Jeanette M. Johnstone

Oxidative stress (OS) arises from an imbalance between antioxidant defenses and the generation of reactive oxygen species (ROS), both of which are influenced by the levels and composition of trace elements. The Micronutrients for ADHD in Youth randomized controlled trial demonstrated behavioral improvements following 8 weeks of multinutrient supplementation in 54% of children compared to 18% on placebo. This secondary analysis examined the relationship between plasma minerals and OS-related parameters [biological antioxidant potential (BAP), glutathione peroxidase (GPx), glutathione reductase (GR), and reactive oxygen metabolites (ROM)] in 71 children (44 multinutrient, 27 placebo; median age 10.4 years). Correlation analysis revealed that selenium and zinc improved antioxidant response measured as GPx change in both treatment groups ( r = 0.26, p = 0.03) and BAP in multinutrient group ( r = 0.37, p = 0.01), respectively, while chromium change was inversely related to BAP ( r =-0.41, p = 0.005) in the multinutrient group. BAP change was moderated by baseline selenium (β=-9.45, p = 0.006), zinc (β=-2.13, p < 0.001), and chromium (β = 68.9, p = 0.02), where children in the multinutrient group with low selenium, low zinc, and high chromium at baseline experienced BAP increases. Selenium also exhibited pro-oxidant effects: ROM change correlated positively with change in selenium in multinutrient group only ( r = 0.34, p = 0.03). Baseline copper predicted ROM change (β = 0.213, p < 0.001), and ROM change correlated positively with changes in copper in both groups ( r = 0.51, p < 0.001) and negatively with Mn ( r =-0.24, p = 0.05), while iron did not moderate OS. Multinutrient supplementation may enhance antioxidant defenses in children who had low plasma zinc and selenium, while potential pro-oxidant effects in those with higher selenium and chromium warrant further investigation. Clinical Trial Registry number for MADDY RCT : NCT 03252522.

Objective: While individual nutrients have shown effects on inflammatory mechanisms, the effects of multinutrients (vitamins + minerals, antioxidants, and amino acids) on inflammation are unknown. We investigated whether 8 weeks of multinutrient supplementation, in a randomized controlled trial of 83 children with ADHD, would alter immune factors compared to placebo. Methods: Multiplex technology was used to measure 25 immune factors in blood samples collected at baseline and week 8. Immune factors were compared between multinutrient and placebo groups using the Mann-Whitney test. Linear mixed effects models evaluated immune factor change over time. To understand the functional relevance of the immune factors affected by multinutrient supplementation, pathway analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.7 Bioinformatics Resources. Results: Interleukin (IL)-5 and IL-13 levels differed following multinutrient supplementation versus placebo ( p = .005 and .03, respectively). IL-5 decreased by 1.3% in the multinutrient group (95% CI [−8.6%, 6.7%]) and increased by 17.5% in the placebo group (95% CI [6.9%, 29.2%]). IL-13 decreased by 11.4% in the multinutrient group (95% CI [−18.2%, −4.0%]), compared to a 2.4% increase in the placebo group (95% CI [−7.2%, 13.1%]). When comparing immune factors between treatment responders versus non-responders in the multinutrient group, there was a 4.3% increase in IL-15 in multinutrient responders (95% CI [−6.8%, 16.8%]) and a 14.3% decrease in non-responders ( p = .03, 95% CI [−24.9%, −2.4%]). Pathway analysis identified T helper type 2 (Th2) signaling pathways affected by multinutrient supplementation, including IL-17 and cytokine-cytokine receptor interaction pathways. Conclusion: Th2 immune factors may be influenced by multinutrient supplementation and associated with behavioral improvements in ADHD.

Attention-deficit/hyperactivity disorder (ADHD) affects up to 10% of children, often presenting with emotional dysregulation (irritability, anger). The kynurenine pathway, by which the amino acid tryptophan is converted into both neuroprotective and neurotoxic metabolites, was investigated for its role in ADHD pathophysiology. The MADDY study was an 8-week, multi-site, randomized controlled trial of a multinutrient supplement versus placebo in children 6-12 years old with symptoms of ADHD and emotional dysregulation. Participants from two U.S. sites (n = 84) provided baseline and week 8 urinary samples, analyzed via liquid chromatography-mass spectrometry for neurotransmitter levels. Linear mixed-effects models assessed change over time for seven analytes. Missing values were imputed, and results adjusted for multiple comparisons. Baseline neurotransmitter concentrations were not different between treatment groups. Changes over time in the seven analytes were not different between treatment groups. Nine participants had neurotransmitter levels below the lower limit of detection and were imputed; demographic characteristics were not different between these and other participants. Eight weeks of multinutrient supplementation did not change concentrations of urinary tryptophan, serotonin, or kynurenines in this sample of children 6-12 years old with ADHD and emotional dysregulation.

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: NCT 03252522

Objectives Histamine, a critical regulator of attention and inflammatory processes, may play a role in symptoms of attention-deficit/hyperactivity disorder (ADHD). Methods Data were from the baseline visit of a multi-site randomized controlled trial in children aged 6–12 with symptoms of ADHD and emotional dysregulation, the Micronutrients for ADHD in Youth (MADDY) study. Parent-reported intake of high-histamine foods was assessed with the VioScreen questionnaire; symptoms of ADHD with the Child & Adolescent Symptom Inventory, version-5 (CASI-5) Inattention and Hyperactivity/Impulsivity subscales, and emotional dysregulation with the Strengths & Difficulties Questionnaire-Dysregulation Profile. Urinary histamine was analyzed with liquid chromatography-mass spectrometry, with reference ranges for children < 10 and 10–12 years old. Results Thirty percent of children < 10 years old and 81% of children 10–12 (57% overall) had urinary histamine levels above the upper limit of the reference range. Urinary histamine was not associated with inattention, hyperactivity/impulsivity, or emotional dysregulation, nor intake of high-histamine foods, in the entire sample (N = 83). In a sensitivity analysis, participants with urinary histamine levels above the reference range had inattention scores 0.26 points higher on the CASI-5 than participants within the reference range (β = 0.26; 95% CI, 0.01, 0.52; p = 0.043). Conclusions In this secondary data analysis, urinary histamine levels were not associated with severity of hyperactivity/impulsivity or emotional dysregulation, or intake of high-histamine foods. Children with high urinary histamine had increased inattention compared to those with normal histamine levels. Limitations include the homogeneity of the sample and the lack of a comparison group without ADHD.

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.

Mood disorders, anxiety, and suicidality in youth are increasing and rapid-acting treatments are urgently needed. One potential is ketamine or its enantiomer esketamine, which was FDA approved in 2019 to treat major depressive disorder with suicidality in adults. This systematic review evaluated the evidence for the clinical use of ketamine to treat mood disorders, anxiety, and suicidality in youth. The PRISMA guidelines were used, and a protocol registered prospectively (https://osf.io/9ucsg/). The literature search included Pubmed/MEDLINE, Ovid/MEDLINE, Scopus, CINAHL, PsychInfo, and Google Scholar. Trial registries and preprint servers were searched, and authors contacted for clarification. Studies reported on the clinical use of ketamine to treat anxiety, depression, bipolar disorder, or suicidality in youth ≤19 years old and assessed symptoms before and after ketamine use. Study screening and data extraction were conducted independently by 2–4 authors. Safety, tolerability, and efficacy data were collected. The Cochrane Risk of Bias guidelines assessed the quality of the evidence. Twenty-two published reports based on 16 studies were identified: 7 case studies, 6 observational studies, 3 randomized trials, and 6 secondary data analyses. Studies reported immediate improvements in depression, anxiety, and suicidality. Improvements were maintained for weeks-months following treatment. Ketamine was well-tolerated with the most common side effects being dizziness, nausea, and mild dissociation. Transient hemodynamic changes were reported, all of which resolved quickly and did not require medical intervention. Initial evidence suggests ketamine is safe and may be effective for mood disorders, anxiety, and suicidality in youth. Further randomized trials are warranted.