Anterior cingulate cortex \u03b3-aminobutyric acid deficits in youth with depression

V Gabbay,G Kang,D C Shungu,R Ostrover,K A Bradley,X Mao

doi:10.1038/tp.2017.187

Abstract

Abnormally low γ-aminobutyric acid (GABA) levels have been consistently reported in adults with major depressive disorder (MDD). Our group extended this finding to adolescents, and documented that GABA deficits were associated with anhedonia. Here we aimed to confirm our prior finding of decreased brain GABA in youth with depression and explore its associations with clinical variables. Forty-four psychotropic medication-free youth with MDD and 36 healthy control (HC) participants (12–21 years) were studied. Participants represent a combined sample of 39 newly recruited youth (MDD=24) and 41 youth from our previously reported study (MDD=20). GABA levels and the combined resonances of glutamate and glutamine (Glx) were measured in vivo in the anterior cingulate cortex using proton magnetic resonance spectroscopy. Youth with depression exhibited significantly lower GABA levels than HC in both the newly reported (P=0.003) and the combined (P=0.003) samples. When depressed participants were classified based on the presence of anhedonia, only the anhedonic MDD subgroup showed reduced GABA levels compared to HC (P=0.002). While there were no associations between any clinical measures and GABA or Glx levels in the new sample, GABA was negatively correlated with only anhedonia severity in the combined MDD group. Furthermore, in the combined sample, hierarchical regression models showed that anhedonia, but not depression severity, anxiety or suicidality, contributed significant variance in GABA levels. This report solidifies the evidence for a GABA deficit early in the course of MDD, which correlates specifically with anhedonia in the disorder.

Highlights

Major depressive disorder (MDD) often emerges during adolescence, a critical developmental period in which many psychiatric conditions first develop.[1]
There were no significant differences between the healthy control (HC) and MDD groups in either the newly recruited or combined samples on any demographic variables, except for ethnicity in the combined sample (Χ2 = 8.42, P = 0.04)
There were no significant correlations between age and γ-aminobutyric acid (GABA)/ W or Glx/W in all participants (HC+MDD) from either the newly recruited (24 MDD, 15 HC) or combined (44 MDD, 36 HC) samples

Summary

Introduction

Major depressive disorder (MDD) often emerges during adolescence, a critical developmental period in which many psychiatric conditions first develop.[1]. Emerging evidence points to dysregulation of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter, in MDD Chief among such evidence is that GABA deficits have been consistently documented in adults with depression,[6,7,8,9] including those with treatment resistant depression.[10] a recent mini-review of neuroimaging studies in adults with depression concluded that GABA levels might serve as a marker for illness state.[11] only a few studies have examined brain GABA levels in youth with depression[12] or youth at risk for depression.[13] Our laboratory extended findings of reduced GABA levels in adults with depression[6,7,8,9] to a younger cohort and reported decreased anterior cingulate cortex (ACC) GABA levels in adolescents with MDD.[12] We further documented a negative association between GABA levels and anhedonia severity.[12]

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