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Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists

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Abstract

Drugs acting at metabotropic glutamate receptors (mGluRs) are among the most promising agents under development for the treatment of psychiatric disorders. The research in this area is at a relatively early stage, as there are no drugs acting at mGluRs that have been approved for the treatment of any psychiatric disorder. However, in the areas of schizophrenia, anxiety disorders and mood disorders, research conducted in animal models appears to translate well into efficacy in human laboratory-based models of psychopathology and in preliminary clinical trials. Further, the genes coding for mGluRs are implicated in the risk for a growing number of psychiatric disorders. This review highlights the best studied mGluR strategies for psychiatry, based on human molecular genetics, studies in animal models and preliminary clinical trials. It describes the potential value of mGluR2 and mGluR5 agonists and positive allosteric modulators for the treatment of schizophrenia. It also reviews evidence that group II mGluR agonists and positive allosteric modulators as well as group I mGluR antagonists might also treat anxiety disorders and some forms of depression, while mGluR2 and group I mGluR antagonists (particularly mGluR5 antagonists) might have antidepressant properties. This review also links growing insights into the role of glutamate in the pathophysiology of these disorders to hypothesized mGluR-related treatment mechanisms.

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Acknowledgements

This work was generously supported by Department of Veterans Affairs (via support for the Alcohol Research Center, Merit Review Grant, National Center for PTSD), the National Institute on Alcohol Abuse and Alcoholism (RO1 AA-11321, K05 AA-14906-01, I-P50 AA-12870), the National Institute of Mental Health (MH P50 MH44866, P50 MH068789, K23-MH-069656), NARSAD and the Yale Center for Clinical Investigation (CTSA).

During 2007–9, Dr Krystal has served as a scientific consultant to the following companies: AstraZeneca Pharmaceuticals, Cypress Bioscience, Forest Laboratories, GlaxoSmithKline, Lohocla Research Corporation, HoustonPharma, Eli Lilly and Company, Pfizer Pharmaceuticals, Schering-Plough Research Institute, SK Life Sciences, Takeda Industries and Transcept Pharmaceuticals. He holds less than $US10 000 in exercisable warrant options with Transcept Pharmaceuticals. He is the principal investigator of a multicentre study in which Janssen Research Foundation has provided drug and some support to the Department of Veterans Affairs. He is a co-sponsor for two patents under review for glutamatergic agents targeting the treatment of depression. Dr Mathew has received grant/research support from Alexza Pharmaceuticals, GlaxoSmithKline, Novartis, National Alliance for Research on Schizophrenia and Depression and Roche Pharmaceuticals, and has received consulting or lecture fees from AstraZeneca Pharmaceuticals and Jazz Pharmaceuticals. Drs Charney and Mathew and Mount Sinai School of Medicine have been named as inventors on a use-patent for ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the US FDA for this indication, Dr Charney and Mount Sinai School of Medicine could benefit financially. Dr Mathew has relinquished his claim to any royalties and will not benefit financially if ketamine is approved for this use. Dr Mathew is currently employed at the Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA. Drs D’Souza, Garakani and Gunduz-Bruce have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    John H. Krystal, D. Cyril D’Souza & Handan Gunduz-Bruce

  2. Schizophrenia Biological Research Center (151-D), VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, Connecticut, 06516, USA

    John H. Krystal, D. Cyril D’Souza & Handan Gunduz-Bruce

  3. Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut, USA

    John H. Krystal & D. Cyril D’Souza

  4. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA

    Sanjay J. Mathew, Amir Garakani & Dennis S. Charney

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  1. John H. Krystal
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Correspondence to John H. Krystal.

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Krystal, J.H., Mathew, S.J., D’Souza, D.C. et al. Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists. CNS Drugs 24, 669–693 (2010). https://doi.org/10.2165/11533230-000000000-00000

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