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

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 current study was to determine the role of mGluR5 in a large group of individuals with MDD compared with healthy control subjects (HCs) in vivo with 3-[F-18]FPEB and positron emission tomography. Furthermore, we sought to determine the role glutamate plays in mGluR5 availability in MDD. METHODS: A total of 65 participants (30 individuals with MDD and 35 HCs) completed 3-[F-18]FPEB positron emission tomography to estimate the primary outcome measure, mGluR5 volume of distribution, and the secondary outcome measure, mGluR5 distribution volume ratio. A subgroup of 39 participants (16 individuals with MDD and 23 HCs) completed proton magnetic resonance spectroscopy to estimate anterior cingulate cortex glutamate, glutamine, and glutamate + glutamine levels relative to creatine. RESULTS: No significant between-group differences were observed in mGluR5 volume of distribution or distribution volume ratio. Compared with HCs, individuals with MDD had higher anterior cingulate cortex glutamate, glutamine, and glutamate + glutamine levels. Importantly, the anterior cingulate cortex mGluR5 distribution volume ratio negatively correlated with glutamate/creatine and glutamate + glutamine/creatine 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 the glutamatergic system in depression.