Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents: relationship to anhedonia.

Adolescent major depressive disorder (MDD), a severe neuropsychiatric illness that is associated with significant morbidity and heightened suicide risk, remains poorly understood because of its inherent heterogeneity and symptomatic overlap with other psychopathologies.1,2 Therefore, investigating specific symptoms of the disorder has the potential to advance our understanding of the neurobiology of MDD. An ideal candidate for such a focused investigation is anhedonia: the reduced capacity to experience pleasure and a core symptom of MDD that is prevalent and highly variable in adolescents with MDD.3,4 Among depressed adolescents, up to 59% are reported to present with significant anhedonia.5 Anhedonia has been associated with dysfunction of the dopaminergic brain system and the neural circuitry of reward.6 However, the direct mechanisms have not been determined. Growing preclinical and clinical evidence has associated dysregulation of both γ-aminobutyric acid (GABA) and glutamate, respectively the major inhibitory and excitatory amino acid neurotransmitters, with anhedonia and MDD pathophysiology.7–10 In support of this view are clinical studies that have reported decreased cerebrospinal fluid and blood GABA levels in melancholic MDD, in which the presence of anhedonia is essential for diagnosis.11,12 In addition, proton magnetic resonance spectroscopy (1H MRS) studies in adults have documented decreases of cortical GABA in melancholic MDD13 and decreases of glutamine (the molecular precursor of GABA and glutamate) in anhedonic depressed patients,14 further implicating these neurotransmitter systems in anhedonia. To the best of our knowledge, no studies to date have investigated brain GABA alterations in adolescents with MDD. In the present study, we aimed to extend prior work in adults to adolescents and assess GABA levels in the anterior cingulate cortex (ACC), a brain region strongly implicated in MDD.15 Structurally, both postmortem and magnetic resonance imaging (MRI) studies of MDD have shown a reduction in volume in the subgenual region of the ACC.16,17 Multiple functional neuroimaging15,18 and 1H MRS studies in adult19–22 and pediatric23,24 populations have supported a role for the ACC in MDD, and as a region that is part of the reward neural circuitry,25–27 the ACC is highly relevant to anhedonia. Based on prior 1H MRS data in adult MDD,22,28 we hypothesized that ACC GABA levels would be decreased in psychotropic medication–free adolescents with MDD compared with group-matched healthy controls (HCs). In secondary analyses and by analogy to melancholic MDD data in adults,11–13 we also postulated that the subset of patients categorized as anhedonic would have decreased ACC GABA levels compared with both nonanhedonic patients and HCs and that ACC GABA levels would negatively correlate with severity of MDD episodes and with anhedonia scores. In light of evidence linking metabolic dysregulation of glutamate and glutamine to MDD and anhedonia,13,14,22 we explored potential group differences in Glx (combined resonances of glutamate and glutamine).