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.

Pretreatment and early-treatment cortical thickness is associated with SSRI treatment response in major depressive disorder

“…This idea that affective, potentially introspective or self-referential, adaptions occur very early in treatment hinges on the notion that there are in fact, relevant pharmacological changes induced immediately, i.e., activation of second messenger systems and alterations to gene expression [47]. Short-term increases in rACC GABA concentration, acquired with MR spectroscopy, have been shown to significantly associate with SSRI clinical response [50], supporting the notion that pharmacoactive alterations can occur in this small time window. The exact biological mechanism underlying short-term thickening of this region is difficult to pinpoint.…”

Whole-slice mapping of GABA and GABA+ at 7T via adiabatic MEGA-editing, real-time instability correction, and concentric circle readout

“…To date, GABA detection via MRS has mainly been conducted in single voxels within the brain, with cortical regions (e.g., occipital and prefrontal lobes) being prominent regions of interest (Brennan et al, 2017;Mahone et al, 2018;Reid et al, 2018). Reports about MRS Imaging (MRSI) are still uncommon (Bogner et al, 2014a;Hnilicová et al, 2016;Jensen et al, 2005), and all of them share the same limitations, namely, large voxel sizes, which hamper the assessment of regional, -anatomically resolved -GABA levels, and also restricted rectangular target volumes to overcome extracranial lipid artifacts, which is problematic for studies of cortical regions.…”

Feasibility of Glutamate and GABA Detection in Pons and Thalamus at 3T and 7T by Proton Magnetic Resonance Spectroscopy

“…Non-invasive, in vivo measurement of glutamate, the major excitatory neurotransmitter, using proton magnetic resonance spectroscopy ( 1 H-MRS) is of interest for studying the mechanisms behind various brain disorders as well as the pharmacokinetics of drugs acting within the central nervous system (Foerster et al, 2013;Brennan et al, 2017;Prisciandaro et al, 2017;Younis et al, 2018). Glutamatergic changes in subcortical structures such as pons and thalamus are particularly of interest (Pioro et al, 1999;Foerster et al, 2013;Adanyeguh et al, 2015;Neill et al, 2016;Bathel et al, 2018;Younis et al, 2018).…”