Glutamate Metabolism in Major Depressive Disorder

Abstract

Objective Emerging evidence suggests abnormalities in amino acid neurotransmitter function and impaired energy metabolism contribute to the underlying pathophysiology of Major Depressive Disorder (MDD). To test whether impairments in energetics and glutamate neurotransmitter cycling are present in MDD we used in vivo 13C magnetic resonance spectroscopy (13C MRS) to measure these fluxes in individuals diagnosed with MDD relative to non-depressed subjects. Method 1H MRS and 13C MRS data were collected on 23 medication-free MDD and 17 healthy subjects. 1H MRS provided total glutamate and GABA concentrations, and 13C MRS, coupled with intravenous infusion of [1-13C]-glucose, provided measures of the neuronal tricarboxylic acid cycle (VTCAN) for mitochondrial energy production, GABA synthesis, and glutamate/glutamine cycling, from voxels placed in the occipital cortex. Results Our main finding was that mitochondrial energy production of glutamatergic neurons was reduced by 26% in MDD subjects (t = 2.57, p = 0.01). Paradoxically we found no difference in the rate of glutamate/glutamine cycle (Vcycle). We also found a significant correlation between glutamate concentrations and Vcycle considering the total sample. Conclusions We interpret the reduction in mitochondrial energy production as being due to either mitochondrial dysfunction or a reduction in proper neuronal input or synaptic strength. Future MRS studies could help distinguish these possibilities.

Meta-analysis of central and peripheral γ-aminobutyric acid levels in patients with unipolar and bipolar depression

“…Our search identified 45 studies: 26 studies for the comparison of patients with current MDE versus healthy controls, [8][9][10][11][12][13][14][15][16][17][18]30,[33][34][35][36][37][38][39][40][41][42][43][44][45][46] 12 studies for the comparison of patients with current MDE before treatment versus after treatment, 12,20,23,25,26,28,36,43,[47][48][49][50] and 11 for the comparison of euthymic patients and controls. 18,[21][22][23]27,29,38,[51][52][53][54] Figure 1 depicts the study selection proce...…”

“…For MRS studies, we calculated SMDs for the following regions of interest (ROIs) independently: the occipital cortex, [8][9][10][11][12]14,15,[20][21][22][23][24][25][26][27][28] the anterior cingulate cortex (ACC), 13,15,16,18,22 the dorsolateral prefrontal cortex (dlPFC), 29,30 the ventromedial prefrontal cortex (vmPFC) 29,30 and the left inferior frontal gyrus. 27 We estimated study heterogeneity using the Q statistic when SMDs were significant.…”

“…[8][9][10][11][12][13][14][15][16]30 This heterogeneity was not explained by medication status, as all studies included unmedicated patients. There was a great heterogeneity among defined ROIs across studies, but subanalyses showed similar findings without changing the level of heterogeneity (e.g., occipital cortex: χ 2 = 30.07, p < 0.001, I 2 = 80%; prefrontal cortex: χ 2 = 6.08, p = 0.05, I 2 = 51%).…”

“…Results of studies assessing GABA levels in individuals with depression appear highly variable according to the type of measure (plasma, CSF, or MRS) or to clinical characteristics of the included depressed samples. For example, MRS studies have reported GABA diminution, [8][9][10] no GABA change, [11][12][13] or GABA increase in participants with depression compared with healthy participants. 14 Furthermore, many authors have described specific implications of GABA neurotransmission according to different clinical characteristics of depression, such as pharmacological resistance, 15 anhedonia, 16 melancholia 9,11 or unipolar or bipolar depression.…”

Ketamine Treatment and Global Brain Connectivity in Major Depression

“…Although speculative in nature, our working hypothesis is that GBCr-under certain circumstances-may reflect overall synaptic strength in a brain region. Considering the tight coupling between synaptic strength, glutamate cycling, and neuroenergetics (Abdallah et al, 2014;Hyder et al, 2013), it is important to highlight that GBCr has been found to positively correlate with rCBF (Liang et al, 2013). Similarly, other GBC-type measures were positively associated with rCBF and cerebral metabolic rate of glucose (Liang et al, 2014;Tomasi et al, 2013).…”