CLOZAPINE-INDUCED AGRANULOCYTOSIS - RISK-FACTORS, MONITORING AND MANAGEMENT

The introduction of clozapine to the pharmacological armamentarium has led to a redefinition of antipsychotic drugs as a class. Clozapine re presents the first genuinely atypical antipsychotic drug from both a c linical and a pharmacological perspective. Despite its clinical advant ages, the use of clozapine has been limited by a propensity to induce agranulocytosis in 1% of the patients who are treated with this compou nd. This article reviews the indications for clozapine treatment and t he present knowledge base regarding the incidence, monitoring and mana gement of agranulocytosis. As agranulocytosis cannot be prevented, kno wledge of risk factors is important. The risk factors that have been d elineated include: increasing age, female gender, specific human leuco cyte antigen (HLA) halotypes and the duration of exposure to clozapine (with 76% of cases occurring between week 4 and week 18). Among the p atients who develop agranulocytosis, the risk of death is approximatel y 2%. In addition to agranulocytosis, patients receiving clozapine may manifest several benign and asymptomatic blood dyscrasias including le ucocytosis, lymphopenia, eosinophilia and thrombocytosis. White blood cell counts must be followed weekly for the first 18 weeks of treatmen t and less frequently (every 2 or 4 weeks) thereafter in all patients receiving clozapine (in the US, white blood cell counts must be follow ed weekly for the duration of clozapine treatment). Assessment should be more frequent when there is a downward trend in the absolute neutro phil count. There is also evidence for the occurrence of a white blood cell upward spike prior to a decline in this parameter. This latter f inding has been shown to be highly sensitive, but only moderately spec ific. If agranulocytosis does occur, a bone marrow aspiration and the addition of granulocyte colony-stimulating factor or granulocyte-macro phage colony-stimulating factor may be indicated. The psychiatric mana gement of patients receiving clozapine who develop agranulocytosis oft en entails psychiatric hospitalisation. Rechallenge of these patients with clozapine is contraindicated. Risperidone may offer a clinical al ternative after the patients have recovered haematologically. The mech anisms of clozapine-induced agranulocytosis remain unknown, however th ere are several postulated mechanisms. These include a direct toxic ef fect on the bone marrow, the formation of toxic free radicals, or an i mmune-mediated mechanism involving the formation of antigranulocyte or antimyeloid antibodies.