Antipsychotic Medications Anti-psychotic Drugs clozapine, Clozaril

Antipsychotic: clozapine, Clozaril

Generic Name: clozapine
Brand Name(s): Clozaril
Common Use: Antipsychotic

Clozapine, a dibenzodiazepine derivative, is an atypical antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by conventional antipsychotics. Clozapine exerts potent anticholinergic, adrenolytic, antihistaminic and antiserotonergic activity.

Patients on rare occasions may report an intensification of dream activity during clozapine therapy. Rapid eye movement (REM) sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep. As is true of more typical antipsychotic drugs, clinical EEG studies have shown that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave activity and spike and wave complexes may also develop.

The management of symptoms of treatment-resistant schizophrenia. Due to the significant risk of agranulocytosis and seizure associated with its use, clozapine should be limited to treatment-resistant schizophrenic patients who are non-responsive to, or intolerant of, conventional antipsychotic drugs. Non-responsiveness is defined as the lack of satisfactory clinical response, despite treatment with appropriate courses of at least 2 marketed chemically-unrelated antipsychotic drugs. Intolerance is defined as the inability to achieve adequate benefit with conventional antipsychotic drugs because of dose-limiting, intolerable adverse effects.

Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response to clozapine should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated.

Clozapine can be used only if regular, weekly hematological examinations can be guaranteed. Clozapine is available only through a distribution system that ensures: weekly hematological testing prior to the delivery of the next week's supply of medication, maintenance of a central database that monitors the hematological results of patients on clozapine and provides feedback to the treating physician; and participation in a national database; registration of the patient, treating physician and dispensing pharmacist with the system.

Contraindications
Patients with myeloproliferative disorders, a history of drug-induced agranulocytosis or severe granulocytopenia. Clozapine should not be used simultaneously with other agents known to suppress bone marrow function.Other contraindications include severe CNS depression or comatose states, severe hepatic, renal or cardiac disease, and uncontrolled epilepsy.

Adverse Side Effects

The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever. The most common side effects are drowsiness, hypersalivation, tachycardia and sedation.
Initially, drowsiness and sedation may be encountered, especially where relatively large doses of clozapine are given. Generally, this effect tends to subside with continued therapy or dose reduction. Clozapine may cause EEG changes, including the occurrence of spike and wave complexes and may lower the seizure threshold. On rare occasions it may induce episodes of delirium. Extrapyramidal symptoms are limited mainly to tremor, akathisia and rigidity and if such effects occur, they tend to be mild and transient.
Hypersalivation, a common adverse reaction associated with clozapine therapy, may be profuse, especially during sleep, but may be diminished by dose reduction or the use of peripherally-acting anticholinergic medication. Dry mouth, blurred vision and an increase in body temperature may occur.
In contrast to conventional antipsychotics, clozapine produces little or no prolactin response in humans. Consequently, prolactin dependent effects such as decreased libido, impotence, galactorrhea and amenorrhea are seldom associated with clozapine therapy. With continued treatment, considerable weight gain has been seen in some patients. Therapeutic doses of clozapine, to date, even on long-term treatment, have not been associated with symptoms of thyroid dysfunction.
Constipation, nausea and weight gain have been reported occasionally. Increases in hepatic enzymes and, in rare cases, cholestatic jaundice have also been reported.

Overdose

The signs and symptoms associated with clozapine overdose are: drowsiness, lethargy, coma, areflexia, confusion, agitation, delirium, hyperreflexia, convulsions, hypersalivation, mydriasis, blurred vision, thermolability, tachycardia, hypotension, collapse, cardiac arrhythmias, heart block, and respiratory depression. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. In managing overdosage, the physician should consider the possibility of multiple drug involvement.

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