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

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. 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. 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. 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.