• Katherine M Appleton, Hannah M Sallis, Rachel Perry, Andrew R Ness, and Rachel Churchill.
• Department of Psychology, Bournemouth University, Poole House, Fern Barrow, Poole, UK, BH12 5BB.
• Cochrane Db Syst Rev. 2015 Nov 5; 2015 (11): CD004692CD004692.

BackgroundMajor depressive disorder (MDD) is highly debilitating, difficult to treat, has a high rate of recurrence, and negatively impacts the individual and society as a whole. One emerging potential treatment for MDD is n-3 polyunsaturated fatty acids (n-3PUFAs), also known as omega-3 oils, naturally found in fatty fish, some other seafood, and some nuts and seeds. Various lines of evidence suggest a role for n-3PUFAs in MDD, but the evidence is far from conclusive. Reviews and meta-analyses clearly demonstrate heterogeneity between studies. Investigations of heterogeneity suggest differential effects of n-3PUFAs, depending on severity of depressive symptoms, where no effects of n-3PUFAs are found in studies of individuals with mild depressive symptomology, but possible benefit may be suggested in studies of individuals with more severe depressive symptomology.ObjectivesTo assess the effects of n-3 polyunsaturated fatty acids (also known as omega-3 fatty acids) versus a comparator (e.g. placebo, anti-depressant treatment, standard care, no treatment, wait-list control) for major depressive disorder (MDD) in adults. Search MethodsWe searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Registers (CCDANCTR) and International Trial Registries over all years to May 2015. We searched the database CINAHL over all years of records to September 2013.Selection CriteriaWe included studies in the review if they: were a randomised controlled trial; provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and were conducted in adults with MDD. Primary outcomes were depressive symptomology (continuous data collected using a validated rating scale) and adverse events. Secondary outcomes were depressive symptomology (dichotomous data on remission and response), quality of life, and failure to complete studies.Data Collection And AnalysisWe used standard methodological procedures as expected by Cochrane.Main ResultsWe found 26 relevant studies: 25 studies involving a total of 1438 participants investigated the impact of n-3PUFA supplementation compared to placebo, and one study involving 40 participants investigated the impact of n-3PUFA supplementation compared to antidepressant treatment.For the placebo comparison, n-3PUFA supplementation results in a small to modest benefit for depressive symptomology, compared to placebo: standardised mean difference (SMD) -0.32 (95% confidence interval (CI) -0.12 to -0.52; 25 studies, 1373 participants, very low quality evidence), but this effect is unlikely to be clinically meaningful (an SMD of 0.32 represents a difference between groups in scores on the HDRS (17-item) of approximately 2.2 points (95% CI 0.8 to 3.6)). The confidence intervals include both a possible clinically important effect and a possible negligible effect, and there is considerable heterogeneity between the studies. Although the numbers of individuals experiencing adverse events were similar in intervention and placebo groups (odds ratio (OR) 1.24, 95% CI 0.95 to 1.62; 19 studies, 1207 participants; very low-quality evidence), the confidence intervals include a significant increase in adverse events with n-3PUFAs as well as a small possible decrease. Rates of remission and response, quality of life, and rates of failure to complete studies were also similar between groups, but confidence intervals are again wide.The evidence on which these results are based is very limited. All studies contributing to our analyses were of direct relevance to our research question, but we rated the quality of the evidence for all outcomes as low to very low. The number of studies and number of participants contributing to all analyses were low, and the majority of studies were small and judged to be at high risk of bias on several measures. Our analyses were also likely to be highly influenced by three large trials. Although we judge these trials to be at low risk of bias, they contribute 26.9% to 82% of data. Our effect size estimates are also imprecise. Funnel plot asymmetry and sensitivity analyses (using fixed-effect models, and only studies judged to be at low risk of selection bias, performance bias or attrition bias) also suggest a likely bias towards a positive finding for n-3PUFAs. There was substantial heterogeneity in analyses of our primary outcome of depressive symptomology. This heterogeneity was not explained by the presence or absence of comorbidities or by the presence or absence of adjunctive therapy.Only one study was available for the antidepressant comparison, involving 40 participants. This study found no differences between treatment with n-3PUFAs and treatment with antidepressants in depressive symptomology (mean difference (MD) -0.70 (95% CI -5.88 to 4.48)), rates of response to treatment or failure to complete. Adverse events were not reported in a manner suitable for analysis, and rates of depression remission and quality of life were not reported.Authors' ConclusionsAt present, we do not have sufficient high quality evidence to determine the effects of n-3PUFAs as a treatment for MDD. Our primary analyses suggest a small-to-modest, non-clinically beneficial effect of n-3PUFAs on depressive symptomology compared to placebo; however the estimate is imprecise, and we judged the quality of the evidence on which this result is based to be low/very low. Sensitivity analyses, funnel plot inspection and comparison of our results with those of large well-conducted trials also suggest that this effect estimate is likely to be biased towards a positive finding for n-3PUFAs, and that the true effect is likely to be smaller. Our data, however, also suggest similar rates of adverse events and numbers failing to complete trials in n-3PUFA and placebo groups, but again our estimates are very imprecise. The one study that directly compares n-3PUFAs and antidepressants in our review finds comparable benefit. More evidence, and more complete evidence, are required, particularly regarding both the potential positive and negative effects of n-3PUFAs for MDD.

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