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

ω-3 fatty acid supplementation did not significantly improve CDRS-R depression scores compared to placebo in pediatric MDD.

• Adjusted mean difference in CDRS-R scores was 0.77 (95% CI, -1.39 to 2.93; P = .49) points
• Mean CDRS-R scores decreased similarly in both groups: at 12 weeks, 45.93 (11.98) in ω-3 group vs 46.08 (12.99) in placebo group
• At 36 weeks, mean CDRS-R scores were 36.50 (13.12) in ω-3 group vs 36.83 (15.46) in placebo group
• Primary outcome was analyzed using a joint mixed-effects and time-to-event model accounting for dropout or initiation of off-trial antidepressant therapy

Response rates at 12 weeks were numerically lower in the ω-3 group than in the placebo group, though the difference was not statistically significant.

• Response (≥30% reduction in CDRS-R scores) occurred in 34 of 109 (31.2%) ω-3 recipients vs 43 of 110 (39.1%) placebo recipients at 12 weeks
• Remission (CDRS-R score ≤28) at 36 weeks occurred in 30 of 94 ω-3 recipients (31.9%) vs 37 of 90 (41.1%) placebo recipients
• All differences in response and remission rates were nonsignificant

There was no significant difference between groups in time to dropout or initiation of off-trial antidepressant therapy.

• The hazard ratio for time to dropout was 1.22 (95% CI, 0.83-1.79; P = .32)
• This outcome was part of the joint primary model that combined mixed-effects trajectory with time-to-event analysis

Biochemical adherence was confirmed by significant increases in the ω-3 index in the supplement group.

• EPA plus DHA levels expressed by the ω-3 index rose by a mean (SD) of 4.33% (1.54%) at 12 weeks in the ω-3 arm
• The ω-3 index rose by a mean (SD) of 4.88% (2.38%) at 36 weeks in the ω-3 arm
• These increases confirmed participant adherence to the study supplement

Secondary outcomes including self-rated depression, quality of life, and suicidality improved over time without significant between-group differences.

• Secondary measures and suicidality improved in both groups without between-group differences
• No statistically significant differences were found on any secondary outcome measure between the ω-3 and placebo groups

Serious adverse events were more frequent in the ω-3 arm than in the placebo arm, though none were judged causally related to study medication.

• A total of 76 serious adverse events were reported in 97 participants
• 31 serious adverse events occurred in the placebo arm and 45 in the ω-3 arm
• These included 28 suicide attempts, but no deaths or permanent disabilities
• None of the serious adverse events were judged to be causally related to the study medication

The trial enrolled 257 youths with moderate-to-severe MDD across 5 Swiss child and adolescent psychiatry centers over approximately 5 years.

• Participants were randomized between April 28, 2017, and March 24, 2022, and followed up for 36 weeks
• Mean (SD) age was 15.7 (1.7) years; 188 (73.2%) were female; mean (SD) baseline CDRS-R score was 58.5 (8.8)
• 129 participants received ω-3 supplements (1 g EPA and 0.5 g DHA, 2:1 ratio, 1.5 g/d) and 128 received medium-chain triglyceride placebo
• All participants received standardized psychotherapy; antidepressant use was permitted per national guidelines
• Analysis was based on intention to treat

The authors recommend future work assessing EPA-enriched formulations and biomarker-guided approaches for pediatric depression.

• Meta-analyses of ω-3 fatty acids for depression have reported inconsistent results, and pediatric evidence is sparse
• The authors note that promotion of unproven supplements may delay evidence-based care
• Future work should assess EPA-enriched formulations and biomarker-guided approaches