EPA but not DHA appears to be responsible for the efficacy of omega-3 LC-PUFA supplementation in depression: evidence from an updated meta-analysis of randomized controlled trials

Background: Epidemiological and case-control data suggest that increased dietary intake of omega-3 long-chain polyunsaturated fatty acids (v 3L C-PUFA) may be of benefit in depression. However, the results of randomized controlled trials are mixed and controversy exists as to whether either eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or both are responsible for the reported benefits. Objective: To update a recently published meta-analysis (Martins JG, J Am Coll Nutr, 2009; 28: 525-42) of double-blind, placebo-controlled, randomized controlled trials examining the effect of v 3L C-PUFA supplementation where depressive symptoms were a reported outcome. The differential effectiveness of EPA versus DHA has been reassessed through meta-regression and subgroup analyses. Design: Studies were selected using the PubMed database on the basis of the following criteria: i) randomized design; ii) placebo controlled; iii) use of an v 3L C-PUFA preparation containing DHA, EPA or both where the relative amounts of each fatty acid could be quantified; and iv) reporting sufficient statistics on scores of a recognizable measure of depressive symptoms. Results: 370 studies wereidentified (22/01/2011) of which35 metthe aboveinclusion criteria(7 additional to Martins JG, 2009) and were therefore included for analysis. Using a random effects model, overall standardized mean depression scores were reduced in response to v 3L C-PUFA supplementation as compared with placebo (standardized mean difference = -0.230, 95% CI = -0.361 to -0.099, p = 0.001). However, significant heterogeneity and evidence of publication bias was present. Meta-regression studies showed a significant effect of EPA:DHA ratio on therapeutic efficacy. Subgroup analyses showed significant effects for: i) baseline debression; ii) diagnostic category (bipolar disorder and major depression showing significant improvement with v 3L C- PUFA supplementation versus mildtomoderate depression, perinatal depression, chronic fatigue and non-clinical populations not); iii) therapeutic as opposed to preventative intervention; iv) adjunctive treatment and to a lesser extent monotherapy; and v) supplement type. Symptoms of depression were not significantly reduced in 2 studies using pure DHA of algal origin (standardized mean difference = -0.111, 95% CI = -0.590 to 0.368, p = 0.649), in 3 studies using a mixture of DHA and EPA ethyl esters (standardized mean difference = -0.027, 95% CI = -0.200 to 0.147, p = 0.764), or in 7 studies using fish oil triglyceride supplements containing greater than 50% DHA (standardized mean difference = 0.027, 95% CI = -0.148 to 0.202, p = 0.763). In contrast, symptoms of depression were significantly reduced in 13 studies using fish oil triglyceride supplements containing greater than 50% EPA (standardized mean difference = -0.513, 95% CI = -0.840 to -0.185, p = 0.002) and in 10 studies using pure EPA ethyl ester (standardized mean difference = -0.360, 95% CI = -0.597 to -0.123, p = 0.003). However, further meta-regression studies showed significant