Clozapine for Schizophrenia

Donald S. Robinson, MD

Consultant, Worldwide Drug Development

Drug treatment of schizophrenia has undergone significant changes since 1990 with the introduction of clozapine, the first of the second-generation “atypical” antipsychotics. The novel pharmacologic profiles of the atypical antipsychotics translate into lower propensity to cause extrapyramidal symptoms (EPS), especially tardive dyskinesia. The atypical antipsychotics offer other therapeutic advantages besides low liability for EPS, including improved treatment compliance, superior efficacy in therapy-resistant patients, and beneficial effects on negative symptoms of schizophrenia.

Clozapine Agranulocytosis

At the time of approval by the FDA in 1990, it was well known that clozapine could cause leukopenia and agranulocytosis, as widely reported during clinical use in Europe. However, because of established efficacy in treatment-resistant schizophrenic patients, the FDA approved clozapine for marketing in the US, but required intensive hematologic monitoring. Weekly blood testing for at least the first year of treatment was set as a pre-condition for dispensing the drug.

In 1998, the FDA approved reduced frequency of hematologic monitoring, allowing bi-weekly testing after 6 months of treatment if there were no abnormalities in blood tests. Despite its status as the most effective antipsychotic drug for treatment-resistant schizophrenic patients, more general use of clozapine has remained limited because of this risk of agranulocytosis, a serious medical complication with potentially fatal outcome despite intensive therapy in a small percentage of afflicted patients.

The pathogenesis of clozapine-induced agranulocytosis was unclear when first introduced into clinical use. Further studies now indicate that the toxic effects of a clozapine metabolite on leukocytes causes acceleration of the physiologic cell death cycle.

Leukocyte Life Cycle During Clozapine Treatment

The polymorphonuclear leukocyte, a cell destined to apoptosis, has a normal life span of only 8–12 hours. Evidence now indicates that unstable reactive metabolites of clozapine produce oxidative stress in neutrophils that accelerates this brief life cycle of the leukocyte, leading in some cases to neutropenia and agranulocytosis.

It remains unclear why such a small proportion of clozapine-treated patients are susceptible to developing leukopenia and agranulocytosis.

Conclusion

Clozapine is highly effective in treating schizophrenia, but until clinical predictors of clozapine agranulocytosis can be identified, patients should continue to be intensively monitored during treatment, particularly during the initial 4–6 months of therapy.