A new study indicates that higher doses of the omega-3 fatty acid eicosapentaenoic acid may alleviate depressive symptoms in overweight individuals with elevated inflammatory markers.
Omega-3 polyunsaturated fatty acids (PUFAs) have been studied in the treatment of many conditions, including bipolar disorder and major depressive disorder. Although meta-analyses indicate that PUFAs may be effective for the treatment of MDD, studies have yielded mixed results. These inconsistencies may reflect different methodologies, as well as the use of different dosages and PUFA preparation, across the studies; however, researchers also believe that certain patients may respond more robustly to supplementation with PUFAs than others.
More specifically, it appears that individuals with MDD associated with chronic low-grade inflammation may receive greater antidepressant benefit from PUFAs. Over the years we have learned that dysregulation of the immune system occurs in patients with depression and may negatively affect outcomes, including response to traditional antidepressants. Previous research indicates that eicosapentaenoic acid (EPA) supplementation is an effective for the treatment of depressive symptoms associated with chronic low-grade inflammation. EPA has potent anti-inflammatory effects and is the precursor of specialized pro-resolving lipid mediators (SPMs) or resolvins (Rv) which play an important role in the resolution of inflammation. Whether or not this decrease in inflammation is at the root of EPA’s antidepressant effects is not clear.
While EPA may help to alleviate depression, we have yet to determine the appropriate dosage and duration of PUFA treatment and to define which populations would receive the greatest benefit from treatment with PUFAs. In a multicenter trial funded by the National Center for Complementary and Integrative Health (NCCIH) David Mischoulon, MD PhD and colleagues from the Depression Clinical Research Program investigated the efficacy of three different doses of EPA versus placebo in a population of patients with inflammatory depression. The participants had a body mass index (BMI) greater than 25 and confirmed markers of inflammation, including elevated levels of high-sensitivity C-reactive protein (hs-CRP ≥ 3). The goal of the study was to determine the most effective dose of EPA and to examine if reductions in inflammatory markers were correlated with antidepressant response.
The highest dose of EPA (4 g/day) had the greatest antidepressant effects. Response rates for EPA at 4 g per day were 64% versus 40% for placebo (odds ratio [OR] = 2.63). Response rates were 38% for EPA at 1 g/day and 36% for EPA at 2 g/day. In participants receiving EPA 4 g/day, they observed a significant correlation between decreases in plasma hs-CRP levels and reduction in depressive symptoms at 12 weeks.
As data emerged in the 1990s suggesting the beneficial effects of omega-3 fatty acids in patients with neurodegenerative and psychiatric disorders, researchers speculated that these benefits were related to the effects of omega-3 fatty acids on membrane fluidity and brain development; however, more recent research has suggested a broader range of mechanisms of action and have further noted that docosahexaenoic acid (DHA) and EPA, while both omega-3 fatty acids, may have different effects on the brain, with studies supporting the use of higher doses of EPA in patients with depression.
This study helps to put a finer point on our understanding of how PUFAs might help to relieve depression in certain individuals. The PUFAs may have many benefits for the brain; however, this study shows a correlation between decreases in inflammation and reductions in depressive symptoms. Furthermore, the beneficial antidepressant and anti-inflammatory effects of PUFAs are seen at much higher doses (4g per day) than used in previous studies , which may help to explain, at least in part, some of the discrepant findings in the literature.
While we often recommend that our depressed patients take omega-3 fatty acids to supplement their treatment, it should be noted that most preparations sold over the counter are mixtures of DHA and EPA and tend to have low levels of EPA (typically around 600 to 800 mg of EPA). Even preparations that are labeled “Super EPA” or “Extra EPA” provide less than 1g of EPA per day. (Information on the content of EPA can be found on the label.)
We also must be cognizant of the fact that the PUFAs may not have as robust antidepressant effects in depressed patients without inflammation. While this study focussed on a specific population with low-grade inflammation (individuals with an elevated BMI), future research will help to better characterize other populations who may receive benefit from treatment with omega-3 fatty acids.
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Mischoulon D, Dunlop BW, Kinkead B, Schettler PJ, et al. Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial. J Clin Psychiatry. 2022 Aug 22;83(5):21m14074.
Lamon-Fava S, Rakofsky JJ, Nierenberg AA, Clain AJ, Mletzko Crowe T, Wong A, Felger JC, Sangermano L, Ziegler TR, Cusin C, Fisher LB, Fava M, Rapaport MH. Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial. J Clin Psychiatry. 2022 Aug 22; 83(5):21m14074.
Lamon-Fava S, So J, Mischoulon D, et al. 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 Leukot Essent Fatty Acids. 2021; 164:102219.
Lamon-Fava S, So J, Mischoulon D, Ziegler TR, Dunlop BW, Kinkead B, Schettler PJ, Nierenberg AA, Felger JC, Maddipati KR, Fava M, Rapaport MH. 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 Leukot Essent Fatty Acids. 2021 Jan; 164:102219.
