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Published Online: 1 July 2011

Reduced Metabotropic Glutamate Receptor 5 Density in Major Depression Determined by [11C]ABP688 PET and Postmortem Study

Alexandra Deschwanden, M.S., Beata Karolewicz, Ph.D., Anteneh M. Feyissa, M.D., Valerie Treyer, Ph.D., Simon M. Ametamey, Ph.D., Anass Johayem, Ph.D., Cyrill Burger, Ph.D., Yves P. Auberson, Ph.D., Judit Sovago, M.D., Ph.D., Craig A. Stockmeier, Ph.D., Alfred Buck, M.D., and Gregor Hasler, M.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 168, Number 7
https://doi.org/10.1176/appi.ajp.2011.09111607
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Abstract

Objective:

Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects.

Method:

Images of mGluR5 receptor binding were acquired using PET with [11C]ABP688, which binds to an allosteric site with high specificity, in 11 unmedicated individuals with major depression and 11 matched healthy comparison subjects. The amount of mGluR5 protein was investigated using Western blot in postmortem brain samples of 15 depressed individuals and 15 matched comparison subjects.

Results:

The PET study revealed lower levels of regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus, and the hippocampus in the depression group relative to the comparison group. Severity of depression was negatively correlated with mGluR5 binding in the hippocampus. The postmortem study showed lower levels of mGluR5 protein expression in the prefrontal cortex (Brodmann's area 10) in the depression group relative to the comparison group, while prefrontal mGluR1 protein expression did not differ between groups.

Conclusions:

The lower levels of mGluR5 binding observed in the depression group are consonant with the lower levels of protein expression in brain tissue in the postmortem depression group. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 168 • Number 7 • July 2011
Pages: 727 - 734
PubMed: 21498461

History

Received: 10 November 2009
Revision received: 10 February 2010
Revision received: 26 April 2010
Revision received: 29 September 2010
Revision received: 8 November 2010
Revision received: 29 December 2010
Accepted: 14 January 2011
Published online: 1 July 2011
Published in print: July 2011

Authors

Details

Alexandra Deschwanden, M.S.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Beata Karolewicz, Ph.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Anteneh M. Feyissa, M.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Valerie Treyer, Ph.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Simon M. Ametamey, Ph.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Anass Johayem, Ph.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Cyrill Burger, Ph.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Yves P. Auberson, Ph.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Judit Sovago, M.D., Ph.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Craig A. Stockmeier, Ph.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Alfred Buck, M.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Gregor Hasler, M.D.
From the PET Center, Division of Nuclear Medicine, University Hospital, Zurich; the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; the Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel; and Psychiatric University Hospital, University of Bern.
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Notes

Address correspondence and reprint requests to Dr. Hasler, Psychiatric University Hospital, Bolligenstrasse 111, 3000 Berne 60, Switzerland; [email protected] (e-mail).

Author Contributions

Ms. Deschwanden and Dr. Karolewicz contributed equally to this article.

Funding Information

Dr. Burger is an equity owner of PMOD Technologies. Drs. Auberson and Sovago work for Novartis Pharma AG (Basel), which is developing and testing drugs targeting the mGlu5 receptor. The other authors report no financial relationships with commercial interests.The PET study was supported by Novartis Pharma AG, OPO Foundation, Zurich; Olga Mayenfisch Foundation, Zurich; Vontobel Foundation, Zurich; Hartmann Muller Foundation, Zurich. The PET data were analyzed at Zurich University Hospital by collaborators (Ms. Deschwanden and Drs. Buck, Treyer, and Hasler) who were independent of Novartis Pharma AG. The postmortem study was supported by grant RR17701 from the IDeA Program of the National Center of Research Resources and by NARSAD (Dr. Karolewicz).

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