Anxiety and Depression: Brian Rothberg and Christopher D. Schneck

46 Anxiety and Depression
BRIAN ROTHBERG and CHRISTOPHER D. SCHNECK
CHAPTER OUTLINE Overview, 1090 Assessment of the Depressed or Anxious

Anxiety, Major Depression, and Medical Patient in Medical Settings, 1097
Illnesses, 1092 Management and Treatment of Major
Diagnosis and Screening of Mood and Depression and Anxiety Disorders, 1099
Anxiety Disorders, 1093
cyclothymia, and dysthymia (also called pervasive depres-

Overview sive disorder). With the latest edition of the Diagnostic and
Statistical Manual of Mental Disorders, fifth edition (DSM-5)
(American Psychiatric Association [APA], 2013), several
Key Points new mood disorder categories have been added, including
disruptive mood dysregulation disorder (chronic, severe
■ Depression and anxiety increase medical morbidity and persistent irritability, along with severe temper outbursts,
mortality. beginning at an early age), premenstrual dysphoric disor-
■ Mood disorders comprise unipolar and bipolar disorders.
der, and two broad and nonspecific depressive diagnoses
■ Anxiety disorders comprise eight disorders, of which
(other specified depressive disorder and unspecified depres-
generalized anxiety disorder (GAD) and panic disorder
are frequently encountered in primary care settings. sive disorder). This chapter focuses on the major mood dis-
■ Treatment of depression and anxiety improves overall orders of depression and bipolar disorder. The category of
health outcomes. anxiety disorders in the new DSM-5 (APA, 2013) contains
■ The majority of patients with mood and anxiety GAD, panic disorder, agoraphobia, specific phobia (e.g., fear
disorders are treated in primary care settings. of heights), and social anxiety disorder (social phobia).
Obsessive-compulsive disorder (OCD) and posttraumatic
stress disorder (PTSD) have been removed from the anxiety
Major depression and anxiety disorders are the two most disorder category. This chapter focuses primarily on GAD
common psychiatric illnesses in the United States and are and panic disorder.
particularly prevalent in primary care settings. Despite
the relative availability of specialty psychiatric care in the EPIDEMIOLOGY
United States, most patients with depression or anxiety
disorder continue to receive their treatment from primary
care physicians. Moreover, patients with both medical Key Points
illness and comorbid mood or anxiety disorder frequently
have poorer outcomes, experience more prolonged and dif- ■ Major depression and anxiety disorders are the two
ficult treatment, and have greater morbidity and mortality most common psychiatric illnesses in the United States.
■ The economic burden of anxiety and depressive
than patients without psychiatric illness (Katon, 2003).
Conversely, treating underlying depressive and anxiety disorders is substantial in terms of workdays lost,
disorders not only improves the emotional well-being of disability, health care expenditures, and mortality.
■ Anxiety and depression are chronic illnesses that
patients but also improves overall health outcomes and
typically run a waxing and waning course.
lowers health care costs. Given their frequency, severity, ■ Prevalence rates for anxiety disorders appear to decline
prevalence, morbidity, and mortality, depression and anxi with advancing age, except for GAD, which may
ety disorders remain important illnesses for primary care increase in geriatric populations.
physicians to identify and treat. ■ Depression is often a highly recurrent illness; each
The broader categories of mood and anxiety disorders episode of depression increases the likelihood of future
comprise a large number of specific illnesses. Describing the episodes.
specific symptoms, epidemiology, assessment, and treat-
ment of each illness is beyond the scope of this chapter;
rather, we examine the illnesses that primary care physi- Prevalence estimates of mental disorders in the United
cians are most likely to encounter in clinical settings and States continue to find that anxiety and mood disorders
provide the most common strategies used in assessment, are the two most common mental disorders in the general
diagnosis, and treatment. Mood disorders include major population (Kessler et al., 2012). Lifetime prevalence for
depression (also called unipolar depression), bipolar disor- anxiety disorders is estimated at 16.6% to 28.8% (Conway
der (which includes bipolar I and bipolar II disorder), et al., 2006; Kessler et al., 2005a) and for major depression
1090
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46 • Anxiety and Depression 1091
is estimated at 14.9% to 16.2% (Kessler et al., 2003). Recent illness in which patients may experience periods of residual
12-month prevalence rates show a similar stratification, symptoms and occasional interepisode remissions (Angst
with anxiety disorders most common (18.1%) followed by et al., 2009). More than one third of patients with panic
mood disorders (9.5%). Lifetime prevalence rates of panic disorder have full remission with treatment, but about 20%
disorder and GAD are 4.7% and 5.7%, respectively (Kessler have an unremitting and chronic course despite treatment
et al., 2005a). Anxiety disorders make up approximately (Katschnig and Amering, 1998).
2% of all office visits to physicians in the United States, but The onset of major depression can occur at any age,
almost 50% occur in primary care settings. In comparison, although the median age of onset is 30 years (Kessler et al.,
approximately 40% of patients presenting with anxiety dis- 2005b). Depression is a highly recurrent illness, and each
orders are seen by psychiatrists (Harman et al., 2002). episode increases the likelihood of future episodes. Whereas
Major depression remains a common disorder and is patients with a single episode have a 50% lifetime chance
associated with substantial symptom severity and role of recurrence, those with three or more episodes have an
impairment (Kessler et al., 2003). One-year prevalence almost 100% chance of recurrence without treatment
rates for major depression are approximately 6% in the (Eaton et al., 2008). Untreated depressive episodes can last
general population followed by dysthymia (1.8%) and 6 months or longer (Kessler et al., 2003). The Sequenced
bipolar disorders (1%-2%). Rates in primary care settings Treatment Alternatives to Relieve Depression (STAR*D)
remain substantially higher, with prevalence of 10% or study found that a substantial number of patients receiving
greater (Spitzer et al., 1994), although many of these first-line treatment may require 8 weeks or more of treat-
patients have depression that is unrecognized by their ment to achieve response or remission (Trivedi et al.,
primary care physician (Schultheis et al., 1999). 2006b). Although most patients recover from their depres-
sive episode and return to normal functioning with treat-
ment, approximately 15% of patients continue to have an
COSTS
unremitting course, with worsening psychosocial function-
Both anxiety and depressive disorders account for substan- ing and a higher risk for suicide (Eaton et al., 2008).
tial health care costs and thus constitute a major public
health and economic concern. As of 2013, the cost of NEUROBIOLOGY AND GENETICS
depression and anxiety disorders in the United States comes
from data between 1990 and 2000 and was calculated to The neurobiology of both depressive and anxiety disorders
be $83.1 billion in 2000, of which $26.1 billion was for is complex and incompletely understood. In contrast to ill-
direct medical costs, $5.4 billion for suicide mortality costs, nesses such as Parkinson or Huntington disease, no single
and $51.5 billion for work-related costs (Greenberg et al., area of brain pathology or anatomic lesion has been impli-
2003). Similarly, estimates from the 1990s placed the cated in the development of anxiety or depression; rather,
annual economic burden of anxiety disorders at $63.1 these illnesses appear to be mediated by dysregulation
billion (in 1998 dollars), of which nonpsychiatric direct of complex interactions between neural circuits (Nestler
medical costs accounted for 54% of the total and direct et al., 2002). In depression, most lines of investigation
psychiatric care accounted for 31% (Greenberg et al., have involved dysregulation of the hypothalamic–pituitary
1999). Not surprisingly, patients with anxiety disorders are axis (HPA) and hippocampus, along with investigations of
much more likely to see their primary care physicians or use neural circuitry mediating mood, reward, sleep, appetite,
emergency services. Patients with pure GAD (i.e., no comor- motivation, and cognition. In particular, hyperactivity of
bid medical illnesses), for example, were 1.6 times more the HPA in some depressed patients has been found to lead
likely to have seen a primary care physician four or more to hippocampal volume reduction, likely by reduction of
times in the past year than those without GAD or depression brain-derived neurotrophic factor (BDNF) and changes in
(Wittchen et al., 2002). Patients with panic disorder were the mechanisms that mediate BDNF expression. However,
almost twice as likely as controls to have visited an emer- whether reduced hippocampal volume is a partial cause or
gency department in the previous 6 months (Roy-Byrne merely a result of depression is currently unclear, and it is
et al., 1999). not seen in all patients diagnosed with depression. Although
epidemiologic studies show that depression appears highly
heritable, with some studies showing that 40% to 50% of
DISEASE COURSE
the risk may be genetic, no one gene appears implicated,
Both anxiety and depressive disorders tend to run a chronic and depression likely is the phenotypic expression of mul-
course, with waxing and waning symptomatology. Illness tiple genetic vulnerabilities coupled with environmental
severity typically worsens the longer the illness remains stresses (physical or emotional trauma, viral illness), physi-
untreated. The age of onset for anxiety disorders varies cal factors (e.g., preexisting or comorbid medical illnesses
greatly, depending on the specific condition. Specific phobias such as hypothyroidism or stroke), and random processes
and separation anxiety, for example, often begin in child- during brain development (Nestler et al., 2002).
hood (median age of onset, 7 years), but panic disorder Neurobiologic research in anxiety disorders has focused
(median age, 21 years) and GAD (median age, 31 years) are on elucidating the neural networks involved in the fear
typically seen in early to mid-adulthood (Kessler et al., response, but despite advances in neuroimaging, the exact
2005b). In elderly persons (>65 years), the prevalence of mechanism of each anxiety disorder has yet to be com-
all anxiety disorders appears to decline, except for GAD, pletely understood. Strategies to understand the neuroana-
which is maintained at 4% prevalence and may increase tomic underpinnings of panic disorder have focused on
over time (Krasucki et al., 1998). GAD is often a recurring translational research using conditioned fear in animals as
1092 PART 2 • Practice of Family Medicine
a model for panic attacks in humans. Patients with panic episodes (either mood or anxiety episodes), poorer response
disorder may have an especially sensitive fear mechanism to treatment, higher suicide rates, more chronic course, and
involving the central nucleus of the amygdala, hippocam- overall poorer prognosis.
pus, thalamus, hypothalamus, periaqueductal gray region, Treatment is complicated by the fewer studies on coex
locus ceruleus, and other brainstem sites (Gorman et al., isting depression and anxiety, providing clinicians with a
2000). Other areas of focus in anxiety disorders have smaller evidence base for treatment decisions. Based on
involved investigations into alterations of interoceptive pro- DSM-IV criteria, patients with comorbid major depressive
cessing of the anterior insula (Mathew et al., 2008). Both disorders are half as likely subsequently to recover from
the insula and the anterior cingulate cortex are thought to panic disorder with agoraphobia or GAD, and comorbid
be the regions of the brain that form a representation of the major depression almost doubles the likelihood of recur-
visceral state of the body. A heightened sensitivity of this rence of panic disorder with agoraphobia (Bruce et al.,
region may underlie the misinterpretation of bodily signals 2005). In addition, children and adolescents with anxiety
in panic disorder. disorders are at eight times the risk of additional depression
Genetic epidemiologic studies have clearly documented (Angold et al., 1999). Practitioners must therefore be
that anxiety disorders aggregate in families and that this aggressive in screening for anxiety disorders in patients
familial link primarily results from genetic factors (Smoller reporting depressive symptoms, as well as screening for
and Faraone, 2008). First-degree relatives of probands with depression in patients reporting anxiety symptoms.
the major anxiety disorders (panic disorder, social anxiety
disorder, specific phobias, OCD) have a four- to sixfold INTERACTION OF DEPRESSION, ANXIETY,
increased risk of the index disorders compared with rela- AND MEDICAL ILLNESS
tives of unaffected probands (Hettema et al., 2001). Genetic
studies of GAD suggest that a common genetic suscepti A complex and reciprocal relationship exists between
bility may apply to “clusters” of anxiety disorders and medical illnesses and comorbid anxiety and depressive dis-
other comorbid disorders (Norrholm and Ressler, 2009). orders. Medical illnesses are associated with higher preva-
An overlap of genes may play a role in the development of lence rates of anxiety and depression, and anxiety and
multiple psychiatric conditions, including anxiety and depression are associated with higher rates of comorbid
depression. medical illnesses. Studies of patients with diabetes, cancer,
stroke, myocardial infarction, HIV-related illness, and
Parkinson disease have higher rates of depression than
Anxiety, Major Depression, patients without such illnesses (Katon, 2003). Common
medical disorders seen in primary care settings have high
and Medical Illnesses comorbidity with anxiety disorders as well. Cardiovascular
disease is associated with a 1.5 times greater risk of both
GAD and panic disorder (Goodwin et al., 2008). Patients
Key Points with back pain or arthritis are almost twice as likely to
have panic attacks or GAD (McWilliams et al., 2004), and
■ Anxiety disorders and major depression often coexist. patients with asthma (pediatric or adult) may have a 30%
■ The more severe the anxiety disorder, the greater the increased likelihood of anxiety disorders (Katon et al.,
likelihood of major depression.
■ Medical illnesses are associated with higher prevalences
2004). The prevalence of anxiety and depression in patients
of anxiety and depression and vice versa. with diabetes is more than double that in the general popu-
■ Medically ill patients with comorbid anxiety or lation (Collins et al., 2009). Almost 100% of patients with
depressive disorders adapt more poorly to physical irritable bowel syndrome have major depression, GAD, or
symptoms, complicating disease management. panic disorder (Lydiard et al., 1993).
Medical illnesses are associated with a higher risk for
mood and anxiety disorders, so the presence of these disor-
INTERACTION OF DEPRESSION AND ANXIETY ders places patients at higher risk for multiple medical con-
ditions. Patients with GAD or panic disorder are almost six
Major depression and anxiety are often found together, times more likely to have a cardiac disorder, three times
and each illness complicates the course and outcome of the more likely to have a gastrointestinal (GI) disorder, twice as
other. Studies have consistently shown that anxiety disor- likely to have respiratory difficulties, and twice as likely to
ders are the most frequently occurring comorbid disorder have migraine headaches than patients without anxiety
with major depression, with 50% to 60% of major depressed disorders (Harter et al., 2003). Depression may be a pre
patients with both illnesses (Zimmerman et al., 2002). dictor for the subsequent development of medical illness.
Whereas anxiety can lead to depression in almost 60% of Several studies found an association between history of
patients, depression leads to anxiety in only 15% of patients major depression and subsequent development of type II
(Mineka et al., 1998). Not surprisingly, the more severe diabetes (Eaton et al., 1996; Kawakami et al., 1999) and
anxiety disorders, OCDs, and trauma related disorders are coronary artery disease (Rugulies, 2002).
more likely to lead to subsequent depression; that is, panic Management of patients with comorbid medical illness
disorder, agoraphobia, OCD, PTSD and GAD more frequently and anxiety or depression is complex. Such patients have
lead to depression than either social phobia or simple higher rates of unexplained symptoms than patients
phobia. In addition, patients with both illnesses often have without these disorders even after adjusting for the severity
an increased severity of symptoms, increased frequency of of medical illness (Katon and Walker, 1998). An increasing
body of literature suggests that patients with medical illness of memory difficulties, become easily distracted, and
and comorbid depression or anxiety adapt more poorly to describe an inability to think clearly. Patients often pace,
chronic symptoms, such as fatigue or pain, and tend to wring their hands, or have an inability to sit still; conversely,
focus on both symptoms of their physical illnesses and they may become greatly slowed or immobilized. In some
physical symptoms associated with other organ symptoms. patients, irritable mood may predominate more than
Not surprisingly, patients with medical illness and comorbid sadness, or they may have explosive, angry outbursts (Fava
depression have 50% higher medical costs than patients and Rosenbaum, 1999). Irritability is especially noted in
with medical illness alone (Katon, 2003). Comorbid patients depressed children and adolescents. In its most severe
are more functionally impaired and have more lost work- forms—major depression with psychotic features—patients
days, poorer quality of life, and higher rates of medical may hear voices telling them to kill themselves or may
utilization (Simon, 2003). Disease management is also develop delusional beliefs, such as having a serious illness
complicated by higher rates of nonadherence to treatment despite numerous tests providing no evidence (APA, 2013).
and self-care regimens, as well as higher rates of risk behav- The essential feature of dysthymia, also called persistent
iors (e.g., smoking, overeating, sedentary lifestyle). Response depressive disorder, is a chronically depressed mood that
to antidepressant treatment may be less robust, as evi- occurs most days for at least 2 years. Patients may have
denced by patients with cardiovascular disease, stroke, and a variety of other symptoms, such as feelings of inade-
diabetes (Katon, 2003). quacy; generalized loss of interest or pleasure; social with-
drawal; feelings of guilt or brooding about the past; and
decreased activity, productivity, or effectiveness (Table
Diagnosis and Screening of Mood 46-2). Neurovegetative symptoms such as insomnia or
hypersomnia, poor appetite or overeating, low energy, and
and Anxiety Disorders poor concentration may be present but are less common
than in major depressive episodes. These patients may state
that they have been depressed for as long as they can
Key Points remember and cannot recall episodes of recovery or remis-
sion of symptoms. In addition, dysthymic patients may peri-
■ Distinguishing unipolar from bipolar depression is odically have superimposed major depressive episodes, often
critical for the proper management of depressed called “double depression” (APA, 2013).
patients. The Mood Disorder Questionnaire (MDQ) may Bipolar disorder is a chronic mood disorder characterized
aid practitioners in detecting bipolar disorder in primary
care settings.
by the presence of mania (bipolar I disorder) or hypomania
■ The Patient Health Questionnaire 9 (PHQ-9) is a
and depression (bipolar II disorder). Manic episodes are dis-
common and easy-to-use screening tool for depression. tinct periods of abnormally and persistent moods that can
■ No standard screening instrument for anxiety disorders be euphoric, expansive, or irritable, co-occurring with per-
has currently been accepted in general practice. sistently increased goal-directed activity or energy, lasting
at least 1 week. Although manic patients are often thought
to be always euphoric, only about 20% of patients experi-
ence pure euphoria; most describe a mix of severe irritabil-
DIAGNOSIS OF MOOD DISORDERS
ity, severe emotional lability, and volatility (Goodwin and
Mood disorders are divided into depressive disorders, bipolar Jamison, 2007). Manic patients often have greatly inflated
disorders, and disorders based on etiology (i.e., mood disor- self-esteem, confidence, decreased need for sleep, pressured
ders caused by general medical conditions and substance- speech, racing or crowded thoughts, distractibility, increased
induced mood disorders). For primary care physicians, involvement in goal-directed activities (e.g., starting many
identification, treatment, and management of depressive projects but being unable to finish any), hypersexuality,
disorders are essential. Bipolar disorders, which are typi- and excessive involvement in pleasurable activities with
cally more complex to identify and treat, are best referred a high potential for painful consequences (APA, 2013).
to mental health professionals for ongoing treatment. Patients can exert great levels of physical activity, appear
Therefore, this chapter concentrates on identifying bipolar tireless, and may become extremely physically agitated.
disorder and distinguishing between unipolar and bipolar Approximately 60% of bipolar I patients experience psy
depression, but it does not delve into the specifics of treating chosis, which may involve delusions of grandeur (feeling
bipolar patients. omnipotent, having special powers or “gifts”), persecution,
The essential feature of a major depressive episode is a or hallucinations (more often auditory as opposed to visual)
period lasting at least 2 weeks during which the patient (Goodwin and Jamison, 2007). The DSM-5 recognizes that
experiences depressed mood or loss of interest or pleasure a patient can be diagnosed with bipolar disorder even when
in almost all activities, a distinct change in usual self, and mania is thought to emerge during treatment with an anti-
clinically significant distress or changes in functioning. It is depressant if the manic symptoms persist at a fully syndro-
accompanied by a constellation of other symptoms, such mal level beyond the physiological effects of the treatment.
as changes in sleep, eating, energy, motivation, and con Despite mania being the defining characteristic of the
centration; difficulty making decisions; and often feelings of disease, depressed moods tend to predominate, with bipolar
hopelessness, worthlessness, and guilt (Table 46-1). Patients I patients experiencing a 3 : 1 ratio of depression to mania
may ruminate about death, feel that life is not worth living, over the course of the illness (Judd et al., 2003).
have thoughts about suicide, may make plans to kill them- Primary care physicians are more likely to encounter
selves, or make suicide attempts. Many patients complain patients with bipolar II disorder than bipolar I disorder.
Table 46-1 Diagnostic Criteria for Major Depressive Episode

A. 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 attributable 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, empty, hopeless) or observation
made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.)
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).
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 gain.)
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
B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
C. The episode is not attributable to the physiological effects of a substance or to another medical condition.
Note: Criteria A-C represent a major depressive episode.
Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability)
may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may
resemble a depressive episode. Although such symptoms may be understandable or considered appropriate to the loss, the presence of a major
depressive episode in addition to the normal response to a significant loss should also be carefully considered. This decision inevitably requires
the exercise of clinical judgment based on the individual’s history and the cultural norms for the expression of distress in the context of loss. In
distinguishing grief from a major depressive episode (MDE), it is useful to consider that in grief the predominant affect is feelings of emptiness
and loss, while in MDE it is persistent depressed mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is likely to
decrease in intensity over days to weeks and occurs in waves, the so-called pangs of grief. These waves tend to be associated with thoughts or
reminders of the deceased. The depressed mood of MDE is more persistent and not tied to specific thoughts or preoccupations. The pain of
grief may be accompanied by positive emotions and humor that are uncharacteristic of the pervasive unhappiness and misery characteristic of
MDE. The thought content associated with grief generally features a preoccupation with thoughts and memories of the deceased, rather than
the self-critical or pessimistic ruminations seen in MDE. In grief, self-esteem is generally preserved, whereas in MDE feelings of worthlessness and
self-loathing are common. If self-derogatory ideation is present in grief, it typically involves perceived failings vis-à-vis the deceased (e.g., not
visiting frequently enough, not telling the deceased how much he or she was loved). If a bereaved individual thinks about death and dying,
such thoughts are generally focused on the deceased and possibly about “joining” the deceased, whereas in
MDE such thoughts are focused on ending one’s own life because of feeling worthless, undeserving of life, or unable to cope with the pain of
depression.
From American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
Bipolar II disorder is characterized by hypomanic and major accompanying symptoms. Because mood disorders are now
depressive episodes, although over the course of the illness, thought to exist along a continuum, ranging from bipolar
it is primarily a disease of depression, with depressive epi- mania to unipolar depression, DSM-5 has recognized that
sodes predominating over hypomanic episodes by a 37 : 1 patients with either diagnosis can have “mixed” symptoms
ratio (Judd et al., 2003). Symptoms of hypomanic episodes of the opposite pole. That is, manic patients may also have
are similar to full manic episodes, but the severity of manic accompanying depressive symptoms (e.g., depressed mood,
behaviors is attenuated, and the extreme functional, occu- suicidal thinking) and depressed patients may have some
pational, and social impairments evident in manic episodes co-occurring symptoms of mania (e.g., racing thoughts,
are absent in hypomania. Current DSM-5 criteria require decreased need for sleep). Patients with either diagnosis
that distinct elevations in mood must be present for at least (bipolar disorder or unipolar depression) may also have
4 days, must be clearly different from the patient’s usual anxious distress, psychosis, or seasonal variation of mood.
nondepressed mood, and must be accompanied by a change Clinicians should therefore recognize that patients with
in the patient’s usual functioning. Because patients primar- either unipolar depression or bipolar disorder may have a
ily seek help during their depressive episodes and typically variety of accompanying symptoms associated with the
do not report hypomanic episodes as abnormal, undiag- opposite pole that ultimately may have an impact on prog-
nosed bipolar disorder remains a major difficulty in primary nosis or treatment. However, the clinical significance of
care settings (Manning et al., 1999). Moreover, bipolar dis- these co-occurring symptoms and their implications for
order may be more common in primary care settings than treatment are still being evaluated.
in general populations. Of 649 patients being treated for
depression in a primary care clinic, 21% screened positive Unipolar Depression versus Bipolar Depression
for bipolar disorder (Hirschfeld et al., 2005), but 10% of Distinguishing unipolar from bipolar depression remains a
patients screened positive for bipolar disorder in a general critical distinction and poses one of the greatest clinical
medical clinic, although 80% of these patients had been challenges for professionals who treat patients with
diagnosed with unipolar depression (Das et al., 2005). mood disorders. Misdiagnosis of bipolar disorder can lead
The DSM-5 introduced several important conceptual to mistreatment (typically with antidepressants alone),
changes in the subclassification of mood disorders and their worsening of mood, switches into mania or mixed states
Table 46-2 Diagnostic Criteria for Dysthymic Disorder Table 46-3 Features Suggesting Bipolar Depression
Depressed mood for most of the day for more days than not as Feature Bipolar Unipolar
indicated either by subjective account or observation by others for
at least 2 years. Substance abuse Very high Moderate
Note: In children and adolescents, mood can be irritable and duration Family history Almost uniform Sometimes
must last for at least 1 year. Seasonality Common Occasional
A. Presence, while depressed, of two (or more) of the following: First episode before age Very common Sometimes
1. Poor appetite or overeating 25 years
2. Insomnia or hypersomnia Postpartum illness Very common Sometimes
3. Low energy or fatigue
4. Low self-esteem Psychotic features before Highly predictive Uncommon
5. Poor concentration or difficulty making decisions age 35
6. Feelings of hopelessness Atypical features Common Occasional
B. During the 2-year period (1 year for children or adolescents) Rapid on/off pattern Typical Unusual
of the disturbance, the person has never been without the
Recurrent major Common Unusual
symptoms in Criteria A and B for more than 2 months
depressive episodes (>3)
at a time.
C. No major depressive episode (see Table 46-1) has been present Antidepressant-induced Predictive Uncommon
during the first 2 years of the disturbance (1 year for children and mania or hypomania
adolescents); that is, the disturbance is not better accounted for Brief episodes (<3 mo) Suggestive Unusual (duration
by chronic major depressive disorder or major depressive disorder usually >3 mo)
in partial remission. Antidepressant tolerance Suggestive Uncommon
D. There has never been a manic episode, a mixed episode, or
a hypomanic episode, and criteria have never been met for Mixed depression Predictive Rare
cyclothymic disorder. (presence of hypomanic
E. The disturbance does not occur exclusively during the course of features within
a chronic psychotic disorder, such as schizophrenia or delusional depressive episode)
disorder. Tension, edginess, More common Less common
F. The symptoms are not caused by the direct physiological effects fearfulness
of a substance (e.g., a drug of abuse, a medication) or a general Somatic symptoms Less common More common
medical condition (e.g., hypothyroidism). (muscular, respiratory,
G. The symptoms cause clinically significant distress or impairment genitourinary)
in social, occupational, or other important areas of functioning.
Modified from Kaye NS. Is your depressed patient bipolar? J Am Board Fam
From American Psychiatric Association. Diagnostic and statistical manual of Pract. 2005;18:271-281; and Perlis RH, Brown E, Baker RW, Nierenberg AA.
mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; Clinical features of bipolar depression versus major depressive disorder in
2013. large multicenter trials. Am J Psychiatry. 2006;163:225-231.
(i.e., presence of both manic and depressive symptoms), primary care physicians because they are a cost-effective
rapid mood swings, worsening psychosocial impairment, way to manage depressed patients over time (Trivedi et al.,
more suicide attempts, and higher mortality (Goldberg and 2006b). Self-report measures obviate the need for trained
Ernst, 2002; Goldberg and Truman, 2003; Schneck et al., office personnel to administer tests. Depression screening
2008). Treatment of patients with bipolar depression is measures do not diagnose depression but do provide critical
rarely straightforward and often requires multiple medica- information regarding symptom severity within a given
tions and medication trials. Antidepressants do not appear period. Almost all measures have a statistically predeter-
to be especially helpful in the treatment of bipolar disorder, mined cutoff score at which depression symptoms are con-
and antidepressants have not yet been shown to improve sidered significant. When a depression screening result is
outcome compared with mood stabilizers alone (Sachs positive, an interview is necessary because screening will
et al., 2007). Although no symptom is pathognomonic for not include many confounding diagnostic variables (e.g.,
bipolar depression, certain features of depression may substance abuse, hypothyroidism, bereavement), and physi-
suggest that a patient’s depression is a manifestation of cian judgment is required. Screening measures do not
bipolar illness. Bipolar depression can present similar to address important clinical features of psychiatric illnesses
unipolar depression, but some depression features may help (e.g., total duration of symptoms, degree of impairment)
distinguish the two (Ghaemi et al., 2004; Perlis et al., 2006) from other comorbid psychiatric conditions.
(Table 46-3). If a primary care physician makes a diagnosis
of bipolar disorder, the patient is best served by referral to a Patient Health Questionnaire 9. The PHQ-9 is often
mental health provider, preferably with expertise in treating used in primary care settings because of its ease of use,
mood disorders. sensitivity to change over time, reliability, and validity
(Kroenke et al., 2001). It uses only the nine depression
Screening Tools for Depression items from the original self-report version of the Primary
Numerous screening measures have been specifically Care Evaluation of Mental Disorders Patient Health
designed to detect depression, and many are sensitive to Questionnaire (PRIME-MD PHQ) (Spitzer et al., 1999).
change over time when used repeatedly at follow-up visits. Major depression is diagnosed if five or more of the depres-
The integration of such tools into clinical practice, referred sive symptoms have been present at least “more than half
to as measurement-based care, may enhance care and improve the days” in the past 2 weeks and if one of the symptoms is
clinical outcome. Measurement tools in the public domain depressed mood or anhedonia. Other depressive syndromes
and sensitive to change over time are most practical for (e.g., minor depression) are diagnosed if two, three, or four
depressive symptoms have been present at least “more than Table 46-4 Diagnostic Criteria for Generalized
half the days” in the past 2 weeks and if one symptom is Anxiety Disorder
depressed mood or anhedonia. One of the nine test items
A. Excessive anxiety and worry (apprehensive expectation),
(“thoughts that you would be better off dead or by hurting occurring more days than not for at least 6 months, about a
yourself in some way”) counts if present at all, regardless number of events or activities
of duration. Using cutoff scores from 9 to 15, sensitivity B. The person finds it difficult to control the worry.
ranges from 68% to 95%, with specificity from 84% to 95%. C. The anxiety and worry are associated with three (or more) of the
following six symptoms:
Using the cutoff score of 9, sensitivity is 95% and specificity 1. Restlessness and feeling keyed up or on edge
84%. 2. Being easily fatigued
3. Difficulty concentrating or mind going blank
Quick Inventory of Depressive Symptomatology— 4. Irritability
Self Report. The 16-item Quick Inventory of Depressive 5. Muscle tension
6. Sleep disturbance
Symptomatology Self Report (QIDS-SR16) is an instrument D. The anxiety, worry, or physical symptoms cause clinically
designed to screen for depression and to follow the changes significant distress or impairment in social, occupational, or other
in severity of depression over time (Rush et al., 2006a). The important areas of functioning.
QIDS-SR16 is a shortened version of the original 30-item E. The disturbance is not caused by the direct physiological effects
of a substance or a general medical condition.
Inventory of Depressive Symptomatology (IDS). Whereas F. The disturbance is not better explained by another mental
the IDS includes criterion symptoms and symptoms typi- disorder.
cally associated with depression, such as anxiety and irrita-
bility, the QIDS assesses only the nine symptom domains From American Psychiatric Association. Diagnostic and statistical manual of
used to characterize depressive episodes (sad mood, concen- mental disorders. 5th ed. Arlington, VA: American Psychiatric Association;
2013.
tration, self-criticism, suicidal ideation, interest, energy or
fatigue, sleep disturbance, changes in appetite or weight,
presence of psychomotor agitation or retardation). The Table 46-5 Diagnostic Criteria for Panic Attack
total score on QIDS ranges from 0 to 27 (0-5, no severity;
An abrupt surge of intense fear or intense discomfort that reaches a
6-10, mild; 11-15, moderate; 16-20, severe; 21-27, very peak within minutes and during which time four (or more) of the
severe). The QIDS was effective in assisting management following symptoms occur:
of depression in the STAR*D study, the largest depression 1. Palpitations, pounding heart, or accelerated heart rate
trial conducted thus far in the United States (Trivedi 2. Sweating
et al., 2006b). 3. Trembling or shaking
4. Sensations of shortness of breath or smothering
Screening for Bipolar Disorder 5. Feeling of choking
6. Chest pain or discomfort
Although no laboratory or imaging tests currently exist to 7. Nausea or abdominal distress
distinguish unipolar depression from bipolar depression, 8. Feeling dizzy, unsteady, lightheaded, or faint
screening questionnaires, as well as certain features of a 9. Chills or heat sensations
patient’s history and symptomatology, may prove helpful. 10. Paresthesias (numbness or tingling sensations)
11. Derealization (feelings of unreality) or depersonalization (being
The MDQ is a tool that combines DSM-IV criteria and clini- detached from oneself)
cal experience to screen for bipolar disorder in primary care 12. Fear of losing control or “going crazy”
settings (Hirschfeld et al., 2000). It is a brief, one-page self- 13. Fear of dying
report questionnaire with 13 yes-or-no items and two addi-
From American Psychiatric Association. Diagnostic and statistical manual of
tional questions regarding functioning and timing of mood mental disorders. 5th ed. Arlington, VA: American Psychiatric Association;
symptoms and typically can be completed in 5 minutes or 2013.
less. Seven or more positive responses to questions about
manic symptoms, plus positive responses to the severity of
impairment (moderate or severe) and coincident timing of duration, or frequency of the worry is out of proportion to
symptoms, yields a positive screen. The specificity and sen- the actual likelihood or impact of the feared event. Patients
sitivity of the MDQ vary widely by clinical setting, having must have at least three associated physical symptoms,
the best combination of  the two when given to patients including restlessness, irritability, muscle tension, disturbed
with suspected mood symptoms (93% specificity; 58% sen- sleep, fatigability, and difficulty concentrating. The list of
sitivity) but performs more poorly in general community associated symptoms can be thought of as symptoms of
samples (97% specificity; 28% sensitivity) (Hirschfeld et al., inner tension (restlessness or edginess, irritability, muscle
2003, 2005). Other screening tools for bipolar disorder do tension) and symptoms associated with the fatiguing effects
not offer the ease of use and higher reliability and validity of chronic anxiety (fatigue, concentration difficulties, sleep
of the MDQ. disturbance) (Table 46-4).
Panic attacks, a collection of distressing physical, cogni-
tive, and emotional symptoms, may occur in a variety of
DIAGNOSIS OF ANXIETY DISORDERS
mental health disorders and are not limited to anxiety dis-
The essential feature of GAD is excessive anxiety and worry orders. Panic attacks are discrete periods of intense fear in
about a number of events or activities, occurring most days the absence of real danger accompanied by at least 4 of 13
over 6 months. Patients have difficulty controlling the cognitive and physical symptoms (Table 46-5). The attacks
worry, report subjective distress, and may experience diffi- have a sudden onset; build to a peak quickly; and are often
culties in social or occupational functioning. The intensity, accompanied by feelings of doom, imminent danger, and a
Table 46-6 Diagnostic Criteria for Panic Disorder Assessment of the Depressed or
A. Recurrent and unexpected panic attacks
B. At least one of the attacks has been followed by 1 month (or
Anxious Patient in Medical Settings
more) of one or both of the following:
1. Persistent concern about having additional panic attacks or
their consequences Key Points
2. A significant maladaptive change in behavior related to the
attacks ■ Patients with anxiety and depressive disorders often
C. The disturbance is not attributable to the physiological effects of
present with somatic complaints.
a substance or a general medical condition.
■ Risk assessment includes identifying modifiable risk
D. The disturbance is not better explained by another mental
disorder. factors and developing a corresponding treatment plan.
■ “Contracts for safety” have no empiric data to support
From American Psychiatric Association. Diagnostic and statistical manual of their effectiveness in risk management.
mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; ■ Worsening symptoms or suicidal ideation may require
2013. psychiatric hospitalization.
need to escape. Symptoms of panic attacks can include Diagnosing anxiety and depressive disorders may prove
somatic complaints (e.g., sweating, chills), cardiovascular especially challenging in medical settings. The majority
symptoms (pounding heart, accelerated heart rate, chest of patients with such illnesses more frequently present
pain), neurologic symptoms (trembling, unsteadiness, with somatic complaints; only a minority present with
lightheadedness, paresthesias), GI symptoms (choking sen- purely psychological symptoms and concerns (Bridges and
sations, nausea), and pulmonary symptoms (shortness of Goldberg, 1985). Difficulties in diagnosis may be secondary
breath). In addition, patients with panic attacks may worry to a patient’s inability to articulate psychological problems,
they are dying or “going crazy” or have the sensation of reticence to speak of emotional difficulties, the short time
being detached from reality. Panic attacks can be listed as a allowed for patient visits, or a primary care physician’s
specifier to all DSM-5 disorders and is not considered a relative lack of training in assessing and treating mental
stand-alone diagnosis. health disorders. Many presenting complaints may be con-
Patients with panic disorder experience recurrent, unex- sistent with symptoms of coexisting medical illnesses,
pected panic attacks followed by at least 1 month of persis- further complicating assessment and likely requiring addi-
tent worry that they will have another panic attack. Patients tional etiologic investigation. Of new patients presenting to
with panic disorder may begin to avoid places where a prior an urban clinic, for example, only 17% presented with
attack occurred or where help may not be available (Table purely psychological symptoms. Of the remaining patients,
46-6). The DSM-5 has separated panic disorder and agora- 32% presented with pure somatization, 27% presented with
phobia into two unique and distinct diagnoses. symptoms for a coexisting medical illness, and 24% pre-
sented with an initial physical complaint that they were
Screening Tools for Anxiety Disorders later able to relate to a psychological problem (Bridges and
At present, screening tools for anxiety disorders have been Goldberg, 1985). However, clinical clues in patients with
developed to recognize anxiety as a broad syndrome, exam- physical complaints may identify a subgroup of patients
ining somatic symptoms (racing heart, lightheadedness) who warrant further evaluation for an anxiety or depres-
or cognitive symptoms (tendency to worry, intensity of sive disorder. This includes patients who present with mul-
worry). Other tools have been used to screen for single, dis- tiple physical symptoms (six or more), have higher ratings
tinct disorders, such as phobias or panic disorder. To date, of symptom severity and lower ratings of overall health,
no clear screening tool or symptom-severity measure has and have an encounter that the physician perceives as “dif-
emerged for use in primary care settings, although newer ficult” (Kroenke et al., 1997).
instruments may be useful for primary care physicians. The Assessment of anxious or depressed patients requires
Generalized Anxiety Disorder 7 (GAD-7) scale was devel- establishing specific psychiatric diagnosis (or diagnoses),
oped and validated in primary care clinics and is a brief, providing a thorough risk assessment (i.e., suicidality,
seven-item self-report screening tool for GAD (Spitzer et al., homicidality, ability or inability to care for self), assessing
2006). The GAD-7 helps identify probable cases of GAD and the severity of the illness, identifying specific target symp-
measure symptom severity. A score of 10 or greater repre- toms to track over time, assessing factors that are likely
sents a reasonable cutoff point for identifying patients with complicating or exacerbating the illness (e.g. medical
GAD, and cutoffs of 5, 10, and 15 correlate to mild, moder- disorders, substance abuse), and gathering collateral infor-
ate, and severe levels of anxiety, respectively. An extended mation whenever possible from family, friends, or other pro-
version of the PHQ includes five questions for panic disorder viders (Table 46-7). Distinguishing bipolar from unipolar
(Spitzer et al., 1999), but its utility as a stand-alone tool depression, as discussed previously, is one of the most
is currently unclear. The Overall Anxiety Severity and important distinctions when establishing a diagnosis. In
Impairment Scale (OASIS) is a five-item continuous measure addition, clinicians should look for the presence of comor-
that can be used across anxiety disorders, with multiple bid anxiety disorders because patients with such disorders
anxiety disorders, and with subthreshold anxiety symp- often require lower initial antidepressant dosing and may
toms. OASIS can be used to measure the severity of anxiety have their anxiety symptoms paradoxically worsen as treat-
symptoms, but it was not developed as a diagnostic tool for ment is initiated unless lower doses are used (Table 46-8).
any specific disorder (Norman et al., 2006). Education on the medical nature of depression and anxiety
Table 46-7 Initial Assessment of Anxious or mirtazapine for patients with insomnia or a more activating
Depressed Patients antidepressant such as bupropion for patients with lethargy
or somnolence. Measurement tools that are symptom spe-
1. Establish diagnosis.
2. Perform risk assessment: cific and sensitive to change over time (e.g., PHQ-9, QIDS-
Suicide risk SR) may help the physician track such changes. In addition,
Risks to others assessing overall functionality (ability to shower, pay bills,
3. Establish severity of illness: shop, prepare meals) is equally important in establishing
Ability to care for self
Functioning and functional impairment
the degree of impairment caused by the patient’s mood
4. Identify specific target symptoms: disorder.
Neurovegetative symptoms (e.g., sleep, appetite, concentration)
Use of measurement scales (e.g., Quick Inventory of Depressive
Symptomatology [QIDS]) DIFFERENTIAL DIAGNOSIS
5. Assess factors complicating illness:
Alcohol or drug use Many medical conditions may cause or mimic depression.
Comorbid or contributing medical conditions Physical disorders that have been associated with depres-
6. Gather input from family and friends if possible. sion include Addison disease, acquired immunodeficiency
syndrome (AIDS), coronary artery disease (especially in
those with myocardial infarction), cancer, multiple sclero-
Table 46-8 Dosing for Common Antidepressant and sis, Parkinson disease, anemia, diabetes, acute infection,
Antianxiety Agents temporal arteritis, hypothyroidism, and especially demen-
tias. It is imperative that the physician complete a neuro-
Usual Daily Starting Dose (mg)
logic evaluation to rule out an underlying disorder as the
Medication Anxiety Depression Daily Dose Range cause of the patient’s depression. In addition, many medi-
SELECTIVE SEROTONIN REUPTAKE INHIBITORS cations may worsen depression, especially cardiovascular
Citalopram 10 20 10-60 drugs, hormones, typical antipsychotic agents, antiinflam-
Escitalopram 5 10 5-30 matory agents, and anticonvulsants.
Fluoxetine 10 20 20-80 Anxiety disorders may be caused or exacerbated by medi-
Fluvoxamine 25 50 100-300 cal conditions, medications taken for other psychiatric or
Paroxetine 10 20 20-60
Sertraline 25 50 50-200 medical disorders, and other substances with stimulant
properties. For example, hyperthyroidism can mimic or ex-
SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS acerbate anxiety disorders, and therefore thyroid function
Desvenlafaxine 50 50 50-100 should be carefully evaluated when patients present with
Duloxetine 30 30 30-120
Venlafaxine 37.5 75 150-300 anxiety symptoms. In addition, lifetime risk of thyroid dys-
function appears higher in patients with panic disorder or
TRICYCLIC ANTIDEPRESSANTS GAD (Simon et al., 2002). Physicians should also assess the
Amitriptyline 25 50 100-300 patient’s use of other medications, especially stimulants
Imipramine 25 50 100-300
Nortriptyline 10 25 50-200
(whether prescribed or obtained from other sources), nico-
Desipramine 25 50 100-300 tine, illicit drugs, and caffeine.
NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITORS
Bupropion — 150 300-450 SUICIDE SCREENING AND ASSESSMENT
NOREPINEPHRINE-SEROTONIN MODULATORS Identifying patients at risk for suicide is a complex and dif-
Mirtazapine 15 30 30-60 ficult task, particularly in the setting of a busy medical prac-
tice. Suicide is currently the 10th leading cause of death for
all ages and the third leading cause of death among the
may prove extremely helpful because both patients and 15- to 24-year age group (Centers for Disease Control and
their families often believe that psychiatric illness is evi- Prevention, 2012). Older men (75 years and older) have the
dence of “weakness” or indicative of some other personal highest suicide rate, at 37.4 per 100,000. Men continue to
failing. Information on prognosis and the expected treat- take their lives at approximately four times the rate of
ment course may lessen pressure and expectations for rapid women and account for almost 80% of all U.S. suicides.
improvement and let the patient know when to expect med- Women in their 40s and 50s have the highest rates of
ication benefit. suicide among women (8 per 100,000), and women con-
Physicians should assess the severity of illness and tinue to make suicide attempts two to three times more often
develop a list of target symptoms to track and measure than men (Krug et al., 2002). Approximately 60% of all
over time to better evaluate treatment response. Tracking suicides are associated with patients with mood disorders
specific symptoms particular to an individual patient’s (Isometsa et al., 1995a), and approximately 50% of patients
depression improves objective assessment of change. Often, who completed suicide had contact with professional help
patients’ neurovegetative symptoms improve before the in the month before their death (Isometsa et al., 1995b).
subjective experience of their mood improves. Assessing Despite no definitive suicide assessment tool being avail-
sleep, appetite, energy level, anxiety, and concentration able, risk factors have been defined that can help identify
allows the physician to select a more appropriate antide- patients at risk for suicide. Suicide screening should include
pressant or anxiolytic by targeting specific symptoms. This assessing current level of depression, severity of symptoms,
may include using a sedating antidepressant such as feelings of hopelessness, current suicidal thoughts and
behaviors (as well as past attempts), use of drugs or alcohol Table 46-9 Initiation of Treatment for Major
(which can increase levels of impulsivity and worsen dys- Depression and Anxiety Disorders
phoria), current levels of anxiety and agitation, access to
1. Educate the patient:
lethal means (especially firearms), presence of psychosis Details of illness
(command hallucinations, poor reality testing), recent Treatment course, prognosis, goal of treatment (remission of
acute stressors, and presence (or absence) of a psychosocial symptoms)
support system (APA, 2003). When possible, additional Importance of general health: exercise, sleep hygiene, nutrition
Inclusion of family when possible
information from family or friends can be helpful in assess- Coordination with other providers
ing statements or behaviors that may indicate a patient’s Resource lists for support groups and therapy referrals
intentions of committing suicide. 2. Select medication from reasonable choices:
Physicians should be alert to suicide risk factors that can Patient history of antidepressant use and response
be modified. Although numerous historical and biologic Family history of antidepressant response
Typical time course to antidepressant response
risk factors cannot be modified (e.g., history of suicide 3. Administer starting dose and initiate dose titration:
attempts, family history of suicide, male gender, history Common side effects of medications
of childhood trauma), other risk factors are amenable to 4. Establish monitoring with measurement-based care (e.g., Quick
intervention. Patients with mood, anxiety, and psychotic Inventory of Depressive Symptomatology [QIDS]).
5. Schedule follow-up in 2 to 4 weeks.
symptoms can be successfully treated with medications.
Substance abuse referral may help a patient actively strug-
gling with substance abuse or dependence or for relapse psychiatric conditions likely to worsen unless their depres-
prevention. Encouraging the patient to mobilize psychoso- sion is treated (e.g., panic, GAD, chronic pain). Treatment
cial resources, such as contacting family members for of depression has clearly been shown to prevent relapse,
support, can provide a measure of safety while the patient shorten current episodes, decrease psychosocial impair-
is recovering from depression. Removing access to firearms ment, decrease risk of suicide, and improve quality of life.
can be especially helpful in preventing rapid access to lethal Mild depression may be treated with symptomatic inter
means during episodes of acute distress and high levels of vention alone (e.g., mild sedative for insomnia), although
impulsivity. Physicians should be aware that “contracts for continuing depressive symptoms or inadequate response to
safety” have not been shown to be effective in preventing purely symptomatic interventions warrants more aggres-
suicide and may provide a false sense of patient safety (Rudd sive treatment of the underlying depression. Patients
et al., 2006). Continued assessment of mood, hopelessness, with psychotic depression typically require treatment with
and suicidal ideation is required throughout the course of both antidepressant and antipsychotic agents, or they may
treatment. Worsening symptoms, along with plans or active require electroconvulsive therapy (ECT). Often, psychoti-
preparations for suicide, may require increased observation cally depressed patients require hospitalization. Patients
or hospitalization. with psychotic depression should be referred to a psy
chiatrist, given the severity of illness and complexity of
treatment.
Management and Treatment Again, the aim of treatment is remission of all depressive
symptoms and a return to the patient’s previous baseline
of Major Depression and functioning. Pharmacotherapy combined with psychother-
Anxiety Disorders apy has been shown to be superior to either modality alone
(de Maat et al., 2008; Thase, 1997); thus, referral to a psy-
The key objective in treating patients with depressive and chotherapist may be helpful, especially for patients with
anxiety disorders is remission of all symptoms. Studies moderate to severe depression. Some patients may choose
in the treatment of major depression have consistently psychotherapy alone to treat depression; psychodynamic
shown that a lack of remission is associated with higher therapy, cognitive-behavioral therapy (CBT), interpersonal
relapse rates, more severe subsequent depressions, shorter therapy, and behavioral activation may prove as effective as
durations between episodes, continued impairment in work medication alone.
settings and social relationships, increased all-cause mor-
tality, and increased risk of suicide (Judd et al., 2000). Selection of Medication
Initiation of treatment should include education about the The effectiveness of antidepressants is generally compara-
expected temporal course of improvement; importance of ble across classes; therefore, selection of an antidepressant
regular eating, activity, social interaction, and sleep; medi- depends mainly on patient preference, side effect profile,
cation selection; follow-up schedule; and safety manage- drug interactions, previous response to a specific medica-
ment if symptoms worsen or suicidal ideation is evident tion, treatment overlap with other psychiatric conditions,
(Table 46-9). and cost (Tables 46-10 and 46-11). Minimal data support
the increased efficacy or speed of onset for any particular
agent, with response rates across clinical trials generally
DEPRESSION
50% to 75% for patients receiving active treatment. The
Pharmacotherapy remains the mainstay treatment of onset of improvement typically takes 3 to 6 weeks, although
depression. Treatment should be considered for the major- the STAR*D study indicates that patients may require up to
ity of depressed patients, especially those who are suicidal, 12 to 14 weeks to achieve remission of symptoms. In fact,
functionally impaired from their depression, experiencing 40% of patients in the multiyear, multisite STAR*D study
a recurrent episode, or who have comorbid medical or who eventually achieved remission in the first level of
Table 46-10 Food and Drug Administration Indications for Antidepressant Therapy
Medication MDD OCD Panic PTSD GAD Soc Anx PMDD Bulimia Other or Off-Label Uses
Amitriptyline (Elavil) X Migraine prophylaxis, chronic pain
Bupropion (Wellbutrin) X Smoking cessation
Citalopram (Celexa) X
Desvenlafaxine (Pristiq) X
Desipramine (Norpramin) X
Duloxetine (Cymbalta) X X Diabetic peripheral neuropathic pain,
fibromyalgia
Escitalopram (Lexapro) X X
Fluoxetine (Prozac) X X X X X Pediatric depression
Fluvoxamine (Luvox) X
Imipramine (Tofranil) X Enuresis
Levomilnacipran (Fetzima) X
Mirtazapine (Remeron) X
Nortriptyline (Pamelor) X
Paroxetine (Paxil) X X X X X X
Sertraline (Zoloft) X X X X X X Premature ejaculation
Venlafaxine (Effexor) X X X X
Vilazodone (Viibryd) X
Vortioxetine (Brintellix) X
GAD, Generalized anxiety disorder; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; PMDD, premenstrual dysphoric disorder;
PTSD, posttraumatic stress disorder; Soc Anx, social anxiety disorder.
Table 46-11 Common Side Effects of Antidepressant Medications

Class or Drug Side Effects Comments
Selective serotonin GI side effects (nausea, diarrhea, heartburn); sexual Likely little difference between SSRIs in rates of
reuptake inhibitor (SSRI) dysfunction (decreased libido, delayed orgasm); headache; sexual side effects; SSRIs have been used to treat
insomnia or somnolence premature ejaculation
Serotonin-norepinephrine Hypertension, sweating, nausea, constipation, dizziness, Risk of increased blood pressure escalates as dose is
reuptake inhibitor (SNRI) sexual dysfunction increased; abrupt withdrawal of venlafaxine may
cause discontinuation syndrome
Tricyclic antidepressant Dry mouth, constipation, blurry vision, orthostatic Use with caution in patients with cardiac conduction
(TCA) hypotension, weight gain, somnolence, headache, delays
sweating, sexual dysfunction
Bupropion Insomnia, dry mouth, tremor, headache, nausea, Contraindicated in patients with seizure disorders or
constipation, dizziness eating disorders; patients generally free of sexual
side effects
Mirtazapine Somnolence, increased appetite, weight gain, dry mouth Sedation may be more pronounced at lower doses
Trazodone Sedation, orthostatic hypotension, priapism Usually used as a sedative–hypnotic
Benzodiazepines Sedation, fatigue, ataxia, slurred speech, memory Risk of dependence or abuse, especially with shorter
impairment, weakness acting benzodiazepines
GI, Gastrointestinal.
treatment with citalopram did not show a response (i.e., antidepressant studies have been conducted in specialty set-
50% improvement in symptoms) until week 8 of treatment tings, but a number of studies in primary care settings have
(Trivedi et al., 2006b). also shown the superiority of antidepressants over placebo
For most patients, initial treatment with a selective sero- (Arroll et al., 2009). Thus, given the comparable speed and
tonin reuptake inhibitor (SSRI), serotonin-norepinephrine efficacy of antidepressants across classes and within classes,
reuptake inhibitor (SNRI), bupropion, or mirtazapine is rea- selection of an antidepressant agent may be primarily
sonable. Tricyclic antidepressants (TCAs) are more often guided by side effect profile, possible secondary uses of anti-
used as second-line agents in the treatment of depression depressants (e.g., treating pain or insomnia), and contrain-
because of their potential toxicity in overdose, greater side dications to particular agents (e.g., bupropion in seizure
effect burden (largely from anticholinergic, antihistaminic, disorder patients). Table 46-8 gives the usual starting doses
and antiadrenergic properties), and potential cardiac com- for treatment of major depression.
plications (conduction delays). Monoamine oxidase (MAO) Serotonin reuptake inhibitors are safe, effective medications
inhibitors are complex drugs to use given their potentially that can treat patients with a variety of psychiatric condi-
fatal drug and dietary interactions and probably should tions. All SSRIs operate by the same mechanism of action
not be prescribed in family practice settings. Most and are considered equally effective in the treatment of
depression. However, failure of one SSRI does not necessar- histamine receptors, mirtazapine is generally more sedating
ily imply failure of all SSRIs; patients may respond prefer- at lower doses than higher. Although currently indicated
entially to one SSRI over another (Rush et al., 2006b). The only for depression, mirtazapine is reported to have general
SSRIs differ substantially by their potential to inhibit par- anxiolytic effects and may be beneficial for patients with
ticular hepatic cytochrome P-450 metabolic pathways and mild to moderate anxiety. With its 5-HT-3 blockade, mir-
by half-life, potency, and presence or absence of active meta tazapine may be helpful when patients complain of nausea
bolites. Clinicians should check for drug interactions in or other GI symptoms or side effects from SSRIs. Mirtazapine
patients receiving complex polypharmacy regimens because also has fewer sexual side effects than the SSRIs and SNRIs
drug–drug interactions are constantly being updated and and has been tried as an antidote to SSRI-induced sexual
changing. For example, fluoxetine is a potent 2D6 inhibitor side effects. Common side effects from mirtazapine include
that can triple TCA and phenytoin levels or increase the weight gain and daytime somnolence (see Table 46-11).
anticoagulation associated with warfarin. Fluoxetine also Bupropion is pharmacologically unique among antide-
has the longest half-life of any SSRI; its active metabolite pressants and is manufactured in immediate-release, slow-
norfluoxetine has a half-life of 10 days. The SSRIs have release (SR), and XR formulations. Although its primary
sexual side effects (decreased libido, delayed orgasm or mechanism of action is unclear, the drug has weak norepi-
anorgasmia) and GI side effects (nausea, diarrhea) (see nephrine and dopamine reuptake inhibition. Bupropion is
Table 46-11). GI side effects likely will remit over time, but an activating drug, making it better suited for patients with
sexual effects typically do not attenuate and may require poor energy or who believe they cannot tolerate a sedating
treatment with other agents, such as a phosphodiesterase medication. It is also virtually free from sexual side effects
inhibitor (e.g., sildenafil) or choosing an antidepressant less and has been used with limited success as an antidote for
likely to cause sexual side effects. patients with SSRI-induced sexual side effects (Clayton
The SNRIs (venlafaxine, duloxetine, desvenlafaxine, and et al., 2004). Bupropion rarely causes weight gain and is
levomilnacipran) are similar in efficacy to the SSRIs, therefore a good choice for patients who are obese or who
although a few studies have suggested a mild advantage believe they cannot tolerate weight gain. Unlike the SSRIs,
of SNRIs over SSRIs (Thase et al., 2001). Although the SNRIs, and TCAs, bupropion does not treat anxiety disor-
SNRIs by definition inhibit the reuptake of both serotonin ders and may even worsen anxiety in patients because of
and norepinephrine, dual-neurotransmitter reuptake inhi- its activating properties. Bupropion carries a black box
bition does not occur with venlafaxine until doses reach warning against its use in patients with a history of seizures
approximately 150 mg/day; below this dose, it acts primar- or eating disorders; the latter group was shown to have
ily as an SSRI. Venlafaxine is available in immediate-release a higher incidence of seizures in clinical trials. Given its
and extended-release (XR) formulations, although most greater propensity for seizures, bupropion dosing should
patients and clinicians favor use of the XR preparation, not be pushed above the FDA-recommended dosing limits.
given its once-daily dosing and lower likelihood of pro Bupropion has also been approved for treatment of smoking
voking a withdrawal syndrome on discontinuation of the cessation and therefore may have particular utility for
drug, more frequently observed with the immediate-release depressed patients who also want to quit smoking.
formulation. Desvenlafaxine, the active metabolite of ven- Vortioxetine is the most recently FDA-approved drug for
lafaxine, is more potent than its parent compound, but any the treatment of major depression (FDA, 2013). Although
advantages over venlafaxine are currently unclear. Unlike it has unique pharmacologic characteristics, acting as
venlafaxine, duloxetine provides dual-neurotransmitter an SSRI, a 5HT1A agonist, a partial agonist at 5-HT1B
reuptake inhibition at any dose, although this does not receptors, and an antagonist at 5-HT3, 5-HT1D, and 5-HT7
appear to confer any advantage over other SNRIs in terms receptors, it is currently unclear to what extent these char-
of efficacy or side effect profile. Duloxetine currently is indi- acteristics contribute to its antidepressant efficacy.
cated for treatment of chronic pain as well as depression, The TCAs are effective medications for treating depres-
but this is likely a class effect of SNRIs and not unique to sion and anxiety, with evidence of being more effective than
duloxetine. Levomilnacipran is an active enantiomer of the the SSRIs for severe depression, but the TCAs confer a
racemic drug milnacipran (approved by the U.S. Food and greater side effect burden than the newer antidepressants
Drug Administration for the treatment of fibromyalgia). and can be fatal in overdose. TCAs are divided into tertiary
It is the most noradrenergically active of the SNRIs, but and secondary amines. Tertiary amines, such as amitripty-
whether this will translate to unique clinical characteris line and imipramine, have greater anticholinergic, anti
tics has yet to be determined. Side effects of SNRIs histaminic, and α-adrenergic blockade side effects than
are similar to SSRIs (see Table 46-11), with the additional secondary amines, such as their respective metabolites nor-
side effects with SNRIs likely caused by increased norad triptyline and desipramine. The TCAs offer an advantage
renergic activity, including dose-related hypertension, over other antidepressants in that blood levels can readily
excessive sweating, and dry mouth (Thase, 2008a; Thase be checked and dosing individualized. Reasonable evidence
et al., 2005). suggests that the TCAs may be more effective in severely
Mirtazapine is a serotonin-norepinephrine modulator depressed patients (Gelenberg et al., 2010). In addition,
that also blocks postsynaptic hydroxytryptamine (HT) nortriptyline has a therapeutic window, with superior anti-
receptors, including those in the 5-HT-3 (serotonin) class. depressant efficacy if levels are maintained at 50 to 150 ng/
Mirtazapine is sedating and can increase appetite and mL. Because of cardiac conduction side effects, however,
therefore may be favored when patients have insomnia the TCAs must be used with caution in patients with con-
or decreased appetite and weight loss. Because of a dose- duction delays or who are taking class I antiarrhythmic
dependent ratio of neurotransmitter blockade involving agents, and electrocardiograms should be checked and
monitored in patients older than 50 years and in those with the PHQ-9 or QIDS, can aid in the objective assessment of
suspected cardiac disease. The TCAs also may cause tachy- improvement. Patients should be followed more frequently
cardia and orthostatic hypotension and thus should be used on initiation of treatment, increasing the time between
with caution in patients at risk for tachyarrhythmias or appointments as the patient improves. Monitoring for side
falls. The greatest single disadvantage to TCAs is their effects, particularly those that patients may be reluctant to
potential lethality in overdose; a typical 10-day supply can bring up spontaneously, such as sexual side effects, can
be lethal, and therefore TCAs should be prescribed cau- improve adherence and the therapeutic alliance. Patients
tiously in patients at high risk for suicide. The TCAs are also should also be monitored for any worsening of mood,
used in a variety of headache and pain syndromes and thus increased irritability, impulsivity, insomnia, sudden switches
may be useful in patients with such comorbidities. into euphoria, or suicidal ideation. Such symptoms may
Trazodone is structurally distinct from the SSRIs, TCAs, suggest bipolar diathesis, in which case discontinuing the
tetracyclics, and MAO inhibitors, but it still inhibits neuro- antidepressant and changing to mood stabilizing agents
nal uptake of serotonin. Although the FDA has approved it may be indicated. Antidepressant doses should be increased
as an antidepressant, trazodone is most often used as a every 2 to 4 weeks until the patient shows a response,
sedative–hypnotic. Whereas dosing as an antidepressant is maximum dose is reached, or side effects limit further
usually 300 to 450 mg, sedative–hypnotic dosing is usually dose changes. Antidepressant doses should continue to be
50 to 150 mg. The risks and side effects of trazodone include pushed until remission is achieved or the patient has under-
sedation, priapism, and myocardial irritability; the latter gone an adequate antidepressant trial (i.e., continuation
effect includes the potential of inducing torsades de pointes. of a therapeutic dose for at least 4 to 8 weeks) (Nierenberg
et al., 2000).
KEY TREATMENT Continuation of Treatment
• All antidepressants are generally equally effective; selec- As noted, physicians are encouraged to push treatment
tion is most often based on side effect profile, previous until symptoms remit, maximum doses are achieved, or side
response, comorbid conditions, drug interactions, and effects become intolerable. After symptoms remit, medica-
cost (Arroll et al., 2009; Trivedi et al., 2006b) (SOR: A). tions should continue for 6 to 9 months because risk
• The SSRIs, the SNRIs, mirtazapine, and bupropion are of relapse is greater if patients discontinue medications pre-
first-line treatments for depression (Rush et al., 2006b) maturely (AHCPR, 1999; Geddes et al., 2003). Patients
(SOR: A). who have had multiple episodes of depression should con-
• Antidepressant doses should be increased every 2 to 4 tinue pharmacotherapy because lifetime relapse rates for
weeks until remission of depressive symptoms is achieved such patients are 50% to 85% (Eaton et al., 2008), and the
or side effects become intolerable (Gelenberg et al., 2010) risk of recurrence increases by 16% with each successive
(SOR: A). episode (Solomon et al., 2000). Ongoing treatment should
• Treatment of depressive episodes ranges from 6 to 9 also be considered for patients who experienced severe
months to years, depending on the number of prior epi- functional impairment, severe suicidal ideation, or serious
sodes, severity of episodes, and risk of relapse (AHCPR, suicide attempts.
1999; Geddes et al., 2003) (SOR:A).
Discontinuation of Treatment
• Psychotherapy has proved effective in treating depres-
sion, either as monotherapy or combined with pharma- For patients who have achieved ongoing remission and
cotherapy (de Maat et al., 2008; Thase, 1997) (SOR: A). want to discontinue their medications, withdrawal of
treatment should be gradual and carefully monitored
(Table 46-13). Timing of discontinuation often depends on
Initiation of Treatment a patient’s current life stressors and the potential conse-
After a patient has been initiated on an antidepressant, quences of depressive relapse (e.g., loss of new job, stress on
dosing should be optimized to treat depressive symptoms recently repaired relationship). Antidepressants should be
to remission while minimizing side effects (Table 46-12). gradually withdrawn to minimize potential withdrawal
Patients should be monitored for improvement in their syndromes and allow for rapid upward titration if depres-
mood and their specific array of depressive symptoms. sive symptoms recur. Physicians should discuss the early
Continued use of measurement-based care tools, such as warning signs of relapse (insomnia, early-morning awak-
ening, loss of interest in activities) and instruct patients to
contact their physicians if such symptoms recur. The risk
Table 46-12 Assessing Antidepressant Treatment of relapse is greatest in the first few months of discontinu-
Monitor the effectiveness of treatment. ing antidepressants, and thus a scheduled appointment in
Continue assessment of specific symptoms. this period is often needed to monitor for relapse. Patients
Assess need for further titration of medication. who relapse after cessation of antidepressants should be
Continue to use measurement-based care.
Assess any worsening of mood, increased irritability, or worsening
suicidal ideation.
Assess adherence to medication regimen. Table 46-13 Discontinuation of Antidepressant Treatment
Assess for medication side effects.
Continue to emphasize nutrition, physical activity, and caring for self. Remission of symptoms for 6-12 mo
Minimize complexity of medication dosing (e.g., once daily or nightly, Tapering of medications rather than abrupt cessation
when possible). Discussion of relapse risks and early warning signs of recurrence
restarted on their previous medication and again titrated to augmenting agent, although a meta-analysis of atypical
remission of symptoms. antipsychotics as augmenting agents found their efficacy
superior to placebo, with a number needed to treat (NNT)
of nine for both response and remission (Nelson and
ANTIDEPRESSANT FAILURE
Papakostas, 2009). Buspirone has also been used as an
Patients who fail antidepressants should be carefully reeval- augmenting agent because its 5-HT-1A receptor agonism
uated, with reconsideration of medication adherence, may enhance SSRI response. In the STAR*D study, 30% of
adequacy of dosing and treatment duration, diagnosis, patients who failed to achieve remission taking citalopram
comorbid psychiatric illnesses, increased stressors, and went on to remit with the addition of buspirone, up to
unaddressed medical or substance comorbidities. Initial 60 mg/day (Trivedi et al., 2006a).
antidepressant failure may be relatively common; only one Combining two antidepressants to treat refractory
third of patients achieved remission after 12 to 14 weeks of depression is based on the theory that targeting a greater
treatment with citalopram in the STAR*D study (Trivedi number of neurotransmitters will lead to improved anti
et al., 2006b). If a patient fails an adequate antidepressant depressant response. Common strategies include combin-
trial, the next strategy is (1) switching to a different anti ing mirtazapine and venlafaxine, bupropion and SSRIs,
depressant within the same class or across classes, (2) or bupropion and SNRIs. Combining drugs of similar class
augmenting the existing antidepressant with a secondary (e.g., SSRI + SSRI or SNRI + SNRI) currently has few data
agent, or (3) adding a second antidepressant to the first. The to support its use. Venlafaxine combined with mirtazapine
choice of strategy depends on patient preference, assess- and citalopram plus bupropion SR were effective in the
ment of benefit from current antidepressant, current side STAR*D study when patients failed to achieve remission on
effects, and psychiatric and medical comorbidities. their current regimen. Adding bupropion to citalopram
Switching antidepressants is generally considered when achieved a remission rate of approximately 30% in patients
the patient has had little to no response to the first agent or whose symptoms failed to remit after 12 weeks of citalo-
is having intolerable side effects. Across-class switches pram therapy. The combination of venlafaxine plus mir-
are most often considered as an initial strategy (e.g., SSRI tazapine was used in a highly treatment-refractory group
to SNRI), although within-class switches may also prove (failed three previous medication trials) and achieved
useful (e.g., fluoxetine to sertraline). Across-class or intra- remission of symptoms in approximately 14% of patients
class switching may yield response rates of 20% to 50% (McGrath et al., 2006).
(Thase, 2008b). In the STAR*D study, switching from cital-
opram to either bupropion SR, venlafaxine, or sertraline KEY TREATMENT
yielded remission rates of 18% to 25% (Rush et al., 2006b).
No clear guidelines exist as how best to cross-taper medica- • Patients who fail antidepressants should be carefully
tions, although it is generally unwise to stop antidepres- reevaluated for medication adherence, adequacy of
sants abruptly because withdrawal syndromes may ensue. dosing and therapy duration, diagnosis, comorbid psychi-
Medications with short half-lives, such as venlafaxine atric illnesses, increased stressors, and unaddressed
(immediate release) or paroxetine, have most often been comorbidities (Trivedi et al., 2006a) (SOR: A).
associated with withdrawal syndromes. Typically, patients • Common strategies used when patients fail an initial anti-
complain of flulike symptoms, electric-like shocks in the depressant treatment are switching antidepressants
back of their heads, or dizziness (Taylor et al., 2006). (either within class or across classes) (Rush et al., 2006b;
Consideration of half-life and slow cross-tapers often yields Thase, 2008b), augmenting with other agents (lithium,
the most tolerable switch. T3, atypical antipsychotics) (Nierenberg et al., 2006;
Augmentation strategies involve adding a second agent Trivedi et al., 2006a), or combining different antidepres-
with no intrinsic antidepressant properties to the existing sants (McGrath et al., 2006) (SOR: A).
antidepressant. These are often considered when a patient
has had a partial response to an antidepressant but has not
reached remission, and switching to an alternate antide- ANXIETY
pressant may risk loss of existing response. The two best
studied augmentation strategies to date are adding lithium There is significant pharmacologic overlap between the
and triiodothyronine (T3). Although many lithium aug- treatment of depression and anxiety disorders. Most
mentation studies are limited by methodologic consider- antidepressants are also effective antianxiety agents, or
ations, response has been seen as quickly as 48 hours or as anxiolytics (see Table 46-10), thus simplifying treatment
long as 2 to 4 weeks. Standard lithium levels of 0.5 to strategies when patients have both disorders. In addition,
1.0 mmol/L have most often been used. T3 augmentation significant overlap also exists between medications that
has yielded similar results, if often better tolerated than effectively treat GAD and panic disorder. Treatment recom-
lithium, usually with doses of 25 to 50 µg/day. Overall mendations for both GAD and panic will be explored sepa-
remission rates in patients unable to achieve antidepressant- rately to highlight some of the treatment differences
alone remission range from 15% to 50% (Nierenberg et al., between the two disorders.
2006). Atypical antipsychotic drugs have also been used as
augmenting agents in nonpsychotic major depression, with Generalized Anxiety Disorder
beneficial results. Aripiprazole currently has an indication Antidepressants are generally considered first-line agents
as an augmenting agent, at 2 to 15 mg/day. To date, no for treatment of GAD because of their efficacy and safety,
other atypical antipsychotic has an FDA indication as an effectiveness in treating comorbid major depression, and
absence of addictive or abuse potential, as seen with benzo- with shorter half-lives, such as immediate-release alpra-
diazepines. As a general rule, starting antidepressant doses zolam or lorazepam. Scheduled dosing of a benzodiazepine
for patients with GAD should be approximately half the provides for a more consistent medication blood level and
lowest starting dose for treatment of depression; many may also be a more effective approach than PRN dosing.
experience a paradoxical worsening of their symptoms on The duration of therapeutic effect for benzodiazepines is
antidepressant initiation if doses are high (see Table 46-8). determined by the rate and extent of drug distribution (lipo-
Patients with anxiety disorders are typically more sensitive philicity) and not necessarily by the rate of elimination.
to antidepressant side effects (see Table 46-11), and thus Benzodiazepines such as diazepam have a longer half-life
starting at lower doses and titrating slowly will likely yield than lorazepam, but because diazepam is more lipophilic, it
better results. has a faster onset of action and shorter duration of effect
The SSRIs and SNRIs are considered first-line treatments, after a single dose (Schatzberg and Nemeroff, 2009). Drug
with numerous studies demonstrating both efficacy and elimination occurs in the liver through microsomal oxida-
effectiveness (Hoffman and Mathew, 2008). A Cochrane tion or glucuronide conjugation. Oxidation is sensitive to
review of antidepressant treatment of GAD that included liver disease and certain medical conditions and medica-
paroxetine, sertraline, venlafaxine, and imipramine found tions (e.g., cimetidine); therefore, benzodiazepines metabo-
a very large effect size, with an NNT of only five patients lized through hepatic oxidation are more likely to show
for one patient to receive benefit, with no clear evidence of unpredictability than those metabolized via conjugation.
one antidepressant superior to another (Kapczinski et al., Benzodiazepines such as temazepam, lorazepam, and oxaz-
2003). At present, the SSRIs escitalopram and paroxetine epam are cleared through hepatic conjugation and are safer
and the SNRIs venlafaxine and duloxetine are the only anti- and better tolerated when oxidative elimination has been
depressants with an FDA indication for GAD (see Table altered.
46-10). No randomized controlled trials (RCTs) have yet Even though the benzodiazepines offer the advantage of
supported the efficacy of fluoxetine or citalopram in the rapid onset and effectiveness, other disadvantages have rel-
treatment of GAD, although their clinical use is based on egated them to second-line agents. Benzodiazepines pose a
the assumption that SSRIs exert a class effect and are likely significant risk of dependency and withdrawal, are poten-
equally effective. The SNRI desvenlafaxine may be effective tially lethal in overdose if mixed with other sedating agents
but currently is indicated only for major depression. (especially alcohol), and are ineffective in treating comorbid
The TCAs, also effective agents for treating GAD, have depression. The benzodiazepines also can impair attention
been relegated to second-line treatment because of side and vigilance and cause dose-dependent anterograde
effects (e.g., anticholinergic, sedative, orthostatic) and amnesia, with limited effect on psychic symptoms, includ-
potential lethality in overdose. Imipramine has the stron- ing worry (Hoehn-Saric et al., 1988). Benzodiazepines
gest data to support its use in GAD (Kapczinski et al., 2003). should generally be considered second- to third-line agents
Although used effectively in the treatment of anxiety disor- as monotherapy in GAD, although they are often used as
ders, MAO inhibitors have significant side effects (risk for adjunctive agents when initiating antidepressant treatment
hypertensive crisis, potential lethal interactions with other to provide immediate relief of anxiety symptoms until anti-
medications) and likely do not have a role in primary care depressant effects begin. Symptom severity and patient
and should be reserved for psychiatric practice. Mirtazapine preference should be considered when deciding whether to
has shown some efficacy in open-label trials (Gambi et al., use an antidepressant as monotherapy or to start a benzo-
2005) but needs further study in RCTs to be considered a diazepine with an antidepressant. A subset of patients may
first-line agent in GAD. Bupropion has a less clear role in benefit from long-term treatment with both an antidepres-
the treatment of anxiety disorders and may worsen rather sant and a benzodiazepine.
than alleviate anxiety symptoms. However, a recent pilot Nonbenzodiazepine and nonantidepressant treatment
study showed that bupropion XL had comparable anxiolytic may also be effective in the treatment of GAD, especially for
efficacy with escitalopram in a 12-week, double-blind RCT patients with mild to moderate symptom severity. Buspirone,
and was well tolerated (Bystritsky et al., 2008). Bupropion an azapirone that exerts 5-HT-1A receptor agonism, carries
may have a role in GAD treatment in the future but cur- an FDA indication for GAD. Buspirone appears useful in the
rently may be considered a second- or third-line agent. treatment of GAD, particularly for patients who have not
Benzodiazepines are also extremely effective for treatment yet received a benzodiazepine (Chessick et al., 2006). In
of GAD and offer the advantage of rapid effect. Their onset clinical practice, buspirone can be used as monotherapy in
of action is typically within hours versus weeks with anti- patients with mild to moderate symptoms, and it is often
depressants. All benzodiazepines are theoretically equally considered an alternative to benzodiazepines as an aug-
effective in GAD, and thus selection of individual agents menting agent to antidepressants. Hydroxyzine, an antihis-
often involves comparing half-lives, metabolic pathways, taminic agent, also carries an FDA indication for GAD and
the presence or absence of active metabolites (particularly has shown efficacy in RCTs (Llorca et al., 2002). Its sedative
in patients with liver disease), and the speed of onset of properties and lack of efficacy in comorbid disorders have
action. Benzodiazepines with shorter half-lives result in the relegated hydroxyzine to a second-line agent. Interestingly,
inconvenience of multiple daily dosing, the risk of rebound a meta-analysis of effect sizes in pharmacotherapy of GAD
anxiety, and the common need to use as-needed (PRN) recently showed that hydroxyzine had a larger effect size
doses as a “rescue” medication when symptoms are inade- (0.45) than the SSRIs (0.36) (Hidalgo et al., 2007). At
quately controlled. Medications such as clonazepam, with present, hydroxyzine may be considered an alternative to
long half-lives, or alprazolam XR, with a slower and more benzodiazepines when no comorbid illnesses are present as
prolonged onset of action, may be more effective than drugs monotherapy. Recent studies of pregabalin have also shown
efficacy in the treatment of GAD. In the meta-analysis cited, (APA, 2009). Because of tolerability and toxicity in over-
pregabalin was found to have the largest effect size (0.5) dose, TCAs are second-line agents for panic.
of all agents (SSRIs, SNRIs, benzodiazepines, azaspirones, The benzodiazepines offer several advantages over anti-
antihistamines, complementary or alternative agents). The depressants in the treatment of panic, including rapid
effect size of pregabalin was determined from two large onset, PRN dosing schedules, and relief of insomnia and
RCTs. In addition, pregabalin was found to be effective in somatic symptoms (Bruce et al., 2003). Similar to use in
relapse prevention compared to placebo over a 6-month GAD, selection of a particular benzodiazepine is based on
trial (Feltner et al., 2008). β-Blockers such as propranolol half-life, speed of onset of action, presence or absence of
and pindolol have also been used in the treatment of GAD. active metabolites, and metabolic pathways (particularly in
Although these can block the physiologic effects of anxiety, patients with liver disease). All benzodiazepines are likely
such as sweating and increased heart rate, β-blockers equally effective in treating panic, although in clinical prac-
appear ineffective in treating the underlying emotional tice, higher potency benzodiazepines (e.g., alprazolam,
component of anxiety, and little empiric evidence supports clonazepam, lorazepam) are used more often than lower
their use in GAD at present. In a recent Cochrane review, potency drugs (e.g., oxazepam). Clonazepam and alpra-
quetiapine is the only atypical antipsychotic to show effec- zolam both are FDA approved for panic disorder, and some
tiveness as a monotherapy in GAD (Depping et. al., 2010), clinicians prefer clonazepam to alprazolam because of clon-
but the FDA denied approval for this indication because azepam’s longer half-life, less frequent dosing, and slower
of the side effect burden outweighing the benefit of the onset of action. Lorazepam and diazepam do not have an
medication. FDA indication for panic but seem to be effective agents in
RCTS and clinical practice (Mitte et al., 2005). The benzo-
diazepines may be considered as first-line monotherapy
KEY TREATMENT when no comorbid conditions exist with panic disorder.
• The SSRIs and SNRIs are considered first-line treatments Agents with rapid onset (alprazolam, lorazepam) may be
for GAD, with the starting dose typically half that used in preferred if taken on a PRN basis or used as a rescue medi-
patients with depression (Hoffman and Mathew, 2008) cation. However, shorter-acting agents can introduce prob-
(SOR: A). lems with interdose rebound anxiety or more difficulty with
• The TCAs are effective in treatment of GAD (SOR: A), adherence to multidose regimens. Agents with longer half-
but their side effect profile and potential lethality have lives, such as clonazepam and alprazolam XR, may be
relegated them to second-line agents (Kapczinski, scheduled once or twice daily to provide more even coverage
et al., 2003). throughout the day but do not provide immediate relief if
• The benzodiazepines offer the advantage of rapid effect taken on a PRN basis.
and proven efficacy (Chessick et al., 2006; Schatzberg Although the benzodiazepines can bring quick relief
and Nemeroff, 2009) (SOR: A), but they carry risk of from panic symptoms, their side effect profile and risk of
abuse and dependence. dependency, abuse, and withdrawal must be considered
• Other agents for the treatment of GAD include hydrox- when deciding on their use. Common side effects include
yzine (Llorca et al., 2002) (SOR: A), buspirone (Chessick sedation, fatigue, ataxia, slurred speech, memory impair-
et al., 2006) (SOR: B), and pregabalin (Feltner et al., ment, and weakness. Geriatric patients taking benzodiaze-
2008) (SOR: B). pines may be at higher risk for falls and fractures (Stone
• Maintenance treatment of GAD reduces the likelihood of et al., 2008). Patients with a substance abuse history may
relapse (Thuile et al., 2009) (SOR: B). need to be monitored closely for signs and symptoms of
abuse; patients actively abusing substances should probably
not be prescribed benzodiazepines. For many of these
PANIC DISORDER patients, discussing clear expectations that prescriptions
will not be rewritten or refilled before a set date can limit
Similar to the treatment of GAD, SSRIs, SNRIs, TCAs, and later conflicts and improve treatment adherence.
benzodiazepines have all been found to be effective for the Evidence for the use of β-blockers in panic disorder is
treatment of panic disorder. The effectiveness of these sparse. β-Blockers have been used to reduce the somatic
agents appears relatively equal, and thus selection of a par- symptoms of panic attacks, such as palpitations, but do not
ticular agent is most often based on tolerability, cost, ability seem to be effective in overall treatment of panic disorder.
to treat comorbid disorders, potential for abuse and toler-
ance, and patient preference. First-line agents to treat panic
KEY TREATMENT
are most often SSRIs and SNRIs. Fluoxetine, paroxetine, ser-
traline, and venlafaxine all have FDA indications for panic • The SSRIs, SNRIs, TCAs, and benzodiazepines have all
disorder (see Table 46-10), although all the SSRIs have data been found to be effective in the treatment of panic dis-
to support their use (Otto et al., 2001). The SNRIs dulox- order (Otto et al., 2001) (SOR: A).
etine and desvenlafaxine do not currently have large RCT • The first-line agents for panic disorder are SSRIs and
evidence to support their use in panic disorder but may have SNRIs, with starting doses typically half that for depres-
efficacy based on class effect. The TCAs are also as effective sion (APA, 2009) (SOR: A).
in treating panic as SSRIs but are less well tolerated because • Benzodiazepines can be used as first-line agents when no
of their anticholinergic and antihistaminic side effects comorbid psychiatric issues are present, including issues
(Bakker et al., 2002). Both imipramine and clomipramine of substance abuse and dependence (Mitte et al., 2005)
have the most data to support their use in panic disorder (SOR: A).
• Maintenance treatment of panic disorder has been shown many as 40% to 60% of patients may be taking CAM thera-
to reduce the likelihood of relapse (Thuile et al., 2009) pies, although patients often do not disclose such use to
(SOR: B). their physicians (Elkins et al., 2005). In addition, because
production of alternative agents is unregulated, variability
in product strength, dosing, and purity is common, which
CONTINUATION OF TREATMENT in turn likely affects the predictability of their outcomes.
IN ANXIETY DISORDERS Given the widespread use of CAM agents and patients’
apparent reluctance to spontaneously disclose such use to
Treatment for anxiety disorders should be continued for 6 their providers, it is incumbent on physicians to inquire
months to 1 year; a more definitive time frame is not yet about such use.
clear. Results from long-term RCTs of antidepressants in The majority of CAM treatments have been used to treat
anxiety disorders indicate that maintenance treatment sig- depression, including St John’s wort (Hypericum perfora-
nificantly reduces the risk of relapse, whatever the disorder tum), S-adenosyl-L-methionine (SAM-e), and omega-3 fatty
(Thuile et al., 2009). Decisions on length of treatment are acids. In a Cochrane review of St John’s wort for treatment
generally made on a case-by-case basis, taking into account of major depression, great heterogeneity was found among
the risk-to-benefit ratio of treatment versus no treatment. the 29 analyzed trials (Linde et al., 2005). St John’s wort
If the decision is to discontinue treatment, the medication was found to be superior to placebo and similarly effective
should be tapered at a rate that takes into account its phar- as standard antidepressants, but findings were more favor-
macokinetics and whether the patient experiences with- able to St John’s wort studies from German-speaking coun-
drawal symptoms (see Table 46-13). tries, where use of the extract has a long tradition. The
more positive results may be caused by physician expertise
OTHER CONSIDERATIONS with the medication, patient selection, or flawed method-
ologies in some research. The larger, placebo-controlled
Antidepressants and Suicidal Ideation studies have yielded mixed results, although compared with
In 2004, the FDA added a black box warning to all anti antidepressants, St John’s wort has generally been better
depressants indicating that the use of antidepressants in tolerated (Shelton, 2009).
children, adolescents, and adults younger than 25 years of SAM-E, a dietary supplement, has been used to treat a
age increased the risk of suicidal thinking and behavior. variety of illnesses, ranging from major depression to osteo-
The warning on antidepressants was based on an analysis arthritis to liver disease. Clinical trials have shown SAM-e
of 372 clinical trials involving 11 antidepressant medica- to be superior to placebo and equivalent to TCAs in treating
tions noting an increase in the number of patients who patients with depression, although the most robust findings
experienced an increase in suicidal ideation and behavior, have been shown with parenteral administration of the
although no increase in actual suicides was observed. drug. Studies using the oral form have yielded more variable
Further analysis of the FDA data revealed a strong age- results. In adjunctive use with antidepressants, only one
dependent relationship, such that the greatest risk was in open-label study has been published to date. SAM-e has
patients younger than 25 years old. In clinical terms, 4 been shown to be safe and well tolerated thus far (Papakostas,
additional patients in 1000, age 18 to 24 years, would be 2009).
expected to experience suicidal ideation or behavior as Omega-3 fatty acids have a variety of health benefits and
a result of taking antidepressants, and an additional 14 may be helpful as augmenting agents in the treatment of
patients in 1000 younger than age 18 years would be major depression. The best studied agents are eicosapentae-
expected to experience worsening. Patients older than 30 noic acid (EPA) and docosahexaenoic acid (DHA). Findings
years showed a reduction in suicidal ideation as a result of in depression are limited by variability in study design
taking antidepressants, with a reduction of 6 patients of and small sample sizes, although the majority of evidence
1000 in adults older than 65 years. The net effect of anti- favors a positive effect in the treatment of mood disorders
depressant use in patients age 25 to 64 years seems moder- (Freeman, 2009).
ately protective against suicidal ideation and more strongly At present, little robust evidence supports the efficacy
protective for adults age 65 years and older (Levenson of CAM agents in the treatment of anxiety disorders.
and Holland, 2006). Antidepressants should be used cau- Kava (Piper methysticum) has preliminary evidence of effi-
tiously in patients younger than age 25 years, with close cacy in GAD, but further testing is needed to determine
monitoring for worsening of mood or thoughts of suicide, its side effects and potential for hepatotoxicity (Sarris and
particularly in the days and weeks after the drug is initi Kavanagh, 2009). A meta-analysis found no statistically
ated. For the majority of depressed patients, the beneficial significant difference between kava and placebo (Hidalgo
effects of antidepressants greatly outweigh the risks (Libby et al., 2007). Given the paucity of current evidence, caution
et al., 2007). should be used when considering kava as a therapeutic
agent.
Nontraditional Therapy
Interest in complementary and alternative medicine (CAM) OTHER TREATMENTS
for health disorders has been growing steadily in the past
several decades. As a result, a greater number of alternative Electroconvulsive Therapy
or complementary agents are being tested in more method- Electroconvulsive therapy involves a brief electrical stimu-
ologically rigorous ways, allowing greater scientific assess- lation of the brain while the patient is anesthetized, induc-
ment of such treatments. Survey evidence suggests that as ing a seizure. ECT remains the most effective treatment for
depression (UK ECT Group, 2003), although the stigma psychotic depression are best treated by specialty providers.
surrounding the treatment, misinformation about its prac- Patients with bipolar disorder should be referred as well,
tice, side effects, and cost have often made it a treatment of especially those with bipolar depressions, because they are
last resort. Although occasionally used as first-line therapy often especially difficult to treat, usually require complex
for severe depression, ECT is often used for multitreatment- polypharmacy, and worsen with inappropriate treatment.
refractory patients, those with psychotic depression, sui- Patients requesting or needing psychotherapy or behavioral
cidal patients (imminent), and depressed patients with therapy may be referred to a mental health provider.
compromised oral intake. A typical course is 6 to 20 treat-
ments, with patients receiving ECT three times a week Summary
during the acute phase, gradually increasing the time For the majority of depressed patients, the beneficial effects
between treatments as improvement becomes apparent. of antidepressants greatly outweigh the risks. CAM treat-
After acute treatment, patients are often returned to anti- ments for depression may be beneficial for some patients,
depressant therapy, although medication efficacy after ECT but study methodology limits their generalizability. ECT is
does not appear to be enhanced (Kellner et al., 2006). still considered the most effective treatment for severe
Physicians should be aware that ECT is safe, well tolerated, depression. VNS and TMS are emerging therapies for the
humane, and effective. treatment of depression.
Vagus Nerve Stimulation and Transcranial
KEY TREATMENT
Magnetic Stimulation
Vagal nerve stimulation (VNS) involves the surgical implan- • Psychotherapy is an important and effective treatment
tation of a nerve stimulator for the left vagus nerve at the strategy for both depression and anxiety. Psychotherapy
cervical level and has been approved for treatment of refrac- combined with pharmacotherapy often yields results
tory depression. VNS is not an acute treatment but has superior to either treatment alone (Furukawa et al.,
shown some long-term benefit for depressed patients 2007; Pampallona et al., 2004) (SOR: A).
(George et al., 2005). Transcranial magnetic stimulation
(TMS) involves the introduction of repetitive magnetic
References
impulses to the right prefrontal cortex in a series of treat-
ments over several weeks. TMS is approved for the treatment The complete reference list is available at

of unipolar depression for patients who have failed one www.expertconsult.com.

trial of antidepressants or for those patients who have
exhibited marked intolerance to antidepressants (O’Reardon Web Resources
et al., 2007).
Patient Resources
Psychotherapy freedomfromfear.org National nonprofit mental health advocacy organiza-
tion focused on anxiety and depressive disorders.
In addition to pharmacologic interventions for depression, www.nih.nimh.gov National Institute of Mental Health. Provides excel
panic disorder, and GAD, psychotherapy continues to be an lent up-to-date information on the symptoms, causes, course, and treat-
effective tool used by psychiatrists and psychotherapists for ment of a number of illnesses. Provides numerous lists and links to
treating mood and anxiety disorders. Although primary resources.
www.ocdfoundation.org The Obsessive-Compulsive Foundation. Provides
care physicians will not administer such treatments, it information and resources on obsessive-compulsive disorder and other
is important to be aware of general psychotherapeutic mental health diagnoses.
concepts and strategies. Several types of therapy have
strong evidence supporting their efficacy in treating both Support for Patients, Family, and Friends
depression and anxiety disorders, including CBT, interper- www.afsp.org American Foundation for Suicide Prevention. Leading
sonal therapy, psychodynamic psychotherapy, problem- national nonprofit dedicated to understanding and preventing suicide
solving therapy, and supportive therapy (Cuijpers et al., through education and research and to reaching out to people with
2008). Some patients may prefer to begin treatment with mood disorders and those impacted by suicide.
www.coloradofederation.org The Federation for Families for Children’s
medications alone, but others may prefer only psychother- Mental Health. The mission of the federation is to promote mental
apy or a combination. Combined pharmacologic and psy- health for all children, youth, and families. The website has numerous
chotherapeutic interventions have generally been shown to links to resources, articles, books, and support groups.
be superior to either approach alone in trials for both www.dbsalliance.org Depression and Bipolar Support Alliance. Provides
anxiety disorders and depression (Furukawa et al., 2007; education to patients and families about mood disorders. Advocates
research funding, improving access to care, fostering self-help, and
Pampallona et al., 2004). decreasing public stigma of these illnesses.
www.healthyminds.org Site created by the American Psychiatric
Referral to Mental Health Providers Association to provide education and resources on mental health issues.
Which patients should be referred to mental health provid- www.nami.org National Alliance on Mental Illness. Grass-roots, self-help,
support, and advocacy group for people with severe mental illnesses,
ers? Referrals may be made because of patient preference or their family members, and friends.
severity of illness or because of the complexity of comorbid www.webmd.com/depression Provides information on the diagnosis and
illnesses. Patients who experience refractory depression or treatment of mood disorders.
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46 Anxiety and Depression

BRIAN ROTHBERG and CHRISTOPHER D. SCHNECK

CHAPTER OUTLINE Overview, 1090 Assessment of the Depressed or Anxious

cyclothymia, and dysthymia (also called pervasive depres-

Table 46-1 Diagnostic Criteria for Major Depressive Episode

Table 46-11 Common Side Effects of Antidepressant Medications

of unipolar depression for patients who have failed one www.expertconsult.com.

Feltner D, Wittchen HU, Kavoussi R, et al: Long-term efficacy of pregabalin

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Anxiety and Depression: Brian Rothberg and Christopher D. Schneck

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Anxiety and Depression: Brian Rothberg and Christopher D. Schneck

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46 Anxiety and Depression

BRIAN ROTHBERG and CHRISTOPHER D. SCHNECK

CHAPTER OUTLINE Overview, 1090 Assessment of the Depressed or Anxious

cyclothymia, and dysthymia (also called pervasive depres-

Table 46-1 Diagnostic Criteria for Major Depressive Episode

Table 46-11 Common Side Effects of Antidepressant Medications

of unipolar depression for patients who have failed one www.expertconsult.com.

Feltner D, Wittchen HU, Kavoussi R, et al: Long-term efficacy of pregabalin

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Feltner D, Wittchen HU, Kavoussi R, et al: Long-term efficacy of pregabalin