Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population

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Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P = 0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P = 0.05). In patients developing neutropenia, ABCB1 3435TT and homozygosity for GSTT1null (glutathione-S-transferase; conjugates reactive clozapine metabolites into glutathione) were more frequent compared with control (34% versus 20%, P = 0.05 and 31% versus 14%, P = 0.03), whereas GSTM1null was less frequent in these patients (31% versus 52%, P = 0.03). To investigate whether combinations of the identified genetic risk factors have a higher predictive value, should be confirmed in a larger case-control study.

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