“Fishing” for novel approaches to depression: Researchers performed randomized dose-finding trial of omega-3 fatty acids for depression with inflammation.
“Mr Vern” is a 35-year-old Caucasian male with a history of recurrent major depressive disorder (MDD), with illness onset in his teens. He has a history of anemia. Recently labs ordered by his primary care physician were significantly for mildly elevated high-sensitivity C-reactive protein (hs-CRP)level (5.0 mg/L). He is adherent with a selective serotonin reuptake inhibitor and clinically stable, as evidenced by no psychiatric hospitalizations in the past 5 years. However, he does have some residual symptoms of depression, including low energy and concentration. At his most recent outpatient clinic visit, he asks about taking an omega-3 fatty acid supplement. As his psychiatrist, would you prescribe omega-3 fatty acids for this patient, and if so, at what dose?
There is mixed evidence for adjunctive treatment with omega-3 polyunsaturated fatty acids (PUFA) in MDD.1,2 The dose and duration of treatment with PUFAs may contribute to heterogeneous findings. Furthermore, it is also possible that subgroups of patients with MDD, such as those with evidence of inflammation in the peripheral blood, may be more likely to respond to treatment with adjunctive PUFAs. There is also evidence that PUFAs decrease inflammation by reducing interleukin-6 (IL-6) and tumor necrosis factor (TNF).2-4
The Current Study
Mischoulon and colleagues5 performed a 12-week, multicenter trial of 3 different doses of PUFAs (versus placebo) in patients with MDD and inflammation (hs-CRP level ≥ 3.0 mg/L and body mass index [BMI] >25). They also investigated the impact of PUFAs on blood markers of inflammation, including plasma interleukin-6 (IL-6) and lipopolysaccharide-stimulated macrophage production of tumor necrosis factor (TNF).
The authors performed a parallel group, double-blind randomized controlled trial at 2 sites in the United States. Inclusion criteria were men and women aged 18 to 80 years with DSM-5 MDD without psychotic features, a BMI > 25, hs-CRP level ≥3.0, and a total Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30), score of ≥ 25 at screening and baseline.
Major exclusion criteria were lifetime neurocognitive disorder, psychotic or bipolar disorder, or anorexia nervosa; substance use disorder in the 3 months prior to screening; current obsessive-compulsive disorder or bulimia nervosa; serious suicidal or homicidal risk; serious or unstable medication illness; malignancy in remission for < 1 year; active autoimmune disorder; concomitant antidepressant use; and scheduled use of anti-inflammatory or other immunomodulating medications.
Omega-3 PUFA capsules had a ratio of eicosapentaenoic acid (EPA):docosahexaenoic acid (DHA) of about 4:1. After screening, subjects were randomized equally to 1, 2, or 4 g EPA/day or placebo, and took 4 capsules twice daily for 12 weeks. Subjects had biweekly study visits, and fasting blood samples for inflammatory biomarkers were obtained at baseline and weeks 4, 8, and 12.
Data on changes in blood inflammatory markers was analyzed using non-parametric rank-order statistics. Data on changes in depressive symptoms were analyzed using mixed model repeated measures analysis. Data on whether changes in inflammatory markers were associated with changes in depressive symptoms was obtained using Spearman rank order correlations.
Sixty-one subjects were randomized to treatment, and treatment groups were not significantly different on baseline demographic or clinical characteristics. Approximately 51 subjects were evaluable for clinical efficacy, and 45 subjects completed the trial with adequate adherence, depressive symptom, and biomarker data.
In the analyses of biomarker data, after 12 weeks, median blood hs-CRP levels decreased in a dose-dependent manner in the PUFA groups compared to placebo. PUFAs failed to demonstrate a (small-to-moderate) effect size of ≥ 0.40 at weeks 8 and 12 for decrease in blood IL-6 or TNF production.
In the clinically evaluable sample (n=51), there were significant decreases in depressive symptoms in all 4 subject groups from week 4 to 12, with no significant between-group differences. In the completer sample (n=45), the EPA 4g/day group had a 64% response rate at week 12, compared to 36% to 40%, although this finding was not statistically significant. There was a significant correlation between the percent change in blood hs-CRP and depressive symptoms at 12 weeks in the EPA 4g/day group (ρ=0.69). Approximately 59% of subjects reported at least 1 (generally mild) adverse event, and no serious adverse events were reported.
The authors performed the first dose-finding trial of EPA in MDD to focus on inflammatory biomarkers. Although they did not find that EPA decreased blood IL-6 or TNF production, they did find that EPA 4 g/d was associated with increased sustained response rates for depression, with concomitant decreases in hs-CRP. Study limitations include the modest sample size, and the fact that treatment response was dichotomized. Data on baseline red blood cell or plasma lipids were not available. Furthermore, subjects were not taking antidepressants, so the effects of PUFAs in treated patients with depression and inflammation remains unclear.
The Bottom Line
High-dose (4 g/day) PUFAs may be effective for depression in some overweight or obese patients with inflammation, and reduction in hs-CRP may play a role.
Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
1. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7(7):CD003177.
2. Liao Y, Xie B, Zhang H, et al. Efficacy of omega-3 PUFAs in depression: a meta-analysis [published correction appears in Transl Psychiatry. 2021 Sep 7;11(1):465]. Transl Psychiatry. 2019;9(1):190.
3. Ellulu MS, Khaza'ai H, Abed Y, et al. Role of fish oil in human health and possible mechanism to reduce the inflammation. Inflammopharmacology. 2015;23(2-3):79-89.
4. Itariu BK, Zeyda M, Hochbrugger EE, et al. Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial [published correction appears in Am J Clin Nutr. 2020 Nov 11;112(5):1405]. Am J Clin Nutr. 2012;96(5):1137-1149.
5. 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.