Clozapine was synthesized in 1959 as part of a project to discover antipsychotic drugs with low potential for extrapyramidal side-effects. It proved to be one of the most interesting and clinically important compounds ever discovered. It was labelled as atypical because of its ability to block amphetamine-induced locomotor activity, one of the most widely accepted models for antipsychotic activity, without producing catalepsy in rodent, the leading indicator for causation of extrapyramidal side-effects in humans. Subsequent clinical studies showed it to have the lowest extrapyramidal side-effects of any antipsychotic drug known. (546> Clinical trials in the 1960s and 1970s suggested it was also superior in efficacy with regard to control of positive symptoms, but given the standards of clinical trials of that era, these conclusions could not be relied upon.(4Z) In 19Z5, 6 years after its introduction in Europe, clozapine's ability to cause granulocytopenia or agranulocytosis was first reported. Six deaths occurred in clozapine-treated patients in a geographically restricted area of Finland over a short period of time. The role of clozapine in these deaths is still uncertain because no other such clustering has ever occurred in Finland, or elsewhere. Nevertheless, clozapine was withdrawn from general use, although it remained available for humanitarian use in patients who had previously received it, for individual cases where it seemed indicated because of its low potential for extrapyramidal side-effects, and for research purposes. (46>
Clozapine was reintroduced in 1989 after it was demonstrated to be superior to chlorpromazine to improve positive and negative symptoms in 300 patients who were resistant to the action of at least three typical neuroleptics. (48> Thirty per cent of the patients treated with clozapine responded after 6 weeks of treatment compared to 4 per cent of the chlorpromazine-treated patients. Subsequent studies have shown that up to 60 to 70 per cent of patients will respond within 6 months of treatment. Patients with shorter duration of illness tend to respond better. Some predictors of response include weight gain and absence of atrophy in the prefrontal cortex. (34> Clozapine has been reported in several studies to reduce the risk of suicide. (34) It has been shown in a large number of studies to improve some aspects of cognitive function, especially verbal fluency, immediate and delayed verbal learning and memory, and attention. (161Z andl8) It has little effect upon executive function. Its advantages for cognitive symptoms may be greater in patients not resistant to neuroleptics than in treatment-resistant patients. Because of the importance of cognitive function for work and social function, the advantages of clozapine for cognition warrant consideration of using it in patients treated with typical antipsychotics or other atypical antipsychotics whose positive symptoms may be controlled, but who have not been able to achieved desired work or social function. Monitoring the white blood count for the development of agranulocytosis or granulocytopenia, as well as improved methods of treating agranulocytosis, have made it much safer to use. The frequency of monitoring varies from country to country but should include weekly monitoring for the first 26 weeks, the peak period of agranulocytosis. This will be discussed in more detail subsequently.
Because of the side-effect profile of clozapine, it is not generally used as a first-line drug. However, any patient with an unsatisfactory response to the typical neuroleptics and at least one atypical antipsychotic should be considered for clozapine treatment. This amounts to at least 20 per cent of schizophrenics, assuming that one-third of the neuroleptic-resistant patients will respond to risperidone, olanzapine, or quetiapine. Determination of clozapine plasma levels is useful whenever patients are not responding adequately. Typical or non-atypical antipsychotic drugs should be discontinued either before beginning clozapine or by eliminating them over a 1- to 2-week period as the dose of clozapine is increased. Because clozapine produces only about 40 to 50 per cent occupancy of striatal D 2 receptors/49' and some of its key advantages are believed to be related to its low D2-receptor blockade, concomitant administration of typical neuroleptic drugs would be predicted to interfere with some of the benefits of clozapine and, thus, should not ordinarily be prescribed with clozapine. However, some patients with persistent positive symptoms despite an adequate trial of clozapine monotherapy might be expected to benefit from the addition of low-dose haloperidol, or its equivalent, to provide additional low level D2-receptor blockade. Clozapine is usually given twice daily, but sometimes more than half of the dose or the entire dose is given at sleep time to minimize sedation. If response is inadequate, various approaches to augment response have been utilized. In addition to adding a low dose of a typical neuroleptic, as mentioned above, it may be useful to augment clozapine treatment with electroconvulsive therapy, valproic acid or other mood stabilizer, anxiolytic drugs, or an antidepressant/34' It is difficult to postulate a rationale for adding another atypical antipsychotic, with the exception of amisulpride, because of their similarity in pharmacology to clozapine. It should be discontinued if side-effects are intolerable, or if there is no apparent response after a 6-month trial of clozapine alone and subsequent trials with augmentation therapy. It should be noted that discontinuation of clozapine can precipitate a severe relapse even when clozapine is slowly tapered/51'
The dose of clozapine in patients with acute mania is comparable to that of schizophrenia. Maintenance doses are lower. Elderly patients with schizophrenia or mood disorders usually respond to doses of 50 to 200 mg/day. The dose in Parkinson's disease is usually between 12.5 and 75 mg/day. (50)
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