Clozapine agranulocytosis from

The seeds of this transformation were sown some years ago. The first so-called atypical antipsychotic, clozapine (Clozaril), was devised in the 1960s. Clozapine was used widely in Europe until a series of deaths from a toxic hematological (blood) side effect called agranulocytosis occurred in the mid-1970s. Clozapine resurfaced in the 1980s and was approved for use (under strict guidelines) in the United States in 1990. Since that time, several other atypical antipsychotics have been approved, and others loom on the horizon. 

Clozapine is considered to be the gold standard of treatment of schizophrenia with patients usually moving onto it after treatment failure with two other antipsychotics. Yet the history of it is quite chequered. When it was first introduced onto the European market in 1975 it was used freely with no restrictions on use. Following the death of eight patients in Finland from agranulocytosis, a very rare (< 1 %) but often fatal condition occur-ing normally within the first few months of use, it was voluntarily taken off the market. 

Agranulocytosis Because of a significant risk of agranulocytosis, a potentially life-threatening adverse reaction, reserve clozapine for use in the treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with clozapine, it... 

Two of three patients suffering from agranulocytosis are female, but any relationship to age or dose of clozapine is unclear. Agranulocytosis is rare in the first 4 weeks of treatment, peaking in incidence during the period between the 5th and 25th weeks of treatment. 

Initially, the mortality rate from clozapine-induced agranulocytosis was about 40%, but it has decreased by more than half. Now, while the mortality rate of agranulocytosis complicated by infection is still 40%, without infection, it is approximately 15%. In U.S. clinical trials, the incidence is about one per 100, but because this outcome is based on only 1,000 patients, it may not be an accurate estimate. It is notable that some who developed clozapine-induced agranulocytosis were later able to tolerate other antipsychotics without a recurrence, again implying a different underlying mechanism. 

Over 10 000 patients have been treated with clozapine in Australia since its introduction in 1993, and the Clozaril monitoring system has ensured that since that time there have been no deaths from agranulocytosis in patients taking clozapine (155). 

Withdrawal of clozapine can lead to resolution of agranulocytosis, but not always. Granulocytopenia, presumably induced by clozapine, persisted in a 53-year-old woman after she switched from clozapine to quetiapine (159). 

Although we include clozapine as a newer atypical antipsychotic medication, it does have a long history and in some texts may be listed as a traditional antipsychotic. Known by the brand name Clozaril, clozapine was originally synthesized in 1957 and in 1960 was one of the first antipsychotics released on the European market (Hippius, 1989). It was believed to be more successful than the typical antipsychotics because it did not seem to have the same negative side-effect profiles. Years later, eight documented cases of death were attributed to infections secondary to clozapine-induced agranulocytosis, and the product was withdrawn from unrestricted use (Davis Casper, 1977). Based on later studies that supported the success of clozapine with strict monitoring for treatment-resistant schizophrenia, the FDA approved it in 1990 (Barnes McEv-edy, 1996). 

Clozapine, which is associated with higher risk of agranulocytosis and seizures, is indicated (25 mg once or twice daily) only in the management of schizophrenic patients who fail to respond adequately to standard antipsychotic drug treatment. On the other hand, it is relatively free from extrapyramidal side effects such as parkinsonism. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces as inactive demethylated, hydroxylated, and N-oxide derivatives. Clozapine has anticholinergic properties and causes tachycardia, and hence poses a serious risk for a patient with compromised cardiovascular function (see also Table 23). 

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