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Randomized Controlled Trial
. 2021 Jan:164:102219.
doi: 10.1016/j.plefa.2020.102219. Epub 2020 Dec 5.

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

Stefania Lamon-Fava  1 , Jisun So  2 , David Mischoulon  3 , Thomas R Ziegler  4 , Boadie W Dunlop  5 , Becky Kinkead  5 , Pamela J Schettler  5 , Andrew A Nierenberg  3 , Jennifer C Felger  5 , Krishna Rao Maddipati  6 , Maurizio Fava  3 , Mark Hyman Rapaport  5
Affiliations
Randomized Controlled Trial

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

Stefania Lamon-Fava et al. Prostaglandins Leukot Essent Fatty Acids. 2021 Jan.

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.

Keywords: Eicosapentaenoic acid (EPA); Omega-3 fatty acids; Pro-resolving lipid mediators (SPM); major depressive disorder (MDD).

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Conflict of interest statement

Conflict of interest: Lamon-Fava S., So J, Rapaport MH, Kinkaid B, Shettler P and Maddipati KR report no conflict of interest. Mischoulon D has received research support from Nordic Naturals, consulted for Pharmavite LLC and Gnosis USA, Inc. Ziegler, TR is receiving research funding from Takeda. Dunlop B has received research support from Acadia, Compass, Aptinyx, Sage, and Takeda, and has served as a consultant to Greenwich Biosciences, Myriad Neuroscience, Otsuka, and Sophren Therapeutics. Felger J has received consulting fees from Otsuka. Fava M has consulted for Axsome, Benckiser Pharmaceuticals, Inc., BioClinica, Inc, Biogen, BioHaven, Cambridge Science Corporation, Cerecor, Gate Neurosciences, Inc., GenOmind, LLC, Gentelon, LLC, Happify, Johnson & Johnson, Lundbeck Inc., Marinus Pharmaceuticals, Methylation Sciences, Inc., Millennium Pharmaceutics, Inc. Minerva Neurosciences, Neuralstem, NeuroRX Inc., Novartis, Otsuka, Pfizer, Premiere Research International, Relmada Therapeutics Inc., Reckitt, Shenox Pharmaceuticals, Stanley Medical Research Institute (SMRI), Taisho, Takeda, Vistagen, National Institute of Drug Abuse (NIDA); National Institutes of Health (NIH), National Institute of Mental Health (NIMH), and PCORI.

Figures

Figure 1.
Figure 1.
Median changes in plasma EPA and EPA-derived lipid mediators at weeks 4, 8 and 12, relative to week 0, by treatment arm. The enzymes involved in the synthesis of the lipid mediators are indicated.
Figure 2.
Figure 2.
Associations of plasma EPA (mol%) with the plasma concentration of EPA-derived lipid mediators at the end of treatment (week 12).
Figure 3.
Figure 3.
Median changes in plasma DHA and DHA-derived lipid mediators at weeks 4, 8 and 12, relative to week 0, by treatment arm. The enzymes involved in the synthesis of the lipid mediators are indicated.
Figure 4.
Figure 4.
Median changes in plasma AA and AA-derived lipid mediators and eicosanoids at weeks 4, 8 and 12, relative to week 0, by treatment arm. The enzymes involved in the synthesis of the lipid mediators are indicated.
Figure 5.
Figure 5.
Plasma levels of SPMs derived from EPA (Panel A), DHA (panel B), and AA (Panel C) in the placebo and the EPA treatment arms. SPMs were variably detected, usually in less than 80% of plasma samples. Only subjects with detectable levels of each SPM are shown in the figure. Medians are based on detectable levels only.
See this image and copyright information in PMC

References

    1. Ross R Atherosclerosis--an inflammatory disease. The New England journal of medicine. 1999;340:115–26. - PubMed
    1. Libby P, Okamoto Y, Rocha VZ and Folco E. Inflammation in atherosclerosis: transition from theory to practice. Circulation journal: official journal of the Japanese Circulation Society. 2010;74:213–20. - PubMed
    1. Morris AA, Zhao L, Ahmed Y, Stoyanova N, De Staercke C, Hooper WC, Gibbons G, Din-Dzietham R, Quyyumi A and Vaccarino V. Association between depression and inflammation--differences by race and sex: the META-Health study. Psychosom Med. 2011;73:462–8. - PMC - PubMed
    1. Kohler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, Stubbs B, Solmi M, Veronese N, Herrmann N, Raison CL, Miller BJ, Lanctot KL and Carvalho AF. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017;135:373–387. - PubMed
    1. Serhan CN and Savill J. Resolution of inflammation: the beginning programs the end. Nature immunology. 2005;6:1191–7. - PubMed

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