Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder

Biol Psychiatry. 2009 May 1;65(9):792-800. doi: 10.1016/j.biopsych.2008.10.025. Epub 2008 Dec 5.


Background: Significant alterations in gamma-aminobutyric acid (GABA) and glutamate levels have been previously reported in major depressive disorder (MDD); however, no studies to date have investigated associations between these amino acid neurotransmitters and treatment resistance.

Methods: The objective of this study was to compare occipital cortex (OCC) and anterior cingulate cortex (ACC) GABA and glutamate+glutamine (Glx) levels measured by proton magnetic resonance spectroscopy ((1)H MRS) in 15 medication-free treatment-resistant depression (TRD) patients with those in 18 nontreatment-resistant MDD (nTRD) patients and 24 healthy volunteers (HVs).

Results: Levels of OCC GABA relative to voxel tissue water (W) were decreased in TRD patients compared with both HV (20.2% mean reduction; p = .001; Cohen's d = 1.3) and nTRD subjects (16.4% mean reduction; p = .007; Cohen's d = 1.4). There was a similar main effect of diagnosis for ACC GABA/W levels (p = .047; Cohen's d = .76) with TRD patients exhibiting reduced GABA in comparison with the other two groups (22.4% to 24.5% mean reductions). Group differences in Glx/W were not significant in either brain region. Only GABA results in OCC survived correction for multiple comparisons.

Conclusions: Our findings corroborate previous reports of decreased GABA in MDD and provide initial evidence for a distinct neuronal amino acid profile in patients who have failed to respond to several standard antidepressants, possibly indicative of abnormal glutamate/glutamine/GABA cycling. Given interest in novel antidepressant mechanisms in TRD that selectively target amino acid neurotransmitter function, the translational relevance of these findings awaits further study.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain / metabolism*
  • Case-Control Studies
  • Depressive Disorder, Major / metabolism*
  • Drug Resistance*
  • Female
  • Glutamic Acid / metabolism*
  • Glutamine / metabolism*
  • Gyrus Cinguli / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy*
  • Male
  • Middle Aged
  • Neurotransmitter Agents / metabolism*
  • Occipital Lobe / metabolism
  • gamma-Aminobutyric Acid / metabolism*


  • Neurotransmitter Agents
  • Glutamine
  • Glutamic Acid
  • gamma-Aminobutyric Acid