Fish-derived omega‑3 fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA exerts well-documented anti-inflammatory effects: EPA competitively inhibits the production of proinflammatory cytokines such as prostaglandin E2 (PGE2) from arachidonic acid (AA), and leads to the production of anti-inflammatory cytokines by the cyclooxygenase (COX) enzymes. EPA may also influence cell signaling and neurotransmitter production in the brain. EPA has also been shown to lower cortisol levels in patients with major depression, equally to antidepressants (fluoxetine).
An extensive body of research indicates that EPA exerts powerful antidepressant and mood-stabilizing effects. Data from many randomized trials and several meta-analyses show that EPA improves mood in patients with depression and bipolar disorder, as well as in patients with depressive symptoms but not necessarily meeting the criteria for major depression. Notably, a meta-analysis found that supplements with EPA content greater or equal to 60% showed benefit on standardized mean depression scores, with an effect size of approximately 50%, while supplements with less EPA were ineffective.
EPA has also been shown to improve the effectiveness of antidepressants. In one study, 42 subjects were randomized to receive 1,800 mg EPA and 400 mg DHA in addition to citalopram (antidepressant), compared to citalopram alone. After nine weeks, patients receiving both citalopram and EPA demonstrated significantly greater improvement in Hamilton Depression Rating scale scores over time, starting at four weeks.
Another study examined the effects of EPA alone (1000 mg), fluoxetine alone (20 mg), or both combined for eight weeks on patients with major depression. This study showed that EPA alone and fluoxetine alone were equally effective in managing the symptoms of depression; however, their combination resulted in the best improvement. The EPA-and-fluoxetine combination was significantly better than fluoxetine or EPA alone from the fourth week of treatment. Response rates, defined as a 50% or greater decrease in baseline depression score, were 50%, 56%, and 81% in the fluoxetine, EPA, and combination groups, respectively.
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