Evaluating Mineral Biomarkers as Mediators and Moderators of Behavioural Improvements in a Randomized Controlled Trial of Multinutrients for Children with ADHD.

Essential minerals are cofactors for synthesis of neurotransmitters supporting cognition and mood. An 8-week fully-blind RCT of multinutrients for ADHD demonstrated three times as many children (age 6-12) had significantly improved behavior ("treatment responders") on multinutrients (54%) compared to placebo (18%). The aim of this secondary study was to evaluate changes in fasted plasma and urinary mineral concentrations following the intervention, and their role as mediators and moderators of treatment response. Fourteen essential or trace minerals were measured in plasma and/or urine at baseline and week 8 from 86 participants (49 multinutrient, 37 placebo). Two-sample t-tests/Mann-Whitney U-tests compared 8-week change between treatment and placebo groups, which were also evaluated as potential mediators. Baseline levels were evaluated as potential moderators, using logistic regression models with clinical treatment response as the outcome. After 8 weeks, plasma boron, chromium (in females only), lithium, molybdenum, selenium, and vanadium, and urinary iodine, lithium, and selenium increased more with multinutrients than placebo, while plasma phosphorus decreased. These changes did not mediate treatment response. However, baseline urinary lithium trended toward moderation: participants with lower baseline urinary lithium were more likely to respond to multinutrients (p=0.058). Additionally, participants with higher baseline iron were more likely to be treatment responders regardless of treatment group (p=0.036.) These results show that multinutrient treatment response among children with ADHD is independent of their baseline plasma mineral levels, while baseline urinary lithium levels show potential as a non-invasive biomarker of treatment response requiring further study.

Problems most concerning to parents of children with ADHD and emotional dysregulation in a randomized controlled trial of multinutrients: MADDY secondary analysis.

OBJECTIVE: With dual focus on structured, objective quantification of parent observations of child's behavior and identifying behaviors most amenable to change, this report examines Parent Target Problems (PTP) as a secondary outcome in a randomized clinical trial (RCT) of children with attention-deficit/ hyperactivity disorder (ADHD) in which one primary outcome, Clinical Global Impression-Improvement, showed a significant advantage of multinutrients over placebo and the other, Likert-type parent ratings, showed significant improvement in both groups, without significant difference between them. METHOD: In a multisite 8-week RCT of broad-spectrum micronutrients ("multinutrients"), parents of children ages 6-12 (N = 126, 73% male, 88% white) with ADHD and emotional dysregulation nominated their child's most concerning problem(s) at baseline and quantified them by frequency, duration, impairment, and consequences. At subsequent visits, parents re-quantified the problem(s). Blinded child psychiatrists independently reviewed the PTPs and rated change at two timepoints compared to baseline. PTPs were grouped into 9 categories. Mean ratings were compared between active and placebo groups and explored by category. RESULTS: By week 8, a significant separation favored multinutrients: 38% of the multinutrient group were "definitely improved" or better, compared to 25% of the placebo group, and ratings of "no change" or "worse" occurred in 35% with placebo versus 23% with multinutrients (p = 0.04). Inattention (72.2%) and emotional dysregulation (69.1%) were the most frequently reported PTP categories. Inattention and internalizing symptoms improved more with multinutrients than placebo (p = 0.01, d = 0.55; p = 0.03, d = 0.80, respectively). The multinutrient advantage was not significant for 7 other symptoms, including hyperactivity/impulsivity, aggression, autistic symptoms, or emotional dysregulation/irritable oppositionality. CONCLUSIONS: This secondary analysis found that the multinutrients, compared to placebo, were associated with improvements in parental concerns overall, and in two domains specifically: inattention and internalizing symptoms (anxiety/depression), but not in seven domains: hyperactivity/impulsivity, aggression, autistic symptoms or physiological symptoms, peer relationships or emotional dysregulation/irritable oppositionality.

Food Related Challenges and Mental Health Among U.S. African Migrants: A Narrative Review.

The United States' (US) African immigrant (AI) population is growing, yet they are underrepresented in health and nutrition research. This population experiences difficulties finding culturally appropriate foods and navigating the US food environment (FE), is highly food insecure (FI), and vulnerable to mental disorders. This review examined the current evidence for AIs' food and mental health outcomes and connections; and identified gaps in the literature and future research opportunities. A literature search was conducted using Google Scholar, PubMed, CINAHL, MEDLINE, and SCOPUS. Twenty-one studies were identified, reporting high (37-85%) FI rates, poor diet quality, and increased risk of mental disorders among participants. Challenges in the FE, lack of transportation, limited access to ethnic foods, low SES, and language barriers were associated with FI and poor diet quality. Similarly, discrimination, substance use, and immigration status were associated with depression and anxiety. However, studies examining the connection between AI's food experience and mental health are lacking. AIs are at a higher risk for FI, poor diet quality, and mental disorders. Ethnic-specific research to understand the connection between their food and mental health is needed to reduce nutrition and mental health disparities.

Treatment response to supplemental nutrients for ADHD is independent of diet quality: the MADDY Study RCT.

OBJECTIVES: The 8-week Micronutrients for ADHD in Youth (MADDY) randomized controlled trial (N = 126, age 6-12) of broad-spectrum multinutrients for ADHD with emotional dysregulation found 3 times as many responders with multinutrients (54%) compared to placebo (18%) by Clinical Global Impression-Improvement (CGI-I). Our primary aim for this analysis tests the hypothesis that those with poor overall diet quality at baseline benefit more. The second aim is to explore whether specific components of diet quality moderate treatment response. METHODS: 124 children (69 multinutrients, 55 placebo) had diet quality assessed using the Healthy Eating Index-2015 (HEI-2015). For each potential moderator, the outcome CGI-I at week 8 (RCT-end), was modeled two ways: (1) as a dichotomous variable: responder/non-responder, with responders defined by a rating of 1 or 2 'very much' or 'much improved,' all else equals non-responder using logistic regression, and (2) as a dimensional improvement outcome from 1 = very much improved to 7 = very much worse, using linear regression. RESULTS: HEI-2015 total score did not moderate treatment response [odds ratio = 1.00 (95% CI: 0.90,1.10), p = 0.984] or improvement [ß = -0.01 (95% CI: -0.06,0.04), p = 0.648]. However, total vegetable intake moderated level of improvement in exploratory analysis [ß = -0.48 (95% CI: -0.82, -0.13), p = 0.007]: those with higher baseline vegetable intake showed greater benefit from multinutrients compared to placebo. CONCLUSIONS: Multinutrients may benefit children with ADHD and irritability regardless of overall diet quality. The finding that higher baseline vegetable intake may improve response to multinutrients deserves further exploration, including dietary effect on gut microbiota and absorption of multinutrients and parental factors.

Dr. Johnstone et al. Reply to Dr. Elmrayed.

We thank Dr. Elmrayed and colleagues1 for highlighting clinical cautions in using broad-spectrum micronutrients to treat attention-deficit/hyperactivity disorder (ADHD) in children, in particular manganese (Mn) levels. We appreciate the opportunity to provide additional information and rationale for the vitamin and mineral doses contained in the studied formula.

Dr. Johnstone et al. Reply to Dr. Hamilton.

We thank Dr. Hamilton1 for his interest in our research and for provoking a more nuanced and detailed approach to analyzing the relationship among treatment assignment, treatment response, and correct treatment guessing in randomized controlled trials; in this case, the Micronutrients for ADHD in Youth (MADDY) study.2.

Micronutrients for ADHD in youth (MADDY) study: comparison of results from RCT and open label extension.

BACKGROUND: The Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth (MADDY) study evaluated the efficacy and safety of a multinutrient formula for children with ADHD and emotional dysregulation. The post-RCT open-label extension (OLE) compared the effect of treatment duration (8 weeks vs 16 weeks) on ADHD symptoms, height velocity, and adverse events (AEs). METHODS: Children aged 6-12 years randomized to multinutrients vs. placebo for 8 weeks (RCT), received an 8-week OLE for a total of 16 weeks. Assessments included the Clinical Global Impression-Improvement (CGI-I), Child and Adolescent Symptom Inventory-5 (CASI-5), Pediatric Adverse Events Rating Scale (PAERS), and anthropometric measures (height and weight). RESULTS: Of the 126 in the RCT, 103 (81%) continued in the OLE. For those initially assigned to placebo, CGI-I responders increased from 23% in the RCT to 64% in the OLE; those who took multinutrients for 16 weeks increased from 53% (RCT) to 66% responders (OLE). Both groups improved on the CASI-5 composite score and subscales from week 8 to week 16 (all p-values < 0.01). The group taking 16 weeks of multinutrients had marginally greater height growth (2.3 cm) than those with 8 weeks (1.8 cm) (p = 0.07). No difference in AEs between groups was found. CONCLUSION: The response rate to multinutrients by blinded clinician ratings at 8 weeks was maintained to 16 weeks; the response rate in the group initially assigned to placebo improved significantly with 8 weeks of multinutrients and almost caught up with 16 weeks. Longer time on multinutrients did not result in greater AEs, confirming an acceptable safety profile.

Fruit and vegetable intake is inversely associated with severity of inattention in a pediatric population with ADHD symptoms: the MADDY Study.

OBJECTIVES: Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder with a U.S. pediatric prevalence of 8-10%. It presents with inattention and hyperactivity/impulsivity; frequently associated with emotional dysregulation (ED) symptoms common in Oppositional Defiant Disorder and Disruptive Mood Dysregulation Disorder. The etiology of ADHD is multi-factorial; symptom severity is associated with diet. This study examines the association of diet quality with ADHD and ED symptoms within a pediatric research cohort. METHODS: Baseline data were analyzed for 134 children aged 6-12 years with symptoms of ADHD and ED enrolled in an RCT of multinutrient supplementation. Diet quality was based on Healthy Eating Index-2015 (HEI-2015). ADHD and ED symptoms were assessed using Child and Adolescent Symptom Inventory-5 and Strengths and Difficulties Questionnaire. Linear regression models, adjusting for covariates when necessary, determined association. RESULTS: The mean HEI Total Score of 63.4 (SD = 8.8) was not significantly associated with any outcome symptoms. However, after adjusting for covariates, HEI component scores for total fruit intake (ß = -0.158, p = .037) and total vegetable intake (ß = -0.118, p = .004) were negatively associated with inattention. CONCLUSIONS: The lack of association with total diet quality could be explained by the relatively good baseline diet quality and mild symptom severity in this sample, along with measurement error from dietary intake estimates and relatively small sample size. These findings suggest that dietary intake may impact inattention in children with ADHD and ED: those eating less fruits and vegetables were likely to have more severe symptoms of inattention. Causality is not established by this cross-sectional analysis.

Pain sensitivity and perceptual sensitivity are associated with severity of emotional dysregulation in children with ADHD: a cross-sectional analysis using the Temperament in Middle Childhood Questionnaire.

PURPOSE: Nearly 50% of children with attention-deficit/hyperactivity disorder (ADHD) experience emotional dysregulation or sensory over-responsiveness; this study examines their association. METHODS: This cross-sectional analysis (n = 124) used data from the Micronutrients for ADHD in Youth (MADDY) Study, which enrolled children aged 6-12 with ADHD and emotional dysregulation. Sensory responsiveness was assessed using two subscales from the factor-analyzed Temperament in Middle Childhood Questionnaire: Pain Sensitivity and Perceptual Sensitivity. Emotional dysregulation was assessed using the Emotional-Problems and Conduct-Problems subscales from the Strengths and Difficulties Questionnaire and a composite score from the Child & Adolescent Symptom Inventory-5. Multivariable linear regression measured the association of pain and perceptual sensitivity with the severity of emotional dysregulation. RESULTS: In adjusted models, pain sensitivity was positively associated with Emotional Problems (ß = 0.97; 95% CI: 0.52, 1.41; p < 0.0001), Conduct Problems (ß = 0.83; 95% CI: 0.44, 1.21; p = 0.0001), and CASI-5 composite (ß = 0.25; 95% CI: 0.16, 0.34; p < 0.0001). Perceptual sensitivity was positively associated with Emotional Problems (ß = 0.75; 95% CI: 0.15, 1.35; p = 0.01) but not Conduct Problems (ß = 0.27; 95% CI: -0.24, 0.77; p = 0.30) or CASI-5 composite (ß = 0.12; 95% CI: -0.01, 0.24; p = 0.07). CONCLUSION: Pain sensitivity was associated with the severity of emotional dysregulation in this ADHD sample. To better understand possible causal links, longitudinal studies are warranted.Implications for rehabilitationEmotional dysregulation and sensory over-responsiveness are both common in children with ADHD and contribute to added challenges in school and family life.Two types of sensory over-responsiveness, pain sensitivity and perceptual sensitivity, were associated with emotional dysregulation in children with ADHD in our study.Sensory over-responsiveness may be a modifiable treatment target.

Household Food Insecurity Is Associated with Symptoms of Emotional Dysregulation in Children with Attention Deficit Hyperactivity Disorder: The MADDY Study.

The association of household food insecurity with symptoms of attention deficit hyperactivity disorder (ADHD) and emotional dysregulation in children was examined in this study. We utilized baseline data from 134 children aged 6-12 years who were enrolled in a clinical trial investigating multinutrient supplementation as a treatment for ADHD and emotional dysregulation. Household food security status was assessed using the 18-item US Household Food Security Survey Module. The symptoms of ADHD and emotional dysregulation disorders (oppositional defiant disorder (ODD) and disruptive mood dysregulation disorder (DMDD)) were assessed using the Child and Adolescent Symptom Inventory-5 and other comorbid emotional dysregulation symptoms were assessed using the Strengths and Difficulties Questionnaire (SDQ). Multiple linear regression determined associations between household food security status and symptoms of ADHD, ODD and DMDD, emotional symptoms and conduct problems. Household food insecurity was associated with more severe emotional symptoms (ß = 2.30; 95% CI = 0.87-3.73; p = 0.002), conduct problems (ß = 1.15; 95% CI = 0.01-2.30; p = 0.049) and total difficulties scores (ß = 4.59; 95% CI = 1.82-7.37; p = 0.001) after adjusting for covariates (child's sex, parent marital status, household income, parental anxiety and other parental psychopathology). In unadjusted analyses, household food insecurity was also associated with increased ODD (ß = 0.58; 95% CI = 0.21-0.95; p = 0.003) and DMDD symptoms (ß = 0.69; 95% CI = 0.20-1.19; p = 0.006), but these associations attenuated to non-significance after adjusting for all covariates. Household food insecurity was associated with more severe emotional dysregulation symptoms. Discussing and addressing food insecurity may be appropriate initial steps for youths with ADHD and emotional dysregulation.

Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youths: A Placebo-Controlled Randomized Clinical Trial.

OBJECTIVE: To evaluate whether micronutrients (vitamins/minerals) benefit attention-deficit/hyperactivity disorder (ADHD) and irritability in a North American pediatric sample. METHOD: A 3-site, 8-week, placebo-controlled, randomized clinical trial of micronutrients was conducted in nonmedicated children aged 6 to 12 years with ADHD and at least 1 impairing irritability symptom by parent report on the Child and Adolescent Symptom Inventory-5 (CASI-5). A priori-defined primary outcomes were Clinical Global Impression-Improvement (CGI-I) (CGI-I of 1 or 2 = treatment responder) and parent-rated CASI-5 composite score of ADHD, oppositional defiant, disruptive mood dysregulation, and peer conflict symptoms, including impairment scores. RESULTS: Of 135 randomized (mean age 9.8 years), 126 youths (93%) comprised the modified intention-to-treat population. Blinding was maintained. For the CGI-I, 54% of the micronutrient and 18% of the placebo group were responders (risk ratio = 2.97, 97.5% CI = 1.50, 5.90, p < .001). CASI-5 composite scores improved significantly for both groups (p < .01), with a mean change of -0.31 (95% CI = -0.39, -0.23) in the micronutrient group and a mean change of -0.28 (95% CI = -0.38, -0.19) in the placebo group. However, the between-group difference was not significant (mean change = -0.02; 97.5% CI = -0.16, 0.12, effect size = 0.07, p = .70). The micronutrient group grew 6 mm more than the placebo group (p = .002). No serious adverse events or clinically significant changes from baseline in blood and urine tests occurred. CONCLUSION: Micronutrients showed global benefit over placebo by blinded clinician rating, but not by parent-report CASI-5 composite rating in a population with ADHD and irritability. Micronutrients showed greater height growth. Micronutrients were well tolerated, and the majority of participants adhered to the number of capsules prescribed. This randomized controlled trial replicates safety and efficacy reported for ADHD in 2 smaller trials of a similar formula containing all vitamins and known essential minerals in amounts between the Recommended Dietary Allowance and Upper Tolerable Intake Level. CLINICAL TRIAL REGISTRATION INFORMATION: Micronutrients for ADHD in Youth (MADDY) Study; https://clinicaltrials.gov; NCT03252522.