Omega-3 fatty acid supplementation for depression in children and adolescents

Mental health disorders including major depressive disorder (MDD) are well recognized as major contributors to the global burden of disease among adolescents. The prevalence of adolescent depression is estimated to have increased by at least 25% during the COVID-19 pandemic, compounding the already challenging problem of insufficient mental health service and service accessibility that existed prepandemic. Omega-3 polyunsaturated fatty acid (PUFA) supplementation is currently recommended as a preventive treatment for depression in high-risk adults as well as a second-line monotherapy for adults with mild to moderate MDD, and adjunctive to antidepressants for adults with moderate to severe MDD. The benefits of omega-3 PUFA intake on depressive illness have been hypothesized to occur as a result of their effect on neurotransmission, maintenance of membrane fluidity, and anti-inflammatory action. A comprehensive synthesis and quantification of the existing evidence on omega-3 PUFA's efficacy in treating depression among children and adolescents is essential for clinicians to provide informed guidance to young people and their families, especially considering the absence of current guidelines for this age group.

Primary objective To determine the impact of omega-3 PUFA supplementation versus a comparator (e.g. placebo, wait list controls, no treatment/supplementation, or standard care) on clinician-diagnosed depression or self-reported depression symptoms in children and adolescents. Secondary objectives To estimate the size of the effect of omega-3 PUFAs on depression symptoms. To estimate the effect of each type of omega-3 PUFA (EPA or DHA), compared with placebo, on depression. To determine if the effect is modified by dosage, format (capsule or liquid), sex, or age. To determine compliance and attrition for omega-3 PUFAs as an intervention for depression in children and adolescents. To determine the safety of omega-3 PUFAs as an intervention for depression in children and adolescents.

We searched CENTRAL, MEDLINE, Embase, three other databases, reference lists of included studies, grey literature, and relevant reviews. The latest search date was 18 May 2023.

We included randomized controlled trials (RCTs) involving males and females aged 19 years or younger with diagnosed depression comparing omega-3 PUFA supplementation to placebo, wait list control, no treatment/supplementation, or standard care.

We used standard Cochrane methods. Our primary outcomes were self-reported depression symptoms and clinically diagnosed resolution of depression. Our secondary outcomes were attrition, adverse effects, and compliance with the intervention. We used GRADE to assess the certainty of evidence for key outcomes.

We included five trials with 228 participants in our meta-analysis. All trials used a placebo comparator; intervention duration ranged from 10 to 16 weeks (median: 12 weeks). Omega-3 PUFA supplementation compared to placebo may reduce self-reported depression symptoms, but the evidence is very uncertain (standardized mean difference [SMD] -0.34, 95% confidence interval [CI] -0.85 to 0.17; lower SMD means greater improvement in depression due to omega-3 PUFA; 5 trials, 185 participants; very low-certainty evidence). Omega-3 PUFA supplementation may have little to no effect on remission of depression symptoms compared to placebo, but the evidence is very uncertain (omega-3 PUFA versus placebo: 50% versus 48%; odds ratio [OR] 1.11, 95% CI 0.45 to 2.75; 4 trials, 127 participants; very low-certainty evidence). Omega-3 PUFA supplementation may result in little to no difference in attrition (dropouts) compared to placebo (omega-3 PUFA versus placebo: 18% versus 19%; OR 0.94, 95% CI 0.46 to 1.90; 5 trials, 228 participants; low-certainty evidence). Omega-3 PUFA supplementation may result in little to no difference in adverse effects, with one study reporting more muscle cramps in the fish oil group (13/27 participants) compared to the placebo group (6/29 participants); one study reported more frequent defecation in the omega-3 group (1/29 participants) and one study identified mild skin rash and unusual/manic behavior in the placebo group (2/27 participants). None of the included studies reported serious adverse effects.

Based on five small studies, omega-3 PUFA supplementation may reduce self-reported depression symptoms, but the evidence is very uncertain. Omega-3 PUFA supplementation may have little to no effect on depression remission compared to placebo, but the evidence is very uncertain. Omega-3 PUFA supplementation may result in little to no difference in attrition or adverse effects. The studies observed no serious adverse effects. This review highlights early-stage research on omega-3 PUFA and depression in young people. The evidence on the effects of omega-3 PUFA supplementation in improving self-reported depression symptoms or achieving depression remission in children and adolescents is very uncertain. While no harms are evident, more data are needed to confirm potential risks. Addressing current limitations in the evidence base through the design and conduct of methodologically rigorous studies - larger sample sizes, varied dosages, eicosapentaenoic acid/docosahexaenoic acid ratios, treatment durations, and safety profiles - is crucial to advance our understanding of the role of omega-3 PUFA supplementation for depression in children and adolescents.