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

Abstract

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.

Figures

FIGURE 1

(A) axial and (B) sagittal images showing ACC and OCC voxel sizes and locations; (C) PRESS 1H MR spectra with “editing” rf pulse (a) off and (b) on. (D) The difference of the spectra in (C) showing: (a) the detected GABA and Glx peaks, with (b–d) best-fit model curves and residuals, which yield the areas under the peaks. The depicted data were acquired in 13 min from a 2.5×2.5×3.0 cm3 ACC voxel, using TE/TR 68/1500 ms, and 256 interleaved excitations (total 512) with editing pulse on or off.

FIGURE 2

GABA/W ratios [arbitrary units (a.u.)] in (A) the occipital cortex (OCC) and (B) the anterior cingulate (ACC) of healthy volunteers (HV), non-treatment-resistant major depression patients (nTRD), and treatment-resistant depression patients (TRD). Group means are displayed to the right of data from individual subjects. In the OCC, TRD patient values are 20.2% lower than HVs (p=.001; Cohen’s d=1.3) and 16.4% lower than nTRD subjects (p=.007; Cohen’s d=1.4). In the ACC, TRD values are 22.4% lower than HVs (p = .08, Cohen’s d=1.03) and 24.5% lower than nTRDs (p = .06, Cohen’s d=0.88). P-values derived by Tukey’s HSD post-hoc tests.