Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression

• Type of Material: Article
• Authors: Ebrahim Haroon, Emory University; C.C. Fleischer, Emory University; Jennifer Felger, Emory University; X Chen, Emory University; BJ Woolwine, Emory University; Trusharth Patel, Emory University; Xiaoping Hu, Emory University; Andrew Miller, Emory University
• Language: English
• Date: 2016-10-01
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/mp.2015.206
• Title of Journal or Parent Work: Molecular Psychiatry
• ISSN: 1359-4184
• Volume: 21
• Issue: 10
• Start Page: 1351
• End Page: 1357
• Grant/Funding Information: his work was funded in part by grants from the National Institute of Mental Health K23MH091254 (EH), KL2TR000455 (JCF), Young Investigator Award from The Brain & Behavior Research Foundation (JCF and EH) and R01MH08760 (AHM).; We acknowledge the support of the BITC-CSI core of the School of Medicine at Emory University, ACTSI-CRN funded by National Center for Advancing Translational Sciences-CTSA Award (UL1TR000454) and Training Support from Advanced Research Institute for Geriatric Mental Health funded by the National Institute of Mental Heath R25MH068502 (EH).
• Keywords: ASTROCYTES; Neurosciences & Neurology; BIPOLAR DEPRESSION; KYNURENINE PATHWAY; Science & Technology; MECHANISMS; Biochemistry & Molecular Biology; C-REACTIVE PROTEIN; Life Sciences & Biomedicine; METAANALYSIS; IN-VIVO; Neurosciences; MOOD DISORDERS; MAGNETIC-RESONANCE-SPECTROSCOPY; Psychiatry; RELEASE
• Research Categories: Health Sciences, Oncology; Engineering, Biomedical; Psychology, Behavioral

Abstract

Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-α to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP.