Pharmacological actions of the atypical antipsychotic drug clozapine: a review

Abstract

Clozapine [8-chloro- 11-(4-methyl- 1-piperazinyl)-3H-dibenzo (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 antipsychotic drugs such as haloperidol and chlorpromazine. Subsequently, clinical studies have shown that clozapine is effective in ameliorating the core symptoms, as well as the negative symptoms, in schizophrenia. However, clozapine has a much lower propensity for inducing neurological side effects after acute or repeated administration compared to various typical neuroleptics. Furthermore, clozapine is therapeutically effective in treating about 30% of schizophrenic patients who are resistant to standard antipsychotic drugs. Based on the above information, clozapine has been designated an atypical antipsychotic drug. However, at this time, it is not entirely clear why clozapine is such a unique antipsychotic drug. To date, there has not been a comprehensive review regarding clozapine's pharmacological profile. Therefore, we will review clozapine's profile in the following areas: 1) affinity for neurotransmitter receptors in the brain; 2) electrophysiology (in vivo, single-cell recording and iontophoresis; in vitro studies); 3) in vivo microdialysis and voltammetry; 4) monoamine turnover or metabolism; 5) intermediate early gene expression; 6) positron emission tomography studies; and 7) molecular biological studies. We will also compare and contrast clozapine's acute and chronic effects, and discuss the merits of various hypotheses that have been put forward to explain clozapine's unique profile.