CLOZAPINE-INDUCED AGRANULOCYTOSIS - INCIDENCE AND RISK-FACTORS IN THEUNITED-STATES

Background. Clozapine is an atypical antipsychotic agent that is more effective than standard neuroleptic drugs in the treatment of patients with refractory schizophrenia. Unlike classic neuroleptic agents, clo zapine is not associated with the development of acute extrapyramidal symptoms or tardive dyskinesia. The main factor limiting its use is th e risk of potentially fatal agranulocytosis, estimated to occur in 1 t o 2 percent of treated patients. After clozapine was approved by the F ood and Drug Administration, it became available for marketing in the United States in February 1990 only as part of a special surveillance system (the Clozaril Patient Management System, or CPMS), in which a w eekly white-cell count was required for the patient to receive a suppl y of the drug. Methods. We evaluated the CPMS data for February 1990 t hrough April 1991 by survival analysis to determine the incidence of a granulocytosis and the effects of potential risk factors such as age a nd sex. Data were available for 11,555 patients who received clozapine during the period after marketing began. Results. Agranulocytosis dev eloped in 73 patients, resulting in death from infectious complication s in 2 patients. Episodes of agranulocytosis occurred in 61 patients w ithin three months after they began treatment. The cumulative incidenc e of this side effect was 0.80 percent (95 percent confidence interval , 0.61 to 0.99) at 1 year and 0.91 percent (95 percent confidence inte rval, 0.62 to 1.20) at 1 1/2 years. The risk of agranulocytosis increa sed with age and was higher among women. Conclusions. The occurrence o f agranulocytosis is a substantial hazard of the administration of clo zapine, but this hazard can be reduced by monitoring the white-cell co unt. The increasing risk of agranulocytosis with age and the reduced i ncidence after the first six months of treatment provide additional gu idelines for the prescription and monitoring of clozapine treatment in the future.