Serotonergic mechanisms as targets for existing and novel antipsychotics

A variety of serotonin (5-HT) receptors, especially 5-HT_2A, 5-HT_1A, 5-HT₆, 5-HT₇, and 5-HT_2C, have been postulated to contribute to the mechanism of action of atypical antipsychotic drugs (APDs), i.e., APDs which cause fewer extrapyramidal side effects (EPS) at clinically optimal doses, in contrast with typical APDs, which are more likely to cause EPS. This advantage, rarely disputed, has made such drugs the preferred treatment for schizophrenia and other indications for APDs. These 5-HT receptors are still of interest as components of novel multireceptor or stand-alone APDs, and potentially to remediate cognitive deficits in schizophrenia. Almost all currently available atypical APDs are 5-HT _2A receptor inverse agonists, as well as dopamine (DA) D₂ receptor antagonists or partial agonists. Amisulpride, an exceptional atypical APD, has 5-HT₇ antagonism to complement its DA D_2/3 antagonism. Some atypical APDs are also 5-HT_1A partial agonists, 5-HT₆, or 5-HT₇ antagonists, or some combination of the above. 5-HT_2C antagonism has been found to contribute to the metabolic side effects of some atypical APDs, whereas 5-HT_2C agonists have potential as stand-alone APDs and/or cognitive enhancers. This review will provide an update of current preclinical and clinical evidence for the role of these five 5-HT receptors in the actions of current APDs and for the development of novel psychotropic drugs.