Modulation of Magnetic Resonance Spectroscopy Levels of Glutamate and GABA by Ketamine in Treatment-Resistant Depression.
Stephanie N Njau, Artemis Zavaliangos-Petropulu, Shantanu Joshi, John O. Brooks, Joseph O'Neill, Woods P Roger, Viviane Norris, Randall Espinoza, Katherine L Narr
Journal of Neuroscience Research 2026 DOI: 10.1002/jnr.70102 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 60 |
| Population | Participants with treatment-resistant depression |
| Interventions | racemic (R S)-ketamine |
| Dose | 0.5 mg/kg |
| Duration | 40-minute intravenous infusion, with measurements before (~within 1 week) and 24 hours after treatment |
| Topics | Depression Ketamine Esketamine |
| Key findings | Ketamine increased dACC glutamate levels only in treatment responders, and lower baseline glutamate predicted greater improvement in depression scores. |
Abstract
Ketamine has emerged as a highly effective intervention for treatment-resistant depression (TRD). Though it acts as a non-competitive antagonist of excitatory N-methyl-D-aspartate receptors (NMDAR), widely expressed in the brain, including on inhibitory γ-aminobutyric acid (GABA)-ergic cells, the mechanisms of its antidepressant action are less clear. To investigate the links between glutamate and GABA neurotransmission and the clinical benefits of ketamine, we used proton magnetic resonance spectroscopy (1H-MRS) to measure both glutamate and GABA levels in the dorsal anterior cingulate cortex (dACC) in 60 participants with TRD before (~within 1 week), and 24 h after a 40-min intravenous infusion with 0.5 mg/kg of racemic (R,S)-ketamine. The 17-item Hamilton Depression Rating Scale (HDRS17) was used as the primary measure of clinical improvement, and a 50% or greater improvement in HDRS17 ratings was used to define treatment responders. Ketamine increased mean dACC glutamate levels in responders only 24 h after treatment (n = 25, p = 0.01). Further, lower glutamate levels at baseline predicted greater improvements in HDRS17 scores at 24 h post treatment (p < 0.0001). However, GABA levels remained stable after treatment irrespective of response status (p = 0.90). Metabolites associated with neuronal integrity (tNAA), metabolic function (tCr), and membrane turnover (tCho), which may serve as complementary biological evidence of ketamine-induced plasticity, also increased with treatment (all p < 0.01). Results provide evidence of sustained enhancements of neurotransmission or other glutamate-related metabolic effects following subanesthetic ketamine in responders and a potential role of ACC glutamate levels as a biomarker of responsivity to ketamine.
Comparable studies
Other observational and cohort studies on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
| Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome Healthy controls and actively depressed patients with treatment-resistant depression... | 2017 | Observational cohort | n = 59 |
| Clinical Predictors of Ketamine Response in Treatment-Resistant Major Depression Treatment-resistant inpatients with DSM-IV-TR-diagnosed major depressive disorder or... | 2014 | Post hoc analysis of pooled data from four studies | n = 108 |
| An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression Drug-free patients with major depressive disorder | 2011 | Observational cohort | n = 14 |
| Efficacy of ketamine therapy in the treatment of depression Drug-free/naïve men with severe depression, no history of psychotic disorder, head... | 2019 | Observational cohort | n = 25 |