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Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway

Molecular Psychiatry volume 13, pages 918–929 (2008)Cite this article

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.

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Acknowledgements

This work was supported in part by grants from the NIH and from the Lieber Center for Schizophrenia Research and Treatment. We thank Dr Karen Duff for her helpful comments on this paper.

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Authors and Affiliations

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

    R R Girgis, J A Javitch & J A Lieberman

  2. New York State Psychiatric Institute, New York, NY, USA

    R R Girgis, J A Javitch & J A Lieberman

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  1. R R Girgis
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  2. J A Javitch
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  3. J A Lieberman
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Correspondence to R R Girgis.

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Girgis, R., Javitch, J. & Lieberman, J. Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway. Mol Psychiatry 13, 918–929 (2008). https://doi.org/10.1038/mp.2008.40

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  • DOI: https://doi.org/10.1038/mp.2008.40

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