Ketamine for mood disorders, anxiety, and suicidality in children and adolescents: a systematic review.

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.

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.

Systematic Review and Meta-Analysis: Do White Noise or Pink Noise Help With Task Performance in Youth With Attention-Deficit/Hyperactivity Disorder or With Elevated Attention Problems?

OBJECTIVE: Public interest in the potential benefits of white, pink, and brown noise for attention-deficit/hyperactivity disorder (ADHD) has recently mushroomed. White noise contains all frequencies of noise and sounds like static; pink or brown noise has more power in the lower frequencies and may sound, respectively, like rain or a waterfall. This meta-analysis evaluated effects on laboratory tasks in individuals with ADHD or elevated ADHD symptoms. METHOD: Eligible studies reported on participants with diagnosis of ADHD or elevated symptoms of ADHD who were assessed in a randomized trial using laboratory tasks intended to measure aspects of attention or academic work involving attention or executive function while exposed to white, pink, and brown noise and compared with a low/no noise condition. Two authors independently reviewed and screened studies for eligibility. A random-effects meta-analysis was conducted with preplanned moderator analyses of age, diagnostic status, and task type. Publication bias was evaluated. The GRADE tool was used to assess certainty of the evidence. Sensitivity analyses were conducted to evaluate robustness. RESULTS: Studies of children and college-age young adults with ADHD or ADHD symptoms (k = 13, N = 335) yielded a small but statistically significant benefit of white and pink noise on task performance (g = 0.249, 95% CI [0.135, 0.363], p < .0001). No studies of brown noise were identified. Heterogeneity was minimal, and moderators were nonsignificant; results survived sensitivity tests, and no publication bias was identified. In non-ADHD comparison groups (k = 11, N = 335), white and pink noise had a negative effect (g = -0.212, 95% CI [-0.355, -0.069], p = .0036). CONCLUSION: White and pink noise provide a small benefit on laboratory attention tasks for individuals with ADHD or high ADHD symptoms, but not for non-ADHD individuals. This article addresses theoretical implications, cautions, risks, and limitations. STUDY PREREGISTRATION INFORMATION: White Noise for ADHD: A Systematic Review And Meta-analysis; https://www.crd.york.ac.uk/prospero; CRD42023393992.

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.

Non-pharmacological interventions for attention-deficit hyperactivity disorder in children and adolescents.

Attention-deficit hyperactivity disorder (ADHD) affects approximately 5% of children and adolescents globally and is associated with negative life outcomes and socioeconomic costs. First-generation ADHD treatments were predominantly pharmacological; however, increased understanding of biological, psychological, and environmental factors contributing to ADHD has expanded non-pharmacological treatment possibilities. This Review provides an updated evaluation of the efficacy and safety of non-pharmacological treatments for paediatric ADHD, discussing the quality and level of evidence for nine intervention categories. Unlike medication, no non-pharmacological treatments showed a consistent strong effect on ADHD symptoms. When considering broad outcomes (eg, impairment, caregiver stress, and behavioural improvement), multicomponent (cognitive) behaviour therapy joined medication as a primary ADHD treatment. With respect to secondary treatments, polyunsaturated fatty acids showed a consistent modest effect on ADHD symptoms when taken for at least 3 months. Additionally, mindfulness and multinutrient supplementation with four or more ingredients showed modest efficacy on non-symptom outcomes. All other non-pharmacological treatments were safe; clinicians might tolerate their use but should educate families of childrenand adolescents with ADHD on the disadvantages, including costs, burden to the service user, absence of proven efficacy relative to other treatments, and delay of proven treatment.

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.

Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study.

OBJECTIVE: The Pediatric Adverse Event Rating Scale (PAERS) measured adverse events of children aged 6-12 years with ADHD and emotional dysregulation in the Micronutrients for ADHD in Youth (MADDY) study, an eight week multi-site randomized clinical trial of a broad-spectrum multinutrient treatment. Treatment sensitivity of the PAERS was assessed by calculating the treatment difference in change of the item scores from baseline to end of the RCT. METHODS: Principal component analysis retained 14 "adverse events" (out of 43 in the PAERS) that reflected ADHD symptoms and emotional dysregulation and was used to group the variables of interest. A combined score ranging from 0 to 5 was created based on symptom presence, functional impairment, and severity. Mean score change was calculated from baseline to week 8 by treatment (multinutrient vs placebo) with intention-to-treat and per-protocol samples. The study has been registered on clinicaltrials.gov as Micronutrients for ADHD in Youth (MADDY) Study, trial registration # NCT03252522 (https://clinicaltrials.gov/ct2/show/NCT03252522). RESULTS: The 126 children in the ITT sample had a mean age of 9.8 (SD = 1.7), with majority (73%) male, and 72% diagnosed with ADHD prior to the study screening. Baseline presence of PAERS symptoms was similar between treatment groups: the highest proportion was ADHD symptoms, followed by Irritable symptoms. The micronutrient group showed a greater decrease (improvement) in the mean anxiety combined score than the placebo group with a between-group difference in change of -0.36 (95% CI: -0.67, -0.04; p = .03) with ITT data and -0.48 (95% CI: -0.81, -0.15; p = .005) with per-protocol (n = 93) data. CONCLUSION: The multinutrient supplement did not result in more adverse events than placebo, suggesting it is a safe intervention. In addition to assessing actual adverse events, the PAERS may be a useful adjunct outcome measure for ADHD behaviors.

Parents' priorities and preferences for treatment of children with ADHD: Qualitative inquiry in the MADDY study.

BACKGROUND: Parents' lived experiences of having a child with ADHD may shape their decision making regarding ADHD treatment options for their child. The aim of this study was to explore parents' experiences of living with a child with ADHD in the family and how their experiences influence their perspectives on treatment preferences and priorities. METHODS: A phenomenological qualitative design was used. Semistructured interviews were conducted with parents of children with ADHD who were enrolled in a multisite randomized controlled trial. Interviews were transcribed verbatim, and transcripts at each site were double coded. Initial codes were derived directly from the text. Qualitative data were analysed with an inductive approach. RESULTS: Twenty-three parents were interviewed: eight from Alberta, Canada; eight from Portland, Oregon, USA; and seven from Columbus, Ohio, USA. Among the parents, 69% were married, 86% completed college education and 52% reported household income over $80,000. Among the children, the mean age was 9.6 years (SD = 1.8 years), 78% were boys and 48% were never medicated for their ADHD. Two major themes emerged from the analysis. Theme 1 was 'impact of ADHD on families within and outside the home' with the following subthemes: 'reconfiguring the home life', 'trial-and-error of accommodations at school' and 'responding to social pressures to fit in'. Theme 2 was 'enabling appropriate and accessible treatments for families' with the following subthemes: 'finding the "right fit" with professionals and treatments' and 'factors influencing inequitable access to treatments'. CONCLUSIONS: Parents described shared experiences and identified similar barriers, preferences and priorities for ADHD treatments regardless of demographic differences by site. Families desired access to family-centred, multimodal approaches to ADHD treatment. Further research is needed to identify the specific structural changes to healthcare, services and policies that will better support this approach.

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.

Classroom-Based Mindfulness Training Reduces Anxiety in Adolescents: Acceptability and Effectiveness of a Cluster-Randomized Pilot Study.

OBJECTIVE: Many high school students experience a high degree of anxiety and perceived stress. This study examined whether a classroom-based mindfulness program or a wellness program were acceptable and effective as anxiety and stress reduction interventions based on students' self-reports. DESIGN SETTING AND PARTICIPANTS: Thirteen health education classes (n=285 students, aged 14-16 years) were randomized by classroom to one of three conditions: mindfulness, wellness, or usual health class only (passive control/ waitlist), for 8 weeks. OUTCOMES: Pre- and post-intervention scores compared self-reported measures of depression, anxiety and stress. RESULTS: Complete data were available from nine classes (n=202 students). Post-intervention anxiety scores were reduced in students who received the mindfulness intervention compared to those who received only their usual health class (ß=-0.07, SE=0.03, P≤0.001; 95% CI=-0.12, -0.02). No significant between group differences were found for depression or stress (P>0.4). Students' satisfaction with the mindfulness intervention they received withstood baseline credibility and expectancy effects: r=0.21, n=67, P=0.17 for credibility; r=-0.001, n=67, P=0.99 for expectancy. However, students' satisfaction with the wellness intervention they received was positively correlated with their pre-intervention expectations, r=0.42, n=47, P>0.001. Fifty-two percent of the 68 students assigned to mindfulness (n=35) used the iPad app for mindfulness home practice at least once; of those, 10% used it 10 or more times. CONCLUSION: Eight weeks of classroom-based mindfulness, with limited home practice, reduced self-reported anxiety compared to usual health class, and withstood baseline expectancy effects in this group of high school students, a majority who come from high income families. CLINICAL IMPLICATIONS: School- or community-based mindfulness may be an appropriate recommendation for adolescents who experience anxiety.

Multinutrients for the Treatment of Psychiatric Symptoms in Clinical Samples: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This systematic review and meta-analysis focused on randomized controlled trials (RCT) of multinutrients consisting of at least four vitamins and/or minerals as interventions for participants with psychiatric symptoms. A systematic search identified 16 RCTs that fit the inclusion criteria (n = 1719 participants) in six psychiatric categories: depression, post-disaster stress, antisocial behavior, behavioral deficits in dementia, attention-deficit/hyperactivity disorder, and autism. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to rate the evidence base. Significant clinical benefit was assessed using minimal clinically important differences (MIDs). Due to heterogeneity in participants, multinutrient formulas, outcome measures, and absence of complete data, only the Attention-Deficit/Hyperactivity Disorder (ADHD) category was eligible for meta-analyses. In ADHD populations, statistically and clinically significant improvements were found in global functioning, Mean Difference (MD) -3.3, p = 0.001, MID -3.26; Standardized Mean Difference (SMD) -0.49 p = 0.001 MD -0.5), clinician ratings of global improvement (MD -0.58, p = 0.001, MID -0.5) and ADHD improvement (MD -0.54, p = 0.002, MID -0.5), and clinician (but not observer) measures of ADHD inattentive symptoms (MD -1.53, p = 0.05, MID -0.5). Narrative synthesis also revealed a pattern of benefit for global measures of improvement, for example: in autism, and in participants with behavioral deficits in dementia. Post-natural disaster anxiety and the number of violent incidents in prison populations also improved. Broad-spectrum formulas (vitamins + minerals) demonstrated more robust effects than formulas with fewer ingredients. This review highlights the need for robust methodology-RCTs that report full data, including means and standard deviations for all outcomes-in order to further elucidate the effects of multinutrients for psychiatric symptoms.

Development of a Composite Primary Outcome Score for Children with Attention-Deficit/Hyperactivity Disorder and Emotional Dysregulation.

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 limitations associated with multiple comparisons. Among the five similar weighting methods, the two best appear to be the equal item and equal subscale weighting methods.

Rationale and design of an international randomized placebo-controlled trial of a 36-ingredient micronutrient supplement for children with ADHD and irritable mood: The Micronutrients for ADHD in Youth (MADDY) study.

BACKGROUND: Attention-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. METHODS: An 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. DISCUSSION: This 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 REGISTRATION: NCT03252522. Registered 26 July 2017.