Are Omega-3s Effective Against Depression? A Meta-Analysis

In Italy, 6% of adults deal with depression, a condition that affects not only their psychological well-being but also their physical health, often limiting daily activities. This is highlighted by the Istituto Superiore di Sanità (ISS) through data from the PASSI Surveillance (Progressi delle Aziende Sanitarie per la Salute in Italia) for the 2022–2023 period, specifying that depressive symptoms are especially prevalent among the elderly, women, people living alone, those in precarious economic or work situations, and individuals with chronic illnesses.

35% of these Italians face the situation without seeking any help. For others, medication and psychotherapy represent the first lines of defense, though they are not always effective. In any case, there is another aspect worth exploring: nutrition.

Indeed, there are nutrients that support the nervous system. The European Food Safety Authority (EFSA) mentions several vitamins and minerals, but specifically when it comes to the brain, it highlights two macronutrients: carbohydrates and fats. Among the latter, one in particular is mentioned: the Omega 3 DHA (docosahexaenoic acid).

Exploring the scientific literature, one finds numerous studies focusing on the potential benefits of the other biologically active Omega 3, eicosapentaenoic acid (EPA). In fact, when it comes to depression, this second Omega 3 might be an even better ally than the first.

Sometimes, the results of these studies have appeared conflicting, but the most recent analyses encourage trying dietary supplementation as a way to better manage the condition.

In particular, a meta-analysis published in 2023 in Prostaglandins, Leukotrienes and Essential Fatty Acids by a group of experts from the University of Roehampton in London (UK) found a significant reduction in the severity of depression in those who took supplements containing EPA and DHA combinations where EPA accounted for at least 60%, with dosages between 1 and 2 grams per day.

Why focus on Omega 3s?

From a theoretical perspective, the idea of using EPA and DHA to support against depression is entirely sensible. These polyunsaturated fats regulate the properties of nerve cell membranes, receptor expression, and nerve impulse transmission; they also modulate neuroplasticity, have neuroprotective, antioxidant, and anti-inflammatory activities, and promote the resolution of ongoing inflammatory processes. All these properties can modulate brain homeostasis, which in turn is associated with mood.

Additionally, both preclinical studies and epidemiological data link depression to Omega 3 deficiency. Correcting these deficiencies through proper supplementation could therefore help improve mood, with EPA and DHA each offering specific effects due to their different roles in inflammation regulation and in maintaining membrane integrity and fluidity.

Omega 3 against depression: results of the first meta-analyses

The first meta-analyses of randomized controlled trials involving Omega 3 supplementation for depression emphasized the heterogeneity of the available data, but also pointed to possible benefits of supplementation. 

In particular, a 2019 meta-analysis published in Translational Psychiatry by a group of Chinese and Canadian experts led by Yuhua Liao and Bo Xie found that supplements containing at least 60% EPA were more effective. In contrast, formulations with a higher proportion of DHA (or DHA alone) did not appear to be effective.

Liao, Xie, and colleagues focused on 25 double-blind, placebo-controlled randomized studies published before December 20, 2017. From the outset, they emphasized that the effectiveness of Omega 3 supplementation for depression depended on dosage and the EPA:DHA ratio. At the end of their analysis, they highlighted the need for more detailed studies on the effectiveness of Omega 3 based on dosage, inflammation levels, and depression severity.

The results of the new meta-analysis

In their most recent systematic review and meta-analysis published in Prostaglandins, Leukotrienes and Essential Fatty Acids, Christos F. Kelaiditis, E. Leigh Gibson, and Simon C. Dyall addressed the limitations inherent in study methodologies and design, once again emphasizing the importance of the type of Omega 3 used and noting that the choice of placebo may also influence the statistical significance of observed benefits.

By including only randomized, placebo-controlled trials that excluded bioactive lipids and individuals with conditions that could affect blood lipid levels (like type 2 diabetes, polycystic ovary syndrome, and liver diseases), Kelaiditis and colleagues aimed to clarify whether EPA and DHA supplements with at least 60% EPA truly reduce depressive symptoms, and whether minimum and maximum effective doses could be established.

The meta-analysis was conducted on three levels:

1) evaluating the overall effect of Omega 3 supplementation on depression by aggregating data from the included studies;

2) evaluating separately studies where EPA made up less than 60% of the EPA + DHA total and those where it was equal to or more than 60%;

3) evaluating separately the effect of EPA doses below 2 g/day and those equal to or greater than 2 g/day.

The first level confirmed the antidepressant efficacy of Omega 3 supplementation over an average of 11 weeks, though it again highlighted the high heterogeneity of results.

The second level revealed that only protocols involving EPA + DHA blends with EPA proportions equal to or greater than 60%, taken for about 11 weeks, were effective.

Finally, the third level — which only included high-EPA interventions — showed that taking 1.1 g of EPA per day for approximately 11 weeks was associated with a significant reduction in depression severity, whereas higher doses (2.1 g/day for over 13 weeks) did not appear effective.

According to the authors, these results “indicate that supplementation with EPA in proportions equal to or greater than 60% of total EPA + DHA, at doses equal to or greater than 1 g/day and less than 2 g/day, is associated with a statistically significant reduction in depression symptoms.”

Emphasizing alignment with previous meta-analyses, the experts added that — since 70% of the included studies involved clinically diagnosed depression — these findings demonstrate the actual clinical potential of EPA. 

“Further studies will be necessary to fully clarify EPA dosage effects, taking into account baseline diet and other confounding factors,” Kelaiditis and colleagues added, also noting that “confirmation of therapeutic effects with high EPA:DHA ratios supports observations that [different] Omega 3 polyunsaturated fatty acids have distinct and divergent properties.”

Other supporting opinions

A few months after the publication of Kelaiditis and colleagues' meta-analysis, a systematic review with meta-analysis of randomized controlled trials by an Iranian team published in the British Journal of Nutrition reached similar conclusions. According to its authors, “dose-response analysis indicates a U-shaped effect in patients with depression, with the greatest improvement at 1.5 g per day.” 

This publication also highlights another interesting point: Omega 3 supplementation may help improve depressive symptoms in individuals already affected by the condition, but it does not appear to prevent its onset. 

Why is EPA more effective?

According to Kelaiditis and colleagues, “EPA’s greater efficacy in depression may be linked to its anti-inflammatory effects.” In fact, it is EPA (not DHA) that gives rise to molecules capable of counteracting inflammatory mediators involved in depression onset. 

Additionally, only EPA has been linked to neurogenesis — a process also stimulated by antidepressants and associated with reduced depression-related behaviors — and the two Omega 3s may compete with each other for membrane incorporation, affecting membrane structure, cellular signal transmission, and bioactive compound synthesis.

However, experts also note that the form in which Omega 3s are consumed (ethyl esters, triglycerides, or phospholipids) might also make a difference.

Only further research will clarify all these aspects. Follow the Omegor Blog for updates on this topic!

References:

European Commission. Food and Feed Information Portal Database. Last viewed 06/05/25

Istituto Superiore di Sanità. PASSI Surveillance. Data for Italy: Depression. Last viewed 06/05/25

Liao Y, Xie B, Zhang H, He Q, Guo L, Subramanieapillai M, Fan B, Lu C, McIntyre RS. Efficacy of omega-3 PUFAs in depression: A meta-analysis. Transl Psychiatry. 2019 Aug 5;9(1):190. doi: 10.1038/s41398-019-0515-5. Erratum in: Transl Psychiatry. 2021 Sep 7;11(1):465. doi: 10.1038/s41398-021-01582-6

Kelaiditis CF, Gibson EL, Dyall SC. Effects of long-chain omega-3 polyunsaturated fatty acids on reducing anxiety and/or depression in adults; A systematic review and meta-analysis of randomised controlled trials. Prostaglandins Leukot Essent Fatty Acids. 2023 May;192:102572. doi: 10.1016/j.plefa.2023.102572

Norouziasl R, Zeraattalab-Motlagh S, Jayedi A, Shab-Bidar S. Efficacy and safety of n-3 fatty acids supplementation on depression: a systematic review and dose-response meta-analysis of randomised controlled trials. Br J Nutr. 2024 Feb 28;131(4):658-671. doi: 10.1017/S0007114523002052

Serefko A, Jach ME, Pietraszuk M, Świąder M, Świąder K, Szopa A. Omega-3 Polyunsaturated Fatty Acids in Depression. Int J Mol Sci. 2024 Aug 8;25(16):8675. doi: 10.3390/ijms25168675