Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression

• Type of Material: Article
• Authors: Mandakh Bekhbat, Emory University; Karen Chu, Emory University; Ngoc-Anh Le, Atlanta VA Medical Center; Bobbi J. Woolwine, Emory University; Ebrahim Haroon, Emory University; Andrew Miller, Emory University; Jennifer Felger, Emory University
• Language: English
• Date: 2018-12-01
• Publisher: Pergamon-Elsevier Science Ltd.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Ltd
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.psyneuen.2018.09.004
• Title of Journal or Parent Work: Psychoneuroendocrinology
• Volume: 98
• Start Page: 222
• End Page: 229
• Grant/Funding Information: Funding sources: This work was supported by grants R21MH0771172, R01MH087604, and R25MH101079 (Dr. Miller), R01MH109637 (Dr. Felger) and R01MH H107033 (Dr. Haroon) from the National Institute of Mental Health; by Centocor Ortho Biotec Services LLC, and by grants BBRF22296 from the Brain and Behavioral Research Foundation and CADF49143 from the Dana Foundation (Dr. Felger).; n addition, the study was supported in part by PHS Grants UL1TR000454 from the Clinical and Translational Science Award program, and by the NIH/NCI under award number P30CA138292.
• Keywords: Endocrinology & Metabolism; TNF-ALPHA; Metabolism; RHEUMATOID-ARTHRITIS; OBESITY; INSULIN-RESISTANCE; Life Sciences & Biomedicine; Lipids; Neurosciences & Neurology; INFLAMMATION; PREDICTORS; EPIDEMIOLOGY; C-reactive protein; CARDIOVASCULAR-DISEASE; Neurosciences; Depression; METABOLISM; Inflammation; Science & Technology; Tumor necrosis factor; Glucose; Psychiatry; ADIPONECTIN
• Research Categories: Health Sciences, Public Health; Psychology, General

Abstract

The tumor necrosis factor (TNF) antagonist infliximab was previously found to reduce depressive symptoms in patients with treatment-resistant major depression (TRD) who exhibited high baseline inflammation, as reflected by plasma C-reactive protein (CRP) >5 mg/L. Further predictors of antidepressant response to infliximab included differential expression of peripheral blood gene transcripts that were related not only to inflammation but also to glucose and lipid metabolism. To determine whether plasma biomarkers of glucose and lipid metabolism were similarly associated with antidepressant response to infliximab and with relevant gene transcripts, we measured concentrations of glucose, insulin, and protein hormones that regulate glucose homeostasis and metabolism (leptin, resistin, and adiponectin), as well as cholesterols, triglycerides, and non-esterified fatty acids (NEFA), in medically-stable TRD outpatients at baseline and 2 weeks after the first infusion of infliximab (n = 26) or placebo (n = 26). Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. We found that baseline cholesterol (total, low-density lipoprotein [LDL], and non-high-density lipoprotein [non-HDL]), triglycerides and NEFA were elevated in patients who exhibited an antidepressant response to infliximab (all p < 0.05) but not placebo (all p > 0.299). HDL and non-HDL cholesterol concentrations also correlated with two lipid-related gene transcripts that were predictive of antidepressant response (r = 0.33 to 0.39, p < 0.05). Although not associated with response to infliximab, resistin correlated with numerous glucose-related transcripts (r = −0.32 to 0.37, p < 0.05) and was higher at 2 weeks post-infusion in patients treated with infliximab compared to placebo (p = 0.028). Concentrations of cholesterol (total, LDL, HDL, non-HDL) were also lower at 2 weeks in patients treated with infliximab compared to placebo, but only in those patients with CRP >5 mg/L at baseline (all p < 0.05). These results are consistent with previous work showing that high inflammation in patients with depression is associated with metabolic alterations, which together predict response to both traditional and experimental antidepressant therapies. Additionally, our findings suggest a causal relationship between increased inflammation and high cholesterol in depression, as a single infusion of infliximab reduced cholesterol in TRD patients with high CRP compared to placebo.