Reconsidering the glutamate hypothesis of obsessive-compulsive disorder: A systematic review of proton magnetic resonance spectroscopy studies in unmedicated participants

Glutamatergic dysfunction in cortico-striato-thalamo-cortical (CSTC) circuits is a hypothesized cause of obsessive-compulsive disorder (OCD). Numerous proton magnetic resonance spectroscopy (¹H MRS) studies have examined this question, yet no systematic review has been conducted in unmedicated participants with OCD. We searched PubMed, Web of Science, and Embase for ¹H MRS studies examining glutamate (Glu) and the related metabolites glutamine (Gln) and γ-aminobutyric acid (GABA), which are associated with Glu in the Glu-Gln-GABA cycle, as well as the composite measure of Glu and Gln (Glx). Twenty studies were included in this systematic review; 17 examined cross-sectional differences in metabolite levels between participants with OCD and healthy controls, 12 examined associations between metabolite levels and OCD severity, and six examined treatment-associated changes in metabolite levels. Some studies assessed multiple outcomes. Findings across these ¹H MRS studies provide limited evidence to support the glutamate hypothesis of OCD and implicate GABA instead, although further studies of glutamatergic function are needed to definitively address it. Our findings highlight the need for further research on the role of GABA in OCD, involving larger samples of unmedicated participants, advanced ¹H MRS techniques, and multimodal imaging approaches to simultaneously assess metabolite levels and function.