Clozapine is an antipsychotic drug used to alleviate the symptoms and signs of schizophrenia—a form of severe mental illness— which is characterized by loss of contact with reality, hallucinations, delusions, and unusual behavior. In the United States, the drug is also known by the brand name Clozaril.
Clozapine is principally used to reduce the signs and symptoms of severe schizophrenic illness. The drug is intended for use in patients with severe schizophreniawho have not responded to any other antipsychotic drug. Clozapine is also used in patients with severe schizophrenia when other antipsychotic medications have caused intolerable side effects.
Clozapine is considered an atypical antipsychotic drug. Atypical antipsychotics differ from typical antipsychotics in their effectiveness in schizophrenia and their profile of side effects. Clozapine may reduce the signs and symptoms of schizophrenia in a large proportion of treatment-resistant schizophrenic patients who do not respond to typical antipsychotics. Moreover, the drug is less likely than typical antipsychotics to cause tardive dyskinesiaand other extrapyramidal side effects. Tardive dyskinesia is a syndrome of involuntary, uncoordinated movements that may not disappear or may only partially improve after the drug is stopped. Tardive dyskinesia involves involuntary movements of the tongue, jaw, mouth or face or other groups of skeletal muscles. The incidence of tardive dyskinesia increases with increasing age and with increasing dosage. It
Clozapine was the first atypical antipsychotic drug to be developed. In the late 1980s, clozapine was tested in severely ill schizophrenic patients who had been treated with a typical antipsychotic drug but had not shown much improvement. A significant proportion of these patients improved as a result of treatment with clozapine.
The superiority of clozapine in treatment-resistant patients is considered an important advance, but the drug is not without problems. Clozapine is generally considered the most toxic of the antipsychotic drugs. It causes agranulocytosis, a life-threatening depletion of white blood cells, in 1-2% of patients. It also causes epileptic seizuresand adverse effects on the heart and blood pressure more frequently than other antipsychotic medicines. Clozapine is usually reserved for the most severely ill schizophrenic patients who have not responded to other treatments. Other atypical antipsychotic drugs have been developed in recent years, and they are considered safer to use than clozapine.
The mechanisms of action of antipsychotic drugs are not completely understood. The effect of clozapine is believed to be related to its actions in blocking neurotransmission due to the neurotransmittersdopamine and serotonin in a region of the braincalled the limbic system, which is involved with emotions and motivation. The actions of clozapine may target the limbic system more specifically than those of typical antipsychotic drugs.
Clozapine is available as Clozaril, the only brand, as 25- and 100-mg tablets.
The usual dosage of clozapine is 300–600 mg per day; however, some patients may require daily dosages of up to 900 mg. To minimize side effects, the initial dose of clozapine is 12.5 mg (one-half tablet) twice a day, and the dose is increased by 25–50 mg each day, until the dose reaches 300–450 mg per day. The daily dosage of the drug is then determined based on the individual patient's response, but increases should not exceed 100 mg once or twice a week.
Clozapine may cause agranulocytosis, a life-threatening depletion of white blood cells. The blood cells affected by clozapine defend the body against infections by bacteria and other microorganisms, and patients with agranulocytosis are subject to severe infections. Clozapine treatment is reserved for the most severely ill schizophrenic patients who have not responded to other treatments. Clozapine is available only through a distribution system that assures close monitoring of white blood cells. Patients must have white blood cell counts determined before starting treatment, once every week for the first six months, once every other week after that,
Clozapine may cause epileptic seizures in about 5% of patients. The frequency of seizures goes up as the dose of the drug is increased. Patients who experience seizures on clozapine should usually have the drug discontinued or the dose reduced. Neuroleptic malignant syndrome (NMS), a dangerous condition with high fever, muscular rigidity, rapid pulse, sweating, and altered mental state, may occur with all antipsychotic medications, including clozapine. NMS requires immediate medical treatment.
Clozapine frequently causes sedation and may interfere with driving and other tasks requiring alertness. The drug may increase the effects of alcohol and sedatives. Clozapine may cause low blood pressure and sudden drops in blood pressure on standing up, which may cause dizziness or fainting. Elevated heart rate may occur in 25% of patients; this effect may be a serious risk for patients with heart disease. Clozapine-induced fever, unrelated to any illness, may occur. The fever usually subsides within a few days, but it may require stopping the drug.
The safety and effectiveness of clozapine in children under 16 years old have not been established. Elderly patients may be particularly sensitive to sedation, low blood pressure, and other side effects. The drug should be used with caution in older patients. Clozapine should be used in pregnant women only when strictly necessary. The drug has not been adequately studied in pregnancy. In animal studies, however, clozapine has not produced harmful effects on the fetus. Clozapine may be secreted in breast milk, and breast-feeding may not be advisable.
Clozapine may cause many side effects. The following side effects are grouped by the body system affected:
- Cardiovascular: decreases of blood pressure, especially on arising from a seated or lying position, which may cause dizziness or fainting; rapid heart rate, changes in heart rhythm and electrocardiogram.
- Nervous system: sedation, increased seizure tendency.
- Digestive system: increased appetite, excessive salivation, nausea, constipation, abnormal liver tests, elevated blood sugar.
- Autonomic: blurred vision, exacerbation of glaucoma, dry mouth, nasal congestion, decreased sweating; difficulty urinating, particularly in men with enlarged prostate.
- Skin: rashes.
- Body as a whole: weight gain, fever.
Clozapine may interact with many other drugs. Patients should inform their physicians about all other drugs they are taking before starting treatment. Because of the risk of agranulocytosis, clozapine should not be given along with medications that suppress production of blood cells.
Clozapine may intensify the effects of drugs causing sedation, including alcohol, barbiturates, narcotic pain medications, minor tranquilizers, and antihistamines. Similarly, clozapine may cause excessive reductions of blood pressure in patients taking other medicines that lower blood pressure. Clozapine may also intensify side effects of drugs that cause blurred vision, dry mouth, diminished sweating in hot weather, and constipation. Many other antipsychotics and antidepressants cause such side effects.
Clozapine may potentiate (increase) the effects of other medications that also lower seizure threshold (make it more likely to have seizure), such as steroid drugs, the asthma medication theophylline, and many other psychiatric drugs. Patients with epilepsy may require adjustment in their dosage of anti-seizure medications. Lithium may increase the risk of seizures and other nervous system adverse effects when given with clozapine.
Certain drugs that are eliminated by the liver may interfere with the elimination of clozapine from the body, causing higher blood levels and increased side effects. Conversely, clozapine may interfere with the elimination of other drugs that are eliminated by the liver. Antidepressants that affect brain serotonin levels may increase blood levels of clozapine, possibly causing increased side effects.
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Richard Kapit, M.D.