Are omega-3s effective against depression? A meta-analysis

In Italy, 6 percent of adults are dealing with depression, a condition that compromises not only their psychological well-being but also their physical well-being, with consequences that, all too often, limit daily activities. This is underlined by the Istituto Superiore di Sanità (Iss) through the data of the PASSI (Progress of Health Authorities for Health in Italy) Surveillance for the two-year period 2022-2023, pointing out that those who have to deal with depressive symptoms are mainly the elderly, women, those who live alone, in precarious economic or work situations, and those who live with a chronic disease.

Thirty-five percent of these Italians cope without seeking any help. For the others, medication and psychotherapy are the first lines of defense, which, however, do not always prove effective. And, in any case, there is also another aspect on which it may be worth trying to act: nutrition.

In fact, there is no shortage of nutrients allied to the nervous system. The European Food Safety Authority (Efsa) cites several vitamins and minerals, but when speaking specifically about the brain it shines a spotlight on two macronutrients: carbohydrates and fats. Among the latter it mentions one in particular: omega 3 DHA (docosahexaenoic acid).

Browsing, then, through the scientific literature, it is possible to stumble upon numerous research studies that shine a spotlight on the possible benefits of the other biologically active Omega 3, eicosapentaenoic acid (EPA). Indeed, when it comes to depression, this second Omega 3 may be an even better ally than the first.

Sometimes the results of these studies have seemed conflicting, but the most recent analyses encourage trying the route of dietary supplementation for better management of the condition.

Specifically, a meta-analysis published in 2023 in Prostaglandins, Leukotrienes and Essential Fatty Acids by a group of experts at the University of Roehampton in London, UK, found a significant reduction in the severity of depression in those taking supplements containing combinations of EPA and DHA in which EPA is present in a proportion of at least 60 percent and at dosages between 1 and 2 grams per day.

Why focus on Omega 3?

From a theoretical point of view, the idea of using EPA and DHA as support against depression makes complete sense. In fact, these polyunsaturated fats regulate the properties of nerve cell membranes, receptor expression, and nerve impulse transmission; they also regulate neuroplasticity, exert neuroprotective, antioxidant, and anti-inflammatory activities, and promote the resolution of inflammatory processes that are already in place. All these properties can modulate brain homeostasis, thus its balance, which is in turn associated with mood.

Added to this is the fact that both preclinical studies and epidemiological data associate depression with Omega 3 deficiencies. Correcting these with adequate supplementation could therefore help improve mood, with specific effects for EPA and DHA, which are differentially involved in the regulation of inflammation and membrane integrity and fluidity.

Omega 3 against depression: results of first meta-analysis

Early meta-analyses of randomized controlled trials involving Omega 3 administration in the management of depression have highlighted the heterogeneity of the available data, while at the same time highlighting the possible benefits of supplementation. 

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

Liao, Xie and colleagues focused on 25 randomized double-blind, placebo-controlled trials published in the scientific literature before December 20, 2017. Already in their introduction, they emphasized how the efficacy of Omega 3 supplementation against depression was influenced by dosage and the ratio of EPA to DHA. At the end of their analysis, they highlighted the need for more in-depth study of the effectiveness of Omega 3s as a function of their dosage, levels of inflammation, and severity of depression.

The results of the new meta-analysis

In their most recent systematic review with meta-analysis published in Prostaglandins, Leukotrienes and Essential Fatty Acids, Christos F. Kelaiditis, E. Leigh Gibson and Simon C. Dyall considered the limitations inherent in the methodology used and the design of the studies on the topic, again emphasizing the importance of the type of Omega 3 used and adding that the choice of placebo could also influence the significance of the benefits that emerged.

By including in their analysis only randomized controlled trials against placebo that did not contain bioactive lipids and did not involve individuals with conditions that could alter blood lipid levels (such as type 2 diabetes, polycystic ovary, and liver disease), Kelaiditis and colleagues sought to clarify whether EPA and DHA supplements containing at least 60 percent EPA really succeed in reducing symptoms of depression and whether minimum and maximum effective doses can be established.

The meta-analysis was conducted at three levels:

1) Assessing the effect of Omega 3 intake on depression by pooling, where possible, all data collected in the studies included in the meta-analysis;

2) separately evaluating studies in which the percentage of EPA was less than 60 percent of total EPA + DHA and those in which it was greater than or equal to 60 percent of total EPA + DHA;

3) separately evaluating the effect of EPA doses less than 2 g per day or greater than or equal to 2 g per day.

The first level of analysis confirmed the antidepressant efficacy of taking Omega 3 for an average of 11 weeks, but again highlighted the high heterogeneity of the results.

In contrast, the second level of analysis showed that only protocols involving the intake, for about 11 weeks, of mixtures of EPA + DHA with a percentage of EPA greater than or equal to 60 percent were effective.

Finally, the third level of analysis, in which only interventions with supplements high in EPA (greater than or equal to 60 percent of total EPA + DHA) were included, found that taking 1.1 g of EPA per day for about 11 weeks was associated with a significant reduction in depression severity, while higher dosages (2.1 g per day for more than 13 weeks) did not appear to be effective.

According to the authors, these results "indicate that supplementation with EPA in percentages greater than or equal to 60 percent of total EPA+DHA, at dosages greater than or equal to 1 g per day and less than 2 grams per day, is associated with a statistically significant reduction in depression symptom severity."

Emphasizing the concordance between their findings and those of previous meta-analyses, the experts add that given the type of studies included (which in 70 percent of cases had involved patients with a clinical diagnosis of depression), what emerges is actual clinical potential for EPA. 

"Further studies will be needed to fully elucidate the effects of EPA dosing, taking into account baseline diet and other confounding factors," Kelaiditis and colleagues continue, also adding that "confirmation of therapeutic effects with high EPA:DHA ratios supports the observations that [different] Omega 3 polyunsaturated fatty acids have a distinct and divergent nature."

Other supporting opinions

A few months after the publication of the meta-analysis by Kelaiditis and colleagues, a systematic review with meta-analysis of randomized controlled trials published by an Iranian group of experts in the British Journal of Nutrition came to 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 reveals another interesting aspect: supplementation with Omega 3 could help improve the symptoms of depression in people who have already developed the condition, while it would not be able to prevent its onset. 

Why is EPA more effective?

According to Kelaiditis and colleagues, "the greater efficacy of EPA in depression could be associated with its anti-inflammatory effects." In fact, it is EPA (and not DHA) that is the Omega 3 from which molecules that can counteract the inflammatory mediators involved in the onset of depression are obtained.

In addition, only EPA has been associated with neurogenesis-a process also stimulated by antidepressants and associated with the reduction of depression-related behaviors-and the two Omega 3s could counteract each other and compete for incorporation within membranes-with consequences for their structure, signal transmission in cells, and synthesis of bioactive compounds.

However, experts also do not rule out that it may be the form in which Omega 3 is taken (ethyl esters, triglycerides or phospholipids) that makes the difference.

Only new research will clarify all these issues. Follow the Omegor Blog for new updates on the topic!

Bibliographic references:

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

National Institute of Health. 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 randomized 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 randomized 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.