ω-3 Fatty Acids in Pediatric Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Meta-analyses of ω-3 fatty acids for depression have reported inconsistent results, and pediatric evidence is sparse. Promotion of unproven supplements may delay evidence-based care. Objective: To evaluate whether adjunctive ω-3 fatty acid supplementation improves outcomes in moderate-to-severe pediatric major depressive disorder (MDD). Design, Setting, and Participants: In a multicenter, double-blind, placebo-controlled randomized clinical trial at 5 Swiss child and adolescent psychiatry centers, 257 youths with MDD were enrolled and randomized between April 28, 2017, and March 24, 2022, and followed up for 36 weeks, with final analysis from July 1, 2022, to January 26, 2023. Analysis was based on intention to treat. Interventions: Participants received ω-3 fatty acids, 1.5 g/d (1 g of eicosapentaenoic acid [EPA] and 0.5 g of docosahexaenoic acid [DHA], 2:1 ratio), or medium-chain triglyceride placebo in combination with standardized psychotherapy. Antidepressant use was permitted per national guidelines. Main Outcomes and Measures: The primary outcome was the trajectory of Children's Depression Rating Scale-Revised (CDRS-R) scores analyzed with a joint mixed-effects and time-to-event model accounting for dropout or initiation of off-trial antidepressant therapy. Secondary outcomes included response (≥30% reduction in CDRS-R scores), remission (CDRS-R score ≤28), self-rated depression, quality of life, suicidality, and safety. Results: Of 257 randomized participants (mean [SD] age, 15.7 [1.7] years; 188 [73.2%] female; mean [SD] CDRS-R score, 58.5 [8.8]), 129 received ω-3 supplements and 128 received placebo. The mean (SD) CDRS-R scores decreased similarly in both groups: at 12 weeks, 45.93 (11.98) vs 46.08 (12.99); at 36 weeks, 36.50 (13.12) vs 36.83 (15.46). The adjusted mean difference in CDRS-R scores was 0.77 (95% CI, -1.39 to 2.93; P = .49) points. The hazard ratio for time to dropout was 1.22 (95% CI, 0.83-1.79; P = .32). Response occurred in 34 of 109 (31.2%) ω-3 recipients vs 43 of 110 (39.1%) placebo recipients at 12 weeks; remission occurred at 36 weeks in 30 of 94 ω-3 recipients (31.9%) vs 37 of 90 (41.1%) placebo recipients (all differences were nonsignificant). Secondary measures and suicidality improved without between-group differences. EPA plus DHA levels expressed by the ω-3 index rose by a mean (SD) of 4.33% (1.54%) and 4.88% (2.38%) at 12 and 36 weeks, respectively, in the ω-3 arm, confirming adherence. A total of 76 serious adverse events were reported in 97 participants, with 31 occurring in the placebo arm and 45 in the ω-3 arm. These included 28 suicide attempts, but no deaths or permanent disabilities. None of these were judged to be causally related to the study medication. Conclusions and Relevance: In this randomized clinical trial, adjunctive ω-3 administration, 1.5 g/d (EPA:DHA, 2:1), did not outperform placebo in youths with MDD. Future work should assess EPA-enriched formulations and biomarker-guided approaches. Trial Registration: ClinicalTrials.gov Identifier: NCT03167307.