3545Psychiatric Disorders CHAPTER 452

processing of the fear stimulus occurs through the lateral nucleus of the

amygdala, extending through the central nucleus and projecting to the

periaqueductal gray region, lateral hypothalamus, and paraventricular

hypothalamus.

TREATMENT

Phobic Disorders

Beta blockers (e.g., propranolol, 20–40 mg orally 2 h before the

event) are particularly effective in the treatment of “performance

anxiety” (but not general social phobia) and appear to work by

blocking the peripheral manifestations of anxiety such as perspiration, tachycardia, palpitations, and tremor. MAOIs alleviate social

phobia independently of their antidepressant activity, and paroxetine, sertraline, fluvoxamine CR, and venlafaxine XR have received

FDA approval for treatment of social anxiety. Benzodiazepines can

be helpful in reducing fearful avoidance, but the chronic nature of

phobic disorders limits their usefulness.

Behaviorally focused psychotherapy is an important component

of treatment because relapse rates are high when medication is used

as the sole treatment. Cognitive-behavioral strategies are based

on the finding that distorted perceptions and interpretations of

fear-producing stimuli play a major role in perpetuation of phobias.

Individual and group therapy sessions teach the patient to identify

specific negative thoughts associated with the anxiety-producing

situation and help to reduce the patient’s fear of loss of control. In

desensitization therapy, hierarchies of feared situations are constructed, and the patient is encouraged to pursue and master gradual exposure to the anxiety-producing stimuli.

Patients with social phobia, in particular, have a high rate of

comorbid alcohol abuse, as well as of other psychiatric conditions

(e.g., eating disorders), necessitating the need for parallel management of each disorder if anxiety reduction is to be achieved.

■ STRESS DISORDERS

Clinical Manifestations Patients may develop anxiety after exposure to extreme traumatic events such as the threat of personal death

or injury or the death of a loved one. The reaction may occur shortly

after the trauma (acute stress disorder) or be delayed and subject to

recurrence (PTSD) (Table 452-6). In both syndromes, individuals

experience associated symptoms of detachment and loss of emotional

responsivity. The patient may feel depersonalized and unable to recall

TABLE 452-6 Diagnostic Criteria for Posttraumatic Stress Disorder

A. Exposure to actual or threatened death, serious injury, or sexual violence in one (or more) of the following ways:

1. Directly experiencing the traumatic event(s).

2. Witnessing, in person, the event(s) as it occurred to others.

3. Learning that the traumatic event(s) occurred to a close family member or close friend. In cases of actual or threatened death of a family member or friend, the

event(s) must have been violent or accidental.

4. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s) (e.g., first responders collecting human remains; police officers

repeatedly exposed to details of child abuse).

B. Presence of one (or more) of the following intrusion symptoms associated with the traumatic event(s), beginning after the traumatic event(s) occurred:

1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s).

2. Recurrent distressing dreams in which the content and/or affect of the dream are related to the traumatic event(s).

3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event(s) were recurring. (Such reactions may occur on a

continuum, with the most extreme expression being a complete loss of awareness of present surroundings.)

4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s).

5. Marked physiologic reactions to internal or external cues that symbolize or resemble an aspect of the traumatic event(s).

C. Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the traumatic event(s) occurred, as evidenced by one or both of the following:

1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s).

2. Avoidance of or efforts to avoid external reminders (people, places, conversations, activities, objects, situations) that arouse distressing memories, thoughts, or

feelings about or closely associated with the traumatic event(s).

D. Negative alterations in cognitions and mood associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred as evidenced by

two (or more) of the following:

1. Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia and not to other factors such as head injury,

alcohol, or drugs).

2. Persistent and exaggerated negative beliefs or expectations about oneself, others, or the world (e.g., “I am bad,” “No one can be trusted,” “The world is

completely dangerous,” “My whole nervous system is permanently ruined”).

3. Persistent, distorted cognitions about the cause or consequences of the traumatic event(s) that lead the individual to blame himself/herself or others.

4. Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame).

5. Markedly diminished interest or participation in significant activities.

6. Feelings of detachment or estrangement from others.

7. Persistent inability to experience positive emotions (e.g., inability to experience happiness, satisfaction, or loving feelings).

E. Marked alterations in arousal and reactivity associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by

two (or more) of the following:

1. Irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical aggression toward people or objects.

2. Reckless or self-destructive behavior.

3. Hypervigilance.

4. Exaggerated startle response.

5. Problems with concentration.

6. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep).

F. Duration of the disturbance (criteria B, C, D, and E) is >1 month.

G. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

H. The disturbance is not attributable to the physiologic effects of a substance (e.g., medication, alcohol) or another medical condition.

Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (Copyright © 2013). American Psychiatric Association. All Rights

Reserved.

3546 PART 13 Neurologic Disorders

specific aspects of the trauma, although typically it is reexperienced

through intrusions in thought, dreams, or flashbacks, particularly

when cues of the original event are present. Patients often actively avoid

stimuli that precipitate recollections of the trauma and demonstrate a

resulting increase in vigilance, arousal, and startle response. Patients

with stress disorders are at risk for the development of other disorders

related to anxiety, mood, and substance abuse (especially alcohol).

Between 5 and 10% of Americans will at some time in their life satisfy

criteria for PTSD, with women more likely to be affected than men. A

validated four-item screen for PTSD (PC-PTSD) is available.

Risk factors for the development of PTSD include a past psychiatric history and personality characteristics of high neuroticism and

extroversion. Twin studies show a substantial genetic influence on all

symptoms associated with PTSD, with less evidence for an environmental effect.

Etiology and Pathophysiology It is hypothesized that in PTSD

there is excessive release of norepinephrine from the locus coeruleus

in response to stress and increased noradrenergic activity at projection

sites in the hippocampus and amygdala. These changes theoretically

facilitate the encoding of fear-based memories. Greater sympathetic

responses to cues associated with the traumatic event occur in PTSD,

although pituitary adrenal responses are blunted. In addition to fear

learning, changes in threat detection (insula overactivity), executive

function, emotional regulation, and contextual learning have been

documented. Predictive biomarkers include increased heart rate and

serum lactate, decreased coagulation, insulin resistance, and alterations

in glycolysis and fatty acid uptake.

TREATMENT

Stress Disorders

Acute stress reactions are usually self-limited, and treatment typically involves the short-term use of benzodiazepines and supportive/

expressive psychotherapy. The chronic and recurrent nature of

PTSD, however, requires a more complex approach using drug and

behavioral treatments. PTSD is highly correlated with peritraumatic

dissociative symptoms and the development of an acute stress disorder at the time of the trauma. The SSRIs (paroxetine and sertraline

are FDA approved for PTSD), venlafaxine, fluoxetine, and topiramate can all reduce anxiety, symptoms of intrusion, and avoidance

behaviors. Recently, the psychedelic agent MDMA demonstrated

efficacy as an adjunct to intensive psychotherapeutic intervention,

as did stellate ganglion block. Low-dose trazodone and mirtazapine,

sedating antidepressants, are frequently used at night to help with

insomnia. Benzodiazepines and SSRIs, however, should not be given

in the early aftermath of trauma. Psychotherapeutic strategies for

PTSD help the patient overcome avoidance behaviors and demoralization and master fear of recurrence of the trauma; therapies that

encourage the patient to dismantle avoidance behaviors through

stepwise focusing on the experience of the traumatic event, such as

trauma-focused cognitive-behavioral and processing therapy and

prolonged exposure therapy utilizing augmented or virtual reality

are the most effective. Debriefing after the traumatic event does not

prevent PTSD and may exacerbate symptoms.

■ OBSESSIVE-COMPULSIVE DISORDER

Clinical Manifestations Obsessive-compulsive disorder (OCD)

is characterized by obsessive thoughts and compulsive behaviors that

impair everyday functioning. Fears of contamination and germs are

common, as are handwashing, counting behaviors, and having to check

and recheck such actions as whether a door is locked. The degree to

which the disorder is disruptive for the individual varies, but in all

cases, obsessive-compulsive activities take up >1 h per day and are

undertaken to relieve the anxiety triggered by the core fear. Patients

often conceal their symptoms, usually because they are embarrassed by

the content of their thoughts or the nature of their actions. Physicians

must ask specific questions regarding recurrent thoughts and behaviors, particularly if physical clues such as chafed and reddened hands or

patchy hair loss (from repetitive hair pulling, or trichotillomania) are

present. Comorbid conditions are common, the most frequent being

depression, other anxiety disorders, eating disorders, and tics. OCD

has a lifetime prevalence of 2–3% worldwide. Onset is usually gradual,

beginning in early adulthood, but childhood onset is not rare. The

disorder usually has a waxing and waning course, but some cases may

show a steady deterioration in psychosocial functioning.

Etiology and Pathophysiology A genetic contribution to OCD

is suggested by twin studies, but no susceptibility gene for OCD has

been identified to date. Insulin signaling has been implicated in some

recent reports. Family studies show an aggregation of OCD with

Tourette’s disorder, and both are more common in males and in firstborn children.

The anatomy of obsessive-compulsive behavior is thought to include

the orbital frontal cortex, caudate nucleus, and globus pallidus. The

caudate nucleus appears to be involved in the acquisition and maintenance of habit and skill learning, and interventions that are successful

in reducing obsessive-compulsive behaviors also decrease metabolic

activity measured in the caudate.

TREATMENT

Obsessive-Compulsive Disorder

Clomipramine, fluoxetine, fluvoxamine, paroxetine, and sertraline

are approved for the treatment of OCD in adults (and all but paroxetine are also approved for children). Clomipramine is a TCA that

is often tolerated poorly owing to anticholinergic and sedative side

effects at the doses required to treat the illness (25–250 mg/d); its

efficacy in OCD is unrelated to its antidepressant activity. Fluoxetine

(5–60 mg/d), fluvoxamine (25–300 mg/d), paroxetine (40–60 mg/d),

and sertraline (50–150 mg/d) are as effective as clomipramine and

have a more benign side-effect profile. Venlafaxine and duloxetine

also have shown efficacy but are not FDA approved. Only 50–60%

of patients with OCD show adequate improvement with pharmacotherapy alone. In treatment-resistant cases, augmentation with other

serotonergic agents such as buspirone, or with a neuroleptic or benzodiazepine, may be beneficial, and in severe cases, deep-brain stimulation has been found to be effective. When a therapeutic response

is achieved, long-duration maintenance therapy is usually indicated.

For many individuals, particularly those with time-consuming

compulsions, behavior therapy and exposure response prevention

will result in as much improvement as that afforded by medication.

Effective techniques include the gradual increase in exposure to

stressful situations, maintenance of a diary to clarify stressors, and

homework assignments that substitute new activities for compulsive behaviors.

MOOD DISORDERS

Mood disorders are characterized by a disturbance in the regulation

of mood, behavior, and affect. Mood disorders are subdivided into (1)

depressive disorders, (2) bipolar disorders, and (3) depression in association with medical illness or alcohol and substance abuse (Chaps. 453

through 457). Major depressive disorder (MDD) is differentiated from

bipolar disorder by the absence of a manic or hypomanic episode. The

relationship between pure depressive syndromes and bipolar disorders

is not well understood; MDD is more frequent in families of bipolar

individuals, but the reverse is not true. In the most recent Global Burden of Disease Study conducted by the World Health Organization

(2019), depression was the single largest factor contributing to disability,

which had increased 61% as measured by disability-adjusted life-years

(DALYs) since 1990. Moreover, the COVID pandemic has been associated with a major increase in reported symptoms of depression and anxiety worldwide. In the United States, lost productivity directly related to

mood disorders has been estimated at $55.1 billion per year.

3547Psychiatric Disorders CHAPTER 452

■ DEPRESSION IN ASSOCIATION

WITH MEDICAL ILLNESS

Depression occurring in the context of medical illness is difficult to

evaluate. Depressive symptomatology may reflect the psychological

stress of coping with the disease, may be caused by the disease process

itself or by the medications used to treat it, or may simply coexist in

time with the medical diagnosis.

Virtually every class of medication includes some agent that can

induce depression. Antihypertensive drugs, anticholesterolemic agents,

and antiarrhythmic agents are common triggers of depressive symptoms. Iatrogenic depression should also be considered in patients

receiving glucocorticoids, antimicrobials, systemic analgesics, antiparkinsonian medications, and anticonvulsants. To decide whether

a causal relationship exists between pharmacologic therapy and a

patient’s change in mood, it may sometimes be necessary to undertake

an empirical trial of an alternative medication.

Between 20–30% of cardiac patients manifest a depressive disorder;

an even higher percentage experience depressive symptomatology

when self-reporting scales are used. Depressive symptoms following

unstable angina, myocardial infarction, cardiac bypass surgery, or

heart transplant impair rehabilitation and are associated with higher

rates of mortality and medical morbidity. Depressed patients often

show decreased variability in heart rate (an index of reduced parasympathetic nervous system activity), which may predispose individuals

to ventricular arrhythmia and increased morbidity. Depression also

appears to increase the risk of coronary heart disease, possibly through

increased platelet aggregation. TCAs are contraindicated in patients

with bundle branch block, and TCA-induced tachycardia is an additional concern in patients with congestive heart failure. SSRIs appear

not to induce ECG changes or adverse cardiac events and thus are

reasonable first-line drugs for patients at risk for TCA-related complications. SSRIs may interfere with hepatic metabolism of anticoagulants,

however, causing increased anticoagulation.

In patients with cancer, the mean prevalence of depression is 25%,

but depression occurs in 40–50% of patients with cancers of the

pancreas or oropharynx. This association is not due to the effect of

cachexia alone, as the higher prevalence of depression in patients with

pancreatic cancer persists when compared to those with advanced gastric cancer. Initiation of antidepressant medication in cancer patients

has been shown to improve quality of life as well as mood. Psychotherapeutic approaches, particularly group therapy, may have some effect

on short-term depression, anxiety, and pain symptoms.

Depression occurs frequently in patients with neurologic disorders,

particularly cerebrovascular disorders, Parkinson’s disease, dementia,

multiple sclerosis, and traumatic brain injury. One in five patients

with left-hemisphere stroke involving the dorsolateral frontal cortex

experiences major depression. Late-onset depression in otherwise cognitively normal individuals increases the risk of a subsequent diagnosis

of Alzheimer’s disease. All classes of antidepressant agents are effective

against these depressions, as are, in some cases, stimulant compounds.

SNRIs such as duloxetine or levomilnacipran may be more effective in

depression associated with chronic pain.

The reported prevalence of depression in patients with diabetes

mellitus varies from 8–27%, with the severity of the mood state correlating with the level of hyperglycemia and the presence of diabetic

complications. Treatment of depression may be complicated by effects

of antidepressive agents on glycemic control. MAOIs can induce hypoglycemia and weight gain, whereas TCAs can produce hyperglycemia

and carbohydrate craving. SSRIs and SNRIs, like MAOIs, may reduce

fasting plasma glucose, but are easier to use and may also improve

dietary and medication compliance.

Hypothyroidism is frequently associated with features of depression, most commonly depressed mood and memory impairment.

Hyperthyroid states may also present in a similar fashion, usually in

geriatric populations. Improvement in mood usually follows normalization of thyroid function, but adjunctive antidepressant medication

is sometimes required. Patients with subclinical hypothyroidism can

also experience symptoms of depression and cognitive difficulty that

respond to thyroid replacement.

TABLE 452-7 Criteria for a 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

another medical condition.)

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).

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

>5% of body weight in a month), or decrease or increase in appetite nearly

every day.

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 physiologic effects of a substance or to

another medical condition.

D. The occurrence of the major depressive episode is not better explained

by seasonal affective disorder, schizophrenia, schizophreniform disorder,

delusional disorder, or other specified and unspecified schizophrenia

spectrum and other psychotic disorders.

E. There has never been a manic episode or a hypomanic episode.

Source: Reprinted with permission from the Diagnostic and Statistical Manual of

Mental Disorders, 5th ed. (Copyright © 2013). American Psychiatric Association. All

Rights Reserved.

The lifetime prevalence of depression in HIV-positive individuals has

been estimated at 22–45%. The relationship between depression and

disease progression is multifactorial and likely to involve psychological

and social factors, alterations in immune function, and central nervous

system (CNS) disease. Chronic hepatitis C infection is also associated

with depression, which may worsen with interferon-α treatment.

Some chronic disorders of uncertain etiology, such as chronic fatigue

syndrome (Chap. 450) and fibromyalgia (Chap. 373), are strongly

associated with depression and anxiety; patients may benefit from

antidepressant treatment or anticonvulsant agents such as pregabalin.

■ DEPRESSIVE DISORDERS

Clinical Manifestations Major depression is defined as depressed

mood on a daily basis for a minimum duration of 2 weeks (Table 452-7).

An episode may be characterized by sadness, indifference, apathy, or

irritability and is usually associated with changes in sleep patterns,

appetite, and weight; motor agitation or retardation; fatigue; impaired

concentration and decision-making; feelings of shame or guilt; and

thoughts of death or dying. Patients with depression have a profound

loss of pleasure in all enjoyable activities, exhibit early-morning awakening, feel that the dysphoric mood state is qualitatively different from

sadness, and often notice a diurnal variation in mood (worse in morning hours). Patients experiencing bereavement or grief may exhibit

many of the same signs and symptoms of major depression, although

the emphasis is usually on feelings of emptiness and loss, rather than

anhedonia and loss of self-esteem, and the duration is usually limited.

In certain cases, however, the diagnosis of major depression may be

warranted even in the context of a significant loss.

3548 PART 13 Neurologic Disorders

Approximately 15% of the population experiences a major depressive episode at some point in life, and 6–8% of all outpatients in

primary care settings satisfy diagnostic criteria for the disorder.

Depression is often undiagnosed, and even more frequently, it is

treated inadequately. If a physician suspects the presence of a major

depressive episode, the initial task is to determine whether it represents

unipolar or bipolar depression or is one of the 10–15% of cases that

are secondary to general medical illness or substance abuse. Physicians

should also assess the risk of suicide by direct questioning, as patients

are often reluctant to verbalize such thoughts without prompting. If

specific plans are uncovered or if significant risk factors exist (e.g., a

past history of suicide attempts, profound hopelessness, concurrent

medical illness, substance abuse, or social isolation), the patient must

be referred to a mental health specialist for immediate care. The physician should specifically probe each of these areas in an empathic and

hopeful manner, being sensitive to denial and possible minimization

of distress. The presence of anxiety, panic, or agitation significantly

increases near-term suicidal risk. Approximately 4–5% of all depressed

patients will commit suicide; most will have sought help from physicians within 1 month of their deaths.

In some depressed patients, the mood disorder does not appear to

be episodic and is not clearly associated with either psychosocial dysfunction or change from the individual’s usual experience in life. Persistent depressive disorder (dysthymic disorder) consists of a pattern of

chronic (at least 2 years), ongoing depressive symptoms that are usually

less severe and/or less numerous than those found in major depression,

but the functional consequences may be equivalent to or even greater;

the two conditions are sometimes difficult to separate and can occur

together (“double depression”). Many patients who exhibit a profile of

pessimism, disinterest, and low self-esteem respond to antidepressant

treatment. Persistent and chronic depressive disorders occur in ~2% of

the general population.

Depression is approximately twice as common in women as in

men, and the incidence increases with age in both sexes. Twin studies

indicate that the liability to major depression of early onset (before age

25 years) is largely genetic in origin. Negative life events can precipitate

and contribute to depression, but genetic factors influence the sensitivity of individuals to these stressful events. In most cases, both biologic

and psychosocial factors are involved in the precipitation and unfolding of depressive episodes. The most potent stressors appear to involve

death of a relative, assault, or severe marital or relationship problems.

Unipolar depressive disorders usually begin in early adulthood and

recur episodically over the course of a lifetime. The best predictor of

future risk is the number of past episodes; 50–60% of patients who

have a first episode have at least one or two recurrences. Some patients

experience multiple episodes that become more severe and frequent

over time. The duration of an untreated episode varies greatly, ranging

from a few months to ≥1 year. The pattern of recurrence and clinical progression in a developing episode are also variable. Within an

individual, the nature of episodes (e.g., specific presenting symptoms,

frequency, and duration) may be similar over time. In a minority of

patients, a severe depressive episode may progress to a psychotic state

and in elderly patients, depressive symptoms can be associated with

cognitive deficits mimicking dementia (“pseudodementia”). A seasonal

pattern of depression, called seasonal affective disorder, may manifest

with onset and remission of episodes at predictable times of the year.

This disorder is more common in women, with symptoms of anergy,

fatigue, weight gain, hypersomnia, and episodic carbohydrate craving.

The prevalence increases with distance from the equator, and improvement may occur by altering light exposure.

Etiology and Pathophysiology Although evidence for genetic

transmission of unipolar depression is not as strong as in bipolar disorder, monozygotic twins have a higher concordance rate (46%) than

dizygotic siblings (20%), with little support for any effect of a shared

family environment. Large-scale genome-wide association studies

(GWAS) involving hundreds of thousands of cases and controls have

identified several hundred loci across the genome, some of which are

unique to major depression, but others of which overlap with findings

from disparate psychiatric disorders, indicating possible pleiotropy.

Epigenetic changes are also likely to contribute to risk.

Neuroendocrine abnormalities that reflect the neurovegetative signs

and symptoms of depression include increased cortisol and corticotropinreleasing hormone (CRH) secretion, a decreased inhibitory response

of glucocorticoids to dexamethasone, and a blunted response of

thyroid-stimulating hormone (TSH) level to infusion of thyroidreleasing hormone (TRH). Antidepressant treatment leads to normalization of these abnormalities. Major depression is also associated with

changes in levels of proinflammatory cytokines and neurotrophins,

an increase in measures of oxidative stress and cellular aging, telomere shortening, epigenetic changes, and mitochondrial dysfunction.

Alterations in the gut microbiome may also be involved.

Diurnal variations in symptom severity and alterations in circadian

rhythmicity of a number of neurochemical and neurohumoral factors

suggest that a primary defect may be present in regulation of biologic

rhythms. Patients with major depression show consistent findings of a

decrease in rapid eye movement (REM)–sleep onset (REM latency), an

increase in REM density, and, in some subjects, a decrease in stage IV

delta slow-wave sleep.

Although antidepressant drugs inhibit neurotransmitter uptake

within hours, their therapeutic effects typically emerge over several

weeks, implicating adaptive changes in second messenger systems

and neurotrophic and transcription factors as possible mechanisms

of action.

TREATMENT

Depressive Disorders

Treatment planning requires coordination of short-term strategies to induce remission combined with longer-term maintenance

designed to prevent recurrence. The most effective intervention

for achieving remission and preventing relapse is medication, but

combined treatments, incorporating psychotherapy to help the

patient cope with decreased self-esteem and demoralization,

improve outcomes, as do self-help strategies such as exercise

(Fig. 452-1). Approximately 40% of primary care patients

with depression drop out of treatment and discontinue medication if symptomatic improvement is not noted within a month,

unless additional support is provided. Outcome improves with

(1) increased intensity and frequency of visits during the first

4–6 weeks of treatment, (2) supplemental educational materials,

and (3) psychiatric consultation as indicated. Despite the widespread use of SSRIs and other second-generation antidepressant

drugs, there is no convincing evidence that these classes of antidepressants are more efficacious than TCAs. Between 60–70% of all

depressed patients respond to any drug chosen, if it is given in a

sufficient dose for 6–8 weeks.

A rational approach to selecting which antidepressant to use

(Table 452-1) involves matching the patient’s preference and medical history with the metabolic and side-effect profile of the drug

(Tables 452-2 and 452-3). A previous response, or a family history

of a positive response, to a specific antidepressant often suggests

that drug should be tried first. Before initiating antidepressant

therapy, the physician should evaluate the possible contribution of

comorbid illnesses and consider their specific treatment. In individuals with suicidal ideation, particular attention should be paid

to choosing a drug with low toxicity if taken in overdose. Newer

antidepressant drugs are distinctly safer in this regard; nevertheless,

the advantages of TCAs have not been completely superseded. The

existence of generic equivalents makes TCAs relatively cheap, and

for secondary tricyclics, particularly nortriptyline and desipramine,

well-defined relationships among dose, plasma level, and therapeutic response exist. The steady-state plasma level achieved for a

given drug dose can vary more than tenfold between individuals,

and plasma levels may help in interpreting apparent resistance

to treatment and/or unexpected drug toxicity. The principal side

effects of TCAs are antihistaminergic (sedation) and anticholinergic

3549Psychiatric Disorders CHAPTER 452

(constipation, dry mouth, urinary hesitancy, blurred vision). TCAs

are contraindicated in patients with serious cardiovascular risk

factors, and overdoses of tricyclic agents can be lethal, with desipramine carrying the greatest risk. It is judicious to prescribe only a

10-day supply when suicide is a risk. Most patients require a daily

dose of 150–200 mg of imipramine or amitriptyline or its equivalent to achieve a therapeutic blood level of 150–300 ng/mL and a

satisfactory remission; some patients show a partial effect at lower

doses. Geriatric patients may require a low starting dose and slow

escalation. Ethnic differences in drug metabolism are significant,

with Hispanic, Asian, and black patients generally requiring lower

doses to achieve a comparable blood level.

Second-generation antidepressants are similar to tricyclics in

their effect on neurotransmitter reuptake, although some also

have specific actions on catecholamine and indolamine receptors

as well. Amoxapine is a dibenzoxazepine derivative that blocks

norepinephrine and serotonin reuptake and has a metabolite that

shows a degree of dopamine blockade. Long-term use of this drug

carries a risk of tardive dyskinesia. Maprotiline is a potent noradrenergic reuptake blocker that has little anticholinergic effect but

may produce seizures. Bupropion is a novel antidepressant whose

mechanism of action is thought to involve enhancement of noradrenergic function. It has no anticholinergic, sedating, or orthostatic side effects and has a low incidence of sexual side effects. It

may, however, be associated with stimulant-like side effects, may

lower seizure threshold, and has an exceptionally short half-life,

requiring frequent dosing. An extended-release preparation is

available.

SSRIs such as fluoxetine, sertraline, paroxetine, citalopram, and

escitalopram cause a lower frequency of anticholinergic, sedating,

and cardiovascular side effects but a possibly greater incidence of

gastrointestinal complaints, sleep impairment, and sexual dysfunction than do TCAs. Akathisia, involving an inner sense of restlessness and anxiety in addition to increased motor activity, may also be

more common, particularly during the first week of treatment. One

concern is the risk of “serotonin syndrome,” which is thought to

result from hyperstimulation of brainstem 5-HT1A receptors and is

characterized by myoclonus, agitation, abdominal cramping, hyperpyrexia, hypertension, and potentially death. Serotonergic agonists

taken in combination should be monitored closely for this reason.

Considerations such as half-life, compliance, toxicity, and drugdrug interactions may guide the choice of a particular SSRI. Fluoxetine and its principal active metabolite, norfluoxetine, for example,

have a combined half-life of almost 7 days, resulting in a delay of

5 weeks before steady-state levels are achieved and a similar delay for

complete drug excretion once their use is discontinued; paroxetine

appears to incur a greater risk of withdrawal symptoms with abrupt

discontinuation. All the SSRIs may impair sexual function, resulting

in diminished libido, impotence, or difficulty in achieving orgasm.

Sexual dysfunction frequently results in noncompliance and should

be asked about specifically. Sexual dysfunction can sometimes be

ameliorated by lowering the dose, by instituting weekend drug holidays (two or three times a month), or by treatment with amantadine

(100 mg tid), bethanechol (25 mg tid), buspirone (10 mg tid), or

bupropion (100–150 mg/d). Paroxetine appears to be more anticholinergic than either fluoxetine or sertraline, and sertraline carries a

lower risk of producing an adverse drug interaction than the other

two. Rare side effects of SSRIs include angina due to vasospasm and

prolongation of the prothrombin time. Escitalopram is the most

specific of currently available SSRIs and appears to have no significant inhibitory effects on the P450 system.

Venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran

block the reuptake of both norepinephrine and serotonin but

produce relatively little in the way of traditional tricyclic side

effects. Vortioxetine, also a 5HT1a agonist, and vilazodone block

reuptake of serotonin but have negligible effects on norepinephrine reuptake, although vortioxetine may increase norepinephrine

levels through wide effects on serotonergic receptors, as a 5HT1a

agonist, 5HT1b partial agonist, and a 5HT1d, 5HT3, and 5HT7

antagonist. Unlike the SSRIs, venlafaxine and vortioxetine have

relatively linear dose-response curves. Patients on immediate-release venlafaxine should be monitored for a possible increase in

diastolic blood pressure, and multiple daily dosing is required

because of the drug’s short half-life. An extended-release form is

available and has a somewhat lower incidence of gastrointestinal

side effects. Mirtazapine is a tetracyclic that has a unique spectrum of activity, as it increases noradrenergic and serotonergic

neurotransmission through a blockade of central α2

-adrenergic

receptors and postsynaptic 5-HT2

 and 5-HT3

 receptors. It is also

strongly antihistaminic and, as such, may produce sedation. Levomilnacipran is the most noradrenergic of the SNRIs and theoretically may be appropriate for patients with more severe fatigue

and anergia.

With the exception of citalopram and escitalopram, each of the

SSRIs may inhibit one or more cytochrome P450 enzymes. Depending on the specific isoenzyme involved, the metabolism of a number

of concomitantly administered medications can be dramatically

affected. Fluoxetine and paroxetine, for example, by inhibiting 2D6,

can cause dramatic increases in the blood level of type 1C antiarrhythmics, whereas sertraline, by acting on 3A4, may alter blood

levels of carbamazepine or digoxin. Depending on drug specificity

for a particular CYP enzyme for its own metabolism, concomitant

medications or dietary factors, such as grapefruit juice, may in turn

affect the efficacy or toxicity of the SSRI.

The MAOIs are highly effective, particularly in atypical

depression, but the risk of hypertensive crisis following intake

of tyramine-containing food or sympathomimetic drugs makes

them inappropriate as first-line agents. Transdermal selegiline may

avert this risk at low dose. Common side effects include orthostatic hypotension, weight gain, insomnia, and sexual dysfunction.

MAOIs should not be used concomitantly with SSRIs, because of

the risk of serotonin syndrome, or with TCAs, because of possible

hyperadrenergic effects.

Electroconvulsive therapy is at least as effective as medication,

but its use is reserved for treatment-resistant cases and delusional

Determine whether there is a history of good response to a medication

in the patient or a first-degree relative; if yes, consider treatment with

this agent if compatible with considerations in step 2.

Evaluate patient characteristics and match to drug; consider health

status, side effect profile, convenience, cost, patient preference, drug

interaction risk, suicide potential, and medication compliance history.

Begin new medication at 1/3 to 1/2 target dose if drug is a TCA,

bupropion, venlafaxine, or mirtazapine, or full dose as tolerated if drug

is an SSRI.

If problem side effects occur, evaluate possibility of tolerance; consider

temporary decrease in dose or adjunctive treatment.

If unacceptable side effects continue, taper drug over 1 week and

initiate new trial; consider potential drug interactions in choice.

Evaluate response after 6 weeks at target dose; if response is

inadequate, increase dose in stepwise fashion as tolerated.

If inadequate response after maximal dose, consider tapering and

switching to a new drug vs adjunctive treatment; if drug is a TCA, obtain

plasma level to guide further treatment.

FIGURE 452-1 A guideline for the medical management of major depressive

disorder. SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

3550 PART 13 Neurologic Disorders

depressions. Repetitive transcranial magnetic stimulation (rTMS)

is approved for treatment-resistant depression and has been

shown to have efficacy in several controlled trials. Vagus nerve

stimulation (VNS) has also recently been approved for treatmentresistant depression, but its degree of efficacy is controversial.

Some meta-analyses of low-intensity transcranial current stimulation (tCS) have shown a positive benefit over sham treatment,

but whether this is comparable to or synergistic with antidepressant treatment is unclear. In off-label usage, intravenous

ketamine, a dissociative anesthetic, and intranasal esketamine

(an isomer that has FDA approval in treatment-resistant cases)

have been shown to have short-term antidepressant efficacy,

often after a single administration, suggesting a possible utility in

addressing suicidality. Questions remain, however, about the risk/

benefit ratio over the longer term. Psilocybin, a hallucinogen,

has also shown some potential benefit in controlled administration. Lastly, deep brain stimulation of the ventral anterior limb

of the internal capsule and of the subcallosal cingulate region

have demonstrable efficacy in randomized experimental trials of

treatment-resistant depression.

Postpartum depression may respond to any of the above interventions, but the FDA has recently approved the specific usage of

brexanolone (Zulresso), administered in a continuous intravenous

infusion over 60 h and found to result in symptomatic relief for

at least 30 days. Sedation and loss of consciousness are possible

adverse effects.

Regardless of the treatment undertaken, the response should

be evaluated after ~2 months. Three-quarters of patients show

improvement by this time, but if remission is inadequate, the patient

should be questioned about compliance, and an increase in medication dose should be considered if side effects are not troublesome. If

this approach is unsuccessful, referral to a mental health specialist

is advised. Strategies for treatment resistance include selection

of an alternative drug, combinations of antidepressants, and/or

adjunctive treatment with other classes of drugs, including lithium,

thyroid hormone, l-methylfolate, s-adenosylmethionine, n-acetyl

cysteine, atypical antipsychotic agents, and dopamine agonists. In

switching to a different monotherapy, other drugs from the same

class appear to be as likely to be efficacious as choosing a drug from

a different class. A large randomized trial (STAR-D) was unable to

show preferential efficacy, but the addition of certain atypical antipsychotic drugs (quetiapine extended-release; aripiprazole; brexpiprazole) has received FDA approval, as has usage of a combined

medication, olanzapine and fluoxetine (Symbyax). Patients whose

response to an SSRI wanes over time may benefit from the addition

of buspirone (10 mg tid) or pindolol (2–5 mg tid) or small amounts

of a TCA such as nortriptyline (25 mg bid or tid). Most patients

will show some degree of response, but aggressive treatment should

be pursued until remission is achieved, and drug treatment should

be continued for at least 6–9 months to prevent relapse. In patients

who have had two or more episodes of depression, indefinite maintenance treatment should be considered. Pharmacogenomic testing

focusing on cytochrome p450 allelic variation may sometimes be

helpful in identifying individuals who are poor or rapid metabolizers, but assessing pharmacodynamic gene variants has not been

shown to be cost-effective or affect clinical outcomes.

It is essential to educate patients both about depression and the

benefits and side effects of medications they are receiving. Advice

about stress reduction and cautions that alcohol may exacerbate

depressive symptoms and impair drug response are helpful. Patients

should be given time to describe their experience, their outlook,

and the impact of the depression on them and their families.

Occasional empathic silence may be as helpful for the treatment

alliance as verbal reassurance. Controlled trials have shown that

cognitive-behavioral and interpersonal therapies are effective in

improving psychological and social adjustment and that a combined treatment approach is more successful than medication alone

for many patients.

TABLE 452-8 Criteria for a Manic Episode

A. A distinct period of abnormally and persistently elevated, expansive, or

irritable mood and abnormally and persistently increased goal-directed

activity or energy, lasting at least 1 week and present most of the day, nearly

every day (or any duration if hospitalization is necessary).

B. During the period of the mood disturbance and increased energy or activity,

three (or more) of the following symptoms (four if the mood is only irritable)

are present to a significant degree and represent a noticeable change from

usual behavior:

1. Inflated self-esteem or grandiosity.

2. Decreased need for sleep (e.g., feels rested after only 3 h of sleep).

3. More talkative than usual or pressure to keep talking.

4. Flight of ideas or subjective experience that thoughts are racing.

5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant

external stimuli), as reported or observed.

6. Increase in goal-directed activity (either socially, at work or school, or

sexually) or psychomotor agitation (i.e., purposeless non-goal-directed

activity).

7. Excessive involvement in activities that have a high potential for painful

consequences (e.g., engaging in unrestrained buying sprees, sexual

indiscretions, or foolish business investments).

C. The mood disturbance is sufficiently severe to cause marked impairment in

social or occupational functioning or to necessitate hospitalization to prevent

harm to self or others, or there are psychotic features.

D. The episode is not attributable to the physiologic effects of a substance

(e.g., a drug of abuse, a medication, or other treatment) or another medical

condition.

Source: Reprinted with permission from the Diagnostic and Statistical Manual of

Mental Disorders, 5th ed. (Copyright © 2013). American Psychiatric Association. All

Rights Reserved.

■ BIPOLAR DISORDER

Clinical Manifestations Bipolar disorder is characterized by

unpredictable swings in mood from mania (or hypomania) to depression. Some patients suffer only from recurrent attacks of mania, which

in its pure form is associated with increased psychomotor activity;

excessive social extroversion; decreased need for sleep; impulsivity and

impaired judgment; and expansive, elated, grandiose, and sometimes

irritable mood (Table 452-8). In severe mania, patients may experience

delusions and paranoid thinking indistinguishable from schizophrenia.

One-half of patients with bipolar disorder present not with euphoria

but with a mixture of psychomotor agitation and activation, accompanied by dysphoria, anxiety, and irritability. It may be difficult to distinguish such a mixed state from agitated depression. In some bipolar

patients (bipolar II disorder), the full criteria for mania are lacking, and

the requisite recurrent depressions are separated by periods of mild

activation and increased energy (hypomania). In cyclothymic disorder,

there are numerous hypomanic periods, usually of relatively short

duration, alternating with clusters of depressive symptoms that fail,

either in severity or duration, to meet the criteria of major depression.

The mood fluctuations are chronic and should be present for at least

2 years before the diagnosis is made.

Manic episodes typically emerge over a period of days to weeks, but

onset within hours is possible, usually in the early-morning hours. An

untreated episode of either depression or mania can be as short as several

weeks or last as long as 8–12 months, and rare patients have an unremitting chronic course. The term rapid cycling is used for patients who have

four or more episodes of either depression or mania in a given year. This

pattern occurs in 15% of all patients, most of whom are women. In some

cases, rapid cycling is linked to an underlying thyroid dysfunction, and

in others, it is iatrogenically triggered by prolonged antidepressant treatment. Approximately one-half of patients have sustained difficulties in

work performance and psychosocial functioning, with depressive phases

being more responsible for impairment than mania.

Bipolar disorder is common, affecting ~1.5% of the population

in the United States. Onset is typically between 20–30 years of age,

but many individuals report premorbid symptoms in late childhood

or early adolescence. The prevalence is similar for men and women;

women are likely to have more depressive and men more manic

3551Psychiatric Disorders CHAPTER 452

TABLE 452-9 Clinical Pharmacology of Mood Stabilizers

AGENT AND DOSING SIDE EFFECTS AND OTHER EFFECTS

Lithium Common Side Effects

Starting dose: 300 mg bid or tid

Therapeutic blood level:

0.8–1.2 meq/L

Nausea/anorexia/diarrhea, fine tremor,

thirst, polyuria, fatigue, weight gain, acne,

folliculitis, neutrophilia, hypothyroidism

Blood level is increased by thiazides,

tetracyclines, and NSAIDs

Blood level is decreased by bronchodilators,

verapamil, and carbonic anhydrase inhibitors

Rare side effects: Neurotoxicity, renal

toxicity, hypercalcemia, ECG changes

Valproic Acid Common Side Effects

Starting dose: 250 mg tid

Therapeutic blood level:

50–125 μg/mL

Nausea/anorexia, weight gain, sedation,

tremor, rash, alopecia

Inhibits hepatic metabolism of other

medications

Rare side effects: Pancreatitis, hepatotoxicity,

Stevens-Johnson syndrome

Carbamazepine/Oxcarbazepine Common Side Effects

Starting dose: 200 mg bid for

carbamazepine, 150 mg bid for

oxcarbazepine

Nausea/anorexia, sedation, rash, dizziness/

ataxia

Therapeutic blood level:

4–12 μg/mL for carbamazepine

Carbamazepine, but not oxcarbazepine,

induces hepatic metabolism of other

medications

Rare side effects: Hyponatremia,

agranulocytosis, Stevens-Johnson syndrome

Lamotrigine Common Side Effects

Starting dose: 25 mg/d Rash, dizziness, headache, tremor, sedation,

nausea

Rare side effect: Stevens-Johnson syndrome

Abbreviations: ECG, electrocardiogram; NSAIDs, nonsteroidal anti-inflammatory drugs.

episodes over a lifetime. Recognizing a bipolar diathesis in an individual who presents with a depressive episode but no history of mania

is difficult but essential in optimizing treatment planning, because

antidepressants may be contraindicated and result in symptom worsening and cycle acceleration. Suggestive features of bipolarity include a

childhood onset, a history of antidepressant treatment failure, atypical

features of hypersomnolence and weight gain, and marked irritability

or impulsivity.

Differential Diagnosis The differential diagnosis of mania

includes secondary mania induced by stimulant or sympathomimetic

drugs, hyperthyroidism, AIDS, neurologic disorders such as Huntington’s or Wilson’s disease, frontotemporal dementia, and cerebrovascular accidents. Comorbidity with alcohol and substance abuse is

common, either because of poor judgment and increased impulsivity

or because of an attempt to self-treat the underlying mood symptoms

and sleep disturbances.

Etiology and Pathophysiology Genetic predisposition to bipolar

disorder is evident from family studies; the concordance rate for monozygotic twins approaches 80%. A number of risk genes that have been

identified to date overlap with those conveying risk for other psychiatric disorders, such as schizophrenia and autism, implying some degree

of shared pathophysiology. Replicated loci include the alpha subunit

of the L-type calcium channel (CACNA1C), teneurin transmembrane

protein 4 (ODZ4), ankyrin 3 (ANK3), neurocan (NCAN), and tetratricopeptide repeat and ankyrin repeat containing 1 (TRANK1). Common variants convey little individual risk, but collectively account for

25% of heritability. A few rarer, more penetrant variants have also been

reported, but no causative mutations have as yet been confirmed. Similarly, no clear biomarkers have been identified, but there is evidence

for circadian rhythm dysregulation and oxidative stress, mitochondrial,

and endoplasmic reticulum abnormalities. Reported MRI findings

include grey matter thinning in frontal, temporal, and parietal cortex.

TREATMENT

Bipolar Disorder

(Table 452-9) Lithium carbonate is the mainstay of treatment in

bipolar disorder, although sodium valproate and carbamazepine,

as well as a number of second-generation antipsychotic agents

(aripiprazole, asenapine, cariprazine, olanzapine, quetiapine, risperidone, ziprasidone), also have FDA approval for the treatment of

acute mania. Oxcarbazepine is not FDA approved, but appears to

enjoy carbamazepine’s spectrum of efficacy. The response rate to

lithium carbonate is 70–80% in acute mania, with beneficial effects

appearing in 1–2 weeks. Lithium also has a prophylactic effect in

prevention of recurrent mania and, to a lesser extent, in the prevention of recurrent depression, which is more difficult to treat than

unipolar depression. A simple cation, lithium is rapidly absorbed

from the gastrointestinal tract and remains unbound to plasma or

tissue proteins. Some 95% of a given dose is excreted unchanged

through the kidneys within 24 h.

Serious side effects from lithium are rare, but minor complaints

such as gastrointestinal discomfort, nausea, diarrhea, polyuria,

weight gain, skin eruptions, alopecia, and edema are common. Over

time, urine-concentrating ability may be decreased, but significant

nephrotoxicity is relatively rare. Lithium exerts an antithyroid effect

by interfering with the synthesis and release of thyroid hormones.

More serious side effects include tremor, poor concentration and

memory, ataxia, dysarthria, and incoordination.

In the treatment of acute mania, lithium is initiated at 300 mg

bid or tid, and the dose is then increased by 300 mg every 2–3 days

to achieve blood levels of 0.8–1.2 meq/L. Because the therapeutic

effect of lithium may not appear until after 7–10 days of treatment,

adjunctive usage of lorazepam (1–2 mg every 4 h) or clonazepam

(0.5–1 mg every 4 h) may be beneficial to control agitation. Antipsychotics are indicated in patients with severe agitation who respond

only partially to benzodiazepines. Patients using lithium should be

monitored closely, because the blood levels required to achieve a

therapeutic benefit are close to those associated with toxicity.

Valproic acid may be more effective than lithium for patients

who experience rapid cycling (i.e., more than four episodes a year)

or who present with a mixed or dysphoric mania. Tremor and

weight gain are the most common side effects; hepatotoxicity and

pancreatitis are rare toxicities.

The recurrent nature of bipolar mood disorder necessitates

maintenance treatment. A sustained blood lithium level of at least

0.8 meq/L is important for optimal prophylaxis and has been shown

to reduce the risk of suicide, a finding not yet apparent for other

mood stabilizers. Combinations of mood stabilizers together or with

atypical antipsychotic drugs are sometimes required to maintain

mood stability. Quetiapine extended release, olanzapine, risperidone,

and lamotrigine have been approved for maintenance treatment as

sole agents, in combination with lithium and with aripiprazole and

ziprasidone as adjunctive drugs. Lurasidone, olanzapine/fluoxetine,

and quetiapine are also approved to treat acute depressive episodes

in bipolar disorder. Compliance is frequently an issue and often

requires enlistment and education of concerned family members.

Efforts to identify and modify psychosocial factors that may trigger

episodes are important, as is an emphasis on lifestyle regularity

(social rhythm therapy). Mobile apps for smartphones that alert the

individual and clinician to changes in activity and speech are proving useful in early detection of behavioral change and in delivering

clinical interventions and education. Antidepressant medications

are sometimes required for the treatment of severe breakthrough

depressions, but their use should generally be avoided during maintenance treatment because of the risk of precipitating mania or accelerating the cycle frequency. Alternative off-label agents for bipolar

depression include pramipexole, modafinil, omega-3 fatty acids,

and N-acetyl cysteine; interventions such as ECT, light therapy,

3552 PART 13 Neurologic Disorders

and rTMS may also be effective. Loss of efficacy over time may be

observed with any of the mood-stabilizing agents. In such situations,

an alternative agent or combination therapy is usually helpful.

SOMATIC SYMPTOM DISORDER

Many patients presenting in general medical practice, perhaps as many

as 5–7%, will experience a somatic symptom(s) as particularly distressing and preoccupying, to the point that it comes to dominate their

thoughts, feelings, and beliefs and interferes to a varying degree with

everyday functioning. Although the absence of a medical explanation

for these complaints was historically emphasized as a diagnostic element, it has been recognized that the patient’s interpretation and elaboration of the experience is the critical defining factor and that patients

with well-established medical causation may qualify for the diagnosis.

Multiple complaints are typical, but severe single symptoms can occur

as well. Comorbidity with depressive and anxiety disorders is common

and may affect the severity of the experience and its functional consequences. Personality factors may be a significant risk factor, as may a

low level of educational or socioeconomic status or a history of recent

stressful life events. Cultural factors are relevant as well and should

be incorporated into the evaluation. Individuals who have persistent

preoccupations about having or acquiring a serious illness, but who

do not have a specific somatic complaint, may qualify for a related

diagnosis—illness anxiety disorder. The diagnosis of conversion disorder (functional neurologic symptom disorder) is used to specifically

identify those individuals whose somatic complaints involve one or

more symptoms of altered voluntary motor or sensory function that

cannot be medically explained and that cause significant distress or

impairment or require medical evaluation.

In factitious illnesses, the patient consciously and voluntarily produces physical symptoms of illness. The term Munchausen’s syndrome

is reserved for individuals with particularly dramatic, chronic, or

severe factitious illness. In true factitious illness, the sick role itself is

gratifying. A variety of signs, symptoms, and diseases have been either

simulated or caused by factitious behavior, the most common including chronic diarrhea, fever of unknown origin, intestinal bleeding or

hematuria, seizures, and hypoglycemia. Factitious disorder is usually

not diagnosed until 5–10 years after its onset, and it can produce

significant social and medical costs. In malingering, the fabrication

derives from a desire for some external reward such as a narcotic medication or disability reimbursement.

TREATMENT

Somatic Symptom Disorder and Related Disorders

Patients with somatic symptom disorder are frequently subjected

to many diagnostic tests and exploratory surgeries in an attempt

to find their “real” illness. Such an approach is doomed to failure

and does not address the core issue. Successful treatment is best

achieved through behavior modification, in which access to the

physician is tightly regulated and adjusted to provide a sustained

and predictable level of support that is less clearly contingent on the

patient’s level of presenting distress. Visits can be brief and should

not be associated with a need for a diagnostic or treatment action.

Although the literature is limited, some patients may benefit from

antidepressant treatment.

Any attempt to confront the patient usually creates a sense of

humiliation and causes the patient to abandon treatment from that

caregiver. A better strategy is to introduce psychological causation

as one of a number of possible explanations in the differential

diagnoses that are discussed. Without directly linking psychotherapeutic intervention to the diagnosis, the patient can be offered a

face-saving means by which the pathologic relationship with the

health care system can be examined and alternative approaches to

life stressors developed. Specific medical treatments also may be

indicated and effective in treating some of the functional consequences of conversion disorder.

FEEDING AND EATING DISORDERS

■ CLINICAL MANIFESTATIONS

Feeding and eating disorders constitute a group of conditions in which

there is a persistent disturbance of eating or associated behaviors that

significantly impair an individual’s physical health or psychosocial

functioning. In DSM-5 the described categories (with the exception

of pica) are defined to be mutually exclusive in a given episode, based

on the understanding that although they are phenotypically similar in

some ways, they differ in course, prognosis, and effective treatment

interventions. Compared with DSM-IV-TR, three disorders (i.e.,

avoidant/restrictive food intake disorder, rumination disorder, pica)

that were previously classified as disorders of infancy or childhood

have been grouped together with the disorders of anorexia and bulimia

nervosa. Binge-eating disorder is also now included as a formal diagnosis; the intent of each of these modifications is to encourage clinicians

to be more specific in their codification of eating and feeding pathology.

■ PICA

Pica is diagnosed when the individual, aged >2 years, eats one or more

nonnutritive, nonfood substances for a month or more and requires

medical attention as a result. There is usually no specific aversion to

food in general but a preferential choice to ingest substances such as

clay, starch, soap, paper, or ash. The diagnosis requires the exclusion

of specific culturally approved practices and has not been commonly

found to be caused by a specific nutritional deficiency. Onset is most

common in childhood, but the disorder can occur in association with

other major psychiatric conditions in adults. An association with pregnancy has been observed, but the condition is only diagnosed when

medical risks are increased by the behavior.

■ RUMINATION DISORDER

In this condition, individuals who have no demonstrable associated

gastrointestinal or other medical condition repeatedly regurgitate their

food after eating and then either rechew or swallow it or spit it out. The

behavior typically occurs on a daily basis and must persist for at least

1 month. Weight loss and malnutrition are common sequelae, and

individuals may attempt to conceal their behavior, either by covering

their mouth or through social avoidance while eating. In infancy, the

onset is typically between 3 and 12 months of age, and the behavior

may remit spontaneously, although in some it appears to be recurrent.

■ AVOIDANT/RESTRICTIVE FOOD

INTAKE DISORDER

The cardinal feature of this disorder is avoidance or restriction of food

intake, usually stemming from a lack of interest in or distaste of food

and associated with weight loss, nutritional deficiency, dependency on

nutritional supplementation, or marked impairment in psychosocial

functioning, either alone or in combination. Culturally approved practices, such as fasting or a lack of available food, must be excluded as

possible causes. The disorder is distinguished from anorexia nervosa

by the presence of emotional factors, such as a fear of gaining weight

and distortion of body image in the latter condition. Onset is usually

in infancy or early childhood, but avoidant behaviors may persist into

adulthood. The disorder is equally prevalent in males and females and

is frequently comorbid with anxiety and cognitive and attention-deficit

disorders and situations of familial stress. Developmental delay and

functional deficits may be significant if the disorder is long-standing

and unrecognized.

■ ANOREXIA NERVOSA

Individuals are diagnosed with anorexia nervosa if they restrict their

caloric intake to a degree that their body weight deviates significantly

from age, gender, health, and developmental norms and if they also

exhibit a fear of gaining weight and an associated disturbance in body

image. The condition is further characterized by differentiating those

who achieve their weight loss predominantly through restricting intake

or by excessive exercise (restricting type) from those who engage in

recurrent binge eating and/or subsequent purging, self-induced vomiting, and usage of enemas, laxatives, or diuretics (binge-eating/purging