Modulation of GABA and glutamate by ketamine in depression: A systematic review and meta-analysis of magnetic resonance spectroscopy studies

Why clinicians should know about it

• Picked for Biochemistry (medical) (paper of the day, 23 September 2026): Meta‑analysis of ¹H‑MRS GABA/glutamate after ketamine

Abstract

Disrupted excitation-inhibition (E/I) balance involving GABA and glutamate (Glu) is implicated in the pathophysiology of depression. Ketamine, an NMDA receptor antagonist with rapid antidepressant properties, may modulate this balance, yet proton magnetic resonance spectroscopy (¹H-MRS) studies report inconsistent findings regarding the direction, magnitude, and timing of neurochemical effects. Static ¹H-MRS metabolite concentrations, however, do not directly index neuronal excitation or inhibition; the E=Glx/Glu and I = GABA framework adopted here, as used commonly in the field, is an assumed convention rather than a validated physiological equivalence. We conducted a systematic review and meta-analysis evaluating ketamine's influence on GABA, Glu, and Glx levels and their relationship to clinical outcomes in adults with depression. Multiple databases were searched from inception through October 16, 2025; of 1046 identified studies, 11 met inclusion criteria. Included studies demonstrated significant methodological variability across infusion protocols, metabolite selection, MRS acquisition timing, and brain region of interest. Meta-analyses from limited evidence base did not demonstrate statistically significant treatment-related alterations in any metabolite. The anterior cingulate and prefrontal cortices were most frequently examined regions. The quality of included studies was generally good, despite methodological heterogeneity. One RCT found percent reduction in Glx/GABA ratio positively correlated with symptom improvement. Only a few studies examined ketamine blood levels relative to metabolite changes. Current ¹H-MRS evidence does not confirm significant ketamine-related neurochemical alterations, likely reflecting methodological heterogeneity in timing, acquisition techniques, and brain regions examined rather than a true absence of effect. E/I balance shows promise as a treatment response predictor. Rigorous RCTs with standardized protocols, larger sample sizes, uniform dosing, and systematic biomarker investigations are needed to clarify ketamine's neurochemical mechanism and optimize ketamine's clinical application in treatment-resistant depression.

Abstract as published, via PubMed.