The role of GABA, glutamate, and Glx levels in treatment of major depressive disorder: A systematic review and meta-analysis.

This systematic review and meta-analysis aims to explore a possible role of gamma-aminobutyric acid (GABA) and glutamate, as measured by Magnetic Resonance Spectroscopy (MRS), in the treatment outcomes of people with Major Depressive Disorder (MDD). Despite the prevalence of MDD and various treatment modalities, the neurobiological mechanisms of each remain poorly understood. We synthesised data from 41 longitudinal studies comprising 918 individuals with MDD, spanning four primary treatment modalities: selective serotonin reuptake inhibitors (SSRIs), ketamine, repetitive transcranial magnetic stimulation (rTMS), and electroconvulsive therapy (ECT). Pooled analyses revealed a significant increase in Glx levels post-treatment across modalities, with this effect persisting in responder-only subgroups and analyses restricted to prefrontal regions. In contrast, no consistent changes were observed in GABA or glutamate levels following treatment. These results suggest that modulation of Glx, but not bulk GABA or glutamate, may be a common neurobiological mechanism underlying therapeutic response in MDD. However, a role for GABAergic systems cannot be excluded, as functionally relevant changes may occur without detectable shifts in overall concentration. We recommend future studies prioritise reporting by responder status and employ higher-field MRS techniques to more precisely characterise treatment-related bulk metabolite changes.