The role of serotonin in antipsychotic drug action

Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact that antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT_2a receptor antagonists and relatively weaker dopamine D2 antagonists. These agents share in common low extrapyramidal side effects at clinically effective doses and possibly greater efficacy to reduce negative symptoms. As a group, they also have a superior effect on cognitive function and greater ability to treat mood symptoms in both patients with schizophrenia or affective disorders than typical antipsychotic drugs. The atypical antipsychotic agents vary in their affinities for other types of 5-HT as well as dopamine, muscarinic, adrenergic, and histaminic receptors, some, or all of which, may contribute to their differences in efficacy and side effect profile. Of the other 5-HT receptors which these drugs directly, the 5-HT_1a and 5-HT_2c receptors are the strongest candidates for contributing to their antipsychotic action and low EPS profile. The 5-HT₆ and 5-HT₇ receptors may also be of some importance. Stimulation of the 5-HT_1a receptor appears to produce many of the same effects as antagonism of the 5-HT_2a receptor while antagonism of the 5-HT_2c receptor appears to diminish some of the actions of 5-HT_2a receptor antagonism. Future antipsychotic drug development can include targeting multiple serotonin receptor subtypes.