Omega-3 polyunsaturated fatty acids and mortality risk in depression: immune-inflammatory mediation in NHANES 1999–2018

Abstract Background Immune-inflammatory deregulation in depression may contribute to elevated risk of subsequent mortality. While dietary omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), are known to confer neuroprotective effects for their anti-inflammatory properties, population-based evidence regarding their survival benefits and underlying mechanisms in depression remain scarce. This study aimed to investigate association between dietary omega-3 PUFAs and mortality risk in depressed individuals and identify immune-inflammatory mediation underlying mortality reductions. Methods Totally, 6,782 depressed individuals aged 20 years and above in 10 cycles (1999–2018) of the National Health and Nutrition Examination Survey (NHANES) were analyzed. Omega-3 PUFAs intake (total and individual) was assessed through 24-hour dietary recalls. Cox proportional hazard models were used to calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for morality risk across omega-3 PUFA quartiles. Quantile-based g-computation model determined individual PUFA contributions, while mediation analysis evaluated the role of Geriatric Nutritional Risk Index (GNRI) and Systemic Immune-Inflammation Index (SII) in mortality reductions. Results Over the follow-up period of 679,294 person years, 1,281 deaths were documented. The HRs for the highest versus lowest quartile of omega-3 PUFAs were 0.76 (95% CI: 0.62, 0.94) for total mortality, 0.72 (95% CI: 0.50, 1.02) for CVD mortality, 0.82 (95% CI: 0.50, 1.35) for cancer mortality, and 0.77 (95% CI: 0.59, 1.00) for other-cause mortality. DPA showed the strongest association (58.40% weight for total mortality reduction, P = 0.002; 59.80% for other causes, P = 0.011), while EPA contributed most to cardiovascular mortality reductions (60.4%, P = 0.046). Mediation analysis revealed GNRI accounted for 8.1% of PUFA-mortality association (10.5% for DPA), with SII mediating 6.9% of DPA-specific benefit. Conclusion Higher intake of omega-3 PUFAs, predominantly EPA and DPA, were associated with a lower mortality risk in depressed individuals, partially mediated by immune-nutritional pathways. These findings underscore omega-3 PUFAs as potential dietary adjuncts for improving survival in depression through immunomodulation. Further long-term clinical studies are warranted to validate the survival benefits of omega-3 PUFAs in patients with depression.