Mechanism of clozapine-induced agranulocytosis : current status of research and implications for drug development.

Clozapine is an atypical antipsychotic agent that has several advantages over conventional antipsychotics, not least of which is its superior efficacy. However, the high risk of agranulocytosis (0.8% of patients) associated with clozapine therapy has resulted in restricted indications for its use.The mechanism of clozapine-induced agranulocytosis is not clear. The target cells affected are the myeloid precursors, although the mature neutrophil may also be targeted simultaneously. There is no convincing evidence of direct toxicity of the parent compound or its stable metabolites (demethyl-clozapine and clozapine N-oxide). Clozapine is also metabolised by liver microsomes, peripheral blood neutrophils and their bone marrow precursors to a chemically reactive intermediate that has been postulated to be a nitrenium ion. This toxic metabolite has been shown to covalently bind to neutrophil proteins, suggesting that it may be involved in the pathogenesis of the toxicity. However, it is not clear how toxicity is mediated. The nitrenium ion may bind to essential cellular proteins and disrupt neutrophil function or, alternatively, it may act as a hapten and initiate an immune reaction resulting in immune-mediated destruction of the neutrophil. Indirect evidence exists to support both mechanisms, although clear direct evidence is still lacking. The role of cytokines and apoptosis in the pathogenesis of the agranulocytosis is unclear.The reason why only approximately 1% of individuals who are treated with clozapine are affected by agranulocytosis has not been elucidated. Evidence exists to implicate both the major histocompatibility complex antigens and heat shock protein variants in determining individual susceptibility, although more patients of different ethnic backgrounds need to be studied.The ultimate aim of research into clozapine-induced agranulocytosis should be to either prospectively predict which individuals are going to develop agranulocytosis and/or to develop analogues that retain efficacy but are not toxic. The former is complicated by the fact that predisposition may be multifactorial, and thus prediction may require multiple tests that may be of statistical but not absolute validity. The latter depends on identifying the mechanism of toxicity and the chemical characteristics of clozapine that are responsible for the toxicity. This knowledge may allow rational design of new analogues that do not cause agranulocytosis.