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reference
Mischoulon D, Dunlop BW, Kinkead B, et al. Omega-3 fatty acids in severe depression with high inflammation: a dose-finding randomized clinical trial.J Department of Psychiatry.2022;83(5):21m14074.
Study objective
Comparison of omega-3 fatty acid administration with placebo on inflammatory markers and depression symptoms in depressed patients with a body mass index (BMI) above 25 kg/m2
Key to take away
In depressed patients with a BMI over 25 kg/m24 grams per day of eicosapentaenoic acid (EPA) moderately reduced inflammation and significantly reduced symptoms of depression.
design
Randomized controlled trial
Participant
Researchers recruited 61 unmedicated adults (75% female, mean age 45.5 years) with a BMI greater than 25 kg/m2; 45 patients completed the study.
intervention
In the intervention group, participants received 1 gram, 2 grams, or 4 grams of EPA per day (each capsule contained 590 mg of EPA and 152 mg of docosahexaenoic acid (DHA)), with a ratio of 3.9:1 EPA to DHA. The control group received a placebo made from soybean oil (consisting of 54% omega-6 and 6% omega-3, without EPA component).
Evaluated study parameters
- Interleukin-6-Spiegel im Blut (IL-6)
- Hochempfindliches C-reaktives Protein im Plasma (hs-CRP)
- Produktion von Lipopolysaccharid (LPS)-stimuliertem Tumornekrosefaktor (TNF) durch Zytokine mononukleärer Zellen im peripheren Blut (PBMC)
- Ergebnisse des Inventars depressiver Symptome (IDS-C30).
Primary outcome
Whether administration of omega-3 fatty acids compared to placebo affects inflammatory markers and depression symptoms in patients with major depression.
Key findings
In 45 volunteers who completed the study, taking 4 grams of EPA per day was significantly correlated with a decrease in the percent change in plasma hs-CRP and the percent change in symptom reduction as recorded via the IDS-C30 at 12 weeks (P=0.19).
AAll groups recorded within-group improvements, with rResponse rates for EPA 4 g/d of 64% versus 40% for placebo (odds ratio (OR) = 2.63); 38% for EPA 1 g/day; and 36% for EPA 2 g/d (all P>0.05).
No EPA dose resulted in an effect size reduction of ≥0.35 in plasma IL-6 or mitogen-stimulated TNF.
transparency
This study was funded by the National Center for Complementary and Integrated Health (NCCIH) of the National Institutes of Health. Mischoulon received research support from Nordic Naturals and many of the other 16 authors disclosed industry relationships. You can find these under “Relevant financial relationships”.
Implications and limitations for practice
This paper was written by clinical researchers known in the field of using nutritional supplements to support mental health. Over the last decade, both David Mischoulon and Maurizio Fava have expanded our knowledge base on the use of fish oils and folic acid in depressed patients.1This new study expands our understanding of the optimal dosage of fish oil for depression, the effective ratio of EPA to DHA, and particularly which patients might benefit most.
In this work, depressed and inflammatory obese patients received either 1 gram, 2 grams, or 4 grams of EPA (contained in an EPA to DHA fish oil ratio of nearly 4:1) per day or a placebo. The results suggest that taking 4 grams of EPA per day may help obese, depressed patients with high hs-CRP levels reduce inflammation and improve symptoms of depression within 12 weeks. This study also shows that even lower amounts of EPA supplementation (both 1 gram and 2 grams) also reduced plasma hs-CRP in a dose-dependent manner, while the soybean oil placebo had little effect. Additionally, each treatment group intervention reduced IDS-C30 scores (meaning fewer depression symptoms), with the 4 gram dose showing the greatest response at 64%; The 1-gram and 2-gram doses resulted in a response rate of 36% to 40%, while the placebo had an overall response rate of 20%. Of note in this study was that the placebo group did not significantly outperform both the 1- and 2-gram EPA dosages. From a clinical perspective, this suggests that using 4 grams of EPA per day is likely to improve the therapeutic effect over lower doses.
Interestingly, there were also some placebo patients who responded. These participants already had lower baseline IDS-C30 levels (meaning they were already less depressed) and lower baseline interleukin-6 levels (less inflammation), which could mean that the soybean oil (with mostly omega-6 and some omega-3) did enough to shift these measurements in patients with milder depression and inflammation. Adverse events were minor and lowest in the treatment group, with no patient having to discontinue treatment in any group.
What's special about this study is that the participants didn't take any antidepressants.
This paper adds to research supporting the use of fish oil in depressed, obese patients. However, there are some clinical considerations. First, this work is based on a small sample size, as the authors hoped that at least 100 subjects would fully participate in the study. This smaller number of subjects can increase the number of false positive results. Second, this study would have provided an opportunity to examine both basal fatty acid levels and fatty acid changes and how these might correlate with changes in symptomology and inflammation in these patients. Basal fatty acid content is an indicator of future results of antidepressant treatment.2In the future, we as clinicians may want to start tracking this parameter to better understand who might benefit most from fatty acid administration. Finally, a recent meta-analysis suggests that an optimal ratio of EPA to DHA may actually be closer to 3:2.3Michael Lewis, another well-known researcher and expert in the use of fish oil for brain health,4has also suggested in personal communication that the optimal EPA to DHA ratio may be 3:2. This study confirms previous research on the effectiveness of fish oil with higher EPA content, despite the ratio differences.
What's special about this study is that the participants didn't take any antidepressants. This gives naturopathic and integrative physicians the opportunity to clearly evaluate the benefit of using fish oil as monotherapy in our concurrently obese and inflamed patient populations. I believe that combined therapies, including naturopathic lifestyle, diet and relaxation work, aimed at reducing obesity and inflammation would likely produce an even stronger result than using fish oil alone. Furthermore, this paper highlights that higher dosages are required to achieve a therapeutic result. We doctors often minimize the dosage in our patients because patients tend to take fewer gel capsules, because the gel capsules are too large, or because they do not prefer a liquid dose.
Finally, I find that synergistic natural active ingredients together with fish oil can have a better effect than fish oil alone. For example, in patients with inflammation, the use of curcumin, also known as an effective monotherapy for relieving symptoms of depression,5can enhance the anti-inflammatory and mood-enhancing effects of fish oil.
Disclosure of Conflicts of Interest
Peter Bongiorno, ND, LAc, is a consultant for Pure Encapsulations/Douglas Laboratories.