Mischoulon D, Dunlop BW, Kinkead B, et al. Omega-3 fatty acids for major depressive disorder with high inflammation: a randomized dose-finding clinical trial. J Clin Psychiatry. 2022;83(5):21m14074.
To compare omega-3 fatty acid administration vs placebo on inflammatory markers and symptoms of depression in depressed patients with a body mass index (BMI) above 25 kg/m2
In depressed patients with a BMI above 25 kg/m2, 4 grams of eicosapentaenoic acid (EPA) per day moderately lowered inflammation and significantly lowered symptoms of depression.
Randomized, controlled trial
Researchers recruited 61 nonmedicated adults (75% female, median 45.5 years of age) with a BMI greater than 25 kg/m2; 45 patients completed the study.
In the intervention group, participants received 1 gram, 2 grams, or 4 grams per day EPA (each capsule had 590 mg EPA and 152 mg docosahexaenoic acid [DHA]), with a ratio of 3.9:1 EPA to DHA. The control group received a placebo made from soybean oil (comprised of 54% omega-6 and 6% omega-3, with no EPA component).
Study Parameters Assessed
- Blood interleukin-6 levels (IL-6)
- Plasma high-sensitivity C-reactive protein (hs-CRP)
- Production of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) by peripheral blood mononuclear cell cytokines (PBMC)
- Inventory of Depressive Symptoms (IDS-C30) scores
Whether omega-3 fatty acid administration vs placebo affects inflammatory markers and symptoms of depression in patients with major depression.
In 45 volunteers who completed the study, ingesting 4 grams EPA per day correlated significantly with a decrease in percent change of plasma hs-CRP and percent change of symptom reduction as recorded via the IDS-C30 at 12 weeks (P=0.19).
All groups had intragroup improvements, with response rates for EPA 4 g/d of 64%, vs 40% for placebo (odds ratio [OR]=2.63); 38% for EPA 1 g/d; and 36% for EPA 2 g/d (all P>0.05).
No EPA dose produced a ≥0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF.
This study was funded by the National Institutes of Health’s National Center for Complementary and Integrated Health (NCCIH). Mischoulon received research support from Nordic Naturals, and many of the other 16 authors disclosed industry relationships. These can be found under “Relevant Financial Relationships.”
Practice Implications & Limitations
This paper is authored by clinical researchers well-known in the field of using supplements to support mental health. For the last decade, both David Mischoulon and Maurizio Fava have increased our knowledge base for employing fish oils and folate in depressed patients.1 This new study furthers our understanding of the optimal dosing of fish oil for depression, the effective ratio of EPA to DHA, and specifically which patients may benefit the most.
In this work, depressed and inflamed obese patients were given either 1 gram, 2 grams, or 4 grams EPA (included in a nearly 4:1 ratio of EPA to DHA fish oil) per day or a placebo. The results suggest that ingesting 4 grams a day of EPA can help obese, depressed patients with high levels of hs-CRP both lower inflammation and improve symptoms of depression within 12 weeks. This study also shows that even lower levels of EPA supplementation (both 1 gram and 2 grams) also lowered plasma hs-CRP in a dose-dependent manner, while the soybean oil placebo had little effect. Additionally, each treatment group intervention lowered IDS-C30 scores (meaning fewer depression symptoms), with the 4-gram dose demonstrating the greatest response of 64%; the 1-gram and 2-gram doses resulted in a 36% to 40% response rate, while placebo showed a 20% response rate overall. Notable in this study was that the placebo group nonsignificantly outperformed both 1- and 2-gram EPA dosing. So, from a clinical perspective, this suggests using 4-gram EPA per day is likely to improve therapeutic effect over lower doses.
Interestingly, there were some placebo patients who did respond as well. Those participants already had lower baseline IDS-C30 scores (meaning they were less depressed already) and lower baseline interleukin-6 scores (less inflammation), which could mean that the soy oil (with mostly omega-6 and some omega-3) was enough to shift these measurements in patients with milder levels of depression and inflammation. Adverse events were minor in nature and lowest in the treatment group, with no patient needing to discontinue in any group.
Unique to this study is that the participants were not taking any antidepressant drugs.
This paper adds to the body of research supporting the use of fish oil for depressed, obese patients. However, there are some clinical considerations. First, this work is based on a small sample size, as the authors were hoping for at least 100 subjects to fully participate in the study. This smaller subject number may increase the level of false positive results. Secondly, this study would have been an opportunity to study both baseline fatty acid levels and changes in fatty acids, and how these may correlate with changes in symptomology and inflammation in these patients. Levels of baseline fatty acids are a predictor of future antidepressant-treatment results.2 In the future, we, as clinicians, may want to start tracking this parameter to better understand who may benefit most from fatty acid administration. Finally, recent a meta-analysis suggests an optimal ratio of EPA to DHA may actually be closer to a 3:2 ratio.3 Michael Lewis, another well-known researcher and expert in fish oil use for brain health,4 has also suggested, via personal communication, that the optimal EPA to DHA ratio may be 3:2. So, this study corroborates prior research on the effectiveness of fish oil higher in EPA, despite the ratio differences.
Unique to this study is that the participants were not taking any antidepressant drugs. This gives naturopathic and integrative physicians an opportunity to clearly evaluate, as a monotherapy, the benefits of using fish oil in our patient populations of concomitantly obese and inflamed patients. It is my opinion that combined therapies including naturopathic lifestyle, diet, and relaxation work aimed at lowering adiposity and inflammation would probably create an even more powerful result than using fish oil alone. Furthermore, this paper underscores that higher-end doses are needed to achieve a therapeutic result. Oftentimes we clinicians may minimize dosing in our patients because patients tend to prefer taking fewer gel caps, or because the gel cap size is too large, or because they may not prefer a liquid dose.
Lastly, I find synergistic natural agents along with fish oil can have a better effect than fish oil alone. For example, in patients with inflammation, the use of curcumin, which is also known as an effective monotherapy to lower symptoms of depression,5 may further enhance the anti-inflammatory and mood-enhancing effect we see with fish oil.
Peter Bongiorno, ND, LAc, is a consultant for Pure Encapsulations/Douglas Laboratories.