Modulation of GABA and glutamate by ketamine in depression: A systematic review and meta-analysis of magnetic resonance spectroscopy studies.
Balwinder Singh, Hossam M Ali, Alessandro Miola, Nicolas A. Nunez, Manoela V. Fogaça, Luke A. Jelen, Larry J. Prokop, Gerard Sanacora, Carlos A. Zarate, Mark A Frye, John D Port
Neuropsychopharmacology September 21, 2026 DOI: 10.1038/s41386-026-02562-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Peer reviewed |
|---|---|
| Population | Adults with depression |
| Intervention | Ketamine |
| Topics | Depression Esketamine Ketamine |
| Key findings | Meta-analyses of 11 studies found no statistically significant ketamine-related alterations in GABA, glutamate, or Glx levels in adults with depression. The authors attribute the null findings to methodological heterogeneity in timing, acquisition techniques, and brain regions rather than a true absence of effect, and suggest E/I balance may hold promise as a treatment response predictor; one randomized trial reported that percent reduction in the Glx/GABA ratio positively correlated with symptom improvement. |
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.
Comparable studies
Other systematic reviews and meta-analyses on ketamine for depression, most cited first.
Citations in the library
Cites 14
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder JAMA Psychiatry March 1, 2019
- An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression The International Journal of Neuropsychopharmacology November 1, 2011
- Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression JAMA Network Open August 12, 2020
- Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study. Nature Medicine July 24, 2025
and 9 more in the library