Omega-3 fatty acids, specialized pro-resolving mediators, and depression: A mechanistic meta-analysis of precursors...

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), especially eicosapentaenoic acid (EPA), exhibit adjunctive antidepressant efficacy despite negligible detectable levels in the brain. Emerging evidence implicates specialized pro‑resolving mediators (SPMs); bioactive n-3 PUFA metabolites offer a coherent pathway by actively resolving inflammation, enhancing tissue repair, and supporting neuronal function. To test whether n‑3 PUFA supplementation activates pro‑resolving biology in humans, this meta‑analysis quantified effects on circulating SPM precursors.

We systematically searched PubMed, EMBASE, Web of Science, GOED, and the Cochrane Library (up to May 18, 2026) to identify RCTs examining the impact of n-3 PUFAs supplementation on circulating SPM precursors 18-hydroxyeicosapentaenoic acid (18-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHA). Meta-analysis was performed using Review Manager 5.4.1 with random-effects models.

Eleven RCTs, comprising 810 participants, were included. N-3 PUFAs supplementation significantly and robustly increased the concentrations of both circulating SPM precursors: 18-HEPE (SMD = 1.05, 95% CI 0.54-1.55, Z = 4.08, P = 0.0001) and 17-HDHA (SMD = 0.69, 95% CI 0.19-1.18, Z = 2.72, P = 0.006). Importantly, subgroup analyses revealed that this increase was selectively amplified in patient populations characterized by a significant inflammatory, metabolic, and oxidative burden, including peripheral artery disease (PAD), chronic kidney disease (CKD), MDD with comorbid obesity, and pregnancy, but was negligible in healthy infants.

N-3 PUFA supplementation significantly increased circulating 18-HEPE and 17-HDHA, indicating greater availability of upstream EPA- and DHA-derived SPM precursors across mixed human populations. However, whether these precursor changes translate into increased downstream SPM production or clinical antidepressant effects remains uncertain and requires dedicated trials in MDD populations. PROSPERO registration number: CRD420251138493.