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 clozap ine as a pharmacotherapy for the treatment of neuroleptic non-responde rs and neuroleptic intolerant schizophrenic subjects remain elusive. W e 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 dop amine D-2 receptors in the caudate nucleus and putamen underlie the ex trapyramidal side effects of conventional neuroleptics. In contrast, w e propose that clozapine acts in the prefrontal cortex, specifically t argeting an as yet unidentified DA receptor of the D-2 family, to exer t therapeutic actions in neuroleptic non-responders. We suggest that t he ability of clozapine to augment extracellular dopamine levels in th e prefrontal cortex may represent a key mechanism contributing to the therapeutic effects of this drug, and suggest some alternative approac hes which might be expected to result in effects similar to those of c lozapine.