Human neutrophils show decreased survival upon long-term exposure to clozapine

Objective: Clozapine is an atypical antipsychotic prescribed for treatment-resistant schizophrenic patients, but treatment with clozapine is strictly limited because it can induce lethal-hematologic side effects. We investigated the effects of short- and long-term exposure of human neutrophils derived from healthy subjects to clozapine and compared them with the effects of reactive metabolite of clozapine, olanzapine, and doxorubicin. Methods: Neutrophils were exposed to clozapine and olanzapine (1, 10, 50, or 100 μM), reactive metabolite of clozapine (50 or 100 μM), or doxorubicin (0.2 μM) and cultured for a short (2 hr) or long (24 or 48 hr) duration, and then the survival rate of neutrophils was calculated. Results: Decreased human neutrophil survival was observed in short-term exposure to clozapine (100 μM) and long-term exposure to clozapine even at a lower concentration (50 μM). A similar phenomenon was observed in reactive metabolite of clozapine and long-term exposure to doxorubicin (0.2 μM), but not to olanzapine (1–100 μM). Conclusions: The effect of long-term exposure to clozapine on neutrophil survival is plausibly associated with delayed onset of agranulocytosis after initial exposure. Our results suggest that human neutrophils are vulnerable to clozapine and its reactive metabolite in a concentration- and time-dependent manner.