Muscarinic mechanisms of antipsychotic atypicality

The interactions of the atypical antipsychotic drugs (APD) clozapine, olanzapine, risperidone, quetiapine and ziprasidone with muscarinic receptors were reviewed. Only clozapine and olanzapine have marked affinity for muscarinic receptors in radioligand binding studies; however, the affinity of these compounds is considerably lower than classical muscarinic antagonists. Although functional assays in cell lines transfected with muscarinic receptors suggest that olanzapine and clozapine have weak partial agonist activity at muscarinic receptors, particularly M4 receptors, studies in vitro and in vivo indicate that the compounds function as antagonists. In animal studies and in humans, clozapine has pronounced antimuscarinic effects whereas olanzapine has weak antimuscarinic effects. However, olanzapine significantly occupies central muscarinic receptors in humans. Overall, the role of muscarinic receptors in the antipsychotic effects of clozapine and olanzapine is controversial and complex.