Clozapine (Clozaril), a tricyclic dibenzodiazepine, is used for the symptomatic management of psychotic disorders and is considered an atypical antipsychotic drug. It is currently used primarily for the treatment of patients with schizophrenia or schizoaffective disorders who are at risk for recurrent suicidal behavior and who have encountered nonresponse or adverse, intolerable extra-pyramidal side effects with more classical antipsychotics (chlorpromazine, haloperidol).
Although clozapine was developed about 30 years ago and the initial results were promising, the development of several fatal cases of agranulocytosis resulted in the discontinued use of this agent. Seizures, an increased risk of fatal myocarditis, and orthostatic hypotension have also been associated with the use of clozapine. The use of clozapine has regained interest for several reasons. Patients who did not respond to treatment with other antipsychotics improved when clozapine was administered. Also, the agranulocytosis that occurs in approximately 1% to 2% of patients can be controlled with close hematologic monitoring. However, because of the significant risk of agranulocytosis and seizure associated with its use, clozapine should only be used in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments, either because of insufficient effectiveness or the inability to achieve an effective dose because of intolerable adverse reactions from those drugs.
Treatment is usually started with dosages of 25 to 75 mg/day with a gradual increase to reach a final dose of 300 to 450 mg/day within approximately 2 weeks of the initiation of treatment. Once the desired effect is achieved, the dose may be gradually decreased to keep the patient on the lowest possible effective dose.
Patients being treated with clozapine should be closely monitored during treatment for adverse reactions. Treatment must include monitoring of white blood cell count and absolute neutrophil count. Clozapine treatment should be discontinued in patients failing to show an acceptable clinical response. In addition, in patients exhibiting beneficial clinical responses, the need for continuing treatment should be periodically reevaluated.
Clozapine is metabolized to desmethylated and N-oxide derivatives. The desmethyl metabolite (norclozapine) has only limited activity, and N-oxide metabolite is inactive.