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Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Jul;2(5):449-456. doi: 10.1016/j.bpsc.2017.03.019. Epub 2017 Apr 6.

Metabotropic Glutamate Receptor 5 and Glutamate Involvement in Major Depressive Disorder: A Multimodal Imaging Study.

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Yale University School of Medicine, Department of Psychiatry, New Haven, CT.
Clinical Neuroscience Division, VA National Center for PTSD, West Haven, CT.
Denali Therapeutics Inc., South San Francisco, CA.
Yale University School of Medicine, Department of Radiology and Biomedical Imaging, New Haven, CT.
Novartis, Institutes for BioMedical Research, Basel.
Columbia University, Department of Psychiatry, New York, NY.
Division of Molecular Therapeutics, New York State Psychiatric Institute.
Columbia University, Department of Pharmacology, New York, NY.



Preclinical and postmortem studies have implicated the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of major depressive disorder (MDD). The goal of the present study was to determine the role of mGluR5 in a large group of individuals with MDD compared to healthy controls (HC) in vivo with [18F]FPEB and positron emission tomography (PET). Furthermore, we sought to determine the role glutamate plays on mGluR5 availability in MDD.


Sixty-five participants (30 MDD and 35 HC) completed [18F]FPEB PET to estimate the primary outcome measure - mGluR5 volume of distribution (VT), and the secondary outcome measure - mGluR5 distribution volume ratio (DVR). A subgroup of 39 participants (16 MDD and 23 HC) completed proton magnetic resonance spectroscopy (1H MRS) to estimate anterior cingulate (ACC) glutamate, glutamine, and Glx (glutamate + glutamine) levels relative to creatine (Cr).


No significant between-group differences were observed in mGluR5 VT or DVR. Compared to HC, individuals with MDD had higher ACC glutamate, glutamine, and Glx levels. Importantly, the ACC mGluR5 DVR negatively correlated with glutamate/Cr and Glx/Cr levels.


In this novel in vivo examination, we show an inverse relationship between mGluR5 availability and glutamate levels. These data highlight the need to further investigate the role of glutamatergic system in depression.


1H MRS; MDD; PET; [18F]FPEB; glutamate; mGluR5

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