Glutamate Metabolism in Major Depressive Disorder
Publication: American Journal of Psychiatry
Abstract
Objective:
Emerging evidence suggests that abnormalities in amino acid neurotransmitter function and impaired energy metabolism contribute to the underlying pathophysiology of major depressive disorder. To test whether impairments in energetics and glutamate neurotransmitter cycling are present in major depression, we used carbon-13 magnetic resonance spectroscopy (13C MRS) to measure these fluxes in individuals diagnosed with major depression relative to healthy comparison subjects.
Method:
Proton (1H) MRS and 13C MRS data were collected for 23 medication-free individuals with major depression 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 for mitochondrial energy production, GABA synthesis, and glutamate/glutamine cycling from voxels situated in the occipital cortex.
Results:
Mitochondrial energy production of glutamatergic neurons was 26% lower in the depression group. Paradoxically, no difference was found in the rate of the glutamate/glutamine cycle (Vcycle). A significant correlation was observed between glutamate concentrations and Vcycle in the overall sample.
Conclusions:
The authors 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.
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History
Received: 19 January 2014
Revision received: 4 April 2014
Accepted: 2 June 2014
Published ahead of print: 31 October 2014
Published online: 1 December 2014
Published in print: December 01, 2014
Authors
Funding Information
Brain and Behavior Research Foundation10.13039/100000874: GFM
National Institute of Mental Health10.13039/100000025: R01 MH071676, K02 MH076222
National Institute on Drug Abuse10.13039/100000026: R01 DA021785, T32-DA022975
Dr. Abdallah has received consulting fees from Genentech. Dr. Krystal has served as a consultant to AbbVie, Eli Lilly, Janssen, Naurex, and Novartis; he holds stock in BioHaven Pharmaceutical Holding Company; and he is named on patents or patent applications related to dopamine and noradrenergic reuptake inhibitors in the treatment of schizophrenia, the targeting of the glutamatergic system for the treatment of neuropsychiatric disorders, and the intranasal administration of ketamine to treat depression. Dr. Mason has received consulting fees from UCB Pharma. Dr. Sanacora has received grant support or consulting fees from Abbott, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Hoffman-La Roche, Johnson & Johnson, Merck, Novartis, Noven Pharmaceuticals, and Takeda; he has received grant support from AstraZeneca, Bristol-Myers Squibb, Hoffman-La Roche, Eli Lilly, Merck, Naurex, and Johnson & Johnson; he is named on a patent application by Yale University related to the targeting of the glutamatergic system for the treatment of neuropsychiatric disorders; and he holds shares in BioHaven Pharmaceutical Holding Company. The other authors report no financial relationships with commercial interests.Supported by NIH grants R01 MH071676 and K02 MH076222 (to Dr. Sanacora), a grant from the Stanley Foundation (to Dr. Mason), a grant from NARSAD (to Dr. Mason), and NIH grant R01 DA021785 (to Dr. Mason). Salary support for Dr. Abdallah was provided by NIMH grant K23 MH101498 and NIDA grant T32 DA022975 (NeuroImaging Science Training Program). Support was also provided by the NIH National Center for Advancing Translational Science under award UL1 TR000142.Metrics & Citations
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