Anxiety disorders, the most prevalent psychiatric illnesses in the general community, are present in 15–20% of medical clinic patients. Anxiety, defined as a subjective sense of unease, dread, or foreboding, can indicate a primary psychiatric condition or can be a component of, or reaction to, a primary medical disease. The primary anxiety disorders are classified according to their duration and course and the existence and nature of precipitants.
When evaluating the anxious patient, the clinician must first determine whether the anxiety antedates or postdates a medical illness or is due to a medication side effect. Approximately one-third of patients presenting with anxiety have a medical etiology for their psychiatric symptoms, but an anxiety disorder can also present with somatic symptoms in the absence of a diagnosable medical condition.
Panic disorder is defined by the presence of recurrent and unpredictable panic attacks, which are distinct episodes of intense fear and discomfort associated with a variety of physical symptoms, including palpitations, sweating, trembling, shortness of breath, chest pain, dizziness, and a fear of impending doom or death (Table 391-1). Paresthesias, gastrointestinal distress, and feelings of unreality are also common. Diagnostic criteria require at least 1 month of concern or worry about the attacks or a change in behavior related to them. The lifetime prevalence of panic disorder is 1–3%. Panic attacks have a sudden onset, developing within 10 minures and usually resolving over the course of an hour, and they occur in an unexpected fashion. The frequency and severity of panic attacks vary, ranging from once a week to clusters of attacks separated by months of well-being. The first attack is usually outside the home, and onset is typically in late adolescence to early adulthood. In some individuals, anticipatory anxiety develops over time and results in a generalized fear and a progressive avoidance of places or situations in which a panic attack might recur. Agoraphobia, which occurs commonly in patients with panic disorder, is an acquired irrational fear of being in places where one might feel trapped or unable to escape (Table 391-2). Typically, it leads the patient into a progressive restriction in lifestyle and, in a literal sense, in geography. Frequently, patients are embarrassed that they are housebound and dependent on the company of others to go out into the world and do not volunteer this information; thus physicians will fail to recognize the syndrome if direct questioning is not pursued.
Table 391-1 Diagnostic Criteria for Panic Attack |Favorite Table|Download (.pdf)
Table 391-1 Diagnostic Criteria for Panic Attack
|A discrete period of intense fear or discomfort, in which four or more of the following symptoms developed abruptly and reached a peak within 10 minutes:|
|1. Palpitations, pounding heart, or accelerated heart rate|
|3. Trembling or shaking|
|4. Sensations of shortness of breath or smothering|
|5. Feeling of choking|
|6. Chest pain or discomfort|
|7. Nausea or abdominal distress|
|8. Feeling dizzy, unsteady, lightheaded, or faint|
|9. Derealization (feelings of unreality) or depersonalization (being detached from oneself)|
|10. Fear of losing control or going crazy|
|11. Fear of dying|
|12. Paresthesias (numbness or tingling sensations)|
|13. Chills or hot flushes|
Table 391-2 Diagnostic Criteria for Agoraphobia |Favorite Table|Download (.pdf)
Table 391-2 Diagnostic Criteria for Agoraphobia
|1. Anxiety about being in places or situations from which escape might be difficult (or embarrassing) or in which help may not be available in the event of having an unexpected or situationally predisposed panic attack or panic-like symptoms. Agoraphobic fears typically involve characteristic clusters of situations that include being outside the home alone; being in a crowd or standing in a line; being on a bridge; and traveling in a bus, train, or automobile.|
|2. The situations are avoided (e.g., travel is restricted) or else are endured with marked distress or with anxiety about having a panic attack or panic-like symptoms, or require the presence of a companion.|
|3. The anxiety or phobic avoidance is not better accounted for by another mental disorder such as social phobia (e.g., avoidance limited to social situations because of fear of embarrassment), specific phobia (e.g., avoidance limited to a single situation like elevators), obsessive-compulsive disorder (e.g., avoidance of dirt in someone with an obsession about contamination), posttraumatic stress disorder (e.g., avoidance of stimuli associated with a severe stressor), or separation anxiety disorder (e.g., avoidance of leaving home or relatives).|
A diagnosis of panic disorder is made after a medical etiology for the panic attacks has been ruled out. A variety of cardiovascular, respiratory, endocrine, and neurologic conditions can present with anxiety as the chief complaint. Patients with true panic disorder will often focus on one specific feature to the exclusion of others. For example, 20% of patients who present with syncope as a primary medical complaint have a primary diagnosis of a mood, anxiety, or substance-abuse disorder, the most common being panic disorder. The differential diagnosis of panic disorder is complicated by a high rate of comorbidity with other psychiatric conditions, especially alcohol and benzodiazepine abuse, which patients initially use in an attempt at self-medication. Some 75% of panic disorder patients will also satisfy criteria for major depression at some point in their illness.
When the history is nonspecific, physical examination and focused laboratory testing must be used to rule out anxiety states resulting from medical disorders such as pheochromocytoma, thyrotoxicosis, or hypoglycemia. Electrocardiogram (ECG) and echocardiogram may detect some cardiovascular conditions associated with panic such as paroxysmal atrial tachycardia and mitral valve prolapse. In two studies, panic disorder was the primary diagnosis in 43% of patients with chest pain who had normal coronary angiograms and was present in 9% of all outpatients referred for cardiac evaluation. Panic disorder has also been diagnosed in many patients referred for pulmonary function testing or with symptoms of irritable bowel syndrome.
Etiology and Pathophysiology
The etiology of panic disorder is unknown but appears to involve a genetic predisposition, altered autonomic responsivity, and social learning. Panic disorder shows familial aggregation; the disorder is concordant in 30–45% of monozygotic twins, and genomewide screens have identified suggestive risk loci. Acute panic attacks appear to be associated with increased noradrenergic discharges in the locus coeruleus. Intravenous infusion of sodium lactate evokes an attack in two-thirds of panic disorder patients, as do the α2-adrenergic antagonist yohimbine, cholecystokinin tetrapeptide (CCK-4), and carbon dioxide inhalation. It is hypothesized that each of these stimuli activates a pathway involving noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe. Agents that block serotonin reuptake can prevent attacks. Panic-disorder patients have a heightened sensitivity to somatic symptoms, which triggers increasing arousal, setting off the panic attack; accordingly, therapeutic intervention involves altering the patient's cognitive interpretation of anxiety-producing experiences as well as preventing the attack itself.
Treatment: Panic Disorder
Achievable goals of treatment are to decrease the frequency of panic attacks and to reduce their intensity. The cornerstone of drug therapy is antidepressant medication (Tables 391-3, 391-4, and 391-5). Selective serotonin reuptake inhibitors (SSRIs) benefit the majority of panic disorder patients and do not have the adverse effects of tricyclic antidepressants (TCAs). Fluoxetine, paroxetine, sertraline, and the selective serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine have received approval from the U.S. Food and Drug Administration (FDA) for this indication. These drugs should be started at one-third to one-half of their usual antidepressant dose (e.g., 5–10 mg fluoxetine, 25–50 mg sertraline, 10 mg paroxetine, venlafaxine 37.5 mg). Monoamine oxidase inhibitors (MAOIs) are also effective and may specifically benefit patients who have comorbid features of atypical depression (i.e., hypersomnia and weight gain). Insomnia, orthostatic hypotension, and the need to maintain a low-tyramine diet (avoidance of cheese and wine) have limited their use, however. Antidepressants typically take 2–6 weeks to become effective, and doses may need to be adjusted based upon the clinical response.
Table 391-3 Antidepressants |Favorite Table|Download (.pdf)
Table 391-3 Antidepressants
|Name||Usual Daily Dose, mg||Side Effects||Comments|
|Fluoxetine (Prozac)||10–80||Headache; nausea and other GI effects; jitteriness; insomnia; sexual dysfunction; can affect plasma levels of other medicines (except sertraline); akathisia rare||Once-daily dosing, usually in the morning; fluoxetine has very long half-life; must not be combined with MAOIs|
|Amitriptyline (Elavil)||150–300||Anticholinergic (dry mouth, tachycardia, constipation, urinary retention, blurred vision); sweating; tremor; postural hypotension; cardiac conduction delay; sedation; weight gain||Once-daily dosing, usually qhs; blood levels of most TCAs available; can be lethal in O.D. (lethal dose = 2 g); nortriptyline best tolerated, especially by elderly|
|Mixed Norepinephrine/Serotonin Reuptake Inhibitors and Receptor Blockers|
|Venlafaxine (Effexor)||75–375||Nausea; dizziness; dry mouth; headaches; increased blood pressure; anxiety and insomnia||Bid-tid dosing (extended release available); lower potential for drug interactions than SSRIs; contraindicated with MAOIs|
|Desvenlafaxine, (Pristiq)||50–400||Nausea, dizziness, insomnia||Primary metabolite of venlafaxine. No increased efficacy with higher dosing|
|Duloxetine (Cymbalta)||40–60||Nausea, dizziness, headache, insomnia, constipation||May have utility in treatment of neuropathic pain and stress incontinence|
|Mirtazapine (Remeron)||15–45||Somnolence; weight gain; neutropenia rare||Once daily dosing|
|Bupropion (Wellbutrin)||250–450||Jitteriness; flushing; seizures in at-risk patients; anorexia; tachycardia; psychosis||Tid dosing, but sustained release also available; fewer sexual side effects than SSRIs or TCAs; may be useful for adult ADD|
|Trazodone (Desyrel)||200–600||Sedation; dry mouth; ventricular irritability; postural hypotension; priapism rare||Useful in low doses for sleep because of sedating effects with no anticholinergic side effects|
|Nefazodone (Serzone)||300–600||Sedation; headache; dry mouth; nausea; constipation||Discontinued sale in United States and several other countries due to risk of liver failure|
|Amoxapine (Asendin)||200–600||Sexual dysfunction||Lethality in overdose; EPS possible|
|Phenelzine (Nardil)||45–90||Insomnia; hypotension; anorgasmia; weight gain; hypertensive crisis; toxic reactions with SSRIs; narcotics||May be more effective in patients with atypical features or treatment-refractory depression|
|Transdermal selegiline (Emsam)||6–12||Local skin reaction hypertension||No dietary restrictions with 6 mg dose|
Table 391-4 Management of Antidepressant Side Effects |Favorite Table|Download (.pdf)
Table 391-4 Management of Antidepressant Side Effects
|Symptoms||Comments and Management Strategies|
|Nausea, loss of appetite||Usually short-lived and dose-related; consider temporary dose reduction or administration with food and antacids|
|Diarrhea||Famotidine, 20–40 mg/d|
|Constipation||Wait for tolerance; try diet change, stool softener, exercise; avoid laxatives|
|Sexual dysfunction||Consider dose reduction; drug holiday|
|Anorgasmia/impotence; impaired ejaculation||Bethanechol, 10–20 mg, 2 h before activity, or cyproheptadine, 4–8 mg 2 h before activity, or bupropion, 100 mg bid or amantadine, 100 mg bid/tid|
|Orthostasis||Tolerance unlikely; increase fluid intake, use calf exercises/support hose; fludrocortisone, 0.025 mg/d|
|Anticholinergic||Wait for tolerance|
|Dry mouth, eyes||Maintain good oral hygiene; use artificial tears, sugar-free gum|
|Tremor/jitteriness||Antiparkinsonian drugs not effective; use dose reduction/slow increase; lorazepam, 0.5 mg bid, or propranolol, 10–20 mg bid|
|Insomnia||Schedule all doses for the morning; trazodone, 50–100 mg qhs|
|Sedation||Caffeine; schedule all dosing for bedtime; bupropion, 75–100 mg in afternoon|
|Headache||Evaluate diet, stress, other drugs; try dose reduction; amitriptyline, 50 mg/d|
|Weight gain||Decrease carbohydrates; exercise; consider fluoxetine|
|Loss of therapeutic benefit over time||Related to tolerance? Increase dose or drug holiday; add amantadine, 100 mg bid, buspirone, 10 mg tid, or pindolol, 2.5 mg bid|
Table 391-5 Possible Drug Interactions with Selective Serotonin Reuptake Inhibitors |Favorite Table|Download (.pdf)
Table 391-5 Possible Drug Interactions with Selective Serotonin Reuptake Inhibitors
|Monoamine oxidase inhibitors||Serotonin syndrome—absolute contraindication|
|Serotonergic agonists, e.g., tryptophan, fenfluramine||Potential serotonin syndrome|
|Drugs that are metabolized by P450 isoenzymes: tricyclics, other SSRIs, antipsychotics, beta blockers, codeine, triazolobenzodiazepines, calcium channel blockers||Delayed metabolism resulting in increased blood levels and potential toxicity|
|Drugs that are bound tightly to plasma proteins, e.g., warfarin||Increased bleeding secondary to displacement|
|Drugs that inhibit the metabolism of SSRIs by P450 isoenzymes, e.g., quinidine||Increased SSRI side effects|
Because of anticipatory anxiety and the need for immediate relief of panic symptoms, benzodiazepines are useful early in the course of treatment and sporadically thereafter (Table 391-6). For example, alprazolam, starting at 0.5 mg qid and increasing to 4 mg/d in divided doses, is effective, but patients must be monitored closely, as some develop dependence and begin to escalate the dose of this medication. Clonazepam, at a final maintenance dose of 2–4 mg/d, is also helpful; its longer half-life permits twice-daily dosing, and patients appear less likely to develop dependence on this agent.
Table 391-6 Anxiolytics |Favorite Table|Download (.pdf)
Table 391-6 Anxiolytics
|Name||Equivalent PO Dose, mg||Onset of Action||Half-life, h||Comments|
|Diazepam (Valium)||5||Fast||20–70||Active metabolites; quite sedating|
|Flurazepam (Dalmane)||15||Fast||30–100||Flurazepam is a prodrug; metabolites are active; quite sedating|
|Triazolam (Halcion)||0.25||Intermediate||1.5–5||No active metabolites; can induce confusion and delirium, especially in elderly|
|Lorazepam (Ativan)||1||Intermediate||10–20||No active metabolites; direct hepatic glucuronide conjugation; quite sedating|
|Alprazolam (Xanax)||0.5||Intermediate||12–15||Active metabolites; not too sedating; may have specific antidepressant and antipanic activity; tolerance and dependence develop easily|
|Chlordiazepoxide (Librium)||10||Intermediate||5–30||Active metabolites; moderately sedating|
|Oxazepam (Serax)||15||Slow||5–15||No active metabolites; direct glucuronide conjugation; not too sedating|
|Temazepam (Restoril)||15||Slow||9–12||No active metabolites; moderately sedating|
|Clonazepam (Klonopin)||0.5||Slow||18–50||No active metabolites; moderately sedating|
|Buspirone (BuSpar)||7.5||2 weeks||2–3||Active metabolites; tid dosing—usual daily dose 10–20 mg tid; nonsedating; no additive effects with alcohol; useful for controlling agitation in demented or brain-injured patients|
Early psychotherapeutic intervention and education aimed at symptom control enhances the effectiveness of drug treatment. Patients can be taught breathing techniques, be educated about physiologic changes that occur with panic, and learn to expose themselves voluntarily to precipitating events in a treatment program spanning 12–15 sessions. Homework assignments and monitored compliance are important components of successful treatment. Once patients have achieved a satisfactory response, drug treatment should be maintained for 1–2 years to prevent relapse. Controlled trials indicate a success rate of 75–85%, although the likelihood of complete remission is somewhat lower.
Generalized Anxiety Disorder
Patients with generalized anxiety disorder (GAD) have persistent, excessive, and/or unrealistic worry associated with muscle tension, impaired concentration, autonomic arousal, feeling “on edge” or restless, and insomnia (Table 391-7). Onset is usually before age 20 years, and a history of childhood fears and social inhibition may be present. The lifetime prevalence of GAD is 5–6%; the risk is higher in first-degree relatives of patients with the diagnosis. Interestingly, family studies indicate that GAD and panic disorder segregate independently. More than 80% of patients with GAD also suffer from major depression, dysthymia, or social phobia. Comorbid substance abuse is common in these patients, particularly alcohol and/or sedative/hypnotic abuse. Patients with GAD worry excessively over minor matters, with life-disrupting effects; unlike in panic disorder, complaints of shortness of breath, palpitations, and tachycardia are relatively rare.
Table 391-7 Diagnostic Criteria for Generalized Anxiety Disorder |Favorite Table|Download (.pdf)
Table 391-7 Diagnostic Criteria for Generalized Anxiety Disorder
|A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance).|
|B. The person finds it difficult to control the worry.|
|C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms present for more days than not for the past 6 months): (1) restlessness or feeling keyed up or on edge; (2) being easily fatigued; (3) difficulty concentrating or mind going blank; (4) irritability; (5) muscle tension; (6) sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep).|
|D. The focus of the anxiety and worry is not confined to features of an axis I disorder [e.g., the anxiety or worry is not about having a panic attack (as in panic disorder), being embarrassed in public (as in social phobia), being contaminated (as in obsessive-compulsive disorder), being away from home or close relatives (as in separation anxiety disorder), gaining weight (as in anorexia nervosa), having multiple physical complaints (as in somatization disorder), or having a serious illness (as in hypochondriasis)], and the anxiety and worry do not occur exclusively during posttraumatic stress disorder.|
|E. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.|
|F. The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism) and does not occur exclusively during a mood disorder, a psychotic disorder, or a pervasive developmental disorder.|
Etiology and Pathophysiology
All anxiogenic agents act on the γ-aminobutyric acid (GABA)A receptor/chloride ion channel complex, implicating this neurotransmitter system in the pathogenesis of anxiety and panic attacks. Benzodiazepines are thought to bind two separate GABAA receptor sites: type I, which has a broad neuroanatomic distribution, and type II, which is concentrated in the hippocampus, striatum, and neocortex. The antianxiety effects of the various benzodiazepines and side effects such as sedation and memory impairment are influenced by their relative binding to type I and type II receptor sites. Serotonin [5-hydroxytryptamine (5HT)] and 3α-reduced neuractive steroids (allosteric modulators of GABAA) also appear to have a role in anxiety, and buspirone, a partial 5HT1A receptor agonist, and certain 5HT2A and 5HT2C receptor antagonists (e.g., nefazodone) may have beneficial effects.
Treatment: Generalized Anxiety Disorder
A combination of pharmacologic and psychotherapeutic interventions is most effective in GAD, but complete symptomatic relief is rare. A short course of a benzodiazepine is usually indicated, preferably lorazepam, oxazepam, or temazepam. (The first two of these agents are metabolized via conjugation rather than oxidation and thus do not accumulate if hepatic function is impaired.) Treatment should be initiated at the lowest dose possible and prescribed on an as-needed basis as symptoms warrant. Benzodiazepines differ in their milligram per kilogram potency, half-life, lipid solubility, metabolic pathways, and presence of active metabolites. Agents that are absorbed rapidly and are lipid soluble, such as diazepam, have a rapid onset of action and a higher abuse potential. Benzodiazepines should generally not be prescribed for >4–6 weeks because of the development of tolerance and the risk of abuse and dependence. Withdrawal must be closely monitored as relapses can occur. It is important to warn patients that concomitant use of alcohol or other sedating drugs may be neurotoxic and impair their ability to function. An optimistic approach that encourages the patient to clarify environmental precipitants, anticipate his or her reactions, and plan effective response strategies is an essential element of therapy.
Adverse effects of benzodiazepines generally parallel their relative half-lives. Longer-acting agents, such as diazepam, chlordiazepoxide, flurazepam, and clonazepam, tend to accumulate active metabolites, with resultant sedation, impairment of cognition, and poor psychomotor performance. Shorter-acting compounds, such as alprazolam and oxazepam, can produce daytime anxiety, early morning insomnia, and, with discontinuation, rebound anxiety and insomnia. Although patients develop tolerance to the sedative effects of benzodiazepines, they are less likely to habituate to the adverse psychomotor effects. Withdrawal from the longer half-life benzodiazepines can be accomplished through gradual, stepwise dose reduction (by 10% every 1–2 weeks) over 6–12 weeks. It is usually more difficult to taper patients off shorter-acting benzodiazepines. Physicians may need to switch the patient to a benzodiazepine with a longer half-life or use an adjunctive medication such as a beta blocker or carbamazepine, before attempting to discontinue the benzodiazepine. Withdrawal reactions vary in severity and duration; they can include depression, anxiety, lethargy, diaphoresis, autonomic arousal, and, rarely, seizures.
Buspirone is a nonbenzodiazepine anxiolytic agent. It is nonsedating, does not produce tolerance or dependence, does not interact with benzodiazepine receptors or alcohol, and has no abuse or disinhibition potential. However, it requires several weeks to take effect and requires thrice-daily dosing. Patients who were previously responsive to a benzodiazepine are unlikely to rate buspirone as equally effective, but patients with head injury or dementia who have symptoms of anxiety and/or agitation may do well with this agent. Escitalopram, paroxetine, and venlafaxine are FDA approved for the treatment of GAD, usually at doses that are comparable to their efficacy in major depression. Benzodiazepines are contraindicated during pregnancy and breast-feeding.
Anticonvulsants with GABAergic properties may also be effective against anxiety. Gabapentin, oxcarbazepine, tiagabine, pregabalin, and divalproex have all shown some degree of benefit in a variety of anxiety-related syndromes. Agents that selectively target GABAA receptor subtypes are currently under development, and it is hoped that these will lack the sedating, memory-impairing, and addicting properties of benzodiazepines.
The cardinal feature of phobic disorders is a marked and persistent fear of objects or situations, exposure to which results in an immediate anxiety reaction. The patient avoids the phobic stimulus, and this avoidance usually impairs occupational or social functioning. Panic attacks may be triggered by the phobic stimulus or may occur spontaneously. Unlike patients with other anxiety disorders, individuals with phobias usually experience anxiety only in specific situations. Common phobias include fear of closed spaces (claustrophobia), fear of blood, and fear of flying. Social phobia is distinguished by a specific fear of social or performance situations in which the individual is exposed to unfamiliar individuals or to possible examination and evaluation by others. Examples include having to converse at a party, use public restrooms, and meet strangers. In each case, the affected individual is aware that the experienced fear is excessive and unreasonable given the circumstance. The specific content of a phobia may vary across gender, ethnic, and cultural boundaries.
Phobic disorders are common, affecting ∼10% of the population. Full criteria for diagnosis are usually satisfied first in early adulthood, but behavioral avoidance of unfamiliar people, situations, or objects dating from early childhood is common.
In one study of female twins, concordance rates for agoraphobia, social phobia, and animal phobia were found to be 23% for monozygotic twins and 15% for dizygotic twins. A twin study of fear conditioning, a model for the acquisition of phobias, demonstrated a heritability of 35–45%, and a genomewide linkage scan identified a risk locus on chromosome 14 in a region previously implicated in a mouse model of fear. Animal studies of fear conditioning have indicated that 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 hours 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, and venlafaxine 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, as relapse rates are high when medication is used as the sole treatment. Cognitive-behavioral strategies are based upon 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.
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 391-8). In both syndromes, individuals experience associated symptoms of detachment and loss of emotional responsivity. The patient may feel depersonalized and unable to recall specific aspects of the trauma, though 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.
Table 391-8 Diagnostic Criteria for Posttraumatic Stress Disorder |Favorite Table|Download (.pdf)
Table 391-8 Diagnostic Criteria for Posttraumatic Stress Disorder
A. The person has been exposed to a traumatic event in which both of the following were present:
- 1. The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others.
- 2. The person's response involved intense fear, helplessness, or horror.
B. The traumatic event is persistently reexperienced in one (or more) of the following ways:
- 1. Recurrent and intrusive distressing recollections of the event, including images, thoughts, or perceptions.
- 2. Recurrent distressing dreams of the event.
- 3. Acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations, and dissociative flashback episodes, including those that occur on awakening or when intoxicated).
- 4. Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event.
- 5. Physiologic reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event.
C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by three or more of the following:
- 1. Efforts to avoid thoughts, feelings, or conversations associated with the trauma
- 2. Efforts to avoid activities, places, or people that arouse recollections of the trauma
- 3. Inability to recall an important aspect of the trauma
- 4. Markedly diminished interest or participation in significant activities
- 5. Feeling of detachment or estrangement from others
- 6. Restricted range of affect (e.g., unable to have loving feelings)
- 7. Sense of a foreshortened future (e.g., does not expect to have a career, marriage, children, or a normal life span)
D. Persistent symptoms of increased arousal (not present before the trauma), as indicated by two (or more) of the following:
- 1. Difficulty falling or staying asleep
- 2. Irritability or outbursts of anger
- 3. Difficulty concentrating
- 4. Hypervigilance
- 5. Exaggerated startle response
|E. Duration of the disturbance (symptoms in criteria B, C, and D) is more than 1 month|
|F. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.|
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.
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 employing 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. TCAs such as imipramine and amitriptyline, the MAOI phenelzine, and the SSRIs can all reduce anxiety, symptoms of intrusion, and avoidance behaviors, as can prazosin, an α1 antagonist. Propranolol and opiates such as morphine, given during the acute stress period may have beneficial effects in preventing the development of PTSD. Trazodone, a sedating antidepressant, is frequently used at night to help with insomnia (50–150 mg qhs). Carbamazepine, valproic acid, or alprazolam have also independently produced improvement in uncontrolled trials. 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 are the most effective.
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 hour 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. A genomewide association study (GWAS) reported linkage to chromosome 2p23.2; however, no susceptibility gene for OCD has been identified to date. Family studies show an aggregation of OCD with Tourette's disorder, and both are more common in males and in first-born 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, and sertraline are approved for the treatment of OCD. 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), and sertraline (50–150 mg/d) are as effective as clomipramine and have a more benign side effect profile. 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 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 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. 392, 393, and 394). 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 Global Burden of Disease Study conducted by the World Health Organization, unipolar major depression ranked fourth among all diseases in terms of disability-adjusted life-years and was projected to rank second by the year 2020. In the United States, lost productivity directly related to mood disorders has been estimated at $55.1 billion per year.
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 and 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 developing 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. Both TCA and SSRI agents are effective against these depressions, as are stimulant compounds and, in some patients, MAOIs.
The reported prevalence of depression in patients with diabetes mellitus varies from 8 to 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, while TCAs can produce hyperglycemia and carbohydrate craving. SSRIs, like MAOIs, may reduce fasting plasma glucose, but they 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.
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. 389) and fibromyalgia (Chap. 335), are strongly associated with depression and anxiety; patients may benefit from antidepressant treatment or anticonvulsant agents such as pregabalin.
Major depression is defined as depressed mood on a daily basis for a minimum duration of 2 weeks (Table 391-9). 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).
Table 391-9 Criteria for a Major Depressive Episode |Favorite Table|Download (.pdf)
Table 391-9 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 due to a general medical condition, or mood-incongruent delusions or hallucinations.
- 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful)
- 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)
- 3. Significant weight loss when not dieting or weight gain (e.g., a change of >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 do not meet criteria for a mixed episode|
|C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning|
|D. The symptoms are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism)|
|E. The symptoms are not better accounted for by bereavement (i.e., after the loss of a loved one), the symptoms persist for >2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation|
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. Dysthymic disorder consists of a pattern of chronic (at least 2 years), ongoing, mild depressive symptoms that are less severe and less disabling than those found in major depression; the two conditions are sometimes difficult to separate, however, and can occur together (“double depression”). Many patients who exhibit a profile of pessimism, disinterest, and low self-esteem respond to antidepressant treatment. Dysthymic disorder exists in ∼5% of primary care patients. The term minor depression is used for individuals who experience at least two depressive symptoms for 2 weeks but who do not meet the full criteria for major depression. Despite its name, minor depression is associated with significant morbidity and disability and also responds to pharmacologic treatment.
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) 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; in elderly patients, depressive symptoms may 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, whose symptoms are 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.
Neuroendocrine abnormalities that reflect the neurovegetative signs and symptoms of depression include: (1) increased cortisol and corticotropin-releasing hormone (CRH) secretion, (2) an increase in adrenal size, (3) a decreased inhibitory response of glucocorticoids to dexamethasone, and (4) a blunted response of thyroid-stimulating hormone (TSH) level to infusion of thyroid-releasing hormone (TRH). Antidepressant treatment leads to normalization of these abnormalities. Major depression is also associated with an upregulation of proinflammatory cytokines, which also normalizes with antidepressant treatment.
Diurnal variations in symptom severity and alterations in circadian rhythmicity of a number of neurochemical and neurohumoral factors suggest that biologic differences may be secondary to a primary defect 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 transcription factors as possible mechanisms of action.
The pathogenesis of depression is discussed in detail in Chap. 390.
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 treatment, incorporating psychotherapy to help the patient cope with decreased self-esteem and demoralization, improves outcome (Fig. 391-1). 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 this class of antidepressant is more efficacious than TCAs. Between 60 and 70% of all depressed patients respond to any drug chosen, if it is given in a sufficient dose for 6–8 weeks. There is no ideal antidepressant; no current compound combines rapid onset of action, moderate half-life, a meaningful relationship between dose and blood level, a low side effect profile, minimal interaction with other drugs, and safety in overdose.
A guideline for the medical management of major depressive disorder. SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
A rational approach to selecting which antidepressant to use involves matching the patient's preference and medical history withthe metabolic and side effect profile of the drug (Tables 391-4 and 391-5). A previous response, or a family history of a positive response, to a specific antidepressant often suggests that that drug 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. The SSRIs, and other newer antidepressant drugs are distinctly safer in this regard; nevertheless, the advantages of TCAs have not been completely superseded. The existence of generic equivalents make 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 antihistamine (sedation) and anticholinergic (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 than whites to achieve a comparable blood level. P450 profiling using genetic chip technology may be clinically useful in predicting individual sensitivity.
Second-generation antidepressants include amoxapine, maprotiline, trazodone, and bupropion. 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 tardivedyskinesia. 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,” thought to result from hyperstimulation of brainstem 5HT1A receptors and 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 drug-drug 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 its use is discontinued. 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 specific inhibitory effects on the P450 system.
Venlafaxine, desvenlafaxine, and duloxetine block the reuptake of both norepinephrine and serotonin but produce relatively little in the way of traditional tricyclic side effects. Unlike the SSRIs, venlafaxine has a relatively linear dose-response curve. Patients 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 TCA that has a unique spectrum of activity. It increases noradrenergic and serotonergic neurotransmission through a blockade of central α2-adrenergic receptors and postsynaptic 5HT2 and 5HT3 receptors. It is also strongly antihistaminic and, as such, may produce sedation.
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, while sertraline, by acting on 3A4, may alter blood levels of carbamazepine, or digoxin.
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 depressions. Transcranial magnetic stimulation (TMS) 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 treatment-resistant depression, but its degree of efficacy is controversial. Deep brain stimulation is another treatment that is being used experimentally in treatment resistant cases.
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 then include selection of an alternative drug, combinations of antidepressants, and/or adjunctive treatment with other classes of drugs, including lithium, thyroid hormone, atypical antipsychotic agents, and dopamine agonists. A large randomized trial (STAR-D) was unable to show preferential efficacy, but the addition of atypical antipsychotic drugs has received FDA approval. 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 desipramine (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 more months to prevent relapse. In patients who have had two or more episodes of depression, indefinite maintenance treatment should be considered.
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.
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 impairment in judgment; and expansive, grandiose, and sometimes irritable mood (Table 391-10). In severe mania, patients may experience delusions and paranoid thinking indistinguishable from schizophrenia. One-half of patients with bipolar disorder present with a mixture of psychomotor agitation and activation with dysphoria, anxiety, and irritability. It may be difficult to distinguish mixed mania 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 least2 years before the diagnosis is made.
Table 391-10 Criteria for a Manic Episode |Favorite Table|Download (.pdf)
Table 391-10 Criteria for a Manic Episode
|A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary)|
B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
- 1. Inflated self-esteem or grandiosity
- 2. Decreased need for sleep (e.g., feels rested after only 3 hours 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)
- 6. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation
- 7. Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
|C. The symptoms do not meet criteria for a mixed episode.|
|D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.|
|E. The symptoms are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).|
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, almost all 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 and 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 episodes over a lifetime.
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, 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%. Patients with bipolar disorder also appear to have altered circadian rhythmicity, and lithium may exert its therapeutic benefit through a resynchronization of intrinsic rhythms keyed to the light/dark cycle. A detailed discussion of the pathogenesis of bipolar disorder is presented in Chap. 390.
Treatment: Bipolar Disorder
(Table 391-11) Lithium carbonate is the mainstay of treatment in bipolar disorder, although sodium valproate and olanzapine are equally effective in acute mania, as is lamotrigine in the depressed phase. 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. 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 hours.
Table 391-11 Clinical Pharmacology of Mood Stabilizers |Favorite Table|Download (.pdf)
Table 391-11 Clinical Pharmacology of Mood Stabilizers
|Agent and Dosing
||Side Effects and Other Effects
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
Blood level is decreased by bronchodilators,
verapamil, and carbonic anhydrase inhibitors
Rare side effects: Neurotoxicity, renal toxicity, hypercalcemia, ECG changes
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,
Common Side Effects
Starting dose: 200 mg bid for
carbamazepine, 150 mg bid for
Therapeutic blood level: 4–12 μg/mL for
Nausea/anorexia, sedation, rash, dizziness/ataxia
Carbamazepine, but not
oxcarbazepine, induces hepatic metabolism of other medications
Rare side effects: Hyponatremia, agranulocytosis,
Common Side Effects
|Starting dose: 25 mg/d
Rash, dizziness, headache, tremor, sedation, nausea
Rare side effect:
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 does not usually occur. 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. There is suggestive, but not conclusive, evidence that lithium is teratogenic, inducing cardiac malformations in the first trimester.
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 hours) or clonazepam (0.5–1 mg every 4 hours) 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, since the blood levels required to achieve a therapeutic benefit are close to those associated with toxicity.
Valproic acid may be better 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.
Carbamazepine and oxcarbazepine, although not formally approved by the FDA for bipolar disorder, have clinical efficacy in the treatment of acute mania. Second-generation antipsychotic drugs (olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, and asenapine) have also been shown to be effective, either alone or in combination with a mood stabilizer. An increased risk of weight gain and other metabolic abnormalities is a concern with these agents.
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 risk of suicide, a finding not yet apparent for other mood stabilizers. 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. 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. 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.
Consensus guidelines for the treatment of acute mania and bipolar depression are described in Table 391-12.
Table 391-12 Consensus Guidelines on the Drug Treatment of Acute Mania and Bipolar Depression |Favorite Table|Download (.pdf)
Table 391-12 Consensus Guidelines on the Drug Treatment of Acute Mania and Bipolar Depression
|Mania with psychosis
Valproic acid with
valproic acid alone
|Severe depression with psychosis
risperidone; consider ECT
|Severe depression without psychosis
|Mild to moderate depression
lamotrigine alone; add
bupropion if needed
Schizophrenia is a heterogeneous syndrome characterized by perturbations of language, perception, thinking, social activity, affect, and volition. There are no pathognomonic features. The syndrome commonly begins in late adolescence, has an insidious (and less commonly acute) onset, and, often, a poor outcome, progressing from social withdrawal and perceptual distortions to recurrent delusions and hallucinations. Patients may present with positive symptoms (such as conceptual disorganization, delusions, or hallucinations) or negative symptoms (loss of function, anhedonia, decreased emotional expression, impaired concentration, and diminished social engagement) and must have at least two of these for a 1-month period and continuous signs for at least 6 months to meet formal diagnostic criteria. As individuals age, positive psychotic symptoms tend to attenuate and some measure of social and occupational function may be regained. “Negative” symptoms predominate in one-third of the schizophrenic population and are associated with a poor long-term outcome and a poor response to drug treatment. However, marked variability in the course and individual character of symptoms is typical.
The four main subtypes of schizophrenia are catatonic, paranoid, disorganized, and residual. Many individuals have symptoms of more than one type. Catatonic-type describes patients whose clinical presentation is dominated by profound changes in motor activity, negativism, and echolalia or echopraxia. Paranoid-type describes patients who have a prominent preoccupation with a specific delusional system and who otherwise do not qualify as having disorganized-type disease, in which disorganized speech and behavior are accompanied by a superficial or silly affect. In residual-type disease, negative symptomatology exists in the absence of delusions, hallucinations, or motor disturbance. The term schizophreniform disorder describes patients who meet the symptom requirements but not the duration requirements for schizophrenia, and schizoaffective disorder is used for those who manifest symptoms of schizophrenia and independent periods of mood disturbance. Prognosis depends not on symptom severity but on the response to antipsychotic medication. A permanent remission without recurrence does occasionally occur. About 10% of schizophrenic patients commit suicide.
Schizophrenia is present in 0.85% of individuals worldwide, with a lifetime prevalence of ∼1–1.5%. An estimated 300,000 episodes of acute schizophrenia occur annually in the United States, resulting in direct and indirect costs of $62.7 billion.
The diagnosis is principally one of exclusion, requiring the absence of significant associated mood symptoms, any relevant medical condition, and substance abuse. Drug reactions that cause hallucinations, paranoia, confusion, or bizarre behavior may be dose-related or idiosyncratic; parkinsonian medications, clonidine, quinacrine, and procaine derivatives are the most common prescription medications associated with these symptoms. Drug causes should be ruled out in any case of newly emergent psychosis. The general neurologic examination in patients with schizophrenia is usually normal, but motor rigidity, tremor, and dyskinesias are noted in one-quarter of untreated patients.
Epidemiology and Pathophysiology
Epidemiologic surveys identify several risk factors for schizophrenia, including genetic susceptibility, early developmental insults, winter birth, and increasing parental age. Genetic factors are involved in at least a subset of individuals who develop schizophrenia. Schizophrenia is observed in ∼6.6% of all first-degree relatives of an affected proband. If both parents are affected, the risk for offspring is 40%. The concordance rate for monozygotic twins is 50%, compared to 10% for dizygotic twins. Schizophrenia-prone families are also at risk for other psychiatric disorders, including schizoaffective disorder and schizotypal and schizoid personality disorders, the latter terms designating individuals who show a lifetime pattern of social and interpersonal deficits characterized by an inability to form close interpersonal relationships, eccentric behavior, and mild perceptual distortions. The pathogenesis of schizophrenia is discussed in detail in Chap. 390.
Antipsychotic agents (Table 391-14) are the cornerstone of acute and maintenance treatment of schizophrenia and are effective in the treatment of hallucinations, delusions, and thought disorders, regardless of etiology. The mechanism of action involves, at least in part, binding to dopamine D2/D3 receptors in the ventral striatum; the clinical potencies of traditional antipsychotic drugs parallel their affinities for the D2 receptor, and even the newer “atypical” agents exert some degree of D2 receptor blockade. All neuroleptics induce expression of the immediate-early gene c-fos in the nucleus accumbens, a dopaminergic site connecting prefrontal and limbic cortices. The clinical efficacy of newer atypical neuroleptics, however, may involve N-methyl-D-aspartate (NMDA) receptor blockade, α1- and α2-noradrenergic activity, altering the relationship between 5HT2 and D2 receptor activity, as well as faster dissociation of D2 binding and effects on neuroplasticity.
Table 391-14 Antipsychotic Agents |Favorite Table|Download (.pdf)
Table 391-14 Antipsychotic Agents
|Name||Usual PO Daily Dose, mg||Side Effects||Sedation||Comments|
|Chlorpromazine (Thorazine)||100–1000||Anticholinergic effects; orthostasis; photosensitivity; cholestasis; QT prolongation||+ + +||EPSEs usually not prominent; can cause anticholinergic delirium in elderly patients|
|Trifluoperazine (Stelazine)||2–50||Fewer anticholinergic side effects||+ +||Well tolerated by most patients|
|Perphenazine (Trilafon)||4–64||Fewer EPSEs than with higher potency agents.||++||Little weight gain|
|Loxapine (Loxitane)||30–100||Frequent EPSEs||+ +|
|Molindone (Moban)||30–100||Frequent EPSEs||0|
|Haloperidol (Haldol)||5–20||No anticholinergic side effects; EPSEs often prominent
||0/+||Often prescribed in doses that are too high; long-acting injectable forms of haloperidol and fluphenazine available|
|Fluphenazine (Prolixin)||1–20||Frequent EPSEs||0/+|
|Thiothixene (Navane)||2–50||Frequent EPSEs||0/+|
|Clozapine (Clozaril)||150–600||Agranulocytosis (1%); weight gain; seizures; drooling; hyperthermia||+ +||Requires weekly WBC count for first 6 months, then biweekly if stable|
|Risperidone (Risperdal)||2–8||Orthostasis||+||Requires slow titration; EPSEs observed with doses >6 mg qd|
|Olanzapine (Zyprexa)||10–30||Weight gain||+ +||Mild prolactin elevation|
|Quetiapine (Seroquel)||350–800||Sedation; weight gain; anxiety||+ + +||Bid dosing|
|Ziprasidone (Geodon)||120–200||Orthostatic hypotension||+/++||Minimal weight gain; increases QT interval|
|Aripiprazole (Abilify)||10–30||Nausea, anxiety, insomnia||0/+||Mixed agonist/antagonist|
|Paliperidone (Invega)||3–12||Restlessness, EPSEs||+||Active metabolite of risperidone|
|Iloperidone (Fanapt)||12–24||Dizziness, hypotension||0/+||Requires dose titration|
|Asenapine (Saphris)||10–20||Dizziness, EPSEs, weight gain||++||Sublingual tablets; bid dosing|
|Lurasidone (Latuda)||40–80||Nausea, EPSEs||++||Uses CYP3A4|
Conventional neuroleptics differ in their potency and side-effect profile. Older agents such as chlorpromazine and thioridazine, are more sedating and anticholinergic and more likely to cause orthostatic hypotension, while higher potency antipsychotics such as haloperidol, perphenazine, and thiothixene, are more likely to induce extrapyramidal side effects. The model “atypical” antipsychotic agent is clozapine, a dibenzodiazepine that has a greater potency in blocking the 5HT2 than the D2 receptor and a much higher affinity for the D4 than the D2 receptor. Its principal disadvantage is a risk of blood dyscrasias. Paliperidone is a recently approved agent that is a metabolite of risperidone and shares many of its properties. Unlike other antipsychotics, clozapine does not cause a rise in prolactin level. Approximately 30% of patients who do not benefit from conventional antipsychotic agents will have a better response to this drug, which also has a demonstrated superiority to other antipsychotic agents in preventing suicide; however, its side-effect profile makes it most appropriate for treatment-resistant cases. Risperidone, a benzisoxazole derivative, is more potent at 5HT2 than D2 receptor sites, like clozapine, but it also exerts significant α2 antagonism, a property that may contribute to its perceived ability to improve mood and increase motor activity. Risperidone is not as effective as clozapine in treatment-resistant cases but does not carry a risk of blood dyscrasias. Olanzapine is similar neurochemically to clozapine but has a significant risk of inducing weight gain. Quetiapine is distinct in having a weak D2 effect but potent α1 and histamine blockade. Ziprasidone causes minimal weight gain and is unlikely to increase prolactin but may increase QT prolongation. Aripiprazole also has little risk of weight gain or prolactin increase but may increase anxiety, nausea, and insomnia as a result of its partial agonist properties.
Antipsychotic agents are effective in 70% of patients presenting with a first episode. Improvement may be observed within hours or days, but full remission usually requires 6–8 weeks. The choice of agent depends principally on the side effect profile and cost of treatment or on a past personal or family history of a favorable response to the drug in question. Atypical agents appear to be more effective in treating negative symptoms and improving cognitive function. An equivalent treatment response can usually be achieved with relatively low doses of any drug selected (i.e., 4–6 mg/d of haloperidol, 10–15 mg of olanzapine, or 4–6 mg/d of risperidone). Doses in this range result in >80% D2 receptor blockade, and there is little evidence that higher doses increase either the rapidity or degree of response. Maintenance treatment requires careful attention to the possibility of relapse and monitoring for the development of a movement disorder. Intermittent drug treatment is less effective than regular dosing, but gradual dose reduction is likely to improve social functioning in many schizophrenic patients who have been maintained at high doses. If medications are completely discontinued, however, the relapse rate is 60% within 6 months. Long-acting injectable preparations (risperidone) are considered when noncompliance with oral therapy leads to relapses. In treatment-resistant patients, a transition to clozapine usually results in rapid improvement, but a prolonged delay in response in some cases necessitates a 6- to 9-month trial for maximal benefit to occur.
Antipsychotic medications can cause a broad range of side effects, including lethargy, weight gain, postural hypotension, constipation, and dry mouth. Extrapyramidal symptoms such as dystonia, akathisia, and akinesia are also frequent with first-generation agents and may contribute to poor adherence if not specifically addressed. Anticholinergic and parkinsonian symptoms respond well to trihexyphenidyl, 2 mg bid, or benztropine mesylate, 1–2 mg bid. Akathisia may respond to beta blockers. In rare cases, more serious and occasionally life-threatening side effects may emerge, including hyperprolactinemia, ventricular arrhythmias, gastrointestinal obstruction, retinal pigmentation, obstructive jaundice, and neuroleptic malignant syndrome (characterized by hyperthermia, autonomic dysfunction, muscular rigidity, and elevated creatine phosphokinase levels). The most serious adverse effects of clozapine are agranulocytosis, which has an incidence of 1%, and induction of seizures, which has an incidence of 10%. Weekly white blood cell counts are required, particularly during the first 3 months of treatment.
The risk of type 2 diabetes mellitus appears to be increased in schizophrenia, and second-generation agents as a group produce greater adverse effects on glucose regulation, independent of effects on obesity, than traditional agents. Clozapine, olanzapine, and quetiapine seem more likely to cause hyperglycemia, weight gain, and hypertriglyceridemia than other atypical antipsychotic drugs. Close monitoring of plasma glucose and lipid levels are indicated with the use of these agents.
A serious side effect of long-term use of first generation antipsychotic agents is tardive dyskinesia, characterized by repetitive, involuntary, and potentially irreversible movements of the tongue and lips (bucco-linguo-masticatory triad), and, in approximately half of cases, choreoathetosis. Tardive dyskinesia has an incidence of 2–4% per year of exposure, and a prevalence of 20% in chronically treated patients. The prevalence increases with age, total dose, and duration of drug administration. The risk associated with second-generation agents appears to be much lower. The cause may involve formation of free radicals and perhaps mitochondrial energy failure. Vitamin E may reduce abnormal involuntary movements if given early in the syndrome.
The CATIE study, a large-scale investigation of the effectiveness of antipsychotic agents in “real world” patients, revealed a high rate of discontinuation of treatment over 18 months. Olanzapine showed greater effectiveness than quetiapine, risperidone, perphenazine, or ziprasidone but also a higher discontinuation rate due to weight gain and metabolic effects. Surprisingly, perphenazine, a first-generation agent, showed little evidence of inferiority to newer drugs.
Drug treatment of schizophrenia is by itself insufficient. Educational efforts directed toward families and relevant community resources have proved to be necessary to maintain stability and optimize outcome. A treatment model involving a multidisciplinary case-management team that seeks out and closely follows the patient in the community has proved particularly effective.