Objective: Study goals were to (1) provide a rationale for developing a composite primary outcome score that includes symptom severity for attention-deficit/hyperactivity disorder (ADHD) and emotional dysregulation, plus symptom-induced impairment; (2) demonstrate weighting methods to calculate the composite score using a sample of children diagnosed with ADHD and aggression; and (3) identify the optimal weighting method most sensitive to change, as measured by effect sizes. Methods: We conducted secondary data analyses from the previously conducted Treatment of Severe Childhood Aggression (TOSCA) study. Children aged 6-12 years were recruited through academic medical centers or community referrals. The composite primary outcome comprised the ADHD, oppositional defiant disorder, disruptive mood dysregulation disorder, and peer conflict subscales from the Child and Adolescent Symptom Inventory (CASI), a DSM (Diagnostic and Statistical Manual)-referenced rating scale of symptom severity and symptom-induced impairment. Five weighting methods were tested based on input from senior statisticians. Results: The composite score demonstrated a larger (Cohen's d) effect size than the individual CASI subscales, irrespective of the weighting method (10%-55% larger). Across all weighting methods, effect sizes were similar and substantial: approximately a two-standard deviation symptom reduction (range: -1.97 to -2.04), highest for equal item and equal subscale weighting, was demonstrated, from baseline to week 9, among all TOSCA participants. The composite score showed a medium positive correlation with the Clinical Global Impressions-Severity scores, 0.46-0.47 for all weighting methods. Conclusions: A composite score that included severity and impairment ratings of ADHD and emotional dysregulation demonstrated a more robust pre-post change than individual subscales. This composite may be a more useful indicator of clinically relevant improvement in heterogeneous samples with ADHD than single subscales, avoiding some of the statistical

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) is a chronic neurodevelopmental disorder affecting up to 9% of children and substantial numbers of adults. Existing pharmacologic treatments often improve symptoms, but concerns exist over side effects, stigma, potential long-term health effects, and residual irritability, often treated with adjunctive antipsychotics. To address public and clinician demand for non-pharmacologic evidence-based treatments, this study will examine efficacy of a 36-ingredient micronutrient (vitamin/mineral) supplement as treatment for children with ADHD and irritability.MethodsAn international team of experts in ADHD, mood dysregulation, nutrition, epidemiology, and clinical trials conferred to develop/refine a protocol powered to detect a medium effect. The study will employ a fully-blind randomized controlled trial (RCT) design, comparing the micronutrient supplement to matched placebo in 135 children aged 6–12 with ADHD symptoms and irritability, based on the parent-rated Child and Adolescent Symptom Inventory-5 (CASI-5). Irritability will be measured by at least one symptom of oppositional defiant disorder (ODD) or disruptive mood dysregulation disorder (DMDD). Based on research suggesting an irritable ADHD subtype, the primary outcome will be a composite score comprised of the CASI-5 subscales: ADHD, ODD, DMDD, and the Peer Conflict Scale, which assesses anger and aggression perpetrated towards peers. Participants will provide biological samples (blood, urine, saliva, hair and stool) to explore the micronutrients’ mechanisms of action.DiscussionThis study is the first adequately powered RCT in North America to examine both behavioral responses to, and biological mechanisms of, micronutrients for ADHD and irritability in children. If found efficacious, broad-spectrum micronutrients, given at therapeutic doses, may provide an evidence-based alternative to prescription medications for ADHD and associated irritability.Trial registrationNCT03252522. Registered 26 July 2017

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Objectives Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder commonly diagnosed in childhood. Current pharmaceutical treatment options provide a poor long-term risk: benefit ratio with little knowledge of the long-term effects. A broad-spectrum multi-nutrient formula has shown promise in children, but its effects on nutrient status and the underlying metabolome interactions have not been characterized. Methods Blood samples from medication-free children (n = 74) with ADHD enrolled in a double–blind randomized placebo-controlled multinutrient trial (RCT) were collected at baseline and 8 weeks post-intervention. Following RCT is an 8-week open label phase during which all participants took the active supplement. Symptoms were assessed using the Child and Adolescent Symptom Inventory 5. Double-blinded plasma samples will be analyzed for tyrosine, phenylalanine, tryptophan, magnesium, and zinc. Untargeted LC-MS metabolomics using HILIC chromatography and a high resolution QTof will assess very polar analytes in plasma extracts. Linear modeling will elucidate the influence of treatment, sampling time, and ADHD symptom score on plasma nutrient and plasma metabolite concentration. Results Preliminary findings of the open label phase show a significant improvement in inattention (P = 0.0435), hyperactivity (P = 0.0068), ODD (P = 0.0108) and DMDD (P = 0.0119). We hypothesize that these improvements in ADHD symptoms will be correlated with increased circulating concentrations of tyrosine, phenylalanine, tryptophan, magnesium, zinc, and metabolites involved in neurotransmitter synthesis and/or branched chain amino acid metabolism. Conclusions Preliminary findings indicate improvements of ADHD symptoms of inattention, hyperactivity, ODD and DMDD following 8 weeks of open label multi-nutrient supplementation. Results of the double-blinded phase are expected to mirror those observed in the open label phase, with increases in nutrients in those receiving the multinutrient. Funding Sources The sample analyses were supported by NIH Award Number Grant P30 CA016058, OSU, and OSUCCC. Foundation for the Center of Excellence in Mental Health, Canada; The Ohio State University Department of Human Sciences, College of Education and Human Ecology; The Ohio State University Wexner Medical Center, Clinical Research Center.

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