or lifelong therapy. However, a series of risk
factors have emerged indicating which patients may require maintenance therapy; they include the
following:
- A lifetime history of three or more episodes of major depressive disorder
- The presence of double depression
- At least two severe episodes of major depressive disorder within the past 5 years
- Depressive disorders that are complicated by comorbid substance use or anxiety disorders
- An age greater than 60 years at the onset of major depressive disorder
Most of these predictors come from longitudinal data gleaned from the NIMH Collaborative
Depression Study (Keller and Berndt 2002).
The largest body of data about the value of maintenance therapy has come from two large studies
that were performed at the University of Pittsburgh. The first study, by Frank et al. (1990),
investigated the efficacy of maintenance with pharmacotherapy, psychotherapy, and combined
therapy for adults who had had three or more episodes of major depressive disorder. In this study,
the pharmacotherapies, both alone and in combination with ITP, were more successful than ITPPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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alone or placebo. A second analysis from this study (Kupfer et al. 1992) demonstrated that
individuals maintained the response to pharmacotherapy when the dosage was kept at the same
level used during the acute treatment phase, and attempts to decrease the medication level by 50%
led to relapse into major depressive disorder. Reynolds et al. (1999) published the results of a
study with a very similar design, with elderly patients with recurrent major depressive disorder. In
this study, both pharmacotherapy and psychotherapy maintenance therapies were efficacious in
preventing a new episode of depression. There also have been interesting studies investigating the
efficacy of fluoxetine, paroxetine, and extended-release venlafaxine as maintenance therapies.
These studies also suggest that maintenance therapy is valuable for people with major depressive
disorder (Dombrovski et al. 2007; Keller et al. 2007a, 2007b).
As is the case with continuation therapy, there are many unanswered questions regarding
maintenance therapy. At this time, no studies have demonstrated what techniques to use if an
individual’s condition worsens during maintenance therapy. Another question is whether there are
certain individuals who might not require lifelong maintenance therapy. A theoretical issue is the
concept that medication may “poop out” and become less effective over time (Zimmerman and
Thongy 2007). Although it is clear that some patients lapse into a new episode of depression
despite the use of maintenance medication, it is not at all clear what the reasons for relapse are. To
date, no careful studies have investigated the role of depressive disorders’ progression and the
need to alter pharmacotherapies. Just as individuals with hypertension, myocardial disease, or
diabetes frequently need to have their treatment modified over a period of time, patients with
major depressive disorder may need modifications over the course of treatment. We do not know
whether this represents a lack of effectiveness of existing pharmacotherapies or the interaction of
the aging body with progression of a diseased state.
In summary, although it is clear that maintenance therapy for depression is beneficial to our
patients and their families, a great deal more investigation is needed about the necessary length of
treatment, what to do when someone’s condition worsens, and the underlying biology of the illness
and the patient’s response to therapy.
CONCLUSION
Over the past decade we have seen remarkable advances in our knowledge about the etiology,
pathophysiology, and course of major depressive disorder and the prognosis for patients. The
general consensus is that most people with major depressive disorder have a chronic lifelong
condition that will wax and wane over time. An increasing body of evidence supports the postulate
that some people with major depressive disorder have a disease that varies in presentation and
symptom severity after the initial episode. Many people seem to traverse between having a
full-blown episode of major depressive disorder and experiencing residual symptoms of depression,
euthymia, minor depression, or new depressive symptoms. If the current evidence is correct, it
suggests that our treatment approaches must be broadened to take into account both the chronic
nature of the illness and its varied presentation. The implications for treatment are twofold: 1) we
need to treat people until they achieve complete remission, and 2) we need to consider
continuation and maintenance treatment for far more people than we have previously.
Although the field has made significant progress with information from the STAR*D trial, there are
many important unanswered questions. We have limited data about the persistence of remission
even after vigorous acute treatment. Only one study has investigated the need for continuation
augmentation therapy, and that study suggested that it was not of significant value (Rapaport et al.
2006). No studies have addressed how patients whose condition worsens during continuation or
maintenance therapy should be managed. However, the future is bright because of advances in
basic biological investigations of depression. Imaging data are beginning to clearly define specific
brain regions that seem to be altered in certain individuals with major depressive disorder.
Preclinical studies are elucidating the roles of the function of a variety of neurotransmitter and
neurohormonal systems in the pathogenesis of depression, including the noradrenergic system, the
serotonergic system, the HPA axis, the immune system, and the NMDA system. Thus, with advancesPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
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in preclinical animal models, clinical research, and genetics, we will begin to identify specific
disorders that fall within the current rubric of major depressive disorder. This biologically informed
approach to treatment will allow us to develop better and more personalized treatment plans.
REFERENCES
Adams F, Quesada JR, Gutterman JU: Neuropsychiatric manifestations of human leukocyte
interferon therapy in patients with cancer. JAMA 252:938–941, 1984 [PubMed]
Akiskal HS, Judd LL, Gillin JC, et al: Subthreshold depressions: clinical and polysomnographic
validation of dysthymic, residual and masked forms. J Affect Disord 45:53–63, 1997 [PubMed]
Allen JJ, Schnyer RN, Chambers AS, et al: Acupuncture for depression: a randomized controlled
trial. J Clin Psychiatry 67:1665–1673, 2006 [PubMed]
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd
Edition. Washington, DC, American Psychiatric Association, 1980
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th
Edition. Washington, DC, American Psychiatric Association, 1994
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th
Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000a
American Psychiatric Association: Practice guideline for the treatment of patients with major
depressive disorder (revision). Am J Psychiatry 157 (4 suppl):1–45, 2000b
Amsterdam JD, Maislin G, Winokur A, et al: The oCRH stimulation test before and after clinical
recovery from depression. J Affect Disord 14:213–222, 1988 [PubMed]
Angst F, Stassen HH, Clayton PJ, et al: Mortality of patients with mood disorders: follow-up over
34–38 years. J Affect Disord 68:167–181, 2002 [PubMed]
Angst J, Angst F, Gerber-Werder R, et al: Suicide in 406 mood-disorder patients with and without
long-term medication: a 40 to 44 years’ follow-up. Arch Suicide Res 9:279–300, 2005 [PubMed]
Antunes HK, Stella SG, Santos RF, et al: Depression, anxiety and quality of life scores in seniors
after an endurance exercise program. Rev Bras Psiquiatr 27:266–271, 2005 [PubMed]
Arana GW, Baldessarini RJ, Ornsteen M: The dexamethasone suppression test for diagnosis and
prognosis in psychiatry: commentary and review. Arch Gen Psychiatry 42:1193–1204, 1985
[PubMed]
Beck AT, Beamesderfer A: Assessment of depression: the depression inventory. Mod Probl
Pharmacopsychiatry 7:151–169, 1974 [PubMed]
Beck AT, Rush AJ, Shaw BF, et al: Cognitive Therapy of Depression. New York, Guilford, 1979
Beck JS: Cognitive Therapy: Basics and Beyond. New York, Guilford, 1995
Beekman AT, Deeg DJ, Braam AW, et al: Consequences of major and minor depression in later life: a
study of disability, well-being and service utilization. Psychol Med 27:1397–1409, 1997 [PubMed]
Beekman AT, Geerlings SW, Deeg DJ, et al: The natural history of late-life depression: a 6-year
prospective study in the community. Arch Gen Psychiatry 59:605–611, 2002 [PubMed]
Binder EB, Salyakina D, Lichtner P, et al: Polymorphisms in FKBP5 are associated with increased
recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet
36:1319–1325, 2004 [PubMed]
Borgstrom S, von Eyben FE, Flodgren P, et al: Human leukocyte interferon and cimetidine for
metastatic melanoma. N Engl J Med 307:1080–1081, 1982 [PubMed]
Bremne JD, Vermetten E: Stress and development: behavioral and biological consequences. Dev
Psychopathol 13:473–489, 2001 [PubMed]Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
30 of 41
10/05/2009 16:33
Brouwer JP, Appelhof BC, van Rossum EF, et al: Prediction of treatment response by HPA-axis and
glucocorticoid receptor polymorphisms in major depression. Psychoneuroendocrinology
31:1154–1163, 2006 [PubMed]
Brown WA, Shuey I: Response to dexamethasone and subtype of depression. Arch Gen Psychiatry
37:747–751, 1980 [PubMed]
Bump GM, Mulsant BH, Pollock BG, et al: Paroxetine versus nortriptyline in the continuation and
maintenance treatment of depression in the elderly. Depress Anxiety 13:38–44, 2001 [PubMed]
Burt VK, Stein K: Epidemiology of depression throughout the female life cycle. J Clin Psychiatry 63
(suppl 7):9–15, 2002
Butler AC, Chapman JE, Forman EM, et al: The empirical status of cognitive-behavioral therapy: a
review of meta-analyses. Clin Psychol Rev 26:17–31, 2006 [PubMed]
Campbell S, Marriott M, Nahmias C, et al: Lower hippocampal volume in patients suffering from
depression: a meta-analysis. Am J Psychiatry 161:598–607, 2004 [Full Text] [PubMed]
Cannon DS, Tiffany ST, Coon H, et al: The PHQ-9 as a brief assessment of lifetime major depression.
Psychol Assess 19:247–251, 2007 [PubMed]
Capuron L, Gumnick JF, Musselman DL, et al: Neurobehavioral effects of interferon-alpha in cancer
patients: phenomenology and paroxetine responsiveness of symptom dimensions.
Neuropsychopharmacology 26:643–652, 2002 [PubMed]
Carroll BJ: The dexamethasone suppression test for melancholia. Br J Psychiatry 140:292–304,
1982 [PubMed]
Carroll BJ, Fielding JM, Blashki TG: Depression rating scales: a critical review. Arch Gen Psychiatry
28:361–366, 1973 [PubMed]
Caspi A, Sugden K, Moffitt TE, et al: Influence of life stress on depression: moderation by a
polymorphism in the 5-HTT gene. Science 301:386–389, 2003 [PubMed]
Cervilla JA, Molina E, Rivera M, et al: The risk for depression conferred by stressful life events is
modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish
PREDICT-Gene cohort. Mol Psychiatry 12:748–755, 2007 [PubMed]
Clayton P, Auster T: Strategies for the prevention and treatment of suicidal behavior. Focus
6:15–21, 2008
Conklin SM, Manuck SB, Yao JK, et al: High omega-6 and low omega-3 fatty acids are associated
with depressive symptoms and neuroticism. Psychosom Med 69:932–934, 2007 [PubMed]
Coppen A, Abou-Saleh M, Milln P, et al: Dexamethasone suppression test in depression and other
psychiatric illness. Br J Psychiatry 142:498–504, 1983 [PubMed]
Couturier JL: Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of
depression: a systematic review and meta-analysis. J Psychiatry Neurosci 30:83–90, 2005
[PubMed]
Cuijpers P, de Graaf R, van Dorsselaer S: Minor depression: risk profiles, functional disability, health
care use and risk of developing major depression. J Affect Disord 79:71–79, 2004 [PubMed]
de Jong-Meyer R, Hautzinger M, Rudolf GAE, et al: The effectiveness of antidepressants and
cognitive-behavioral therapy combined in patients with endogenous depression: results of analyses
of variance regarding main and secondary outcome criteria [in German]. Z Klin Psychol 25:93–109,
1996
Delgado PL, Charney DS, Price LH, et al: Serotonin function and the mechanism of antidepressant
action: reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch
Gen Psychiatry 47:411–418, 1990 [PubMed]Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
31 of 41
10/05/2009 16:33
DeRubeis RJ, Gelfand LA, Tang TZ, et al: Medications versus cognitive behavior therapy for severely
depressed outpatients: mega-analysis of four randomized comparisons. Am J Psychiatry
156:1007–1013, 1999 [Full Text] [PubMed]
DeRubeis RJ, Hollon SD, Amsterdam JD, et al: Cognitive therapy vs medications in the treatment of
moderate to severe depression. Arch Gen Psychiatry 62:409–416, 2005 [PubMed]
Dimidjian S, Hollon SD, Dobson KS, et al: Randomized trial of behavioral activation, cognitive
therapy, and antidepressant medication in the acute treatment of adults with major depression. J
Consult Clin Psychol 74:658–670, 2006 [PubMed]
Dombrovski AY, Lenze EJ, Dew MA, et al: Maintenance treatment for old-age depression preserves
health-related quality of life: a randomized, controlled trial of paroxetine and interpersonal
psychotherapy. J Am Geriatr Soc 55:1325–1332, 2007 [PubMed]
Drago S, Bergerone S, Anselmino M, et al: Depression in patients with acute myocardial infarction:
influence on autonomic nervous system and prognostic role: results of a five-year follow-up study.
Int J Cardiol 115:46–51, 2007 [PubMed]
Duman RS: Depression: a case of neuronal life and death? Biol Psychiatry 56:140–145, 2004
[PubMed]
Elkin I, Gibbons RD, Shea MT, et al: Initial severity and differential treatment outcome in the
National Institute of Mental Health Treatment of Depression Collaborative Research Program. J
Consult Clin Psychol 63:841–847, 1995 [PubMed]
Elkin I, Shea MT, Watkins JT, et al: National Institute of Mental Health Treatment of Depression
Collaborative Research Program: general effectiveness of treatments. Arch Gen Psychiatry
46:971–982; discussion 983, 1989
Elovainio M, Jokela M, Kivimaki M, et al: Genetic variants in the DRD2 gene moderate the
relationship between stressful life events and depressive symptoms in adults: cardiovascular risk in
young Finns study. Psychosom Med 69:391–395, 2007 [PubMed]
Endicott J, Nee J: Endicott Work Productivity Scale (EWPS): a new measure to assess treatment
effects. Psychopharmacol Bull 33:13–16, 1997 [PubMed]
Endicott J, Nee J, Harrison W, et al: Quality of Life Enjoyment and Satisfaction Questionnaire: a new
measure. Psychopharmacol Bull 29:321–326, 1993 [PubMed]
Even C, Schröder CM, Friedman S, et al: Efficacy of light therapy in nonseasonal depression: a
systematic review. J Affect Disord 108:11–23, 2007 [PubMed]
Fava GA: Well-being therapy: conceptual and technical issues. Psychother Psychosom 68:171–179,
1999 [PubMed]
Fava GA, Grandi S, Zielezny M, et al: Cognitive behavioral treatment of residual symptoms in
primary major depressive disorder. Am J Psychiatry 151:1295–1299, 1994 [Full Text] [PubMed]
Fava GA, Savron G, Grandi S, et al: Cognitive-behavioral management of drug-resistant major
depressive disorder. J Clin Psychiatry 58:278–282; quiz 283–284, 1997
Fava GA, Ruini C, Rafanelli C, et al: Six-year outcome of cognitive behavior therapy for prevention
of recurrent depression. Am J Psychiatry 161:1872–1876, 2004 [Full Text] [PubMed]
Fava M, Rush AJ, Trivedi MH, et al: Background and rationale for the sequenced treatment
alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am 26:457–494, 2003
[PubMed]
Fava M, Alpert J, Nierenberg AA, et al: A double-blind, randomized trial of St John’s wort,
fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol 25:441–447, 2005
[PubMed]Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
32 of 41
10/05/2009 16:33
Feldman G: Cognitive and behavioral therapies for depression: overview, new directions, and
practical recommendations for dissemination. Psychiatr Clin North Am 30:39–50, 2007 [PubMed]
Fergusson DM, Horwood LJ, Ridder EM, et al: Subthreshold depression in adolescence and mental
health outcomes in adulthood. Arch Gen Psychiatry 62:66–72, 2005 [PubMed]
Field T, Ironson G, Scafidi F, et al: Massage therapy reduces anxiety and enhances EEG pattern of
alertness and math computations. Int J Neurosci 86:197–205, 1996 [PubMed]
Fogel J, Eaton WW, Ford DE: Minor depression as a predictor of the first onset of major depressive
disorder over a 15-year follow-up. Acta Psychiatr Scand 113:36–43, 2006 [PubMed]
Frank E, Kupfer DJ, Perel JM, et al: Three-year outcomes for maintenance therapies in recurrent
depression. Arch Gen Psychiatry 47:1093–1099, 1990 [PubMed]
Frank E, Kupfer DJ, Wagner EF, et al: Efficacy of interpersonal psychotherapy as a maintenance
treatment of recurrent depression: contributing factors. Arch Gen Psychiatry 48:1053–1059, 1991a
Frank E, Prien RF, Jarrett RB, et al: Conceptualization and rationale for consensus definitions of
terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen
Psychiatry 48:851–855, 1991b
Frank E, Kupfer DJ, Buysse DJ, et al: Randomized trial of weekly, twice-monthly, and monthly
interpersonal psychotherapy as maintenance treatment for women with recurrent depression. Am J
Psychiatry 164:761–767, 2007 [Full Text] [PubMed]
Freis ED: Mental depression in hypertensive patients treated for long periods with large doses of
reserpine. N Engl J Med 251:1006–1008, 1954 [PubMed]
George MS, Wassermann EM, Williams W A, et al: Daily repetitive transcranial magnetic stimulation
(rTMS) improves mood in depression. Neuroreport 6:1853–1856, 1995 [PubMed]
George MS, Rush AJ, Marangell LB, et al: A one-year comparison of vagus nerve stimulation with
treatment as usual for treatment-resistant depression. Biol Psychiatry 58:364–373, 2005 [PubMed]
George MS, Nahas Z, Borckardt JJ, et al: Brain stimulation for the treatment of psychiatric
disorders. Curr Opin Psychiatry 20:250–254; discussion 247–249, 2007
Gertsik L, Poland RE: Psychoneuroendocrinology, in Textbook of Psychopharmacology. Edited by
Schatzberg A, Nemeroff CB. Washington, DC, American Psychiatric Press, 2004, pp 115–129
Gibbons JL, McHugh PR: Plasma cortisol in depressive illness. J Psychiatr Res 1:162–171, 1962
[PubMed]
Gibbons RD, Hur K, Bhaumik DK, et al: The relationship between antidepressant medication use and
rate of suicide. Arch Gen Psychiatry 62:165–172, 2005 [PubMed]
Gillespie CF, Nemeroff CB: Hypercortisolemia and depression. Psychosom Med 67 (suppl
1):S26–S28, 2005
Ginsberg DL, Schooler NR, Buckley PF, et al: Optimizing treatment of schizophrenia: enhancing
affective/cognitive and depressive functioning. CNS Spectr 10:1–13; discussion 14–15, 2005
Gispen-de Wied CC, Kok FW, Koppeschaar HP, et al: Stimulation of the pituitary-adrenal system
with graded doses of CRH and low dose vasopressin infusion in depressed patients and healthy
subjects: a pilot study. Eur Neuropsychopharmacol 3:533–541, 1993
Glassman AH, Shapiro PA: Depression and the course of coronary artery disease. Am J Psychiatry
155:4–11, 1998 [Full Text] [PubMed]
Gold PW, Loriaux DL, Roy A, et al: Responses to corticotropin-releasing hormone in the
hypercortisolism of depression and Cushing’s disease: pathophysiologic and diagnostic implications.
N Engl J Med 314:1329–1335, 1986 [PubMed]Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
33 of 41
10/05/2009 16:33
Goldapple K, Segal Z, Garson C, et al: Modulation of cortical-limbic pathways in major depression:
treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry 61:34–41, 2004
[PubMed]
Goldney RD, Fisher LJ, Dal Grande E, et al: Subsyndromal depression: prevalence, use of health
services and quality of life in an Australian population. Soc Psychiatry Psychiatr Epidemiol
39:293–298, 2004 [PubMed]
Guy W: ECDEU assessment manual for psychopharmacology. Rockville, MD, U.S. Department of
Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health
Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division
of Extramural Research Programs, 1976
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62, 1960 [PubMed]
Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol
6:278–296, 1967 [PubMed]
Harris PA: The impact of age, gender, race, and ethnicity on the diagnosis and treatment of
depression. J Manag Care Pharm 10 (2 suppl):S2–S7, 2004
Hasin DS, Goodwin RD, Stinson FS, et al: Epidemiology of major depressive disorder: results from
the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry
62:1097–1106, 2005 [PubMed]
Hautzinger M, de Jong-Meyer R, Treiber R, et al: Efficacy of cognitive behavior therapy,
pharmacotherapy, and the combination of both in non-melancholic, unipolar depression [in
German]. Z Klin Psychol 25:130–145, 1996
Heim C, Newport DJ, Heit S, et al: Pituitary-adrenal and autonomic responses to stress in women
after sexual and physical abuse in childhood. JAMA 284:592–597, 2000 [PubMed]
Helmer C, Montagnier D, Pérès K: Descriptive epidemiology and risk factors of depression in the
elderly [in French]. Psychol Neuropsychiatr Vieil 2 (suppl 1):S7–S12, 2004
Henriksson S, Isacsson G: Increased antidepressant use and fewer suicides in Jämtland county,
Sweden, after a primary care educational programme on the treatment of depression. Acta
Psychiatr Scand 114:159–167, 2006 [PubMed]
Hermens ML, van Hout HP, Terluin B, et al: The prognosis of minor depression in the general
population: a systematic review. Gen Hosp Psychiatry 26:453–462, 2004 [PubMed]
Hirschfeld RM: The comorbidity of major depression and anxiety disorders: recognition and
management in primary care. Prim Care Companion J Clin Psychiatry 3:244–254, 2001 [PubMed]
Hirschfeld RM, Klerman GL, Clayton PJ, et al: Personality and depression: empirical findings. Arch
Gen Psychiatry 40:993–998, 1983 [PubMed]
Hollon SD, DeRubeis RJ, Shelton RC, et al: Prevention of relapse following cognitive therapy vs
medications in moderate to severe depression. Arch Gen Psychiatry 62:417–422, 2005 [PubMed]
Holsboer F: Neuroendocrinology of mood disorders, in Psychopharmacology: The Fourth Generation
of Progress. Edited by Bloom FE, Kupfer DJ. New York, Raven, 1995, pp 957–971
Holsboer F: The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology
23:477–501, 2000 [PubMed]
Horowitz A, Reinhardt JP, Kennedy GJ: Major and subthreshold depression among older adults
seeking vision rehabilitation services. Am J Geriatr Psychiatry 13:180–187, 2005 [PubMed]
Howland RH, Schettler PJ, Rapaport MH, et al: Clinical features and functioning of patients with
minor depression. Psychother Psychosom 77:384–389, 2008 [PubMed]
Hu XZ, Rush AJ, Charney D, et al: Association between a functional serotonin transporter promoterPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
34 of 41
10/05/2009 16:33
polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen
Psychiatry 64:783–792, 2007 [PubMed]
Hunt SM, McKenna SP: The QLDS: a scale for the measurement of quality of life in depression.
Health Policy 22:307–319, 1992 [PubMed]
Jacobson NS, Hollon SD: Cognitive-behavior therapy versus pharmacotherapy: now that the jury’s
returned its verdict, it’s time to present the rest of the evidence. J Consult Clin Psychol 64:74–80,
1996 [PubMed]
Jacobson NS, Dobson KS, Truax PA, et al: A component analysis of cognitive-behavioral treatment
for depression. J Consult Clin Psychol 64:295–304, 1996 [PubMed]
Janakiramaiah N, Gangadhar BN, Naga Venkatesha Murthy PJ, et al: Antidepressant efficacy of
Sudarshan Kriya Yoga (SKY) in melancholia: a randomized comparison with electroconvulsive
therapy (ECT) and imipramine. J Affect Disord 57:255–259, 2000 [PubMed]
Joffe H, Hall JE, Soares CN, et al: Vasomotor symptoms are associated with depression in
perimenopausal women seeking primary care. Menopause 9:392–398, 2002 [PubMed]
Joyce PR, McKenzie JM, Carter JD, et al: Temperament, character and personality disorders as
predictors of response to interpersonal psychotherapy and cognitive-behavioural therapy for
depression. Br J Psychiatry 190:503–508, 2007 [PubMed]
Judd LL, Akiskal HS: Delineating the longitudinal structure of depressive illness: beyond clinical
subtypes and duration thresholds. Pharmacopsychiatry 33:3–7, 2000 [PubMed]
Judd LL, Akiskal HS: The clinical and public health relevance of current research on subthreshold
depressive symptoms to elderly patients. Am J Geriatr Psychiatry 10:233–238, 2002 [PubMed]
Judd LL, Rapaport MH, Paulus MP, et al: Subsyndromal symptomatic depression: a new mood
disorder? J Clin Psychiatry 55 (suppl):18–28, 1994
Judd LL, Paulus MP, Wells KB, et al: Socioeconomic burden of subsyndromal depressive symptoms
and major depression in a sample of the general population. Am J Psychiatry 153:1411–1417, 1996
[Full Text] [PubMed]
Judd LL, Akiskal HS, Paulus MP: The role and clinical significance of subsyndromal depressive
symptoms (SSD) in unipolar major depressive disorder. J Affect Disord 45:5–17; discussion 17–18,
1997
Judd LL, Akiskal HS, Maser JD, et al: A prospective 12-year study of subsyndromal and syndromal
depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry 55:694–700,
1998a
Judd LL, Akiskal HS, Maser JD, et al: Major depressive disorder: a prospective study of residual
subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord 50(2–3):97–108,
1998b
Judd LL, Akiskal HS, Zeller PJ, et al: Psychosocial disability during the long-term course of unipolar
major depressive disorder. Arch Gen Psychiatry 57:375–380, 2000 [PubMed]
Judd LL, Rapaport MH, Yonkers KA, et al: Randomized, placebo-controlled trial of fluoxetine for
acute treatment of minor depressive disorder. Am J Psychiatry 161:1864–1871, 2004 [Full Text]
[PubMed]
Kabat-Zinn J: Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress,
Pain, and Illness. New York, Delacorte Press, 1990
Kaplan RM: Quality of life assessment for cost/utility studies in cancer. Cancer Treat Rev 19 (suppl
A):85–96, 1993
Kaplan RM, Anderson JP: An integrated approach to quality of life assessments: the general healthPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
35 of 41
10/05/2009 16:33
policy model, in Quality of Life in Clinical Studies. Edited by Spilker B. New York, Raven, 1990, pp
131–149
Keller MB, Berndt ER: Depression treatment: a lifelong commitment? Psychopharmacol Bull 36
(suppl 2):133–141, 2002
Keller MB, Shapiro RW, Lavori PW, et al: Relapse in major depressive disorder: analysis with the life
table. Arch Gen Psychiatry 39:911–915, 1982 [PubMed]
Keller MB, Klerman GL, Lavori PW, et al: Long-term outcome of episodes of major depression:
clinical and public health significance. JAMA 252:788–792, 1984 [PubMed]
Keller MB, Lavori PW, Mueller TI, et al: Time to recovery, chronicity, and levels of psychopathology
in major depression: a 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry
49:809–816, 1992 [PubMed]
Keller MB, McCullough JP, Klein DN, et al: A comparison of nefazodone, the cognitive
behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic
depression. N Engl J Med 342:1462–1470, 2000 [PubMed]
Keller MB, Trivedi MH, Thase ME, et al: The Prevention of Recurrent Episodes of Depression with
Venlafaxine for Two Years (PREVENT) Study: outcomes from the acute and continuation phases.
Biol Psychiatry 62:1371–1379, 2007a
Keller MB, Trivedi MH, Thase ME, et al: The Prevention of Recurrent Episodes of Depression with
Venlafaxine for Two Years (PREVENT) Study: outcomes from the 2-year and combined maintenance
phases. J Clin Psychiatry 68:1246–1256, 2007b
Kendler KS, Kuhn JW, Vittum J, et al: The interaction of stressful life events and a serotonin
transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen
Psychiatry 62:529–535, 2005 [PubMed]
Kennedy SH, Evans KR, Kruger S, et al: Changes in regional brain glucose metabolism measured
with positron emission tomography after paroxetine treatment of major depression. Am J
Psychiatry 158:899–905, 2001 [Full Text] [PubMed]
Kessler RC, McGonagle KA, Zhao S, et al: Lifetime and 12-month prevalence of DSM-III-R
psychiatric disorders in the United States: results from the National Comorbidity Survey. Arch Gen
Psychiatry 51:8–19, 1994 [PubMed]
Kessler RC, Zhao S, Blazer DG, et al: Prevalence, correlates, and course of minor depression and
major depression in the National Comorbidity Survey. J Affect Disord 45(1–2):19–30, 1997
[PubMed]
Khan A, Brodhead AE, Kolts RL: Relative sensitivity of the Montgomery-Asberg depression rating
scale, the Hamilton depression rating scale and the Clinical Global Impressions rating scale in
antidepressant clinical trials: a replication analysis. Int Clin Psychopharmacol 19:157–160, 2004
[PubMed]
Kling MA, Alesci S, Csako G, et al: Sustained low-grade pro-inflammatory state in unmedicated,
remitted women with major depressive disorder as evidenced by elevated serum levels of the acute
phase proteins C-reactive protein and serum amyloid A. Biol Psychiatry 62:309–313, 2007
[PubMed]
Kripke DF: Photoperiodic mechanisms for depression and its treatment, in Biological Psychiatry.
Edited by Perris C, Struwe G, Jansson B. Elsevier-North Holland Biomedical Press, 1981, pp
1249–1252
Kroenke K, Spitzer RL, Williams JB: The PHQ-9: validity of a brief depression severity measure. J
Gen Intern Med 16:606–613, 2001 [PubMed]
Kupfer DJ: Long-term treatment of depression. J Clin Psychiatry 52 (suppl):28–34, 1991Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
36 of 41
10/05/2009 16:33
Kupfer DJ, Frank E, Perel JM, et al: Five-year outcome for maintenance therapies in recurrent
depression. Arch Gen Psychiatry 49:769–773, 1992 [PubMed]
Kuyken W, Dalgleish T, Holden ER: Advances in cognitive-behavioural therapy for unipolar
depression. Can J Psychiatry 52:5–13, 2007 [PubMed]
Laje G, Paddock S, Manji H, et al: Genetic markers of suicidal ideation emerging during citalopram
treatment of major depression. Am J Psychiatry 164:1530–1538, 2007 [Full Text] [PubMed]
Leon AC, Shear MK, Portera L, et al: Assessing impairment in patients with panic disorder: the
Sheehan Disability Scale. Soc Psychiatry Psychiatr Epidemiol 27:78–82, 1992 [PubMed]
Lewy AJ, Sack RL: Light therapy and psychiatry. Proc Soc Exp Biol Med. 183:11–18, 1986 [PubMed]
Liu Z, Zhu F, Wang G, et al: Association study of corticotropin-releasing hormone receptor1 gene
polymorphisms and antidepressant response in major depressive disorders. Neurosci Lett
414:155–158, 2007 [PubMed]
Lopez AD, Murray CC: The global burden of disease, 1990–2020. Nat Med 4:1241–1243, 1998
[PubMed]
Lopez AD, Mathers CD, Ezzati M, et al: Global and regional burden of disease and risk factors, 2001:
systematic analysis of population health data. Lancet 367:1747–1757, 2006 [PubMed]
Luty SE, Carter JD, McKenzie JM, et al: Randomised controlled trial of interpersonal psychotherapy
and cognitive-behavioural therapy for depression. Br J Psychiatry 190:496–502, 2007 [PubMed]
Maddux RE, Rapaport MH: Psychopharmacology and psychotherapy of subsyndromal depressions, in
Handbook of Chronic Depression: Diagnosis and Therapeutic Management. Edited by Alpert JE, Fava
- New York, Informa Healthcare, 2004, pp 183–206
Maes M: Evidence for an immune response in major depression: a review and hypothesis. Prog
Neuropsychopharmacol Biol Psychiatry 19:11–38, 1995 [PubMed]
Maes M: Major depression and activation of the inflammatory response system, in Cytokines, Stress,
and Depression. Edited by Dantzer R, Wollman EE, Yirmiya R. New York, Kluwer Academic/Plenum,
1999, pp 25–46
Maes M, Meltzer HY, Bosmans E, et al: Increased plasma concentrations of interleukin-6, soluble
interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord
34:301–309, 1995 [PubMed]
Mayberg HS, Brannan SK, Tekell JL, et al: Regional metabolic effects of fluoxetine in major
depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830–843, 2000
[PubMed]
Mayberg HS, Lozano AM, Voon V, et al: Deep brain stimulation for treatment-resistant depression.
Neuron 45:651–660, 2005 [PubMed]
McCullough JP: Treatment for Chronic Depression: Cognitive Behavioral Analysis System of
Psychotherapy. New York, Guilford, 2000
McCusker J, Cole M, Dufouil C, et al: The prevalence and correlates of major and minor depression in
older medical inpatients. J Am Geriatr Soc 53:1344–1353, 2005 [PubMed]
McPherson S, Cairns P, Carlyle J, et al: The effectiveness of psychological treatments for
treatment-resistant depression: a systematic review. Acta Psychiatr Scand 111:331–340, 2005
[PubMed]
Melfi CA, Chawla AJ, Croghan TW, et al: The effects of adherence to antidepressant treatment
guidelines on relapse and recurrence of depression. Arch Gen Psychiatry 55:1128–1132, 1998
[PubMed]
Meyers CA: Mood and cognitive disorders in cancer patients receiving cytokine therapy, inPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
37 of 41
10/05/2009 16:33
Cytokines, Stress, and Depression. Edited by Dantzer R, Wollman EE, Yirmiya R. New York, Kluwer
Academic/Plenum, 1999, pp 75–81
Miller IW, Norman WH, Keitner GI, et al: Cognitive-behavioral treatment of depressed inpatients.
Behav Ther 20:25–47, 1989a
Miller IW, Norman WH, Keitner GI: Cognitive-behavioral treatment of depressed inpatients: six- and
twelve-month follow-up. Am J Psychiatry 146:1274–1279, 1989b
Miller IW, Keitner GI, Schatzberg AF, et al: The treatment of chronic depression, part 3:
psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry
59:608–619, 1998 [PubMed]
Mischoulon D, Fava M: Role of S-adenosyl-L-methionine in the treatment of depression: a review of
the evidence. Am J Clin Nutr 76:1158S–1161S, 2002
Montgomery SA, Åsberg M: A new depression scale designed to be sensitive to change. Br J
Psychiatry 134:382–389, 1979 [PubMed]
Mundt JC, Marks IM, Shear MK, et al: The Work and Social Adjustment Scale: a simple measure of
impairment in functioning. Br J Psychiatry 180:461–464, 2002 [PubMed]
Murck H, Fava M, Alpert J, et al: Hypericum extract in patients with MDD and reversed vegetative
signs: re-analysis from data of a double-blind, randomized trial of hypericum extract, fluoxetine,
and placebo. Int J Neuropsychopharmacol 8:215–221, 2005 [PubMed]
Murray CJ, Lopez AD: Alternative projections of mortality and disability by cause 1990–2020: Global
Burden of Disease Study. Lancet 349:1498–1504, 1997 [PubMed]
Musselman DL, Lawson DH, Gumnick JF, et al: Paroxetine for the prevention of depression induced
by high-dose interferon alfa. N Engl J Med 344:961–966, 2001 [PubMed]
Nemeroff CB, Vale WW: The neurobiology of depression: inroads to treatment and new drug
discovery. J Clin Psychiatry 66 (suppl 7):5–13, 2005
Nemeroff CB, Heim CM, Thase ME, et al: Differential responses to psychotherapy versus
pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc
Natl Acad Sci U S A 100:14293–14296, 2003 [PubMed]
Nunes EV: Substance abuse and depression. Paper presented at the annual meeting of the American
Psychiatric Association, San Francisco, CA, May 2003
Olfson M, Fireman B, Weissman MM, et al: Mental disorders and disability among patients in a
primary care group practice. Am J Psychiatry 154:1734–1740, 1997 [Full Text] [PubMed]
O’Reardon JP, Solvason HB, Janicak PG, et al: Efficacy and safety of transcranial magnetic
stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol
Psychiatry 62:1208–1216, 2007 [PubMed]
Osei-Tutu KB, Campagna PD: The effects of short- vs long-bout exercise on mood, VO2max, and
percent body fat. Prev Med 40:92–98, 2005 [PubMed]
Otto MW, Smits JAJ, Reese HE: Combined psychotherapy and pharmacotherapy for mood and
anxiety disorders in adults: review and analysis. Clinical Psychology: Science and Practice
12:72–86, 2005
Papakostas GI, Shelton RC, Smith J, et al: Augmentation of antidepressants with atypical
antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin
Psychiatry 68:826–831, 2007 [PubMed]
Papiol S, Arias B, Gasto C, et al: Genetic variability at HPA axis in major depression and clinical
response to antidepressant treatment. J Affect Disord 104:83–90, 2007 [PubMed]
Paykel ES, Ramana R, Cooper Z, et al: Residual symptoms after partial remission: an importantPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
38 of 41
10/05/2009 16:33
outcome in depression. Psychol Med 25:1171–1180, 1995 [PubMed]
Paykel ES, Cooper Z, Ramana R, et al: Life events, social support and marital relationships in the
outcome of severe depression. Psychol Med 26:121–133, 1996 [PubMed]
Paykel ES, Scott J, Teasdale JD, et al: Prevention of relapse in residual depression by cognitive
therapy: a controlled trial. Arch Gen Psychiatry 56:829–835, 1999 [PubMed]
Perlis RH: Pharmacogenetic studies of antidepressant response: how far from the clinic? Psychiatr
Clin North Am 30:125–138, 2007 [PubMed]
Petty F, Kramer GL, Hendrickse W: GABA and depression, in Biology of Depressive Disorders, Part A:
A Systems Perspective. Edited by Mann JJ, Kupler DJ. New York, Plenum, 1993, pp 79–108
Pilkington K, Kirkwood G, Rampes H, et al: Yoga for depression: the research evidence. J Affect
Disord 89:13–24, 2005 [PubMed]
Pittenger C, Sanacora G, Krystal JH: The NMDA receptor as a therapeutic target in major depressive
disorder. CNS Neurol Disord Drug Targets 6:101–115, 2007 [PubMed]
Potter GG, Steffens DC: Contribution of depression to cognitive impairment and dementia in older
adults. Neurologist 13:105–117, 2007 [PubMed]
Prien RF, Kupfer DJ, Mansky PA, et al: Drug therapy in the prevention of recurrences in unipolar and
bipolar affective disorders: report of the NIMH Collaborative Study Group comparing lithium
carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry
41:1096–1104, 1984 [PubMed]
Raadsheer FC, Hoogendijk WJ, Stam FC, et al: Increased numbers of corticotropin-releasing
hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients.
Neuroendocrinology 60:436–444, 1994 [PubMed]
Rapaport MH, Judd LL: Minor depressive disorder and subsyndromal depressive symptoms:
functional impairment and response to treatment. J Affect Disord 48:227–232, 1998 [PubMed]
Rapaport MH, Tipp JE, Schuckit MA: A comparison of ICD-10 and DSM-III-R criteria for substance
abuse and dependence. Am J Drug Alcohol Abuse 19:143–151, 1993 [PubMed]
Rapaport MH, Judd LL, Schettler PJ, et al: A descriptive analysis of minor depression. Am J
Psychiatry 159:637–643, 2002 [Full Text] [PubMed]
Rapaport MH, Clary C, Fayyad R, et al: Quality-of-life impairment in depressive and anxiety
disorders. Am J Psychiatry 162:1171–1178, 2005 [Full Text] [PubMed]
Rapaport MH, Gharabawi GM, Canuso CM, et al: Effects of risperidone augmentation in patients with
treatment-resistant depression: results of open-label treatment followed by double-blind
continuation. Neuropsychopharmacology 31:2505–2513, 2006 [PubMed]
Reinherz HZ, Paradis AD, Giaconia RM, et al: Childhood and adolescent predictors of major
depression in the transition to adulthood. Am J Psychiatry 160:2141–2147, 2003 [Full Text]
[PubMed]
Reynolds CF 3rd, Frank E, Perel JM, et al: Nortriptyline and interpersonal psychotherapy as
maintenance therapies for recurrent major depression: a randomized controlled trial in patients
older than 59 years. JAMA 281:39–45, 1999 [PubMed]
Rich CL, Isacsson G: Suicide and antidepressants in south Alabama: evidence for improved
treatment of depression. J Affect Disord 45:135–142, 1997 [PubMed]
Rieckmann N, Burg MM, Gerin W, et al: Depression vulnerabilities in patients with different levels of
depressive symptoms after acute coronary syndromes. Psychother Psychosom 75:353–361, 2006
[PubMed]
Roche Pharmaceuticals: AmpliChip® CYP450 Test. Available at:Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
39 of 41
10/05/2009 16:33
http://www.roche.com/products/product-details.htm?type=product&id=17. Accessed December
Rubin RT, Poland RE, Lesser IM, et al: Neuroendocrine aspects of primary endogenous depression,
I: cortisol secretory dynamics in patients and matched controls. Arch Gen Psychiatry 44:328–336,
1987 [PubMed]
Ruhe HG, Mason NS, Schene AH: Mood is indirectly related to serotonin, norepinephrine and
dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry
12:331–359, 2007 [PubMed]
Rush AJ, Giles DE, Schlesser MA, et al: The Inventory for Depressive Symptomatology (IDS):
preliminary findings. Psychiatry Res 18:65–87, 1986 [PubMed]
Rush AJ, Trivedi MH, Ibrahim HM, et al: The 16-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. Biol Psychiatry 54:573–583, 2003 [PubMed]
Rush AJ, Fava M, Wisniewski SR, et al: Sequenced treatment alternatives to relieve depression
(STAR*D): rationale and design. Control Clin Trials 25:119–142, 2004 [PubMed]
Rush AJ, Bernstein IH, Trivedi MH, et al: An evaluation of the Quick Inventory of Depressive
Symptomatology and the Hamilton Rating Scale for Depression: a Sequenced Treatment
Alternatives to Relieve Depression trial report. Biol Psychiatry 59:493–501, 2006a
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
163:1905–1917, 2006b
Rush AJ, Trivedi MH, Wisniewski SR, et al: Bupropion-SR, sertraline, or venlafaxine-XR after failure
of SSRIs for depression. N Engl J Med 354:1231–1242, 2006c
Ryff CD: Happiness is everything, or is it?: explorations on the meaning of psychological well-being.
J Pers Soc Psychol 57:1069–1081, 1989
Sachar EJ, Hellman L, Fukushima DK, et al: Cortisol production in depressive illness: a clinical and
biochemical clarification. Arch Gen Psychiatry 23:289–298, 1970 [PubMed]
Sackeim HA, Brannan SK, Rush AJ, et al: Durability of antidepressant response to vagus nerve
stimulation (VNS). Int J Neuropsychopharmacol 10:817–826, 2007 [PubMed]
Schiepers OJ, Wichers MC, Maes M: Cytokines and major depression. Prog Neuropsychopharmacol
Biol Psychiatry 29:201–217, 2005 [PubMed]
Schlaepfer TE, Frick C, Zobel A, et al: Vagus nerve stimulation for depression: efficacy and safety in
a European study. Psychol Med 38:651–661, 2008 [PubMed]
Schramm E, van Calker D, Dykierek P, et al: An intensive treatment program of interpersonal
psychotherapy plus pharmacotherapy for depressed inpatients: acute and long-term results. Am J
Psychiatry 164:768–777, 2007 [Full Text] [PubMed]
Segal Z, Teasdale J, Williams M: Mindfulness-Based Cognitive Therapy for Depression. New York,
Guilford, 2002
Sequeira A, Gwadry FG, Ffrench-Mullen JM, et al: Implication of SSAT by gene expression and
genetic variation in suicide and major depression. Arch Gen Psychiatry 63:35–48, 2006 [PubMed]
Shaw BF, Elkin I, Yamaguchi J, et al: Therapist competence ratings in relation to clinical outcome in
cognitive therapy of depression. J Consult Clin Psychol 67:837–846, 1999 [PubMed]
Sluzewska A, Rybakowski J, Bosmans E, et al: Indicators of immune activation in major depression.
Psychiatry Res 64:161–167, 1996 [PubMed]
Smit F, Cuijpers P, Oostenbrink J, et al: Costs of nine common mental disorders: implications forPrint: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
40 of 41
10/05/2009 16:33
curative and preventive psychiatry. J Ment Health Policy Econ 9:193–200, 2006 [PubMed]
Smith CA, Hay PP: Acupuncture for depression. Cochrane Database Syst Rev (2):CD004046, 2005
Smits K, Smits L, Peeters F, et al: Serotonin transporter polymorphisms and the occurrence of
adverse events during treatment with selective serotonin reuptake inhibitors. Int Clin
Psychopharmacol 22:137–143, 2007a
Smits KM, Smits LJ, Schouten JS, et al: Does pretreatment testing for serotonin transporter
polymorphisms lead to earlier effects of drug treatment in patients with major depression? A
decision-analytic model. Clin Ther 29:691–702, 2007b
Søndergård L, Kvist K, Lopez AG, et al: Temporal changes in suicide rates for persons treated and
not treated with antidepressants in Denmark during 1995–1999. Acta Psychiatr Scand
114:168–176, 2006 [PubMed]
Stahl LA, Begg DP, Weisinger RS, et al: The role of omega-3 fatty acids in mood disorders. Curr Opin
Investig Drugs 9:57–64, 2008 [PubMed]
Stewart WF, Ricci JA, Chee E, et al: Cost of lost productive work time among US workers with
depression. JAMA 289:3135–3144, 2003 [PubMed]
Tabuse H, Kalali A, Azuma H, et al: The new GRID Hamilton Rating Scale for Depression
demonstrates excellent inter-rater reliability for inexperienced and experienced raters before and
after training. Psychiatry Res 153:61–67, 2007 [PubMed]
Thase ME: Redefining antidepressant efficacy toward long-term recovery. J Clin Psychiatry 60
(suppl 6):15–19, 1999
Thase ME, Friedman ES, Biggs MM, et al: Cognitive therapy versus medication in augmentation and
switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry 164:739–752, 2007
[Full Text] [PubMed]
Trivedi MH, Rush AJ, Ibrahim HM, et al: The Inventory of Depressive Symptomatology, Clinician
Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology,
Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders:
a psychometric evaluation. Psychol Med 34:73–82, 2004 [PubMed]
Trivedi MH, Fava M, Wisniewski SR, et al: Medication augmentation after the failure of SSRIs for
depression. N Engl J Med 354:1243–1252, 2006a
Trivedi MH, Greer TL, Grannemann BD, et al: Exercise as an augmentation strategy for treatment of
major depression. J Psychiatr Pract 12:205–213, 2006b
Trivedi MH, Greer TL, Grannemann BD, et al: TREAD: TReatment with Exercise Augmentation for
Depression: study rationale and design. Clin Trials 3:291–305, 2006c
Trivedi MH, Rush AJ, Wisniewski SR, et al: Evaluation of outcomes with citalopram for depression
using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry
163:28–40, 2006d
UK ECT Review Group: Efficacy and safety of electroconvulsive therapy in depressive disorders: a
systematic review and meta-analysis. Lancet 361:799–808, 2003
U.S. Department of Health and Human Services: National strategy for suicide prevention. A
collaborative effort of SAMHSA, CDC, NIH, HRSA, HIS. 2001. Available at:
http://mentalhealth.samhsa.gov/suicideprevention/elderly.asp. Accessed December 2, 2008.
van Rossum EF, Binder EB, Majer M, et al: Polymorphisms of the glucocorticoid receptor gene and
major depression. Biol Psychiatry 59:681–688, 2006
Videbech P, Ravnkilde B: Hippocampal volume and depression: a meta-analysis of MRI studies. Am
J Psychiatry 161:1957–1966, 2004 [Full Text] [PubMed]Print: Chapter 53. Treatment of Depression http://www.psychiatryonline.com/popup.aspx?aID=433758&print=yes…
41 of 41
10/05/2009 16:33
Ware JE Jr, Sherbourne CD: The MOS 36-item short-form health survey (SF-36), I: conceptual
framework and item selection. Med Care 30:473–483, 1992 [PubMed]
Ware J Jr, Kosinski M, Keller SD: A 12-Item Short-Form Health Survey: construction of scales and
preliminary tests of reliability and validity. Med Care 34:220–233, 1996 [PubMed]
Warner-Schmidt JL, Duman RS: Hippocampal neurogenesis: opposing effects of stress and
antidepressant treatment. Hippocampus 16:239–249, 2006 [PubMed]
Weissman MM, Klerman GL: Sex differences and the epidemiology of depression. Arch Gen
Psychiatry 34:98–111, 1977 [PubMed]
Weissman MM, Bland RC, Canino GJ, et al: Cross-national epidemiology of major depression and
bipolar disorder. JAMA 276:293–299, 1996 [PubMed]
Wells KB, Stewart A, Hays RD, et al: The functioning and well-being of depressed patients: results
from the Medical Outcomes Study. JAMA 262:914–919, 1989 [PubMed]
Westrin A, Lam RW: Long-term and preventative treatment for seasonal affective disorder. CNS
Drugs 21:901–909, 2007 [PubMed]
Williams JB: A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen
Psychiatry 45:742–747, 1988 [PubMed]
Wisniewski SR, Fava M, Trivedi MH, et al: Acceptability of second-step treatments to depressed
outpatients: a STAR*D report. Am J Psychiatry 164:753–760, 2007 [Full Text] [PubMed]
Zimmerman M, Thongy T: How often do SSRIs and other new-generation antidepressants lose their
effect during continuation treatment? Evidence suggesting the rate of true tachyphylaxis during
continuation treatment is low. J Clin Psychiatry 68:1271–1276, 2007 [PubMed]
Zung WWK: A self-rating depression scale. Arch Gen Psychiatry 12:371–379, 1965
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Course Content
Introduction to Depression and Its Impact
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Understanding Depression: An Overview
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The Psychological Impact of Depression
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Societal and Economic Implications of Depression
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Introduction to Depression Quiz
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Personal Stories: Living with Depression
Understanding the Causes and Risk Factors
Exploring Therapeutic Approaches and Interventions
Advanced Techniques for Managing Symptoms
Developing a Personalized Treatment Plan
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