Examination of possible toxic and immune mechanisms of clozapine-induced agranulocytosis.

We investigated three patients who developed agranulocytosis and seven patients who demonstrated neutropenia during therapy with clozapine as well as five patients who were asymptomatic while on clozapine. One of the three agranulocytic patients had previously developed severe neutropenia during clozapine therapy. We examined mature neutrophils to determine if these cells demonstrated increased susceptibility to clozapine or clozapine metabolites that had been generated chemically. Increased susceptibility was found in the cells of some patients, but it was not a consistent finding. We also examined the effects of clozapine or its chemically-generated metabolites on the development of haematopoietic precursor cells derived from the peripheral blood. Clozapine metabolites, but not clozapine, directly inhibited colony formation of all lineages in a dose-dependent manner; there was no evidence of a specific sensitivity of the myeloid precursors. Acute sera from one of the three patients who developed agranulocytosis was inhibitory to the growth of all precursor cells at a concentration of 10% but none of the plasma were inhibitory. In six patients with neutropenia or agranulocytosis, attempts were made to isolate antigen-specific T cells, wherein the antigen was a hapten carrier complex of clozapine metabolites covalently bound to leukocyte macromolecules. No clozapine metabolite-specific clones to these antigens were detected.