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

Abstract

Background: 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.

Methods: Sixty-five participants (30 MDD and 35 HC) completed [¹⁸F]FPEB PET to estimate the primary outcome measure - mGluR5 volume of distribution (V_T), 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).

Results: No significant between-group differences were observed in mGluR5 V_T 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.

Conclusions: 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.

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

Figure 1. Glutamate level in the anterior cingulate cortex (ACC)

(A) The levels of glutamate (Glu), glutamine (Gln), and glutamate+glutamine (Glx) in the ACC of patients with MDD (red) compared to healthy (blue). (B–D) Scatter plots of the correlations between metabotropic glutamate receptor 5 (mGluR5) distribution volume ratio (DVR) in the whole group and ACC levels of glutamate (B), glutamine (C), and Glx (D). Abbreviations: (A) *, p ≤ 0.05, Bars/Error-bars: Mean/SEM; (B–D) shaded areas are the 95% confidence band of the best-fit line.