Clozapine-induced agranulocytosis. Incidence and risk factors in the United States

N Engl J Med. 1993 Jul 15;329(3):162-7. doi: 10.1056/NEJM199307153290303.


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, clozapine is not associated with the development of acute extrapyramidal symptoms or tardive dyskinesia. The main factor limiting its use is the risk of potentially fatal agranulocytosis, estimated to occur in 1 to 2 percent of treated patients. After clozapine was approved by the Food 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 weekly white-cell count was required for the patient to receive a supply of the drug.

Methods: We evaluated the CPMS data for February 1990 through April 1991 by survival analysis to determine the incidence of agranulocytosis and the effects of potential risk factors such as age and sex. Data were available for 11,555 patients who received clozapine during the period after marketing began.

Results: Agranulocytosis developed in 73 patients, resulting in death from infectious complications in 2 patients. Episodes of agranulocytosis occurred in 61 patients within three months after they began treatment. The cumulative incidence 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 interval, 0.62 to 1.20) at 1 1/2 years. The risk of agranulocytosis increased with age and was higher among women.

Conclusions: The occurrence of agranulocytosis is a substantial hazard of the administration of clozapine, but this hazard can be reduced by monitoring the white-cell count. The increasing risk of agranulocytosis with age and the reduced incidence after the first six months of treatment provide additional guidelines for the prescription and monitoring of clozapine treatment in the future.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Agranulocytosis / blood
  • Agranulocytosis / chemically induced*
  • Agranulocytosis / epidemiology
  • Clozapine / adverse effects*
  • Drug Monitoring
  • Female
  • Follow-Up Studies
  • Humans
  • Incidence
  • Leukocyte Count
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Risk Factors
  • United States / epidemiology


  • Clozapine