1. ¹Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
2. ²New York State Psychiatric Institute, New York, NY, USA

Correspondence: Dr RR Girgis, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, Box 109, New York, NY 10032, USA. E-mail: rg2290@columbia.edu

Received 21 October 2007; Revised 20 February 2008; Accepted 10 March 2008; Published online 15 April 2008.

Abstract

The exact therapeutic mechanism of action of antipsychotic drugs remains unclear. Recent evidence has shown that second-generation antipsychotic drugs (SGAs) are differentially associated with metabolic side effects compared to first-generation antipsychotic drugs (FGAs). Their proclivity to cause metabolic disturbances correlates, to some degree, with their comparative efficacy. This is particularly the case for clozapine and olanzapine. In addition, the insulin signaling pathway is vital for normal brain development and function. Abnormalities of this pathway have been found in persons with schizophrenia and antipsychotic drugs may ameliorate some of these alterations. This prompted us to hypothesize that the therapeutic antipsychotic and adverse metabolic effects of antipsychotic drugs might be related to a common pharmacologic mechanism. This article reviews insulin metabolism in the brain and related abnormalities associated with schizophrenia with the goals of gaining insight into antipsychotic drug effects and possibly also into the pathophysiology of schizophrenia. Finally, we speculate about one potential mechanism of action (that is, functional selectivity) that would be consistent with the data reviewed herein and make suggestions for the future investigation that is required before a therapeutic agent based on these data can be realized.