5-HT2C agonists as therapeutics for the treatment of schizophrenia

Abstract

The 5-HT2C receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT2C receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT2C receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT2C agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT2C agonists in schizophrenia. To this end, the preclinical profile of 5-HT2C agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT2C agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT2C agonists are potential therapeutics for the treatment of psychiatric disorders. © 2012 Springer-Verlag Berlin Heidelberg.