Clozapine induced agranulocytosis, reported

Barnas C, Zwierzina H, Hummer M, et al Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis a case report. J Clin Psychiatry 53 245-247, 1992... 

Table 1 Reported incidences of clozapine-induced agranulocytosis ...

Increased apoptosis of neutrophils has been reported in a 45-year-old woman with clozapine-induced agranulocytosis (142). Withdrawal of clozapine and treatment with granulocyte colony-stimulating factor led to normalization of the blood neutrophil count within 3 weeks. 

In addition to aplastic anemia, more bone marrow selective drug-induced hypoplasias have been reported. For example, clozapine-induced agranulocytosis occurs in... 

Information appears to be limited to this study and the three case reports, but clozapine has not been found to interact with other potent inhibitors of CYP3A4, see Clozapine + Azoles , p.745. An interaction seems unlikely, although the case reports do suggest that rarely some patients may be affected. Bear this interaction in mind in the case of an unexpected response to treatment. Note that infection may be a sign of clozapine-induced agranulocytosis. 

Thus, valproate is often used to reduce the risk for clozapine-induced seizures. Carbamazepine can potentially increase the risk for development of agranulocytosis when coadministered with clozapine, so this combination should be avoided. Carbamazepine increases renal clearance of olanzapine by about 45% and reduces its half-life by about 20%. To date, no pharmacokinetic interactions have been reported between aripiprazole and valproate. 

Clozapine and SSRIs are often used together, because depressive syndromes are common in patients with schizophrenia. Clozapine carries a relatively high risk of agranulocytosis, but this adverse effect is very rarely seen with SSRIs, although a case of possible fluoxetine-induced neutropenia has been described (SEDA-22, 15). Two cases in which the addition of paroxetine to clozapine was associated with neutropenia have been reported (11). The patients had been taking stable doses of clozapine for 6-12 months and had previously tolerated other SSRIs without adverse hematological consequences. In both cases the white cell count recovered when clozapine was withdrawn, although paroxetine was continued. 

A recent study of the atypical antipsychotic clozapine in Asians (Matsuda et al. 1996) found that Korean American patients showed a greater improvement than whites while receiving lower mean doses of clozapine. Korean Americans had lower mean clozapine concentrations than did Caucasians, yet they were more likely to experience anticholinergic and other side effects. No cases of agranulocytosis were reported in Korean American patients, and the incidence in Asians is not known. Clozapine is metabolized by CYP1A2, which is highly inducible, so such differences may be due to differences in diet and other personal habits. 

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