Clozapine is a unique, atypical antipsychotic dibenzoxazebine with unusual efficacy in treating patients with refractory schizophrenia. Randomized studies have shown it to be superior to conventional treatment of this disorder. The use of clozapine, however, has been limited by a 1.6% incidence of life-threatening agranulocytosis. Many times patients who develop agranulocytosis have had meaningful responses and once withdrawn from clozapine experience dramatic psychiatric relapses. Its use in the United States requires weekly blood monitoring, because there exists no predictive tests for the development of agranulocytosis. This proposal will evaluate potential mechanisms of clozapine induced agranulocytosis in patients with schizophrenia. Both toxic and immunologic mechanisms will be explored. Specific emphasis will be placed on the role of clozapine metabolites both as agents which directly suppress the bone marrow and as immunogenic compounds. Due to the prolonged duration of agranulocytosis and the severe marrow suppression there may be either a direct toxic or immune hematopoietic precursors.
The specific aims for this small grant proposal are: 1. To determine whether clozapine or its metabolites are cytotoxic to normal human bone precursors. 2. To search for a cytotoxic antibody in the serum which attacks hematopoietic precursors and identify whether the antibody is dependent on clozapine, a metabolite or complement. 3. To measure the toxicity of the proposed toxic metabolite and/or antibody against hematopoietic precursors taken from affected patients after recovery from clozapine-induced agranulocytosis. 4. To measure plasma levels of potential toxic metabolites to determine whether high levels are associated with bone marrow suppression. This data may help unravel the mechanism of clozapine induced agranulocytosis, may identify a predictive laboratory test to identify high risk patients, and may allow the drug to be more successfully administered to patients with schizophrenia.
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| Gerson, S L; Gullion, G; Yeh, H S et al. (1992) Granulocyte colony-stimulating factor for clozapine-induced agranulocytosis. Lancet 340:1097 |
| Gerson, S L; Lieberman, J A; Friedenberg, W R et al. (1991) Polypharmacy in fatal clozapine-associated agranulocytosis. Lancet 338:262-3 |
