Scientists have widely studied omega-3 fatty acids for their vital role in human health. The volume of research supports the popularity of omega-3 supplements for improving the unbalanced omega-6 to omega-3 ratio that can result from the consumption of the Standard American Diet (SAD). Ongoing research continues to reveal the differing and individual activities of the three major long-chain omega-3 fatty acids (EPA, DHA and DPA), but in almost all cases, omega-3 supplements are a combination of two or more of the three major types. A balance of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is important for maintaining health, but for short periods of time, EPA alone can be beneficial for addressing specific issues and restoring balance.

What is Omega-3 EPA?

EPA is a 20-carbon omega-3 polyunsaturated fatty acid (PUFA) found in cold water fish and some edible algae, and it is also available in concentrated amounts as a dietary supplement. It can also be synthesized from dietary alpha-linolenic acid (ALA), though the conversion rate is inefficient, with less than 15 percent being converted to EPA.₁ It is most widely known, along with DHA, for its role in cardiovascular health, but its effect on mood disorders is equally as impressive.

It is important to note that there have been mixed results from studies that look for a therapeutic effect of supplementing with a combination of long-chain omega-3 PUFA. Different study designs and dosages and ratios of EPA to DHA have made definitive conclusions difficult. However, in studies of the individual roles of EPA and DHA that control for the inclusion of other PUFAs, the therapeutic application of EPA is becoming clearer.₂

One group of researchers looked at 15 double-blind, placebo-controlled trials that administered omega-3 PUFAs to individuals who had depressive episodes as their primary complaint. The analysis uncovered the beneficial effects of EPA alone and noted that DHA may actually block the effects of EPA when supplemented in a 1:1 ratio. Only omega-3 supplements containing at least 60 percent EPA were supported for effectiveness in acute depression.₃

EPA is a precursor of the anti-inflammatory eicosanoids and E-series resolvins, which may account for at least some of its action against depressive symptoms. A randomized, double-blind placebo-controlled study looking at inflammatory biomarkers as its point of reference in subjects with major depressive disorder (MDD) found that those with at least one high biomarker of inflammation showed improved symptoms with high EPA supplementation, but not with high DHA supplementation. Those without high biomarkers of inflammation did not show improvement.₄ It was a small proof-of-concept study, but did offer insights into different depressed populations who respond to EPA as a monotherapy, and provided a foundation for further research into individualizing treatments for depression.

Many theories of omega-3 PUFA action in ameliorating depressive symptoms have revolved around the knowledge that DHA accumulates in brain tissue. However, this cannot account for the evidence that EPA is more effective than DHA in treating depressed patients. EPA does not accumulate in brain tissue, but it is the precursor for DHA and does accumulate in microglial cells, which are front-line defender macrophages of the central nervous system.

Microglial cells are involved in both the promotion and the resolution of neuroinflammation. In response to stress or immune attack the microglia increase levels of proinflammatory cytokines (such as IL1-β, IL-6 and TNF-α).  A study published in January 2020 described EPA’s role in relieving depressive symptoms while also being the first study to describe a proposed mechanism for EPA’s function in relieving microglia-induced neuroinflammation.₅

Using a research-supported model to study depressive symptoms in rats, the authors found four mechanisms of depression that were attenuated more by EPA than DHA.

1. EPA reduced stress-induced cholesterol levels while DHA did not. Increased cell membrane cholesterol levels can reduce membrane fluidity, affecting membrane-bound protein activity.
2. EPA was able to increase stress-reduced noradrenaline in the hippocampus while DHA was not. Noradrenaline is associated with reward behavior and positive emotion in depression.
3. EPA – and not DHA – decreased microglial-induced markers of inflammation (e.g. IL1-β, IL-6 and TNF-α).
4. EPA exerted better neuroprotective properties than DHA by helping to modulate functions involved in neurogenesis, neuronal differentiation, and survival.₅

Many factors can lead to mood disorders including family history, trauma, stress, nutritional status, and medications. A good stress life balance and a nutrient dense diet that contains a balance of fatty acids can provide protective benefits and can help improve symptoms.  Unfortunately, many of those who consume the Standard American Diet suffer from an unbalanced ratio of fatty acids and need a more targeted approach for effective treatment. Maintaining a balance of EPA and DHA along with other fatty acids is important for total health, but assessing patients for their need for EPA, either as monotherapy or alongside medication, may lead to better outcomes.