Review: Omega-3 HUFAs added to antidepressant therapy may reduce depression symptoms

Question In patients with depression, what is the effectiveness of nutraceuticals added to antidepressant therapy? Review scope Included English-language studies assessed any adjunctive, standardized, pharmaceutical-grade, nutrient-based treatment for 21 days in patients who had diagnosed major depressive disorder or ongoing depression (symptoms rated as moderate or above-threshold on a validated scale), were receiving antidepressant drugs, and included >10 patients per treatment group. Primary outcome was depression symptoms measured using a recognized assessment scale. Review methods PubMed, CINAHL, Web of Science, and Cochrane Library (all 1960 to Dec 2015), clinical trial registers, citations to references, and reference lists were searched for uncontrolled, controlled, or quasi-experimental studies. Authors and academic personnel were contacted. 40 studies (mean age 44 y, 69% women, duration 3 to 52 wk), including 31 randomized placebo-controlled trials (RCTs), met selection criteria. Omega-3 highly unsaturated fatty acids (HUFAs) (eicosapentaenoic acid [EPA] plus docosahexaenoic acid [DHA], EPA alone, or ethyl-EPA) were assessed in 8 RCTs; 1-carbon cycle nutraceuticals (S-adenosylmethionine [SAM-e], folic acid, methylfolate, folinic acid, or a combination of folic acid and vitamins B6 and B12) and tryptophan in 7 RCTs each; zinc, inositol, and vitamin C in 2 RCTs each; and creatine, vitamin D3, and an amino acid combination in 1 RCT each. Results for folic acid and omega-3 HUFAs were pooled for meta-analysis and are reported in this abstract. Main results Meta-analyses showed that the addition of folic acid to antidepressant therapy did not affect depression symptoms compared with placebo but addition of omega-3 HUFAs did (Table). Conclusion In patients with major depressive disorder or ongoing depression who were receiving antidepressant drugs, adjunctive omega-3 highly unsaturated fatty acids reduce depression symptoms compared with placebo. Adjunctive nutraceutical treatment vs placebo in patients with major depressive disorder or ongoing depression* Comparison Number of trials (n) Depression symptoms at 3 to 52 wk Standardized mean difference (95% CI) I 2 Folic acid vs placebo 4 (671) 0.49 (0.31 to 1.3) 93% Omega-3 HUFAs vs placebo 8 (448) 0.61 (0.15 to 1.1) 82% *HUFAs = highly unsaturated fatty acids; other abbreviations defined in Glossary. Standardized mean difference between treatment and placebo is based on the change from baseline to study end date. Standardized effect size determined using Hedges g; meta-analysis used a random-effects model. Commentary Primary care and mental health clinicians often encounter questions about a wide range of nutritional supplements for treatment of depression. The meta-analyses by Sarris and colleagues and Hallahan and colleagues assessed potential benefits of omega-3 HUFAs; Sarris and colleagues also evaluated several other supplements and nutraceuticals. Both reviews showed improvements in depression symptoms with omega-3 HUFAs. Sarris and colleagues showed moderate benefit of EPA-predominant HUFAs when added to conventional antidepressant therapy for patients with diagnosed depression. Hallahan and colleagues analyzed a larger number of studies of omega-3 HUFAs and found that improvements in depression symptoms were specific to EPA-predominant rather than DHA-predominant supplements. In further subgroup analysis, they showed benefits of EPA supplements both as adjuvant treatment with conventional antidepressants and as monotherapy (compared with placebo or no treatment), and EPA-predominant supplements improved depression symptoms in patients with diagnosed (i.e., at least moderate severity) depressive disorders, with no clear differences in patients with mild or subthreshold depression. It is important to note that none of the included studies compared omega-3 HUFAs with conventional antidepressant drugs or depression-specific psychotherapy. Given these findings, clinicians can recommend EPA-predominant omega-3 HUFAs to augment antidepressant treatment, should recommend EPA-predominant supplements over mixed or DHA supplements, and can recommend EPA-predominant omega-3 HUFAs as primary treatment for patients who decline more established treatments (conventional antidepressants or psychotherapy). At this time, omega-3 HUFAs cannot be recommended as alternatives to more established treatments for patients with diagnosed depression or moderate or more severe depression symptoms. Sarris and colleagues also examined evidence for several other supplements or nutraceuticals for augmentation of conventional antidepressant treatment. Data were adequate for meta-analysis of folate supplements only, the results of which were inconsistent and showed neither clinical nor statistical improvement. Clinicians cannot recommend folate supplements as an effective adjunct to antidepressant treatment. Clinicians should clearly distinguish recommendations about folate from recommendations for the related supplements methylfolate and SAM-e. Evidence for augmentation with methylfolate and SAM-e was predominantly positive, but not adequate for formal meta-analysis. In plain language, we might say, The evidence seems to show that taking folate along with antidepressants will not help more than a placebo. There is some evidence that taking methylfolate or SAM-e can help, but the evidence is not strong. Clinicians should be clear that this evidence is for methyfolate or SAM-e added to conventional antidepressant treatment and not for use of these supplements as primary treatment or alternatives to more established treatments. Finally, we should consider the lack of effect of omega-3 HUFAs for mild or subthreshold depression in the broader context for treatment of milder depression. For both conventional antidepressant drugs and depression-specific psychotherapy, effectiveness is much clearer for moderate or severe depression and less clear (or nonexistent) for mild depression. This almost certainly does not reflect any biologic or mechanistic distinction between milder and more severe depression. Instead, it reflects the relatively good prognosis of mild depression, leading to high placebo response rates (1, 2). Clinicians might frame this as good news: Omega-3 HUFAs aren't clearly better than a placebo for mild depression because mild depression usually gets better with time and good self-care.