Modulation of Magnetic Resonance Spectroscopy Levels of Glutamate and GABA by Ketamine in Treatment-Resistant Depression.

In people with treatment-resistant depression, a single low-dose ketamine infusion increased glutamate levels in the dorsal anterior cingulate cortex only in those who responded to treatment, and lower pre-treatment glutamate levels predicted greater improvement in depression scores. GABA levels did not change after treatment. Other brain metabolites linked to neuronal health and metabolism also increased. These findings suggest that ketamine's antidepressant effect involves sustained enhancement of glutamate-related neurotransmission and that baseline glutamate levels may help predict who will benefit from ketamine.

Study at a glance

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.