Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators

Authors: LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LIU, MINYING - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DUNLOP, BOADIE - Emory University; KINKEAD, BECKY - University Of Utah; SCHETTLER, PAMELA - University Of Utah; FELGER, JENNIFER - Emory University; ZIEGLER, THOMAS - Emory University; FAVA, MAURIZIO - Massachusetts General Hospital; MISCHOULON, DAVID - Massachusetts General Hospital; RAPAPORT, MARK - University Of Utah

Submitted to: Neuropsychophamacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/26/2022
Publication Date: 1/12/2023
Citation: Lamon-Fava, S., Liu, M., Dunlop, B.W., Kinkead, B., Schettler, P.J., Felger, J.C., Ziegler, T.R., Fava, M., Mischoulon, D., Rapaport, M.H. 2023. Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators. Neuropsychophamacology. https://doi.org/10.1038/s41386-022-01527-7.
DOI: https://doi.org/10.1038/s41386-022-01527-7

Interpretive Summary: Major depressive disorder (MDD) is more common in individuals with obesity than normal-weight individuals. It has been suggested that the chronic low-grade inflammation that accompanies obesity plays an important role in causing MDD by promoting inflammation of the brain and dysregulating neurotransmitters. Therefore, it has been proposed that anti-inflammatory therapies may reduce MDD symptoms. The omega-3 fatty acid eicosapentaenoic acid (EPA), found in fish and fish oil, has anti-inflammatory effects either directly or through its conversion to molecules called specialized pro-resolving lipid mediators (SPMs). In a study conducted in MDD patients with chronic inflammation, we found that 3-month high-dose EPA supplementation was more effective in reducing MDD than placebo or low doses of EPA. In addition, MDD patients receiving EPA supplementation who also experienced greater increases in SPMs were more likely to respond to treatment and experience significant reductions in depression and inflammation than those with lower increases in SPM. These findings indicate that EPA may be an effective treatment option of MDD by promoting anti-inflammatory actions and favoring the resolution of inflammation.

Technical Abstract: Chronic inflammation has been implicated in the pathophysiology of major depressive disorder (MDD). Activating the resolution of inflammation through omega-3 fatty acid supplementation may prove to be a successful therapeutic strategy for the treatment of MDD. MDD patients with body mass index >25 kg/m2 and plasma high-sensitivity C-reactive protein >=3 microg/mL (n=61) were enrolled in a 12-week randomized trial consisting of 4 parallel arms: eicosapentaenoic acid (EPA) 1, 2, and 4 g/d, and placebo. The supplement contained EPA and docosahexaenoic acid (DHA) in a 3.9:1 ratio. Depression symptoms were assessed using the clinician-rated IDS-C30 scale. Plasma fatty acids and pro-resolving lipid mediators (SPMs) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. The response rate (>=50% reduction in IDS-C30 score) was higher in the 4 g/d EPA arm than in the other arms. In the 4 g/d EPA arm, responders had significantly greater increases in 18-hydroxyeicosapentaenoic acid (18-HEPE) and 13-hydroxydocosahexaenoic acid (13-HDHA) than non-responders. Within the 4 g/d EPA arm, the increase in 18-HEPE was significantly associated with reductions in plasma hs-CRP concentrations and IDS-C30 scores. In summary, response rates were greater among MDD patients randomized to EPA 4 g/d supplementation and in those who showed a greater ability to activate the synthesis of 18-HEPE. The inverse association of 18-HEPE with both systemic inflammation and symptoms of depression highlights the activation of the resolution of inflammation as a likely mechanism in the treatment of MDD with omega-3 fatty acid supplementation