Why is this review important?
Major depressive disorder (MDD) is characterised by depressed mood or a markedly decreased pleasure or interest in all activities, or both. It has negative impacts on the individual and on society, often over the long term. One possible treatment for MDD is n-3 polyunsaturated fatty acids (n-3PUFAs), also known as omega-3 oils, naturally found in fatty fish, in some other seafood and in some nuts and seeds. Various lines of evidence suggest that n-3PUFAs may impact on depressive symptoms, but a lot of studies have different findings, making it difficult to draw conclusions.
Who will be interested in this review?
Health professionals, including general practitioners, mental health and psychiatric specialists; individuals with MDD; and the people around them.
What questions does this review aim to answer?
Do n-3PUFAs, compared to an alternative, have an effect on depressive symptoms, negative side effects, rates of recovery, quality of life, and rates of study non-completion, in individuals with MDD?
Which studies were included in the review?
This review is an update of earlier work (Appleton 2015), using the same methods. We searched scientific databases for all randomised controlled trials in adults with MDD, where individuals received either n-3PUFAs or an alternative, that were completed up to January 2021.
We have included 35 relevant studies: 34 of them involving 1924 people compared the effects of n-3PUFAs with those of placebo, and one study involving 40 people compared the effects of n-3PUFAs with those of antidepressants. All studies were of direct relevance to our review, but we considered the certainty of the evidence to be low to very low.
What does the evidence from the review tell us?
At present, we do not have enough high quality evidence to determine the effects of n-3PUFAs as a treatment for MDD. We found a small-to-modest positive effect of n-3PUFAs compared to placebo, but the size of this effect is unlikely to be meaningful to people with MDD, and we considered the evidence to be of low or very low certainty, with many differences between studies. There was also insufficient high quality evidence to determine the effects of n-3PUFAs on negative side effects or numbers not completing studies.
What should happen next?
We need more evidence, particularly to explain the differences between study findings, e.g. by looking at individuals who may or may not benefit from n-3PUFAs. Future studies should also compare n-3PUFAs with usual antidepressant treatment, and investigate the way these treatments may work.
At present, we do not have sufficient high-certainty evidence to determine the effects of n-3PUFAs as a treatment for MDD. Our primary analyses may 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 certainty of the evidence on which this result is based to be low to very low. Our data may also suggest similar rates of adverse events and trial non-completion in n-3PUFA and placebo groups, but again our estimates are very imprecise. Effects of n-3PUFAs compared to antidepressants are very imprecise and uncertain. More complete evidence is required for both the potential positive and negative effects of n-3PUFAs for MDD.
Major 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 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 different effects of n-3PUFAs, depending on the 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. Hence it is important to establish their effectiveness in treating MDD. This review updates and incorporates an earlier review with the same research objective (Appleton 2015).
To assess the effects of n-3 polyunsaturated fatty acids (also known as omega-3 fatty acids) versus a comparator (e.g. placebo, antidepressant treatment, standard care, no treatment, wait-list control) for major depressive disorder (MDD) in adults.
We searched the Cochrane Central Register of Controlled trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO together with trial registries and grey literature sources (to 9 January 2021). We checked reference lists and contacted authors of included studies for additional information when necessary.
We included studies in the review if they: used a randomised controlled trial design; 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 non-completion of studies.
We used standard methodological procedures as expected by Cochrane. We assessed the certainty of the evidence using GRADE criteria.
The review includes 35 relevant studies: 34 studies involving a total of 1924 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 resulted in a small to modest benefit for depressive symptomology, compared to placebo: standardised mean difference (SMD) (random-effects model) −0.40 (95% confidence interval (CI) −0.64 to −0.16; 33 studies, 1848 participants; very low-certainty evidence), but this effect is unlikely to be clinically meaningful. An SMD of 0.40 represents a difference between groups in scores on the HDRS (17-item) of approximately 2.5 points (95% CI 1.0 to 4.0), where the minimal clinically important change score on this scale is 3.0 points. The confidence intervals include both a possible clinically important effect and a possible negligible effect, and there is considerable heterogeneity between studies. Sensitivity analyses, funnel plot inspection and comparison of our results with those of large well-conducted trials also suggest that this effect estimate may be biased towards a positive finding for n-3PUFAs. Although the numbers of individuals experiencing adverse events were similar in intervention and placebo groups (odds ratio (OR) 1.27, 95% CI 0.99 to 1.64; 24 studies, 1503 participants; very low-certainty evidence), the confidence intervals include a small decrease to a modest increase in adverse events with n-3PUFAs. There was no evidence for a difference between n-3PUFA and placebo groups in remission rates (OR 1.13, 95% CI 0.74 to 1.72; 8 studies, 609 participants, low-certainty evidence), response rates (OR 1.20, 95% CI 0.80 to 1.79; 17 studies, 794 participants; low-certainty evidence), quality of life (SMD −0.38 (95% CI −0.82 to 0.06), 12 studies, 476 participants, very low-certainty evidence), or trial non-completion (OR 0.92, 95% CI 0.70 to 1.22; 29 studies, 1777 participants, very low-certainty evidence). The evidence on which these results are based was also very limited, highly heterogeneous, and potentially biased.
Only one study, involving 40 participants, was available for the antidepressant comparison. 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 1.23, 95% CI 0.35 to 4.31), or trial non-completion (OR 1.00, 95% CI 0.21 to 4.71). Confidence intervals are however very wide in all analyses, and do not rule out important beneficial or detrimental effects of n-3PUFAs compared to antidepressants. Adverse events were not reported in a manner suitable for analysis, and rates of depression remission and quality of life were not reported.