The pharmacology underlying the unique antipsychotic efficacy of clozapine

Clozapine is unique in being the only recourse for people with schizophrenia not responding to conventional pharmacotherapy with dopamine D2 antagonists and partial agonists. Yet, after half a century of use, the underlying mechanism of clozapine's relatively greater efficacy remains elusive. There have been many hypotheses relating to various neurotransmitter receptors that have not withstood further study, and some that have not been fully investigated. The recent introduction of the xanomeline-trospium combination for the treatment of schizophrenia has renewed interest in muscarinic receptor mechanisms; like xanomeline, clozapine and particularly its metabolite norclozapine reportedly have partial agonist actions at some muscarinic receptor subtypes. In their recent article, Morrison et al. draw attention to this by highlighting hypersalivation, a common feature of clozapine treatment that is not shared by other antipsychotic agents which they suggest to be a result of muscarinic receptor agonism. However the relatively weak muscarinic activity of clozapine, low brain availability of norclozapine and clinical findings from xanomeline combine to provide little support for muscarinic mechanisms underlying the greater efficacy of clozapine. An alternative hypothesis is that of alpha2 adrenergic receptor antagonism, a feature of clozapine pharmacology that may also contribute to clozapine-induced hypersalivation. Clinical findings with adjunctive alpha2 antagonists demonstrate clozapine-like improvements in antipsychotic efficacy, while both preclinical studies with specific alpha2C antagonists and the relatively high and selective antagonism of alpha2C receptors by clozapine provide support for this mechanism for clozapine's unique efficacy.