Conclusions

The studies reviewed here provide some evidence for the conclusion that the 5-HT2C receptor plays a significant role in key elements of the pathophysiology of schizophrenia, including psychosis, negative symptoms, cognitive impairment, as well as the mechanism of action and side effects of antipsychotic drugs. Since the 5-HT2A receptor is so clearly involved in the action of atypical antipsychotic drugs and aspects of the pathophysiology of schizophrenia and since there is clear evidence for interactions between the 5-HT2A and 5-HT2C receptors, by default, the 5-HT2C receptor is important for schizophrenia. The strongest direct evidence may be the genetic studies that have shown that one or more of three common polymorphisms of the 5-HT2C receptor is associated with positive or negative symptoms, weight gain, and extrapyramidal side effects secondary to treatment on some antipsychotic drugs. In addition, the expression of the 5-HT2C receptor in postmortem specimens from patients with schizophrenia has been reported to be reduced, but this finding needs to be replicated.

The two reports that the cortisol or ACTH response to the 5-HT2A/2C receptor agonist mCPP in patients with schizophrenia predicts subsequent response to treatment with clozapine are inconclusive because this might be related to the 5-HT2A rather than the 5-HT2C component of the action of mCPP. Further studies with 5-HT2C null versus wild-type mice are needed to determine if diminished 5-HT2C receptor function in a mouse model is suggestive of a schizophrenia-like phenotype. Although 5-HT2A receptor stimulation is thought to be the basis for hallucinogenic action of LSD and related drugs, a role for 5-HT2C receptors with regard to hallucinations or delusions in man remains a viable possibility. 5-HT2C antagonism does not seem to be a necessary feature of atypical antipsychotic drug action, but it could have a secondary influence.

Finally, WAY 163909, a 5-HT2C receptor agonist, has shown activity as a cognitive enhancing antipsychotic agent in a variety of animal models. It will be of interest to determine if 5-HT2C agonism has a role as an adjunctive agent in the treatment of schizophrenia.

In summary, there is reason to intensively investigate the role of the 5-HT2C receptor in the pathophysiology of schizophrenia and the action of antipsychotic drugs and to further test 5-HT2C agonists for their ability to improve cognition and psychosis in patients with schizophrenia and related disorders.

Acknowledgments Supported, in part, by a grant from the Weisman Family Foundation and a Distinguished Investigator Award from NARSAD. Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth, M.D., Ph.D. at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda, MD.

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