Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation

• Type of Material: Article
• Authors: Stefania Lamon-Fava, Tufts University; Jisun So, Tufts University; David Mischoulon, Massachusetts General Hospital; Thomas Ziegler, Emory University; Boadie Dunlop, Emory University; Becky Kinkead, Emory University; Pamela Schettler, Emory University; Andrew A Nierenberg, Massachusetts General Hospital; Jennifer Felger, Emory University; Krishna Rao Maddipati, Wayne State University; Maurizio Fava, Massachusetts General Hospital; Mark Rapaport, Emory University
• Language: English
• Date: 2021-01-01
• Publisher: ELSEVIER SCI LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.plefa.2020.102219
• Title of Journal or Parent Work: PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS
• Volume: 164
• Start Page: 102219
• End Page: 102219
• Grant/Funding Information: This work was supported by the National Institutes of Health grant UG3 AT008857.
• Keywords: Biochemistry & Molecular Biology; major depressive disorder (MDD); Endocrinology & Metabolism; TERM; Science & Technology; HUMAN PLASMA; Life Sciences & Biomedicine; ANALOGS; OXYLIPINS; POLYUNSATURATED FATTY-ACIDS; ATHEROSCLEROSIS; OMEGA-3-FATTY-ACIDS; MECHANISMS; Omega-3 fatty acids; RESOLUTION; DOUBLE-BLIND; Cell Biology; Pro-resolving lipid mediators (SPM); Eicosapentaenoic acid (EPA)

Abstract

Background: Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients. Methods: In a 2-site study, 61 MDD patients with body mass index >25 kg/m2 and serum high-sensitivity C-reactive protein ≥3 μg/mL were enrolled in a 12-week randomized trial comparing EPA 1, 2, and 4 g/d to placebo. Plasma EPA (mol%) and SPMs (pg/mL) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. Results: Plasma EPA and SPM concentrations did not change in the placebo group during 12 weeks of treatment. Plasma EPA and EPA-derived metabolites increased significantly and dose-dependently in all EPA supplementation arms. The increase in 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of RvE1–3, was significantly greater with the 4 g/d EPA dose than the other doses from week 4 to 12. RvE1 was undetected in all treatment groups, while RvE2 was detected in half of the subjects both at baseline and after treatment, with dose-dependent increases. RvE3 was detected only after supplementation, dose-dependently. A significant reduction in plasma arachidonic acid (AA), relative to baseline, was observed in all EPA arms. This was in contrast with an increase in AA-derived SPM lipoxin B4 (LXB4) in the 4 g/d arm. Conclusions: Our results show a robust effect of EPA 4 g/d supplementation in increasing plasma EPA and 18-HEPE levels, associated with improved conversion to RvE2–3, and LXB4 levels.