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Original Research

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial

David Mischoulon, MD, PhDa,‡,*; Boadie W. Dunlop, MDb,‡; Becky Kinkead, PhDb; Pamela J. Schettler, PhDb; Stefania Lamon-Fava, MD, PhDc; Jeffrey J. Rakofsky, MDb; Andrew A. Nierenberg, MDa; Alisabet J. Clain, MSa; Tanja Mletzko Crowe, BAb; Andrea Wong, BAb; Jennifer C. Felger, MDb; Lisa Sangermano, BAa; Thomas R. Ziegler, MDd; Cristina Cusin, MDa; Lauren B. Fisher, MDa; Maurizio Fava, MDa,§; and Mark Hyman Rapaport, MDb,e,§

Published: August 22, 2022


Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.

Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.

Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).

Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.

Trial Registration: identifier: NCT02553915

Volume: 83

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