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.

Mixed Agonist–Antagonist Properties of Clozapine at Different Human Cloned Muscarinic Receptor Subtypes Expressed in Chinese Hamster Ovary Cells

“…A number of neurotransmitter receptor systems have been proposed to be involved in the antipsychotic activity of clozapine, including the dopamine D 2 and D 4 , the serotonin 5-HT 2A and 5-HT 2C , and the glutamate receptors (Ashby and Wang, 1996). It is possible that the muscarinic partial agonist activity also contributes to the antipsychotic profile of clozapine, a drug effective in treating both positive and negative symptoms of schizophrenia (Meltzer, 1995).…”

Central Serotonin2C Receptor: From Physiology to Pathology

“…Thus, it was hypothesised that the action of atypical antipsychotic drugs (APDs) depends on their interaction with central 5-HT 2A or 5-HT 2C receptor subtypes, more than with D 2 receptors [34,[178][179][180][181]. In fact, by examining in vitro receptor binding data, Meltzer and collaborators [34] found that typical and atypical APDs could be distinguished on the basis of their 5-HT 2 to D 2 receptor binding ratios.…”

Clozapine Preferentially Increases Dopamine Release in the Rhesus Monkey Prefrontal Cortex Compared with the Caudate Nucleus

“…A recent study of the regulatory effect of chronic antipsychotic drug treatment on dopamine receptors in rhesus monkeys has shown that clozapine is capable of upregulating cortical D 2 receptors (Lidow and Goldman-Rakic 1994) and D 2 mRNAs, although it has little effect on D 2 receptor mRNAs in the striatum (Lidow et al 1997). However, considering the different profile observed with the D 2 antagonist haloperidol, it is more likely that other receptors for which clozapine has moderate to high affinity (Ashby and Wang 1996) are responsible for clozapine's cortical dopamine effects.…”