Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram

Abstract

Little is known about the acute effects of antidepressant treatments on brain glutamate and gamma-amino-butyric acid (GABA) levels, and their association with clinical response. Using proton magnetic resonance spectroscopy (¹H-MRS) we examined longitudinally the effects of citalopram on glutamine/glutamate ratios and GABA levels in the pregenual anterior cingulate cortex (pgACC) of individuals with major depressive disorder (MDD). We acquired ¹H-MRS scans at baseline and at days 3, 7, and 42 of citalopram treatment in nineteen unmedicated individuals with MDD. Ten age- and sex-matched non-depressed comparison individuals were scanned once. The association between 1) baseline metabolites and 2) change in metabolites from baseline to each time point and clinical response (change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 42) was assessed by longitudinal regression analysis using generalized estimating equations. Contrary to our hypotheses, no significant associations emerged between glutamate metabolites and clinical response; however, greater increases (or smaller decreases) in pgACC GABA levels from baseline to days 3 and 7 of citalopram treatment were significantly associated with clinical response. These findings suggest that an acute change in GABA levels in pgACC predicts, and possibly mediates, later clinical response to citalopram treatment in individuals with MDD.

Keywords: Depression; GABA; Glutamate; MRS; Magnetic resonance spectroscopy; SSRI.

Figure 1

Sagittal MRI showing placement of magnetic resonance spectroscopy (MRS) voxel in the pregenual anterior cingulate cortex and sample 3 Tesla proton MRS spectra from the pregenual anterior cingulate cortex at baseline (scan 1), day 3 (scan 2), day 7 (scan 3), and day 42 (scan 4) using J-PRESS (extracted from J = 0.0Hz) and MEGAPRESS sequences. Spectra are displayed with LCModel fit and residual. Cho, choline; Cr, creatine; GABA, gamma-amino-butyric acid; Glu, glutamate; mI, myo-inositol; NAA, N-acetylaspartate.

Figure 2

Two-dimensional spectral plot from the pregenual anterior cingulate cortex showing the J-coupling patterns of the coupled metabolites across J-space. Cho, choline; Cr, creatine; Gln, glutamine; Glu, glutamate; GSH, glutathione; mI, myo-inositol; NAA, N-acetylaspartate.

Figure 3

The mean scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) over 6 weeks of citalopram treatment. Error bars represent 95% confidence interval.