Schizophrenia is characterized by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized speech and behavior, flattened affect (restricted range of emotions), cognitive deficits (impaired reasoning and problem solving), and occupational and social dysfunction. The cause is unknown, but evidence for a genetic component is strong. Symptoms usually begin in adolescence or early adulthood. One or more episodes of symptoms must last ≥ 6 mo before the diagnosis is made. Treatment consists of drug therapy, psychotherapy, and rehabilitation.

Worldwide, the prevalence of schizophrenia is about 1%. The rate is comparable among men and women and relatively constant cross-culturally. The rate is higher among lower socioeconomic classes in urban areas, perhaps because its disabling effects lead to unemployment and poverty. Similarly, a higher prevalence among single people may reflect the effect of illness or illness precursors on social functioning. The average age at onset is 18 yr in men and 25 yr in women. Onset is rare in childhood, but early-adolescent onset or late-life onset (when it is sometimes called paraphrenia) may occur.

Etiology

Although its specific cause is unknown, schizophrenia has a biologic basis, as evidenced by alterations in brain structure (eg, enlarged cerebral ventricles, decreased size of the anterior hippocampus and other brain regions) and by changes in neurotransmitters, especially altered activity of dopamine

and glutamate. Some experts suggest that schizophrenia occurs in
people with neurodevelopmental vulnerabilities and that the onset, remission, and recurrence of symptoms are the result of interactions between these enduring vulnerabilities and environmental stressors.

Neurodevelopmental vulnerability: Vulnerability may result from genetic predisposition; intrauterine, birth, or postnatal complications; or viral CNS infections. Maternal exposure to famine and influenza during the 2nd trimester of pregnancy, birth weight < 2500 g, Rh incompatibility during a 2nd pregnancy, and hypoxia increase risk.

Although most people with schizophrenia do not have a family history, genetic factors have been implicated. People who have a 1st-degree relative with schizophrenia have about a 10% risk of developing the disorder, compared with a 1% risk among the general population. Monozygotic twins have a concordance of about 50%. Sensitive neurologic and neuropsychiatric tests suggest that aberrant smooth-pursuit eye tracking, impaired cognition and attention, and deficient sensory gating occur more commonly among patients with schizophrenia than among the general population. These markers (endophenotypes) also occur among 1st-degree relatives of people with schizophrenia and may represent the inherited component of vulnerability.

Environmental stressors: Stressors can trigger the emergence or recurrence of symptoms in vulnerable people. Stressors may be primarily biochemical (eg, substance abuse, especially marijuana) or social (eg, becoming unemployed or impoverished, leaving home for college, breaking off a romantic relationship, joining the Armed Forces); however, these stressors are not causative. There is no evidence that schizophrenia is caused by poor parenting.

Protective factors that may mitigate the effect of stress on symptom formation or exacerbation include good social support, coping skills, and antipsychotics (see Schizophrenia and Related Disorders: Treatment).

Symptoms and Signs

Schizophrenia is a chronic illness that may progress through several phases, although duration and patterns of phases can vary. Patients with schizophrenia tend to develop psychotic symptoms an average of 12 to 24 mo before presenting for medical care.

Phases: In the premorbid phase, patients may show no symptoms or may have impaired social competence, mild cognitive disorganization or perceptual distortion, a diminished capacity to experience pleasure (anhedonia), and other general coping deficiencies. Such traits may be mild and recognized only in retrospect or may be more noticeable, with impairment of social, academic, and vocational functioning.

In the prodromal phase, subclinical symptoms may emerge; they include withdrawal or isolation, irritability, suspiciousness, unusual thoughts, perceptual distortions, and disorganization. Onset of overt schizophrenia (delusions and hallucinations) may be sudden (over days or weeks) or slow and insidious (over years).

In the middle phase, symptomatic periods may be episodic (with identifiable exacerbations and remissions) or continuous; functional deficits tend to worsen.

In the late illness phase, the illness pattern may be established, and disability may stabilize or even diminish.

Symptom categories: Generally, symptoms are categorized as

Positive: An excess or distortion of normal functions

Negative: Diminution or loss of normal functions

Disorganized: Thought disorders and bizarre behavior

Cognitive: Deficits in information processing and problem solving

Patients may have symptoms from one or all categories.

Positive symptoms can be further categorized as delusions and hallucinations. Delusions are erroneous beliefs. In persecutory delusions, patients believe they are being tormented, followed, tricked, or spied on. In delusions of reference, patients believe that passages from books, newspapers, song lyrics, or other environmental cues are directed at them. In delusions of thought withdrawal or thought insertion, patients believe that others can read their mind, that their thoughts are being transmitted to others, or that thoughts and impulses are being imposed on them by outside forces. Hallucinations may be auditory, visual, olfactory, gustatory, or tactile, but auditory hallucinations are by far the most common. Patients may hear voices commenting on their behavior, conversing with one another, or making critical and abusive comments. Delusions and hallucinations may be extremely vexing to patients.

Negative (deficit) symptoms include blunted affect, poverty of speech, anhedonia, and asociality. With blunted affect, the patient's face appears immobile, with poor eye contact and lack of expressiveness. Poverty of speech refers to decreased speech and terse replies to questions, creating the impression of inner emptiness. Anhedonia may be reflected by a lack of interest in activities and increased purposeless activity. Asociality is shown by a lack of interest in relationships. Negative symptoms often lead to poor motivation and a diminished sense of purpose and goals.

Disorganized symptoms, which can be considered a type of positive symptom, involve thought disorders and bizarre behaviors. Thinking is disorganized, with rambling, non–goal-directed speech that shifts from one topic to another. Speech can range from mildly disorganized to incoherent and incomprehensible. Bizarre behavior may include childlike silliness, agitation, and inappropriate appearance, hygiene, or conduct. Catatonia is an extreme behavior that can include maintaining a rigid posture and resisting efforts to be moved or engaging in purposeless and unstimulated motor activity.

Cognitive deficits include impairment in attention, processing speed, working memory, abstract thinking, problem solving, and understanding of social interactions. The patient's thinking may be inflexible, and the ability to problem solve, understand the viewpoints of other people, and learn from experience may be diminished. Symptoms of schizophrenia typically impair the ability to function and often markedly interfere with work, social relations, and self-care. Unemployment, isolation, deteriorated relationships, and diminished quality of life are common outcomes. Severity of cognitive impairment is a major determinant of overall disability.

Subtypes: Five subtypes of schizophrenia have been described:

Paranoid: Characterized by delusions or auditory hallucinations, with preservation of cognition and affect

Disorganized: Characterized by disorganized speech, disorganized behavior, and flat or inappropriate affect

Catatonic: Characterized by physical symptoms, including either immobility or excessive motor activity and the assumption of bizarre postures

Residual: A clear history of schizophrenia with more prominent symptoms, followed by a prolonged period of mild negative symptoms

Undifferentiated: A mixture of symptoms from the other subtypes

Alternatively, some experts classify schizophrenia into deficit and nondeficit subtypes based on the presence and severity of negative symptoms, such as blunted affect, lack of motivation, and diminished sense of purpose. Patients with the deficit subtype have prominent negative symptoms unaccounted for by other factors (eg, depression, anxiety, an understimulating environment, drug adverse effects). Those with the nondeficit subtype may have delusions, hallucinations, and thought disorders but are relatively free of negative symptoms.

Suicide: About 10% of patients with schizophrenia commit suicide. Suicide is the major cause of premature death among people with schizophrenia and explains, in part, why on average the disorder reduces life span by 10 yr. Patients who have paranoid subtypes with late onset and good premorbid functioning—the very patients with the best prognosis for recovery—are also at the greatest risk of suicide. Because these patients retain the capacity for grief and anguish, they may be more prone to act in despair based on a realistic recognition of the effect of their disorder (see also Suicidal Behavior).

Violence: Schizophrenia is a relatively modest risk factor for violent behavior. Threats of violence and minor aggressive outbursts are far more common than seriously dangerous behavior. Patients more likely to engage in significant violence include those with substance abuse, persecutory delusions, or command hallucinations and those who do not take their prescribed drugs. A very few severely depressed, isolated, paranoid patients attack or murder someone whom they perceive as the single source of their difficulties (eg, an authority, a celebrity, their spouse).

Diagnosis

Combination of history, symptoms, and signs

No definitive test for schizophrenia exists. Diagnosis is based on a comprehensive assessment of history, symptoms, and signs. Information from collateral sources, such as family members, friends, teachers, and coworkers, is often important. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR), the diagnosis requires both of the following:

≥ 2 characteristic symptoms (delusions, hallucinations, disorganized speech, disorganized behavior, negative symptoms) for a significant portion of a 1-mo period

Prodromal or attenuated signs of illness with social, occupational, or self-care impairments evident for a 6-mo period that includes 1 mo of active symptoms

Psychosis due to other medical disorders or substance abuse must be ruled out by history and examination that includes laboratory tests and neuroimaging (see Approach to the Patient With Mental Symptoms: Medical Assessment of the Patient With Mental Symptoms). Although some patients with schizophrenia have structural brain abnormalities present on imaging, these abnormalities are insufficiently specific to have diagnostic value.

Other mental disorders with similar symptoms include several that are related to schizophrenia: brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, and delusional disorder. In addition, mood disorders can cause psychosis in some people. Certain personality disorders (especially schizotypal) cause symptoms similar to those of schizophrenia, although they are usually milder and do not involve psychosis.

Prognosis

During the first 5 yr after onset of symptoms, functioning may deteriorate and social and work skills may decline, with progressive neglect of self-care. Negative symptoms may increase in severity, and cognitive functioning may decline. Thereafter, the level of disability tends to plateau. Some evidence suggests that severity of illness may lessen in later life, particularly among women. Spontaneous movement disorders may develop in patients who have severe negative symptoms and cognitive dysfunction, even when antipsychotics are not used.

Prognosis varies depending on the subtype. Patients with paranoid schizophrenia tend to be less severely disabled and more responsive to available treatments. Patients with the deficit subtype are typically more disabled, have a poorer prognosis, and are more resistant to treatment.

Schizophrenia can occur with other mental disorders. When associated with significant obsessive-compulsive symptoms (see Anxiety Disorders: Symptoms and Signs), prognosis is particularly poor; with symptoms of borderline personality disorder (see Personality Disorders: Borderline personality disorder), prognosis is better. About 80% of people with schizophrenia experience one or more episodes of major depression at some time in their life.

For the first year after diagnosis, prognosis is closely related to adherence to prescribed psychoactive drugs. Overall, one third of patients achieve significant and lasting improvement; one third improve somewhat but have intermittent relapses and residual disability; and one third are severely and permanently incapacitated. Only about 15% of all patients fully return to their pre-illness level of functioning.

Factors associated with a good prognosis include

Good premorbid functioning (eg, good student, strong work history)

Late and/or sudden onset of illness

Family history of mood disorders other than schizophrenia

Minimal cognitive impairment

Few negative symptoms

Paranoid or nondeficit subtype

Factors associated with a poor prognosis include

Young age at onset

Poor premorbid functioning

Family history of schizophrenia

Disorganized or deficit subtype with many negative symptoms

Men have poorer outcomes than women; women respond better to treatment with antipsychotics.

Substance abuse is a significant problem in up to 50% of patients with schizophrenia. Anecdotal evidence suggests that use of marijuana and other hallucinogens is highly disruptive for patients with schizophrenia and should be strongly discouraged. Comorbid substance abuse is a significant predictor of poor outcome and may lead to drug nonadherence, repeated relapse, frequent rehospitalization, declining function, and loss of social support, including homelessness.

Treatment

Antipsychotic drugs

Rehabilitation, including community support services

Psychotherapy

The time between onset of psychotic symptoms and first treatment correlates with the rapidity of initial treatment response, quality of treatment response, and severity of negative symptoms. When treated early, patients tend to respond more quickly and fully. Without ongoing use of antipsychotics after an initial episode, 70 to 80% of patients have a subsequent episode within 12 mo. Continuous use of antipsychotics can reduce the 1-yr relapse rate to about 30%.

General goals are to reduce severity of psychotic symptoms, prevent recurrences of symptomatic episodes and associated deterioration of functioning, and help patients function at the highest level possible. Antipsychotics, rehabilitation with community support services, and psychotherapy are the major components of treatment. Because schizophrenia is a long-term and recurrent illness, teaching patients illness self-management skills is a significant overall goal. (See also the American Psychiatric Association's Practice Guideline for the Treatment of Patients With Schizophrenia, 2nd Edition.)

Drugs are divided into conventional antipsychotics and 2nd-generation antipsychotics (SGAs) based on their specific neurotransmitter receptor affinity and activity. SGAs may offer some advantages both in terms of modestly greater efficacy (although recent evidence casts doubt on SGAs' advantage as a class) and reduced likelihood of an involuntary movement disorder and related adverse effects. However, risk of metabolic syndrome (excess abdominal fat, insulin


resistance, dyslipidemia, and hypertension) is greater with SGAs than with
conventional antipsychotics.

Conventional antipsychotics: These drugs (see Table 1: Schizophrenia and Related Disorders: Conventional Antipsychotics) act primarily by blocking the dopamine

-2 receptor
(dopamine

-2 blockers). Conventional antipsychotics can be classified as high, intermediate,
or low potency. High-potency antipsychotics have a higher affinity for dopamine

receptors
and less for α-adrenergic and muscarinic receptors. Low-potency antipsychotics, which are rarely used, have less affinity for dopamine

receptors and relatively more affinity for α-
adrenergic, muscarinic, and histaminic receptors. Different drugs are available in tablet, liquid, and short- and long-acting IM preparations. A specific drug is selected primarily based on adverse effect profile, required route of administration, and the patient's previous response to the drug.

Table 1

Conventional Antipsychotics

Drug
Daily Dose (Range)*
Usual Adult Dose
Comments

Phenothiazines, aliphatic

Chlorpromazine

†,‡
30–800 mg
400 mg po at bedtime
Prototypic low-potency drug

Also available as a rectal suppository

Phenothiazines, piperidine

Thioridazine

‡
150–800 mg
400 mg po at bedtime
Only drug with an absolute maximum (800 mg/day) because it causes pigmentary retinopathy at higher doses and has a significant anticholinergic effect

Warning about QTc prolongation added to label

Phenothiazines, piperazines

Trifluoperazine

†,‡
2–40 mg
10 mg po at bedtime


Fluphenazine


†‡
0.5–40 mg
7.5 mg po at bedtime
Also available as fluphenazine


decanoate
and fluphenazine



enanthate, which are IM depot forms (dose equivalents are not available)

Perphenazine

†,‡
12–64 mg
16 mg po at bedtime


Dibenzoxazepine

Loxapine


20–250 mg
60 mg po at bedtime
Has affinity for dopamine

-2 and 5-
hydroxytryptamine (serotonin)-2 receptors

Dihydroindolone

Molindone


15–225 mg
60 mg po at bedtime
Possibly associated with weight reduction

Thioxanthene

Thiothixene

†,‡
8–60 mg
10 mg po at bedtime
Has high incidence of akathisia

Butyrophenone

Haloperidol

†,‡
1–15 mg
4 mg po at bedtime
Prototypic high-potency drug

Haloperidol

decanoate
available as an IM depot

Akathisia common

Diphenylbutylpiperidine

Pimozide


1–10 mg
3 mg po at bedtime
Approved only for Tourette's syndrome

*Current recommended dosing for conventional antipsychotics is to initiate at low range of displayed values and titrate upwards gradually to a single dose; dosing at bedtime is recommended. No evidence that rapid dose escalation is more effective.

†These drugs are available in an IM form for acute treatment.

‡These drugs are available as an oral concentrate.

QTc = QT interval corrected for heart rate.


Clinical Calculator




Two conventional antipsychotics (and one SGA) are available as long-acting depot preparations (see Table 2: Schizophrenia and Related Disorders: Depot Antipsychotic Drugs). These preparations are useful for eliminating drug nonadherence. They may also help patients who, because of disorganization, indifference, or denial of illness, cannot reliably take daily oral drugs.
Table 2

Depot Antipsychotic Drugs

Drug*
Dosage
Peak Level†

Fluphenazine



decanoate
12.5–50 mg q 2–4 wk
1 day

Fluphenazine



enanthate
12.5–50 mg q 1–2 wk
2 days

Haloperidol


decanoate
25–150 mg q 28 days (3–5 wk range is acceptable)
7 days

Risperidone


microspheres‡
12.5–50 mg q 2 wk
35 days

*Drugs are given IM with Z-track technique.

†Time until peak level after a single dose is listed.

‡Because of 3-wk lag time between first injection and achievement of adequate blood levels, patients should continue taking oral antipsychotics for 3 wk after the first injection. Assessment of tolerability with oral risperidone

is
recommended before initiating therapy.



Conventional antipsychotics have several adverse effects, such as sedation, cognitive blunting, dystonia and muscle stiffness, tremors, elevated prolactin levels, and weight gain (for treatment of adverse effects, see Table 5: Approach to the Patient With Mental Symptoms: Treatment of Acute Adverse Effects of Antipsychotics). Akathisia (motor restlessness) is particularly unpleasant and may lead to nonadherence. These drugs may also cause tardive dyskinesia, an involuntary movement disorder most often characterized by puckering of the lips and tongue, writhing of the arms or legs, or both. The incidence of tardive dyskinesia is about 5%/yr of drug exposure among patients taking conventional antipsychotics. In about 2%, tardive dyskinesia is severely disfiguring. In some patients, tardive dyskinesia persists indefinitely, even after the drug is stopped. Because of this risk, patients receiving long-term maintenance therapy should be evaluated at least every 6 mo. Rating instruments, such as the Abnormal Involuntary Movement Scale, may be used (see Table 3: Schizophrenia and Related Disorders: Abnormal Involuntary Movement Scale). Neuroleptic malignant syndrome, a rare but potentially fatal adverse effect, is characterized by rigidity, fever, autonomic instability, and elevated CK (see Heat Illness: Neuroleptic Malignant Syndrome).

Table 3

Abnormal Involuntary Movement Scale

Observe patient's gait on the way into the room.

Have patient remove gum or dentures if ill-fitting.

Determine whether patient is aware of any movements.

Have patient sit on a firm, armless chair with hands on knees, legs slightly apart, and feet flat on the floor. Now and throughout the examination, look at the entire body for movements.

Have patient sit with hands unsupported, dangling over the knees.

Ask patient to open mouth twice. Look for tongue movements.

Ask patient to stick out the tongue twice.

Ask patient to tap thumb against each finger for 15 sec with each hand. Observe face and legs.

Have patient stand with arms extended forward.

Rate each item on a 0 to 4 scale for the greatest severity observed:
0 = none
1 = minimal, may be extreme normal
2 = mild
3 = moderate
4 = severe

Movements that occur only on activation are given 1 point less than those that occur spontaneously.

Facial and oral movements
Muscles of facial expression
0 1 2 3 4


Lips and perioral area
0 1 2 3 4


Jaw
0 1 2 3 4


Tongue
0 1 2 3 4

Extremity movements
Arms
0 1 2 3 4


Legs
0 1 2 3 4

Trunk movements
Neck, shoulders, and hips
0 1 2 3 4

Global judgments
Severity of abnormal movements
0 1 2 3 4


Incapacitation due to abnormal movements
0 1 2 3 4


Patient's awareness of abnormal movements (0 = unaware; 4 = severe distress)
0 1 2 3 4

Adapted from Guy W: ECDEU [Early Clinical Drug Evaluation Unit] Assessment Manual for Psychopharmacology. Rockville (MD), National Institute of Health, Psychopharmacology Research Branch, 1976. Copyright 1976 by US Department of Health, Education and Welfare.



About 30% of patients with schizophrenia do not respond to conventional antipsychotics. They may respond to clozapine

, an SGA.

Second-generation antipsychotics: SGAs block dopamine

receptors more selectively
than conventional antipsychotics, decreasing the likelihood of extrapyramidal (motor) adverse effects. Although greater binding to serotonergic receptors was initially thought to contribute to the efficacy of SGAs, recent studies suggest this binding is unrelated to efficacy or adverse effect profile. SGAs also do the following:

Tend to alleviate positive symptoms

May lessen negative symptoms to a greater extent than do conventional antipsychotics (although such differences have been questioned)

May cause less cognitive blunting

Are less likely to have extrapyramidal (motor) adverse effects

Have a lower risk of causing tardive dyskinesia

Increase prolactin slightly or not at all (except risperidone

, which increases prolactin as much
as do conventional antipsychotics)

Clozapine

, the first SGA, is the only SGA shown to be effective in up to 50% of patients
resistant to conventional antipsychotics. Clozapine

reduces negative symptoms, has few or
no motor adverse effects, and has minimal risk of causing tardive dyskinesia, but it has other adverse effects, including sedation, hypotension, tachycardia, weight gain, type 2 diabetes, and increased salivation. It also may cause seizures in a dose-dependent fashion. The most serious adverse effect is agranulocytosis, which can occur in about 1% of patients. Consequently, frequent monitoring of WBCs is required, and clozapine

is generally reserved
for patients who have responded inadequately to other drugs.

Newer SGAs (see Table 4: Schizophrenia and Related Disorders: Second-Generation Antipsychotics*) provide some of the benefits of clozapine

without the risk of
agranulocytosis and are generally preferable to conventional antipsychotics for treatment of an acute episode and for prevention of recurrence. However, in a recent, large, long-term, controlled clinical trial, symptom relief using any of 4 SGAs (olanzapine

, risperidone


,
quetiapine

, ziprasidone


) was no greater than that with perphenazine


, a conventional
antipsychotic. A follow-up study, in which patients who left the study prematurely were randomized to one of the 3 other study SGAs or to clozapine

, demonstrated a clear
advantage of clozapine

over the other SGAs. Hence, clozapine


seems to be the only
effective treatment for patients who have failed treatment with a conventional antipsychotic or an SGA. However, clozapine

remains underused, probably because of lower tolerability and
need for continuous blood monitoring.

Table 4

Second-Generation Antipsychotics*

Drug
Dose Range
Usual Adult Dose
Comment†

Dibenzodiazepine

Clozapine


150–450 mg po bid
400 mg po at bedtime
First SGA

Only one with demonstrated efficacy in patients unresponsive to other antipsychotics

Frequent WBC counts required because agranulocytosis is a risk

Increased risk of seizures and metabolic syndrome

Benzisoxazoles

Risperidone


4–10 mg po at bedtime
4 mg po at bedtime
May cause extrapyramidal symptoms at doses > 6 mg, dose-dependent prolactin elevation, or metabolic syndrome

Only SGA with a long-acting injectable form

Paliperidone
3–12 mg po at bedtime
6 mg po at bedtime
Metabolite of risperidone



Similar to risperidone



Thienobenzodiazepine

Olanzapine


10–20 mg po at bedtime
15 mg po at bedtime
Most common adverse effects: Somnolence, metabolic syndrome, and dizziness

Dibenzothiazepine

Quetiapine


150–375 mg po bid
200 mg po bid
Low potency allowing wide dosing

May cause metabolic syndrome

No anticholinergic effect

Dose titration required because of blocking of α2 receptors

Requires bid dosing

Benzisothiazolylpiperazine

Ziprasidone


40–80 mg po bid
80 mg po bid
Inhibition of serotonin and norepinephrine

reuptake,
possibly with antidepressant effects

Shortest half-life of new drugs

Requires bid dosing with food

IM form available for acute treatment

Low risk of metabolic syndrome

Dihydrocarostyril

Aripiprazole


10–30 mg po at bedtime
15 mg po at bedtime
Dopamine

-2 partial agonist

Low risk of metabolic syndrome

SGA = Second-generation antipsychotic.

*Monitoring for metabolic syndrome and type 2 diabetes is recommended for this class of antipsychotics.

†All SGAs have been associated with increased mortality in elderly patients with dementia.

SGA = second-generation antipsychotic.



Newer SGAs are very similar to each other in efficacy but differ in adverse effects, so drug choice is based on individual response and on other drug characteristics. For example, olanzapine

, which has a relatively high rate of sedation, may be prescribed for patients with
prominent agitation or insomnia; less sedating drugs might be preferred for patients with lethargy. A 4- to 8-wk trial is usually required to assess efficacy. After acute symptoms have stabilized, maintenance treatment is initiated; for it, the lowest dose that prevents symptom recurrence is used. Risperidone

is the only SGA available in a long-acting injectable
formulation.

Weight gain, hyperlipidemia, and elevated risk of type 2 diabetes are the major adverse effects of SGAs. Thus, before treatment with SGAs is begun, all patients should be screened for risk factors, including personal or family history of diabetes, weight, waist circumference, BP, and fasting plasma glucose and lipid profile. Those found to have or be at significant risk of metabolic syndrome may be better treated with ziprasidone

or aripiprazole


than the other
SGAs. Patient and family education regarding symptoms and signs of diabetes, including polyuria, polydipsia, weight loss, and diabetic ketoacidosis (nausea, vomiting, dehydration, rapid respiration, clouding of sensorium), should be provided. In addition, nutritional and physical activity counseling should be provided to all patients when they start taking an SGA. All patients taking an SGA require periodic monitoring of weight, body mass index, and fasting plasma glucose and referral for specialty evaluation if they develop hyperlipidemia or type 2 diabetes.

Rehabilitation and community support services: Psychosocial skill training and vocational rehabilitation programs help many patients work, shop, and care for themselves; manage a household; get along with others; and work with mental health care practitioners. Supported employment, in which patients are placed in a competitive work setting and provided with an on-site job coach to promote adaptation to work, may be particularly valuable. In time, the job coach acts only as a backup for problem solving or for communication with employers.

Support services enable many patients with schizophrenia to reside in the community. Although most can live independently, some require supervised apartments where a staff member is present to ensure drug adherence. Programs provide a graded level of supervision in different residential settings, ranging from 24-h support to periodic home visits. These programs help promote patient autonomy while providing sufficient care to minimize the likelihood of relapse and need for inpatient hospitalization. Assertive community treatment programs provide services in the patient's home or other residence and are based on high staff-to-patient ratios; treatment teams directly provide all or nearly all required treatment services.

Hospitalization or crisis care in a hospital alternative may be required during severe relapses, and involuntary hospitalization may be necessary if patients pose a danger to themselves or others. Despite the best rehabilitation and community support services, a small percentage of patients, particularly those with severe cognitive deficits and those poorly responsive to drug therapy, require long-term institutional or other supportive care.

Psychotherapy: The goal of psychotherapy is to develop a collaborative relationship between the patients, family members, and physician so that patients can learn to understand and manage their illness, take drugs as prescribed, and handle stress more effectively. Although individual psychotherapy plus drug therapy is a common approach, few empirical guidelines are available. Psychotherapy that begins by addressing the patient's basic social service needs, provides support and education regarding the nature of the illness, promotes adaptive activities, and is based on empathy and a sound dynamic understanding of schizophrenia is likely to be most effective. Many patients need empathic psychologic support to adapt to what is often a lifelong illness that can substantially limit functioning.

For patients who live with their families, psychoeducational family interventions can reduce the rate of relapse. Support and advocacy groups, such as the National Alliance for the Mentally Ill, are often helpful to families.

Depressive disorders are characterized by sadness severe enough or persistent enough to interfere with function and often by decreased interest or pleasure in activities. Exact cause is unknown but probably involves heredity, changes in neurotransmitter levels, altered neuroendocrine function, and psychosocial factors. Diagnosis is based on history. Treatment usually consists of drugs, psychotherapy, or both and sometimes electroconvulsive therapy.

The term depression is often used to refer to any of several depressive disorders. Three are classified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) by specific symptoms:

Major depressive disorder (often called major depression)

Dysthymia

Depressive disorder not otherwise specified

Two others are classified by etiology:

Depressive disorder due to a general physical condition

Substance-induced depressive disorder

Depressive disorders occur at any age but typically develop during the mid teens, 20s, or 30s. In primary care settings, as many as 30% of patients report depressive symptoms, but < 10% have major depression.

The term depression is often used to describe the low or discouraged mood that results from disappointments or losses. However, a better term for such a mood is demoralization. The negative feelings of demoralization, unlike those of depression, resolve when circumstances or events improve; the low mood usually lasts days rather than weeks or months, and suicidal thoughts and prolonged loss of function are much less likely.

Etiology

Exact cause is unknown, but genetic and environmental factors contribute.

Heredity accounts for about half of the etiology (less so in late-onset depression). Thus, depression is more common among 1st-degree relatives of depressed patients, and concordance between identical twins is high. Also, genetic factors probably influence the development of depressive responses to adverse events.

Other theories focus on changes in neurotransmitter levels, including abnormal regulation of cholinergic, catecholaminergic (noradrenergic or dopaminergic), and serotonergic (5-hydroxytryptamine) neurotransmission. Neuroendocrine dysregulation may be a factor, with particular emphasis on 3 axes: hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, and growth hormone.

Psychosocial factors also seem to be involved. Major life stresses, especially separations and losses, commonly precede episodes of major depression; however, such events do not usually cause lasting, severe depression except in people predisposed to a mood disorder.

People who have had an episode of major depression are at higher risk of subsequent episodes. People who are introverted and who have anxious tendencies may be more likely to develop a depressive disorder. Such people often do not develop the social skills to adjust to life pressures. Depression may also develop in people with other mental disorders.

Women are at higher risk, but no theory explains why. Possible factors include greater exposure to or heightened response to daily stresses, higher levels of monoamine oxidase (the enzyme that degrades neurotransmitters considered important for mood), higher rates of thyroid dysfunction, and endocrine changes that occur with menstruation and at menopause. In postpartum depression (see Postpartum Care and Associated Disorders: Postpartum Depression), symptoms develop within 4 wk after delivery; endocrine changes have been implicated, but the specific cause is unknown.

In seasonal affective disorder, symptoms develop in a seasonal pattern, typically during autumn or winter; the disorder tends to occur in climates with long or severe winters.

Depressive symptoms or disorders may accompany various physical disorders, including thyroid and adrenal gland disorders, benign and malignant brain tumors, stroke, AIDS, Parkinson's disease, and multiple sclerosis (see Table 1: Mood Disorders: Some Causes of Symptoms in Depression and Mania). Certain drugs, such as corticosteroids, some β-blockers, interferon, and reserpine

, can also result in depressive disorders. Abuse of some
recreational drugs (eg, alcohol, amphetamines) can lead to or accompany depression. Toxic effects or withdrawal of drugs may cause transient depressive symptoms.

Table 1

Some Causes of Symptoms in Depression and Mania

Type of Disorder
Depression
Mania

Connective tissue
SLE
Rheumatic fever

SLE

Endocrine
Addison's disease

Cushing's disease

Diabetes mellitus

Hyperparathyroidism

Hyperthyroidism

Hypothyroidism

Hypopituitarism

Hypogonadism
Hyperthyroidism

Infectious
AIDS

General paresis (parenchymatous neurosyphilis)

Influenza

Infectious mononucleosis

TB

Viral hepatitis

Viral pneumonia
AIDS

General paresis

Influenza

St. Louis encephalitis

Neoplastic
Cancer of the head of the pancreas

Disseminated carcinomatosis


Neurologic
Cerebral tumors

Complex partial seizures (temporal lobe)

Head trauma

Multiple sclerosis

Parkinson's disease

Sleep apnea

Stroke (left frontal)
Complex partial seizures (temporal lobe)

Diencephalic tumors

Head trauma

Huntington's disease

Multiple sclerosis

Stroke

Nutritional
Pellagra

Pernicious anemia


Other*
Coronary artery disease

Fibromyalgia

Renal or hepatic failure


Pharmacologic
Amphetamine withdrawal

Amphotericin B






Anticholinesterase insecticides

Barbiturates

β-Blockers (some, eg, propranolol

)

Cimetidine



Corticosteroids

Cycloserine



Estrogen therapy

Indomethacin



Interferon

Mercury

Methyldopa



Metoclopramide



Oral contraceptives

Phenothiazines

Reserpine



Thallium

Vinblastine



Vincristine


Amphetamines

Certain antidepressants

Bromocriptine



Cocaine

Corticosteroids

Levodopa

Methylphenidate




Sympathomimetic drugs

Mental
Alcoholism and other substance use disorders

Antisocial personality

Anxiety disorders

Dementing disorders in the early phase

Schizophrenic disorders


*Depression commonly occurs in these disorders, but no causal relationship has been established.



Symptoms and Signs

Depression causes cognitive, psychomotor, and other types of dysfunction (eg, poor concentration, fatigue, loss of sexual desire, loss of pleasure), as well as a depressed mood. Other mental symptoms or disorders (eg, anxiety and panic attacks) commonly coexist, sometimes complicating diagnosis and treatment.

Patients with all forms of depression are more likely to abuse alcohol or other recreational drugs in an attempt to self-treat sleep disturbances or anxiety symptoms; however, depression is a less common cause of alcoholism and drug abuse than was once thought. Patients are also more likely to become heavy smokers and to neglect their health, increasing the risk of development or progression of other disorders (eg, COPD).

Depression may reduce protective immune responses. Depression increases risk of cardiovascular disorders, MIs, and stroke, perhaps because in depression, cytokines and factors that increase blood clotting are elevated and heart rate variability is decreased—all potential risk factors for cardiovascular disorders.

Major depression (unipolar disorder): Periods (episodes) that include ≥ 5 mental or physical symptoms and last ≥ 2 wk are classified as major depression. One of the symptoms must be sadness deep enough to be described as despondency or despair (often called depressed mood) or loss of interest or pleasure in usual activities (anhedonia). Other mental symptoms include feelings of worthlessness or guilt, recurrent thoughts of death or suicide, and a reduced ability to concentrate. Physical symptoms include changes in weight or appetite, loss of energy, fatigue, psychomotor retardation or agitation, and sleep disorders (eg, insomnia, hypersomnia, early morning awakening). Patients may appear miserable, with tearful eyes, furrowed brows, down-turned corners of the mouth, slumped posture, poor eye contact, lack of facial expression, little body movement, and speech changes (eg, soft voice, lack of prosody, use of monosyllabic words). Appearance may be confused with Parkinson's disease. In some patients, depressed mood is so deep that tears dry up; they report that they are unable to experience usual emotions and feel that the world has become colorless and lifeless. Nutrition may be severely impaired, requiring immediate intervention. Some depressed patients neglect personal hygiene or even their children, other loved ones, or pets.

Major depression is often divided into subgroups:

Psychotic: This subgroup is characterized by delusions, often of having committed unpardonable sins or crimes, of harboring incurable or shameful disorders, or of being persecuted. Patients with delusions may also have auditory or visual hallucinations (eg, hearing accusatory or condemning voices). If only voices are described, careful consideration should be given to whether the voices represent true hallucinations.

Catatonic: This subgroup is characterized by severe psychomotor retardation or excessive purposeless activity, withdrawal, and, in some patients, grimacing and mimicry of speech (echolalia) or movement (echopraxia).

Melancholic: This subgroup is characterized by loss of pleasure in nearly all activities, inability to respond to pleasurable stimuli, unchanging emotional expression, excessive or inappropriate guilt, early morning awakening, marked psychomotor retardation or agitation, and significant anorexia or weight loss.

Atypical: This subgroup is characterized by a brightened mood in response to positive events and rejection sensitivity, resulting in depressed overreaction to perceived criticism or rejection, feelings of leaden paralysis or anergy, weight gain or increased appetite, and hypersomnia. Symptoms tend to worsen as the day passes.

Dysthymia: Low-level or subthreshold depressive symptoms that persist for ≥ 2 yr are classified as dysthymia. Symptoms typically begin insidiously during adolescence and follow a low-grade course over many years or decades (diagnosis requires a course of ≥ 2 yr); dysthymia may intermittently be complicated by episodes of major depression. Affected patients are habitually gloomy, pessimistic, humorless, passive, lethargic, introverted, hypercritical of self and others, and complaining. Patients with chronic depressive states, whether dysthymia or chronic major depression, are also more likely to have underlying anxiety, substance use, or personality (ie, borderline personality) disorders.

Depression not otherwise specified (NOS): Clusters of symptoms that do not meet criteria for other depressive disorders are classified as depression NOS. For example, minor depressive disorder may involve ≥ 2 wk of any of the symptoms of major depression but fewer symptoms than the 5 required for diagnosing major depression. Brief depressive disorder involves the same symptoms required for diagnosing major depression but lasts only 2 days to 2 wk. Premenstrual dysphoric disorder involves a depressed mood, anxiety, and decreased interest in activities but only during most menstrual cycles, beginning in the luteal phase and ending within a few days after onset of menses.

Mixed anxiety-depression: Although not considered a type of depression in DSM-IV-TR, this condition, also called anxious depression, refers to concurrent mild symptoms common to anxiety and depression. The course is usually chronically intermittent. Because depressive disorders are more serious, patients with mixed anxiety-depression should be treated for depression.

Diagnosis

Clinical criteria (DSM-IV-TR)

CBC, thyroid-stimulating hormone, vitamin B12, and folate levels to rule out physical disorders that can cause depression

Diagnosis is based on identifying the symptoms and signs (see above). Several brief questionnaires are available for screening. They help elicit some depressive symptoms but cannot be used alone for diagnosis. Specific close-ended questions help determine whether patients have symptoms required by DSM-IV-TR criteria for diagnosis of major depression.

Severity is determined by the degree of pain and disability (physical, social, occupational) and by duration of symptoms. A physician should gently but directly ask patients about any thoughts and plans to harm themselves or others (see Suicidal Behavior). Psychosis and catatonia indicate severe depression. Melancholic features indicate severe or moderate depression. Coexisting physical conditions, substance abuse disorders, and anxiety disorders may add to severity.

Differential diagnosis: Depressive disorders must be distinguished from demoralization. Other mental disorders (eg, anxiety disorders) can mimic or obscure the diagnosis of depression. Sometimes more than one disorder is present. Major depression (unipolar disorder) must be distinguished from bipolar disorder (see Mood Disorders: Bipolar Disorders).

In elderly patients, depression can manifest as dementia of depression (formerly called pseudodementia), which causes many of the symptoms and signs of dementia such as psychomotor retardation and decreased concentration (see Delirium and Dementia: Dementia). However, early dementia may cause depression. In general, when the diagnosis is uncertain, treatment of a depressive disorder should be tried.

Differentiating chronic depressive disorders, such as dysthymia, from substance abuse disorders may be difficult, particularly because they can coexist and may contribute to each other.

Physical disorders must also be excluded as a cause of depressive symptoms. Hypothyroidism often causes symptoms of depression and is common, particularly among the elderly. Parkinson's disease, in particular, may manifest with symptoms that mimic depression (eg, loss of energy, lack of expression, paucity of movement). A thorough neurologic examination is needed to exclude this disorder.

Testing: No laboratory findings are pathognomonic for depressive disorders. Tests for limbic-diencephalic dysfunction are rarely indicated or helpful. However, laboratory testing is necessary to exclude physical conditions that can cause depression. Tests include CBC, TSH levels, and routine electrolyte, vitamin B12, and folate levels. Testing for illicit drug use is sometimes appropriate.

Treatment

Support

Psychotherapy

Drugs

Symptoms may remit spontaneously, particularly when they are mild or of short duration. Mild depression may be treated with general support and psychotherapy. Moderate to severe depression is treated with drugs, psychotherapy, or both and sometimes electroconvulsive therapy. Some patients require a combination of drugs. Improvement may not be apparent until after 1 to 4 wk of drug treatment.

Depression, especially in patients who have had > 1 episode, is likely to recur; therefore, severe cases often warrant long-term maintenance drug therapy. (See also the American Psychiatric Association's Guideline Watch: Practice Guideline for the Treatment of Patients With Major Depressive Disorder, 3rd Edition.)

Most people with depression are treated as outpatients. Patients with significant suicidal ideation, particularly when family support is lacking, require hospitalization, as do those with psychotic symptoms or physical debilitation.

Depressive symptoms in patients with substance abuse disorders often resolve within a few months of stopping substance use. Antidepressant treatment is much less likely to be effective while substance abuse continues.

If a physical disorder or drug toxicity could be the cause, treatment is directed first at the underlying disorder. However, if the diagnosis is in doubt or if symptoms are disabling or include suicidal ideation or hopelessness, a therapeutic trial with an antidepressant or a mood-stabilizing drug may help.

Initial support: Until definite improvement begins, a physician should see patients weekly or biweekly to provide support and education and to monitor progress. Telephone calls may supplement office visits.

Patients and loved ones may be worried or embarrassed about the idea of having a mental disorder. The physician can help by explaining that depression is a serious medical disorder caused by biologic disturbances and requires specific treatment and that the prognosis with treatment is good. Patients and loved ones should be reassured that depression does not reflect a character flaw (eg, laziness, weakness). Telling patients that the path to recovery often fluctuates helps them put feelings of hopelessness in perspective and improves adherence.

Encouraging patients to gradually increase simple activities (eg, taking walks, exercising regularly) and social interactions must be balanced with acknowledging their desire to avoid activities. The physician can suggest that patients avoid self-blame and explain that dark thoughts are part of the disorder and will go away.

Psychotherapy: Psychotherapy, often as cognitive-behavioral therapy (individual or group), alone is often effective for milder forms of depression. Cognitive-behavioral therapy is increasingly used to combat the inertia and self-defeating mental set of depressed patients. However, cognitive-behavioral therapy is most useful when combined with antidepressants to treat moderate to severe depression. Cognitive-behavioral therapy may improve coping skills and enhance gains by providing support and guidance, by removing cognitive distortions that prevent adaptive action, and by encouraging patients to gradually resume social and occupational roles. Couple therapy may help reduce conjugal tensions and disharmony. Long-term psychotherapy is usually unnecessary except for patients who have long-term interpersonal conflicts or who are unresponsive to brief therapy.

Selective serotonin reuptake inhibitors (SSRIs): These drugs prevent reuptake of serotonin (5-hydroxytryptamine [5-HT]). SSRIs include citalopram

, escitalopram


, fluoxetine



,
fluvoxamine

, paroxetine


, and sertraline


. Although these drugs have the same
mechanism of action, differences in their clinical properties make selection important. SSRIs have a wide therapeutic margin; they are relatively easy to administer, with little need for dose adjustment (except for fluvoxamine

).

By preventing reuptake of 5-HT presynaptically, SSRIs result in more 5-HT to stimulate postsynaptic 5-HT receptors. SSRIs are selective to the 5-HT system but not specific for the different 5-HT receptors. They stimulate 5-HT1 receptors, with antidepressant and anxiolytic effects, but they also stimulate 5-HT2 receptors, commonly causing anxiety, insomnia, and sexual dysfunction, and 5-HT3 receptors, commonly causing nausea and headache. Thus, SSRIs can paradoxically relieve and cause anxiety.

A few patients may seem more agitated, depressed, and anxious within a week of starting SSRIs or increasing the dose. Patients and their loved ones should be warned of this possibility and instructed to call the physician if symptoms worsen with treatment. This situation should be closely monitored because some patients, especially younger children and adolescents, become increasingly suicidal if agitation, increased depression, and anxiety are not detected and rapidly treated. Recent studies have determined that children, adolescents, and young adults have an increased rate of suicidal ideation, suicide gestures, and suicide attempts during the first few months of taking SSRIs (the same concern may apply to serotonin modulators, serotonin-norepinephrine

reuptake inhibitors, and
norepinephrine

-dopamine


reuptake inhibitors); physicians must balance this risk with
clinical need.

Sexual dysfunction (especially difficulty achieving orgasm but also decreased libido and erectile dysfunction) occurs in one third or more of patients. Some SSRIs cause weight gain. Others, especially fluoxetine


, may cause anorexia in the first few months. SSRIs have few
anticholinergic, adrenolytic, and cardiac conduction effects. Sedation is minimal or nonexistent, but in the early weeks of treatment, some patients tend to be sleepy during the day. Loose stools or diarrhea occurs in some patients.

Drug interactions are relatively uncommon; however, fluoxetine


, paroxetine


, and
fluvoxamine

can inhibit cytochrome P-450 (CYP450) isoenzymes, which can lead to serious
drug interactions. For example, these drugs can inhibit the metabolism of certain β-blockers, including propranolol

and metoprolol



, potentially resulting in hypotension and bradycardia.
Discontinuation symptoms (eg, irritability, anxiety, nausea) can occur if the drug is stopped abruptly; such effects are less likely with fluoxetine


.

Serotonin modulators (5-HT2 blockers): These drugs block primarily the 5-HT2 receptor and inhibit reuptake of 5-HT and norepinephrine

. Serotonin modulators include nefazodone


,
trazodone

, and mirtazapine


. Serotonin modulators have antidepressant and anxiolytic
effects but do not cause sexual dysfunction. Unlike most antidepressants, nefazodone


does not suppress REM (rapid eye movement) sleep and produces restful sleep. Nefazodone

can significantly interfere with drug-metabolizing liver enzymes and has been
associated with liver failure.

Trazodone

is related to nefazodone


but does not inhibit 5-HT reuptake presynaptically.
Unlike nefazodone

, trazodone


has caused priapism (in 1/1000) and, as an α1-
noradrenergic blocker, may cause orthostatic (postural) hypotension. It is very sedating, so its use in antidepressant doses (> 200 mg/day) is limited. It is most often given in 50- to 100-mg doses at bedtime to depressed patients with insomnia.

Mirtazapine

inhibits 5-HT reuptake and blocks α2-adrenergic autoreceptors, as well as 5-
HT2 and 5-HT3 receptors. The result is increased serotonergic function and increased noradrenergic function without sexual dysfunction or nausea. It has no cardiac adverse effects, has minimal interaction with drug-metabolizing liver enzymes, and is generally well tolerated, although it does cause sedation and weight gain, mediated by H1 (histamine) blockade.

Serotonin-norepinephrine reuptake inhibitors: These drugs (eg, venlafaxine

,
duloxetine

) have a dual 5-HT and norepinephrine


mechanism of action, as do tricyclic
antidepressants. However, their toxicity approximates that of SSRIs. Nausea is the most common problem during the first 2 wk; modest dose-dependent increases in BP occur with high doses. Discontinuation symptoms (eg, irritability, anxiety, nausea) often occur if the drug is stopped suddenly. Duloxetine

resembles venlafaxine


in effectiveness and adverse
effects.

Norepinephrine-dopamine reuptake inhibitors: By mechanisms not clearly understood, these drugs favorably influence catecholaminergic, dopaminergic, and noradrenergic function. They do not affect the 5-HT system.

Bupropion


is currently the only drug in this class. It can help depressed patients with
concurrent attention-deficit/hyperactivity disorder or cocaine dependence and those trying to stop smoking. Bupropion


causes hypertension in a very few patients but has no other
effects on the cardiovascular system. Bupropion


can cause seizures in 0.4% of patients
taking doses > 150 mg tid (or > 200 mg sustained-release [SR] bid or > 450 mg extended-release [XR] once/day); risk is increased in patients with bulimia. Bupropion


does not have
sexual adverse effects and interacts little with coadministered drugs, although it does inhibit the CYP2D6 hepatic enzyme. Agitation, which is common, is considerably attenuated by using the SR or XR form.

Heterocyclic antidepressants: This group of drugs, once the mainstay of treatment, includes tricyclic (tertiary amines amitriptyline


and imipramine


and their secondary amine
metabolites nortriptyline

and desipramine


), modified tricyclic, and tetracyclic
antidepressants. Acutely, these drugs increase the availability of primarily norepinephrine


and, to some extent, 5-HT by blocking reuptake in the synaptic cleft. Long-term use downregulates α1-adrenergic receptors on the postsynaptic membrane—a possible final common pathway of their antidepressant activity.

Although effective, these drugs are now rarely used because overdose causes toxicity and they have more adverse effects than other antidepressants. The more common adverse effects of heterocyclics are due to their muscarinic-blocking, histamine-blocking, and α1-adrenolytic actions. Many heterocyclics have strong anticholinergic properties and are thus unsuitable for the elderly and for patients with benign prostatic hypertrophy, glaucoma, or chronic constipation. All heterocyclics, particularly maprotiline

and clomipramine


, lower the
threshold for seizures.

Monoamine oxidase inhibitors (MAOIs): These drugs inhibit the oxidative deamination of the 3 classes of biogenic amines (norepinephrine

, dopamine


, 5-HT) and other
phenylethylamines. MAOIs have little or no effect on normal mood. Their primary value is for treating refractory or atypical depression when SSRIs, tricyclic antidepressants, and sometimes even electroconvulsive therapy is ineffective.

MAOIs marketed as antidepressants in the US (eg, phenelzine

, tranylcypromine


,
isocarboxazid

) are irreversible and nonselective (inhibiting MAO-A and MAO-B). Another
MAOI (selegiline

), which inhibits only MAO-B at lower doses, is available as a patch.

MAOIs that inhibit MAO-A and MAO-B can cause hypertensive crises if a sympathomimetic drug or food containing tyramine or dopamine

is ingested concurrently. This effect is called
the cheese reaction because mature cheese has a high tyramine content. MAOIs are used infrequently because of concern about this reaction. The lower dosage of the selegiline


patch is considered safe to use without specific dietary restrictions, unless the dosage must be higher than starting levels (a 6-mg patch). More selective and reversible MAOIs (eg, moclobemide

, befloxatone), which inhibit MAO-A, are not yet available in the US; they are
relatively free of these interactions. To prevent hypertension and febrile crises, patients taking MAOIs should avoid sympathomimetic drugs (eg, pseudoephedrine


), dextromethorphan




,
reserpine

, and meperidine


as well as malted beers, Chianti wines, sherry, liqueurs, and
overripe or aged foods that contain tyramine or dopamine

(eg, bananas, fava or broad
beans, yeast extracts, canned figs, raisins, yogurt, cheese, sour cream, soy sauce, pickled herring, caviar, liver, extensively tenderized meats). Patients can carry 25-mg tablets of chlorpromazine

and, as soon as signs of such a hypertensive reaction occur, take 1 or 2
tablets as they head to the nearest emergency department.

Common adverse effects include erectile dysfunction (least common with tranylcypromine

),
anxiety, nausea, dizziness, insomnia, pedal edema, and weight gain. MAOIs should not be used with other classes of antidepressants, and at least 2 wk (5 wk with fluoxetine


, which
has a long half-life) should elapse between use of the 2 classes of drugs. MAOIs used with antidepressants that affect the 5-HT system (eg, SSRIs, nefazodone

) may cause
neuroleptic malignant syndrome (malignant hyperthermia, muscle breakdown, renal failure, seizures, and eventual death—see Heat Illness: Neuroleptic Malignant Syndrome). Patients who are taking MAOIs and who also need antiasthmatic or antiallergic drugs, a local anesthetic, or a general anesthetic should be treated by a psychiatrist plus an internist, a dentist, or an anesthesiologist with expertise in neuropsychopharmacology.

Drug choice and administration: Choice of drug may be guided by past response to a specific antidepressant. Otherwise, SSRIs are often the initial drugs of choice. Although the different SSRIs are equally effective for typical cases, certain properties of the drugs make them more or less appropriate for certain patients (see Table 2: Mood Disorders: Antidepressants ).
Table 2


Antidepressants
This table is presented as a PDF and requires the free Adobe PDF reader. Get Adobe Reader



If one SSRI is ineffective, another SSRI can be substituted, but an antidepressant from a different class may be more likely to help. Tranylcypromine

in high doses (20 to 30 mg
po bid) is often effective for depression refractory to sequential trials of other antidepressants; it should be given by a physician experienced in use of MAOIs. Psychologic support of patients and loved ones is particularly important in refractory cases.

Insomnia, a common adverse effect of SSRIs, is treated by reducing the dose or adding a low dose of trazodone

or another sedating antidepressant. Initial nausea and loose stools
usually resolve, but throbbing headaches do not always go away, necessitating a change in drug class. An SSRI should be stopped if it causes agitation. When decreased libido, impotence, or anorgasmia occur during SSRI therapy, dose reduction may help, or a change can be made to another drug class.

SSRIs, which tend to stimulate many depressed patients, should be given in the morning. Giving the entire heterocyclic antidepressant dose at bedtime usually makes sedatives unnecessary, minimizes adverse effects during the day, and improves adherence. MAOIs are usually given in the morning and early afternoon to avoid excessive stimulation.

Therapeutic response with most classes of antidepressants usually occurs in about 2 to 3 wk (sometimes as early as 4 days or as late as 8 wk). For a first episode of mild or moderate depression, the antidepressant should be given for 6 mo, then tapered gradually over 2 mo. If the episode is severe or is a recurrence or if there is suicidal risk, the dose that produces full remission should be continued during maintenance.

For psychotic depression, imipramine

appears to be more effective than monotherapy with
antidepressants from other classes; dosing this drug can be guided by steady-state plasma levels. The addition of an antipsychotic may improve the likelihood of response, but antipsychotic monotherapy appears to be ineffective.

Continued therapy with an antidepressant for 6 to 12 mo (up to 2 yr in patients > 50) is usually needed to prevent relapse. Most antidepressants, especially SSRIs, should be tapered off (by decreasing the dose by about 25%/wk) rather than stopped abruptly; stopping SSRIs abruptly may result in discontinuation syndrome (nausea, chills, muscles aches, dizziness, anxiety, irritability, insomnia, fatigue). The likelihood and severity of withdrawal varies inversely with the half-life of the SSRI.

Medicinal herbs are used by some patients. St. John's wort (see Dietary Supplements: St. John's Wort) may be effective for mild depression, although data are contradictory. St. John's wort may interact with other antidepressants and other drugs. A number of placebo-controlled studies of ω-3 supplementation, used as augmentation or as monotherapy, have suggested that eicosapentaenoic acid 1 to 2 g once/day has useful antidepressant effects.

Electroconvulsive therapy (ECT): Severe suicidal depression, depression with agitation or psychomotor retardation, delusional depression, or depression during pregnancy is often treated with ECT if drugs are ineffective. Patients who have stopped eating may need ECT to prevent death. ECT is also effective for psychotic depression. Response to 6 to 10 ECT treatments is usually dramatic and may be lifesaving. Relapse after ECT is common, and drug therapy is often maintained after ECT is stopped.

Phototherapy: Phototherapy is best known for its effects on seasonal depression but can also be effective in other types of depression. Treatment can be provided at home with 2,500 to 10,000 lux at a distance of 30 to 60 cm for 30 to 60 min/day (longer with a less intense light source). In patients who go to sleep late at night and rise late in the morning, phototherapy is most effective in the morning, sometimes supplemented with 5 to 10 min of exposure between 3 pm and 7 pm. For patients who go to sleep and rise early, phototherapy is most effective between 3 pm and 7 pm.

Other therapies: Psychostimulants (eg, dextroamphetamine


, methylphenidate



) are
sometimes used, often with antidepressants; however, they have not been well studied in controlled clinical trials.

Vagus nerve stimulation involves intermittently stimulating the vagus nerve via an implanted pulse generator. It may be useful for depression refractory to other treatments but usually takes 3 to 6 mo to be effective.

Deep brain stimulation and transcranial magnetic stimulation are still under study.

During adolescence, teens work on becoming more independent. Your teen must cast aside the dependent parent-child relationship. Before he can develop an adult relationship with his parents, a teen must first distance himself from the way he related to his parents in the past. This usually means there will be a certain amount of normal rebellion, defiance, discontent, and restlessness. Emotions usually run high. Mood swings are common. This rebellion continues for about 2 years, but it is not uncommon for it to last for 4 to 6 years.
How do I deal with my teenager’s rebellion?

The following guidelines may help you and your teenager through this difficult time.

Treat your teenager as an adult friend.

By the time your child is 12 years old, start working on developing the kind of relationship you would like to have with your child when she is an adult. Treat your child the way you would like her to treat you when she is an adult. Your goal is mutual respect, support, and the ability to have fun together. Strive for relaxed, casual conversations during bicycling, hiking, shopping, playing catch, driving, cooking, mealtime, working, and other times together. Use praise and trust to help build her self-esteem. Recognize your child’s feelings by listening and making nonjudgmental comments. Remember that listening doesn’t mean you have to solve your teen’s problems.

Avoid criticism about “no-win” topics.

Most negative parent-teen relationships start because the parents criticize their teenager too much. Dressing, talking, and acting differently than adults helps your teen feel independent from you. Your teen will probably like to do the things his friends do. This is an important step in your teens development. Try not to attack your teenager’s clothing, hairstyle, makeup, music, dance steps, friends, recreational interests, room decorations, use of free time, use of money, speech, posture, and philosophy. This doesn’t mean withholding your personal views about these subjects. But allowing your teen to rebel in these harmless areas often prevents testing in major areas, such as drugs, ditching school, or stealing. Step in and try to make a change only if your teenager’s behavior is harmful, illegal, or infringes on your rights (see the sections on house rules).

Another common error is to criticize your teen’s mood or attitude. A negative or lazy attitude can only be changed through good example and praise. The more you dwell on nontraditional (even strange) behaviors, the longer they will last.

Your teenager must learn from trial and error. As she experiments, she will learn to take responsibility for her decisions and actions. Speak up only if your teen is going to do something dangerous or illegal. Otherwise, you must rely on the teen’s own self-discipline, pressure from her friends to behave responsibly, and the lessons learned from the consequences of her actions.

City curfew laws will help control late hours. A school’s requirement for being on time will help your teen want to get enough sleep at night. School grades will hold your teenager accountable for homework and other aspects of school. If your teen has bad work habits, she will lose her job. If your teenager makes a poor choice of friends, she may find her confidences broken or that she gets into trouble. If she doesn’t practice hard for a sport, she will be pressured by the team and coach to do better. If she misspends her allowance or earnings, she will run out of money before the end of the month.

If by chance your teenager asks you for advice about these problem areas, try to describe the pros and cons in a brief, impartial way. Ask some questions to help her think about the main risks. Then conclude your remarks with a comment such as, “Do what you think is best.” Teens need plenty of opportunity to learn from their own mistakes before they leave home and have to solve problems without an ever-present support system.

You have the right and the responsibility to make rules regarding your house and other possessions. A teen’s choices can be tolerated within his own room but they need not be imposed on the rest of the house. You can forbid loud music that interferes with other people’s activities, or incoming telephone calls after 10:00 PM. While you should make your teen’s friends feel welcome in your home, clarify the ground rules about parties or where snacks can be eaten. Your teen can be placed in charge of cleaning his room, washing his clothes, and ironing his clothes. You can insist upon clean clothes and enough showers to prevent or overcome body odor. You must decide whether you will loan him your car, bicycle, camera, radio, TV, clothes, and so forth.

Reasonable consequences for breaking house rules include loss of telephone, TV, stereo, and car privileges. (Time-out is rarely useful in this age group, and spanking can cause to a serious breakdown in your relationship.) If your teenager breaks something, he should repair it or pay for its repair or replacement. If he makes a mess, he should clean it up. If your teen is doing poorly in school, you can restrict TV time. You can also put a limit on telephone privileges and weeknights out. If your teen stays out too late or doesn’t call you when he’s delayed, you can ground him for a day or a weekend. In general, grounding for more than a few days is looked upon as unfair and is hard to enforce.

Some families find it helpful to have a brief meeting after dinner once a week. At this time your teenager can ask for changes in the house rules or bring up family issues that are causing problems. You can also bring up issues (such as your teen’s demand to drive her to too many places and your need for her help in arranging carpools). The family often functions better if the decision-making is democratic. The objective of negotiation should be that everyone wins. The atmosphere can be one of: “Nobody is at fault, but we have a problem. How can we solve it?”

Generally when your teenager is in a bad mood, he won’t want to talk about it with you. If teenagers want to discuss a problem with anybody, it is usually with a close friend. In general, it is best to give your teen lots of space and privacy. This is a poor time to talk to your teen about anything, pleasant or otherwise.

Some talking back is normal. We want our teenagers to express their anger through talking and to challenge our opinions in a logical way. We need to listen. Expect your teenager to present his case passionately, even unreasonably. Let the small stuff go—it’s only words. But don’t accept disrespectful remarks such as calling you a “jerk.” Unlike a negative attitude, these mean remarks should not be ignored. You can respond with a comment like, “It really hurts me when you put me down or don’t answer my question.” Make your statement without anger if possible. If your teen continues to make angry, unpleasant remarks, leave the room. Don’t get into a shouting match with your teenager because this is not a type of behavior that is acceptable in outside relationships.

What you are trying to teach is that everyone has the right to disagree and even to express anger, but that screaming and rude conversation are not allowed in your house. You can prevent some rude behavior by being a role model of politeness, constructive disagreement, and the willingness to apologize.
When should I call my child’s healthcare provider?

Call during office hours if:
You think your teenager is depressed, suicidal, drinking or using drugs, or going to run away.
Your teenager is taking undue risks (for example, reckless driving).
Your teenager has no close friends.
Your teenager’s school performance is declining markedly.
Your teenager is skipping school frequently.
Your teenager’s outbursts of temper are destructive or violent.
You feel your teenager’s rebellion is excessive.
Your family life is seriously disrupted by your teenager.
You find yourself escalating the criticism and punishment.
Your relationship with your teenager does not improve within 3 months after you begin using these approaches.
You have other questions or concerns.