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By S. Charles Schulz, MD, Professor Emeritus; Psychiatrist, University of Minnesota Medical School; Prairie Care Medical Group

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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.

Psychosis refers to symptoms such as delusions, hallucinations, disorganized thinking and speech, and bizarre and inappropriate motor behavior (including catatonia) that indicate loss of contact with reality.

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 early to mid 20s in women and somewhat earlier in men; about 40% of males have their first episode before age 20. Onset is rare in childhood, but early-adolescent onset or late-life onset (when it is sometimes called paraphrenia) may occur.


Although its specific cause is unknown, schizophrenia has a biologic basis, as evidenced by

  • Alterations in brain structure (eg, enlarged cerebral ventricles, thinning of the cortex, decreased size of the anterior hippocampus and other brain regions)

  • 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

  • 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.

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.

Symptoms of schizophrenia typically impair the ability to function and often markedly interfere with work, social relationships, and self-care. Unemployment, isolation, deteriorated relationships, and diminished quality of life are common outcomes.

Phases of schizophrenia

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 [1] 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 in schizophrenia

Generally, symptoms are categorized as

  • Positive: An excess or distortion of normal functions

  • Negative: Diminution or loss of normal functions and affect

  • 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

  • Hallucinations

Delusions are erroneous beliefs that are maintained despite clear contradictory evidence. There are several types of delusions:

  • Persecutory delusions: Patients believe they are being tormented, followed, tricked, or spied on.

  • Delusions of reference: Patients believe that passages from books, newspapers, song lyrics, or other environmental cues are directed at them.

  • 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

Delusions in schizophrenia tend to be bizarre—ie, clearly implausible and not derived from ordinary life experiences (eg, believing that someone removed their internal organs without leaving a scar).

Hallucinations are sensory perceptions that are not perceived by anyone else. They 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: The patient’s face appears immobile, with poor eye contact and lack of expressiveness.

  • Poverty of speech: The patient speaks little and gives terse replies to questions, creating the impression of inner emptiness

  • Anhedonia: There is a lack of interest in activities and increased purposeless activity.

  • Asociality: There is 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

  • 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 example of bizarre behavior, which 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 the following:

  • Attention

  • Processing speed

  • Working memory

  • Abstract thinking

  • Problem solving

  • 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. Severity of cognitive impairment is a major determinant of overall disability.

Subtypes of schizophrenia

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.

The previously recognized subtypes of schizophrenia (paranoid, disorganized, catatonic, residual, undifferentiated) have not proved valid or reliable and are no longer used.


About 5 to 6% of patients with schizophrenia commit suicide, and about 20% attempt it; many more have significant suicidal ideation. 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.

Risk may be especially high for young men with schizophrenia and a substance use disorder. Risk is also increased in patients who have depressive symptoms or feelings of hopelessness, who are unemployed, or who have just had a psychotic episode or been discharged from the hospital.

Patients who have 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.


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).

Symptoms reference


  • Clinical criteria (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5])

  • Combination of history, symptoms, and signs

If the first episode of schizophrenia that meets criteria for the disorder is recognized early and treated, outcome is better.

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 DSM-5, the diagnosis requires both of the following:

  • 2 characteristic symptoms (delusions, hallucinations, disorganized speech, disorganized behavior, negative symptoms) for a significant portion of a 6-mo period (symptoms must include at least one of the first 3)

  • 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

Differential diagnosis

Psychosis due to other medical disorders or to substance abuse must be ruled out by history and examination that includes laboratory tests and neuroimaging (see 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:

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.


The earlier treatment is started, the better the outcome.

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.

Schizophrenia can occur with other mental disorders. When associated with significant obsessive-compulsive symptoms, prognosis is particularly poor; with symptoms of 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

  • Shorter duration of untreated psychosis

Factors associated with a poor prognosis include

  • Young age at onset

  • Poor premorbid functioning

  • Family history of schizophrenia

  • Many negative symptoms

  • Longer duration of untreated psychosis

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.


  • 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 and quality of treatment response. 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%. Drug treatment is continued for 1 to 2 yr after a first episode. If patients have been ill longer, it is given for many years.

General goals for schizophrenia treatment are to

  • Reduce the severity of psychotic symptoms

  • Prevent recurrences of symptomatic episodes and associated deterioration of functioning

  • 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. Providing information about the disorder (psychoeducation) to parents can reduce the relapse rate. (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. Several antipsychotics in both classes can cause long QT syndrome and ultimately increase the risk of fatal arrhythmias; these drugs include thioridazine, haloperidol, olanzapine, risperidone, and ziprasidone.

Conventional antipsychotics

Conventional antipsychotics (see Table: 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 alpha-adrenergic and muscarinic receptors. Low-potency antipsychotics, which are rarely used, have less affinity for dopamine receptors and relatively more affinity for alpha-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 the following:

  • Adverse effect profile

  • Required route of administration

  • The patient’s previous response to the drug

Conventional Antipsychotics


Daily Dose (Range)*

Usual Adult Dose



30–800 mg

400 mg po at bedtime

Prototypic low-potency drug

Also available as a rectal suppository


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


2–40 mg

10 mg po at bedtime


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)


12–64 mg

16 mg po at bedtime


20–250 mg

60 mg po at bedtime

Has affinity for dopamine-2 and 5-hydroxytryptamine (serotonin)-2 receptors


15–225 mg

60 mg po at bedtime

Possibly associated with weight reduction


8–60 mg

10 mg po at bedtime

Has high incidence of akathisia


1–15 mg

8 mg po at bedtime

Prototypic high-potency drug

Haloperidol decanoate available as an IM depot

Akathisia common


1–10 mg

3 mg po at bedtime

Approved only for Tourette 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. There is 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.

Some antipsychotics are available as long-acting depot preparations (see Table: 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.

Depot Antipsychotic Drugs



Peak Level

Aripiprazole, long-acting, injectable

300–400 mg q mo

5–7 days

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

Olanzapine pamoate

210–300 mg q 2 wk or 300–405 mg q 4 wk

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.

Olanzapine pamoate may cause rare, but significant sedation so patients must be observed for 3 h after the injection.

§Because of a 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, weight gain, and lowered seizure threshold in patients with seizures or at risk of seizures (for treatment of adverse effects, see Table: Treatment of Acute Adverse Effects of Antipsychotics). Akathisia (motor restlessness) is particularly unpleasant and may lead to nonadherence; it can be treated with propranolol.

Treatment of Acute Adverse Effects of Antipsychotics




Acute dystonic reactions (eg, oculogyric crisis, torticollis)

Benztropine 2 mg IV or IM (may be repeated once in 20 min)

Diphenhydramine 50 mg IV or IM q 20 min for 2 doses

Benztropine 2 mg po may prevent dystonia when given with an antipsychotic.

Laryngeal dystonia

Lorazepam 4 mg IV over 10 min, then 1–2 mg IV slowly

Intubation may be needed.

Akinesia, severe parkinsonian tremors, bradykinesia

Benztropine 1–2 mg po bid

Diphenhydramine 25–50 mg po tid

In patients with akinesia, the antipsychotic may have to be stopped, and one with a lower potency used.

Akathisia (with other extrapyramidal symptoms)

Amantadine 100–150 mg po bid

Benztropine 1–2 mg po bid

Biperiden 1–4 mg po bid

Procyclidine 2.5–10 mg po bid

Propranolol 10–30 mg po tid

Trihexyphenidyl 2–7 mg po bid or 1–5 mg po tid (or for the sustained-release form, 2–7 mg bid)

The causative drug should be stopped, or a lower dose used.

Akathisia associated with extreme anxiety

Lorazepam 1 mg tid po

Clonazepam 0.5 mg bid po

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. For patients taking conventional antipsychotics, the incidence of tardive dyskinesia is about 5% each year of drug exposure. 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: Abnormal Involuntary Movement Scale). Patients who have schizophrenia and who continue to require an antipsychotic drug may be treated with clozapine or quetiapine, which are SGAs.

Neuroleptic malignant syndrome, a rare but potentially fatal adverse effect, is characterized by rigidity, fever, autonomic instability, and elevated CK.

Abnormal Involuntary Movement Scale

Before or after completing the scoring, clinicians should do the following:

  • 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 of the following items 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.



Range of Possible Scores

Facial and oral movements

Muscles of facial expression

0 1 2 3 4

Lips and perioral area

0 1 2 3 4


0 1 2 3 4


0 1 2 3 4

Extremity movements


0 1 2 3 4


0 1 2 3 4

Trunk movements

Neck, shoulders, and hips

0 1 2 3 4

Global judgment

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

About 95% of all antipsychotics prescribed are SGAs.

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, 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 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)

SGAs may appear to lessen negative symptoms because they are less likely to have parkinsonian adverse effects than 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 (done weekly for the first 6 mo and every 2 wk thereafter, then once/mo after a year) is required, and clozapine is generally reserved for patients who have responded inadequately to other drugs.

Newer SGAs (see Table: 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 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 with anticholinergic effects. In a follow-up study, patients who left the study prematurely were randomized to one of the 3 other study SGAs or to clozapine; this study 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.

Second-Generation Antipsychotics*


Dose Range

Usual Adult Dose



10–30 mg po

15 mg po

Dopamine-2 partial agonist

Low risk of metabolic syndrome


5–10 mg sublingually bid

10 mg sublingually bid

Given sublingually with no food to be consumed for 10 min afterward (tablet should not be swallowed)


2–4 mg po

2–4 mg po

Dopamine-2 partial agonist

Low risk of metabolic syndrome

Helps with major depression

Dose titrated with

  • 1 mg given on days 1–4

  • 2 mg given on days 5–7

  • 4 mg given on day 8 (maximum dose: 4 mg)


1.5–6 mg po

3–6 mg po

Low risk of metabolic syndrome

Most common adverse effects: Somnolence, upset stomach

Dose titrated with

  • 1.5 mg given on day 1

  • 3 mg given on day 2


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


1–12 mg po bid

12 mg po once/day

Because of possible orthostatic hypotension, titrated over 4 days when initiated


40–160 mg po once/day

80 mg po once/day

Given once/day with food

Lower doses used in patients with liver impairment


10–20 mg po at bedtime

15 mg po at bedtime

Most common adverse effects: Somnolence, metabolic syndrome, and dizziness


3–12 mg po at bedtime

6 mg po at bedtime

Metabolite of risperidone

Similar to risperidone


150–375 mg po bid

Extended-release: 400–800 mg po at bedtime

200 mg po bid

Low potency allowing a wide dosing range

May cause metabolic syndrome

No anticholinergic effect

Dose titration required because of blocking of alpha-2 receptors

Bid dosing required for immediate-release formulation; extended release given once at bedtime


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


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

*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. Aripiprazole, olanzapine, and risperidone are 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.

Cognitive remediation therapy helps some patients. This therapy is designed to improve neurocognitive function (eg, attention, working memory, executive functioning) and to help patients learn or relearn how to do tasks. This therapy may enable patients to function better.


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.

In addition to individual psychotherapy, there has been significant development of cognitive behavioral therapy for schizophrenia. For example, this therapy, done in an individual or a group setting, can focus on ways to diminish delusional thoughts.

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 on Mental Illness, are often helpful to families.

Key Points

  • Schizophrenia is characterized by psychosis, hallucinations, delusions, disorganized speech and behavior, flattened affect, cognitive deficits, and occupational and social dysfunction.

  • Suicide is the most common cause of premature death.

  • Threats of violence and minor aggressive outbursts are far more common than seriously dangerous behavior.

  • Treat with antipsychotic drugs early, basing selection primarily on adverse effect profile, required route of administration, and the patient’s previous response to the drug.

  • Psychotherapy helps patients understand and manage their illness, take drugs as prescribed, and handle stress more effectively.

  • With treatment, 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.

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