Mechanisms of action of clozapine in the treatment of neuroleptic-resistant and neuroleptic-intolerant schizophrenia.
The mechanisms of action which account for the effectiveness of clozapine as a pharmacotherapy for the treatment of neuroleptic non-responders and neuroleptic intolerant schizophrenic subjects remain elusive. We review recent data concerning the actions of clozapine in laboratory animals, and discuss the likely sites of action of clozapine and the receptors through which clozapine acts. We suggest that actions at dopamine D(2) receptors in the caudate nucleus and putamen underlie the extrapyramidal side effects of conventional neuroleptics. In contrast, we propose that clozapine acts in the prefrontal cortex, specifically targeting an as yet unidentified DA receptor of the D(2) family, to exert therapeutic actions in neuroleptic non-responders. We suggest that the ability of clozapine to augment extracellular dopamine levels in the prefrontal cortex may represent a key mechanism contributing to the therapeutic effects of this drug, and suggest some alternative approaches which might be expected to result in effects similar to those of clozapine.
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Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry Service, Department of Veterans'Affairs Medical Center, West Haven, CT, USA.