Clozapine
Clozapine
Definition
Clozapine is an antipsychotic drug used to alleviate the symptoms and signs of schizophrenia—a form of severe mental illness—that 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.
Purpose
Clozapine is principally used to reduce the signs and symptoms of severe schizophrenic illness. The drug is intended for use in patients with severe schizophrenia who 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.
Description
Clozapine is considered an atypical antipsychotic drug. Atypical antipsychotics differ from typical anti-psychotics 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 patients with treatment-resistant schizophrenia who do not respond to typical antipsychotics. Moreover, the drug is less likely than typical antipsychotics to cause tardive dyskinesia and 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 may also appear after the use of the antipsychotic has stopped. Women are at greater risk than men for developing tardive dyskinesia. There is no known effective treatment for this syndrome, although gradual (but rarely complete) improvement may occur over a long period.
Clozapine was the first atypical antipsychotic drug to be developed. In the late 1980s, clozapine was tested in severely ill patients with schizophrenia 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 patients resistant to treatment 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 seizures and adverse effects on the heart and blood pressure more frequently than other antipsychotic medicines. Clozapine is usually reserved for the most severely ill patients with schizophrenia 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 neurotransmitters dopamine and serotonin in a region of the brain called 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.
Recently, the effectiveness of clozapine was evaluated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Study. This study evaluated the effectiveness and side effects of newer antipsychotic drugs (sometimes referred to as atypical antipsychotics)—including clozapine—in comparison to a conventional antipsychotic drug in the treatment of schizophrenia.
In Phase I of the study it was found that the newer antipsychotic medications—including clozapine—were not significantly more effective than the less expensive, conventional antipsychotic medications. In Phase II of the study, it was found that participants who had not benefited from their first antipsychotic medication tended to be effectively treated by clozapine. It was further found that for these patients, clozapine worked significantly better than other atypical antipsychotics. The conventional antipsychotic, however, was not included in this phase of the study.
The study results also showed that clozapine is often a good choice of medication for patients who did not respond well to other antipsychotic medications. It was more effective in controlling symptoms than the other atypical antipsychotics under evaluation. For patients whose symptoms are not well-controlled on clozapine, olanzapine and risperidone tended to be more effective than ziprasidone or quetiapine.
Recommended dosage
Clozapine is available as 25 mg 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.
Precautions
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 patients with schizophrenia 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, then once every week for the first six months, once every other week after that, and once a week for the first month after clozapine treatment is stopped.
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 discontinue the drug or reduce the dose. 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 discontinuing 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.
Side effects
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
Interactions
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 increase the effects of other medications that also lower seizure threshold (make it more likely to have seizures), such as steroid drugs, the asthma medication theophylline, and many other psychiatric drugs. Patients with epilepsy may require adjustment in their dosage of antiseizure medications. Lithium may increase the risk of seizures and other nervous system adverse effects when given with clozapine.
KEY TERMS
Agranulocytosis —A blood disorder characterized by a reduction in the number of circulating white blood cells (granulocytes). White blood cells defend the body against infections. Agranulocytosis is a potential side effect of some of the newer antipsychotic medications used to treat schizophrenia.
Antipsychotic drug —A medication used to treat psychotic symptoms of schizophrenia such as hallucinations, delusions, and delirium. These drugs may be used to treat symptoms in other disorders, as well.
Autonomic —The part of the nervous system that governs the heart, involuntary muscles, and glands.
Epilepsy —A neurological disorder characterized by the onset of seizures. Seizures are caused by a disturbance in the electrical activity in the brain and can cause loss of consciousness, muscle spasms, rhythmic movements, abnormal sensory experiences, or altered mental states.
Extrapyramidal side effects —A group of neurological side effects including muscle spasms, involuntary movements, and symptoms that resemble Parkinson’s disease (also called drug-induced parkinsonism).
Parkinson’s disease —A disease of the nervous system most common in people over 60, characterized by a shuffling gait, trembling of the fingers and hands, and muscle stiffness.
Tardive dyskinesia —A condition that involves involuntary movements of the tongue, jaw, mouth or face, or other groups of skeletal muscles. The condition usually occurs either late in antipsychotic therapy or even after the therapy is discontinued. It may be irreversible.
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.
Resources
BOOKS
Preston, John D., John H. O’Neal, and Mary C. Talaga. Handbook of Clinical Psychopharmacology for Therapists. 4th ed. Oakland, CA: New Harbinger Publications, 2004.
Taylor, David, Robert Kerwin, and Carol Paton. The Maudsley 2005-2006 Prescribing Guidelines. New York: Taylor and Francis, 2005.
PERIODICALS
Brunette, Mary F., and others. “Clozapine Use and Relapses of Substance Use Disorder Among Patients With Co-occurring Schizophrenia and Substance Use Disorders.” Schizophrenia Bulletin 32.4 (Oct. 2006): 637–43.
Essock, S. M., and others. “Effectiveness of Switching Antipsychotic Medications.” American Journal of Psychiatry 163.12 (Dec. 2006): 2090–95.
Lamberti, J. Steven, and others. “Prevalence of the Metabolic Syndrome Among Patients Receiving Clozapine.” American Journal of Psychiatry 163.7 (July 2006): 1273–76.
Lieberman, J. A., and others. “Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia.” New England Journal of Medicine 353.12 (Sept. 22, 2005): 1209–23.
Luchins, Daniel J. “In the Aftermath of CATIE: How Should Administrators Value Atypical Antipsychotic Medications?” Administration and Policy in Mental Health and Mental Health Services Research 33.5 (Sept. 2006): 541–43.
McEvoy, J. P., and others. “Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients with Chronic Schizophrenia Who Did Not Respond to Prior Atypical Antipsychotic Treatment.” American Journal of Psychiatry 163.4 (Apr. 2006): 600–610.
Miodownik, Chanoch, and others. “The Effect of Sudden Clozapine Discontinuation on Management of Schizophrenic Patients: A Retrospective Controlled Study.” Journal of Clinical Psychiatry 67.8 (Aug. 2006): 1204–1208.
Rocha, Fábio Lopes, and Cláudia Hara. “Benefits of Combining Aripiprazole to Clozapine: Three Case Reports.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 30.6 (July 2006): 1167–69.
Shaw, Philip, and Judith L. Rapoport. “Decision Making About Children With Psychotic Symptoms: Using the Best Evidence in Choosing a Treatment.” Journal of the American Academy of Child and Adolescent Psychiatry 45.11 (Nov. 2006): 1381–86.
Shaw, Philip, and others. “Childhood-Onset Schizophrenia: A Double-Blind, Randomized Clozapine-Olanzapine Comparison.” Archives of General Psychiatry 63.7 (July 2006): 721–30.
OTHER
CATIE. CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness Schizophrenia Study. 2003. <http://www.catie.unc.edu/schizophrenia>.
National Institutes of Health. CATIE Schizophrenia Trial. 2006. <http://www.clinicaltrials.gov/ct/show/NCT00014001?order=1>.
Richard Kapit, MD
Ruth A. Wienclaw, PhD
Clozapine
Clozapine
Definition
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.
Purpose
Clozapine is principally used to reduce the signs and symptoms of severe schizophrenic illness. The drug is intended for use in patients with severe schizophrenia who 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.
Description
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 dyskinesia and 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 may also appear after use of the antipsychotic has stopped. Women are at greater risk than men for developing tardive dyskinesia. There is no known effective treatment for this syndrome, although gradual (but rarely complete) improvement may occur over a long period.
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 seizures and 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 neurotransmitters dopamine and serotonin in a region of the brain called 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.
Recommended dosage
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.
Precautions
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, and once a week for the first month after clozapine treatment is stopped.
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.
Side effects
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.
Interactions
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.
Resources
BOOKS
American Society of Health-System Pharmacists, Inc. AHFS Drug Information, edited by Gerald K. McEvoy, Pharm.D. Bethesda, MD: American Society of Health-System Pharmacists, Inc., 2001.
Medical Economics staff. Physicians' Desk Reference. 55th ed. Montvale, NJ: Medical Economics Company, Inc., 2001.
Nissen, David, ed. Mosby's GenRx. 11th ed. St. Louis: Mosby, Inc., 2001.
The United States Pharmacopoeia Convention, Inc. USP DI(r) Volume I–. Drug Information for the Health Care Professional. 21st ed. Englewood, CO: Micromedex, Inc., 2001.
The United States Pharmacopeial Convention, Inc. USP DI(r) Volume II–. Advice for the Patient. 21st ed. Englewood, CO: Micromedex, Inc., 2001.
Richard Kapit, M.D.