Does the change in glutamate to GABA ratio correlate with change in depression severity? A randomized, double-blind clinical trial

Mol Psychiatry. 2022 Sep;27(9):3833-3841. doi: 10.1038/s41380-022-01730-4. Epub 2022 Aug 18.


Previous proton magnetic resonance spectroscopy (1H-MRS) studies suggest a perturbation in glutamate and/or GABA in Major Depressive Disorder (MDD). However, no studies examine the ratio of glutamate and glutamine (Glx) to GABA (Glx/GABA) as it relates to depressive symptoms, which may be more sensitive than either single metabolite. Using a within-subject design, we hypothesized that reduction in depressive symptoms correlates with reduction in Glx/GABA in the anterior cingulate cortex (ACC). The present trial is a randomized clinical trial that utilized 1H-MRS to examine Glx/GABA before and after 8 weeks of escitalopram or placebo. Participants completed the 17-item Hamilton Depression Rating Scale (HDRS17) and underwent magnetic resonance spectroscopy before and after treatment. Two GABA-edited MEGA-PRESS acquisitions were interleaved with a water unsuppressed reference scan. GABA and Glx were quantified from the average difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Linear mixed models were utilized to evaluate relationships between change in HDRS17 and change in Glx/GABA using a univariate linear regression model, multiple linear regression incorporating treatment type as a covariate, and Bayes Factor (BF) hypothesis testing to examine strength of evidence. No significant relationship was detected between percent change in Glx, GABA, or Glx/GABA and percent change in HDRS17, regardless of treatment type. Further, MDD severity before/after treatment did not correlate with ACC Glx/GABA. In light of variable findings in the literature and lack of association in our investigation, future directions should include evaluating glutamate and glutamine individually to shed light on the underpinnings of MDD severity. Advancing Personalized Antidepressant Treatment Using PET/MRI,, NCT02623205.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bayes Theorem
  • Depression / drug therapy
  • Depressive Disorder, Major* / drug therapy
  • Depressive Disorder, Major* / metabolism
  • Glutamic Acid* / metabolism
  • Glutamine / metabolism
  • Humans
  • gamma-Aminobutyric Acid / metabolism


  • Glutamic Acid
  • Glutamine
  • gamma-Aminobutyric Acid

Associated data