PHARMACOLOGICAL ACTIONS OF THE ATYPICAL ANTIPSYCHOTIC DRUG CLOZAPINE - A REVIEW

Clozapine [8-chloro-11-(4-methyl-1-piperazinyl)-3 (b,e)(1,4) diazepine ], or clozaril, is a member of the dibenazepine class of antipsychotic drugs. Initially, studies in animals using a number of neurochemical, biochemical, electrophysiological, and behavioral paradigms indicated that clozapine was markedly different from various typical antipsycho tic drugs such as haloperidol and chlorpromazine. Subsequently, clinic al studies have shown that clozapine is effective in ameliorating the core symptoms, as well as the negative symptoms, in schizophrenia. How ever, clozapine has a much lower propensity for inducing neurological side effects after acute or repeated administration compared to variou s typical neuroleptics. Furthermore, clozapine is therapeutically effe ctive in treating about 30% of schizophrenic patients who are resistan t to standard antipsychotic drugs. Based on the above information, clo zapine has been designated an atypical antipsychotic drug. However, at this time, it is not entirely clear why clozapine is such a unique an tipsychotic drug. To date, there has not been a comprehensive review r egarding clozapine's pharmacological profile. Therefore, we will revie w clozapine's profile in the following areas: 1) affinity for neurotra nsmitter receptors in the brain; 2) electrophysiology (in vivo, single -cell recording and iontophoresis; in vitro studies); 3) in vivo micro dialysis and voltammetry; 4) monoamine turnover or metabolism; 5) inte rmediate early gene expression; 6) positron emission tomography studie s; and 7) molecular biological studies. We will also compare and contr ast clozapine's acute and chronic effects, and discuss the merits of v arious hypotheses that have been put forward to explain clozapine's un ique profile. (C) 1996 Wiley-Liss, Inc.