Modulation of GABA and Glutamate by Ketamine in Depression: A Systematic Review of Magnetic Resonance Spectroscopy Studies

Abstract

Proton magnetic resonance spectroscopy (MRS) studies in major depressive disorder (MDD) consistently demonstrate abnormalities in glutamatergic and GABAergic neurotransmission, supporting the hypothesis of cortical excitation/inhibition imbalance in depression. MRS enables in vivo quantification of glutamate, GABA, and Glx (glutamate + glutamine), providing insight into neurochemical changes associated with disease state and treatment response. Ketamine, an NMDA receptor antagonist, is FDA-approved for treatment-resistant depression and acute suicidal ideation in MDD. Its rapid antidepressant effects are thought to involve restoration of excitation/inhibition balance, with modulation of glutamatergic and GABAergic systems. MRS studies show that ketamine administration can acutely modify Glx and GABA levels in the medial prefrontal cortex. However, the direction, magnitude, and regional specificity of these changes are inconsistent across studies, and not all studies replicate these findings. Meta-analyses and systematic reviews indicate that increases in Glx are the most consistent neurochemical correlate of antidepressant response across modalities, including ketamine, SSRIs, rTMS, and ECT. While ketamine modulates glutamatergic and GABAergic metabolites detectable by MRS, the clinical utility of these measures as biomarkers for treatment response remains limited by methodological variability and inconsistent findings. This review examines GABA, glutamate, or Glx changes after ketamine treatment in adults with depression in randomized and non-randomized clinical trials using proton MRS to quantify these metabolites and reporting ketamine-related neurochemical changes via active vs. placebo, pre vs. post-treatment, or associations with ketamine's antidepressant effects.

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