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

Mischoulon D, Dunlop B, Kinkead B, Schettler P, Lamon-Fava S, Rakofsky J, Nierenberg A, Clain A, Crowe T, Wong A, Felger J, Sangermano L, Ziegler T, Cusin C, Fisher L, Fava M, Rapaport M (2022) The Journal of Clinical Psychiatry Aug 22;83(5):21m14074 doi: 10.4088/JCP.21m14074 

Web URL: Read this article on PubMed


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.


Systematic reviews and meta-analyses of clinical trials have already shown that dietary supplementation with the long-chain omega-3 EPA is effective as an adjunctive treatment for patients with clinical depression who do not achieve remission with standard treatments. For a review of this evidence from leading international experts, and detailed clinical treatment guidelines, see:

The expert consensus is that existing clinical trial evidence supports adjunctive treatment with at least 1-2 g/day of EPA daily, from either pure EPA or an EPA/DHA (>2:1) formula.

Given the safety and general health benefits of long-chain omega-3, the expert panel also agreed that supplementation is also a worthwhile option for the treatment of major depression in pregnant women (who also need a minimum of 200mg/day DHA), in children and adolescents, and in the elderly, as well as for prevention in high-risk populations, or as monotherapy. However, clinical trial evidence 
in these areas remains more limited, so further trials are still needed.

Also highlighted was the need for additional research exploring subgroups of patients with depression, including those with partiularly low omega-3 status and/or biomarkers of inflammation.

This new clinical trial therefore explored the effects on both depressive symptoms ad bioarkers of inflammation of three different doses of EPA vs placebo in patients with major depression with overweight or obesity.

Results showed that 4g/day of EPA was superior to either 2g or 1g/day in this population for producing a sustained reduction in depressive symptoms, and that clinical response was also related to reductions in one biomarker of inflammation (high-sensitivity C-reactive protein).

For the related news article, see:

And for more information on this subject, see also: