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

Authors: LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SO, JISUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MISCHOULON, DAVID - Massachusetts General Hospital; ZIEGLER, THOMAS - Emory University; DUNLOP, BOADIE - Emory University; KINKEAD, BECKY - Emory University; SCHETTLER, PAMELA - Emory University; NIERENBERG, ANDREW - Massachusetts General Hospital; FELGER, JENNIFER - Emory University; RAO MADDIPATI, KRISHAN - Wayne State University; FAVA, MAURIZIO - Massachusetts General Hospital; RAPAPORT, MARK - Emory University

Submitted to: Prostaglandins Leukotrienes and Essential Fatty Acids
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/24/2020
Publication Date: 12/4/2020
Citation: Lamon-Fava, S., So, J., Mischoulon, D., Ziegler, T.R., Dunlop, B.W., Kinkead, B., Schettler, P.J., Nierenberg, A.A., Felger, J.C., Rao Maddipati, K., Fava, M., Rapaport, M.H. 2020. 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. Prostaglandins Leukotrienes and Essential Fatty Acids. https://doi.org/10.1016/j.plefa.2020.102219.
DOI: https://doi.org/10.1016/j.plefa.2020.102219

Interpretive Summary: Major depressive disorder (MDD) is more common in conditions associated with chronic inflammation, such as obesity, metabolic syndrome, and type 2 diabetes mellitus. Supplementation with fish oil containing the omega-3 fatty acid eicosapentaenoic acid (EPA) has been shown to lower inflammation. EPA has also been proven to be an effective treatment option in MDD associated with chronic inflammation. Within cells, EPA is enzymatically converted to several molecules termed specialized pro-resolving lipid mediators (SPMs), including resolvins, that serve important roles in reducing inflammation. The objective of our study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites in MDD patients. We studied 42 overweight MDD patients with chronic inflammation. Patients were randomized to four different treatments for 12 weeks: placebo, 1 g/d EPA, 2 g/d EPA and 4 g/d EPA. SPMs and symptoms of depression were measured before and after the 12 weeks of treatment. Plasma EPA and EPA-derived SPMs increased dose-dependently after EPA supplementation. Specifically, in subjects receiving 4 g/d EPA, resolvin E3, which was undetected before supplementation, became detectable in the majority of patients after 12 weeks supplementation. The increase in resolvin E3, which can help reduce inflammation, could have important implications for treating obese patients with MDD.

Technical 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/m^2 and serum high-sensitivity C-reactive protein >=3 micrograms/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.