Multinutrients Decrease Oxidative Stress in Children with ADHD: Mediation/Moderation Analysis of Randomized Controlled Trial Data

BACKGROUND:ADHD is associated with oxidative stress (OS), possibly stemming from deficiencies in essential nutrients. Previous randomized controlled trials (RCTs), including Micronutrients for ADHD in Youth (MADDY), demonstrated improved symptoms in response to treatment with multinutrients compared to placebo. It remains unknown whether multinutrient supplementation influences antioxidant status and OS, and if these factors contributed to improvements observed in children with ADHD in the MADDY RCT. OBJECTIVES:Utilizing samples from the MADDY RCT, (1) compare the change in antioxidant (AO) and OS biomarkers after 8 weeks of multinutrient supplementation vs placebo, and (2) evaluate these biomarkers at baseline, and their change after 8 weeks, as moderators/mediators of treatment response. METHODS:Activity of glutathione peroxidase (GPx) and glutathione reductase (GR) enzymes, plus oxidative stress index (OSI) based on ratio of reactive oxygen metabolites (ROM) to biological antioxidant potential (BAP), were measured in plasma at baseline and week 8. Differences between groups were determined using two-sample t-test or Mann-Whitney U-test. Logistic regression models assessed AO/OS biomarkers for mediation/moderation of treatment response. RESULTS:Plasma from 77 children (aged 9.9 ± 1.7 years; 71% male) treated with multinutrients (n = 45) or placebo (n = 32) was analyzed. After 8 weeks, ROM decreased with multinutrients and increased with placebo (-14.3 vs. +26.8 Carratelli units, p = .017); but no significant differences in OSI, BAP, GPx, and GR between groups. None of the baseline AO/OS biomarker levels were moderators of treatment response. Eight-week change in both OSI and ROM trended toward mediation of treatment response (OR = 0.00058, 95% CI [0.000, 2.30], p = .078 and OR = 0.985, 95% CI [0.968, 1.002], p = 0.086, respectively) but did not reach significance. CONCLUSIONS:Eight weeks of multinutrient supplementation in children with ADHD reduced ROM without significant change in antioxidant status, suggesting decrease in oxidative stress. Given the preliminary signals associating a decrease in OS with symptom improvement following multinutrient supplementation, future research is warranted to understand OS in ADHD pathogenesis. CLINICAL TRIAL REGISTRY:NCT03252522.