Agranulocytosis, clozapine causing

In contrast to other antipsychotic agents, clozapine causes agranulocytosis in a small but significant number of patients—approximately 1-2% of those treated. This serious, potentially fatal effect can develop rapidly, usually between the 6th and 18th weeks of therapy. It is not known whether it represents an immune reaction, but it appears to be reversible upon discontinuance of the drug. Because of the risk of agranulocytosis, patients receiving clozapine must have weekly blood counts for the first 6 months of treatment and every 3 weeks thereafter. 

Unfortunately, potentially fatal agranulocytosis appears in 1-2% of patients treated with clozapine (7). This necessitates frequent blood monitoring, which can be inconvenient and expensive. Furthermore, despite its low potential for causing EPS and TD, clozapine causes other, dose-related side effects that can limit its effectiveness in some patients. The precise pharmacological actions of clozapine responsible for its clinical effectiveness are still being debated. Attempts to duplicate elements cf its complex pharmacological profile have led to the discovery of several new atypical antipsychotic drugs that have been approved in the United States for the treatment of schizophrenia. 

Miscellaneous toxidties Visual impairment caused by retinal deposits has occurred with thioridazine at high doses, this drug may also cause severe conduction defects in the heart that result in fatal ventricular arrhythmias. Sertindole prolongs the QT interval of the ECG the underlying myocardial effect may lead to cardiac arrhythmias. Clozapine causes a small but important (1—2%) incidence of agranulocytosis and at high doses has caused seizures. 

Quetiapine (Seroquel). Another atypical antipsychotic, quetiapine has also been approved by the FDA for the treatment of acute mania. It is usually administered twice daily at doses of 150-750mg/day. Like its counterparts, quetiapine is a well-tolerated medication. Its common side effects are drowsiness, dizziness, and headache. It causes less weight gain than olanzapine or clozapine but more than ziprasidone or aripiprazole. Quetiapine also does not cause agranulocytosis nor does it increase the risk of seizures. It can occasionally cause mild changes in liver function tests, but these usually return to normal even if the patient continues taking quetiapine. 

Clozapine Myeloproliferative disorders uncontrolled epilepsy history of clozapine-induced agranulocytosis or severe granulocytopenia should not be used with other agents having a well-known potential to cause agranulocytosis or suppress bone marrow function. 

Clozapine Drugs having a well known potential to cause agranulocytosis or suppress bone marrow function... 

Clozapine, the first of the class of atypical antipsychotic drugs, rarely causes EPS, and it is the only antipsychotic drug that is not associated with treatment-emergent tardive dyskinesia. Because of the approximately 1% risk of potentially fatal agranulocytosis, the use of clozapine is restricted to patients who have not responded to or cannot tolerate other antipsychotic drugs. 

Dibenzodiazepine Clozapine May benefit treatment-resistant patients little extrapyramidal toxicity May cause agranulocytosis in up to 2% of patients dose-related lowering of seizure threshold... 

Clozaril (Clozapine), for example, can cause agranulocytosis (a potentially lethal suppression of white blood cells by the bone marrow). Parkinsonian symptoms and weight gain occur with risperidone (Risperdal) and olanzapine (Zyprexa). In addition, quetiapine (Seroquel) has been associated with an increased incidence of cataracts. 

Despite its novel therapeutic profile, it was soon evident that clozapine occasionally caused agranulocytosis, a potentially fatal immune condition, in approximately 3% of patients. The use of clozapine was therefore restricted largely to patients who suffered severe side effects with the typical neuroleptics, who were resistant to conventional neuroleptics or who had a high proportion of negative symptoms. Thus, clozapine has served as a useful prototype for the development of new neuroleptics and these will be briefly described. 

Clinical studies have demonstrated that olanzapine has a similar profile to clozapine without causing agranulocytosis preliminary studies also show that it does not cause extrapyramidal side effects or increase prolactin release. Olanzapine has recently been introduced for the treatment of mania. 

The synthesis and discovery of the antipsychotic effects of the piperazinyl-dibenzoazepine, clozapine (Fig. 13.1) and its launch in 1972 was an important turning point in the drug treatment of schizophrenia [1-3]. Clozapine was called an atypical antipsychotic as it did not produce side effects characteristic for compounds of the chlorpromazine- or haloperidol-type (i.e., extrapyramidal symptoms) either in animal models or in the clinic. Its use, however, became very limited when it was recognized that clozapine might cause a severe, and sometimes fatal, form of agranulocytosis. 

Some explanations of the lower risk of agranulocytosis have been advanced after an in vitro cytotoxicity study (209). Like clozapine, olanzapine is oxidized to a reactive nitrenium ion by HOC1, the major oxidant produced in activated neutrophils. However, the olanzapine-reactive metabolite has a lower propensity to cause toxicity to human neutrophils, monocytes, and HL-60 cells than the reactive clozapine nitrenium ion. The lower toxic potential of the olanzapine reactive metabolite, in conjunction with the lower therapeutic plasma concentrations of olanzapine compared with clozapine, may help to explain this difference between the drugs. 

In another case, olanzapine caused agranulocytosis after clozapine had had no effect on the white cell count (204). 

In a 12-week, double-blind, randomized, placebo-controlled study in 40 patients with treatment-resistant schizophrenia (funded by Johnson Johnson Pharmaceutical Research Development), the addition of risperidone to clozapine improved overall symptoms and positive and negative symptoms (49). The adverse events profile of clozapine + risperidone was similar to that of clozapine + placebo. Clozapine + risperidone did not cause additional weight gain, agranulocytosis, or seizures compared with clozapine + placebo. All the patients completed 12 weeks of treatment however, the small sample size precluded definitive conclusions. 

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