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.

The stability and persistence of symptoms in childhood-onset ADHD.

The course of childhood-onset attention deficit hyperactivity disorder (ADHD) varies across individuals; some will experience persistent symptoms while others' symptoms fluctuate or remit. We describe the longitudinal course of ADHD symptoms and associated clinical characteristics in adolescents with childhood-onset ADHD. Participants (aged 6-12 at baseline) from the Longitudinal Assessment of Manic Symptoms (LAMS) study who met DSM criteria for ADHD prior to age 12 were evaluated annually with the Kiddie Schedule for Affective Disorders and Schizophrenia for eight years. At each timepoint, participants were categorized as meeting ADHD criteria, subthreshold criteria, or not having ADHD. Stability of course was defined by whether participants experienced consistent ADHD symptoms, fluctuating symptoms, or remission. The persistence of the symptoms was defined by symptom status at the final two follow-ups (stable ADHD, stable remission, stable partial remission, unstable). Of 685 baseline participants, 431 had childhood-onset ADHD and at least two follow-ups. Half had a consistent course of ADHD, nearly 40% had a remitting course, and the remaining participants had a fluctuating course. More than half of participants met criteria for ADHD at the end of their participation; about 30% demonstrated stable full remission, 15% had unstable symptoms, and one had stable partial remission. Participants with a persistent course and stable ADHD outcome reported the highest number of symptoms and were most impaired. This work builds on earlier studies that describe fluctuating symptoms in young people with childhood-onset ADHD. Results emphasize the importance of ongoing monitoring and detailed assessment of factors likely to influence course and outcome to help young people with childhood-onset ADHD.

A diffusion decision model analysis of the cognitive effects of neurofeedback for ADHD.

OBJECTIVE: To examine cognitive effects of neurofeedback (NF) for attention-deficit hyperactivity disorder (ADHD) as a secondary outcome of a randomized clinical trial. METHOD: In a double-blind randomized clinical trial (NCT02251743), 133 7-10-year olds with ADHD received either 38 sessions of NF (n = 78) or control treatment (n = 55) and performed an integrated visual and auditory continuous performance test at baseline, mid- and end-treatment. We used the diffusion decision model to decompose integrated visual and auditory continuous performance test performance at each assessment into cognitive components: efficiency of integrating stimulus information (v), context sensitivity (cv), response cautiousness (a), response bias (z/a), and nondecision time for perceptual encoding and response execution (Ter). Based on prior findings, we tested whether the components known to be deficient improved with NF and explored whether other cognitive components improved using linear mixed modeling. RESULTS: Before NF, children with ADHD showed main deficits in integrating stimulus information (v), which led to less accurate and slower responses than healthy controls (p = .008). The NF group showed significantly more improvement in integrating auditory stimulus information (v) than control treatment (significant group-by-time-by-modality effect: p = .044). CONCLUSIONS: NF seems to improve v, deficient in ADHD. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cognitive-attentional mechanisms of cooperation-with implications for attention-deficit hyperactivity disorder and cognitive neuroscience.

People's cooperativeness depends on many factors, such as their motives, cognition, experiences, and the situation they are in. To date, it is unclear how these factors interact and shape the decision to cooperate. We present a computational account of cooperation that not only provides insights for the design of effective incentive structures but also redefines neglected social-cognitive characteristics associated with attention-deficit hyperactivity disorder (ADHD). Leveraging game theory, we demonstrate that the source and magnitude of conflict between different motives affected the speed and frequency of cooperation. Integrating eye-tracking to measure motivation-based information processing during decision-making shows that participants' visual fixations on the gains of cooperation rather than its costs and risks predicted their cooperativeness on a trial-by-trial basis. Using Bayesian hierarchical modeling, we find that a situation's prosociality and participants' past experience each bias the decision-making process distinctively. ADHD characteristics explain individual differences in responsiveness across contexts, highlighting the clinical importance of experimentally studying reactivity in social interactions. We demonstrate how the use of eye-tracking and computational modeling can be used to experimentally investigate social-cognitive characteristics in clinical populations. We also discuss possible underlying neural mechanisms to be investigated in future studies.

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.

Donor-recipient specificity and age-dependency in fecal microbiota therapy and probiotic resolution of gastrointestinal symptoms.

Fecal microbiota transplantation (FMT) has proven to be an effective treatment for recurrent Clostridioides difficile infection (rCDI) in both adult and pediatric patients. However, as microbiome development is a critical factor in children, it remains unclear whether adult fecal donors can provide age-appropriate functional restoration in pediatric patients. To address this issue, we conducted an integrated systems approach and found that concordant donor strain engraftment, along with metabolite restoration, are associated with FMT outcomes in both adult and pediatric rCDI patients. Although functional restoration after FMT is not strain-specific, specialized metabolic functions are retained in pediatric patients when adult fecal donors are used. Furthermore, we demonstrated broad utility of high-resolution variant-calling by linking probiotic-strain engraftment with improved gastrointestinal symptoms in adults with irritable bowel syndrome and in children with autism spectrum disorder. Our findings emphasize the importance of strain-level identification when assessing the efficacy of probiotics and microbiota-based therapeutics.

Association Between Stimulant Treatment and Substance Use Through Adolescence Into Early Adulthood.

Importance: Possible associations between stimulant treatment of attention-deficit/hyperactivity disorder (ADHD) and subsequent substance use remain debated and clinically relevant. Objective: To assess the association of stimulant treatment of ADHD with subsequent substance use using the Multimodal Treatment Study of ADHD (MTA), which provides a unique opportunity to test this association while addressing methodologic complexities (principally, multiple dynamic confounding variables). Design, Setting, and Participants: MTA was a multisite study initiated at 6 sites in the US and 1 in Canada as a 14-month randomized clinical trial of medication and behavior therapy for ADHD but transitioned to a longitudinal observational study. Participants were recruited between 1994 and 1996. Multi-informant assessments included comprehensively assessed demographic, clinical (including substance use), and treatment (including stimulant treatment) variables. Children aged 7 to 9 years with rigorously diagnosed DSM-IV combined-type ADHD were repeatedly assessed until a mean age of 25 years. Analysis took place between April 2018 and February 2023. Exposure: Stimulant treatment of ADHD was measured prospectively from baseline for 16 years (10 assessments) initially using parent report followed by young adult report. Main Outcomes and Measures: Frequency of heavy drinking, marijuana use, daily cigarette smoking, and other substance use were confidentially self-reported with a standardized substance use questionnaire. Results: A total of 579 children (mean [SD] age at baseline, 8.5 [0.8] years; 465 [80%] male) were analyzed. Generalized multilevel linear models showed no evidence that current (B [SE] range, -0.62 [0.55] to 0.34 [0.47]) or prior stimulant treatment (B [SE] range, -0.06 [0.26] to 0.70 [0.37]) or their interaction (B [SE] range, -0.49 [0.70] to 0.86 [0.68]) were associated with substance use after adjusting for developmental trends in substance use and age. Marginal structural models adjusting for dynamic confounding by demographic, clinical, and familial factors revealed no evidence that more years of stimulant treatment (B [SE] range, -0.003 [0.01] to 0.04 [0.02]) or continuous, uninterrupted stimulant treatment (B [SE] range, -0.25 [0.33] to -0.03 [0.10]) were associated with adulthood substance use. Findings were the same for substance use disorder as outcome. Conclusions and Relevance: This study found no evidence that stimulant treatment was associated with increased or decreased risk for later frequent use of alcohol, marijuana, cigarette smoking, or other substances used for adolescents and young adults with childhood ADHD. These findings do not appear to result from other factors that might drive treatment over time and findings held even after considering opposing age-related trends in stimulant treatment and substance use.

Adequacy of Children's Psychopharmacology Services: Variations by Race and Clinical Characteristics.

OBJECTIVE: An expert consensus approach was used to determine the adequacy of children's psychopharmacology and to examine whether adequacy varied by demographic or clinical characteristics. METHODS: Data were from the baseline interview of 601 children, ages 6-12 years, who had visited one of nine outpatient mental health clinics and participated in the Longitudinal Assessment of Manic Symptoms study. Children and parents were interviewed with the Kiddie Schedule for Affective Disorders and Schizophrenia and the Service Assessment for Children and Adolescents to assess the child's psychiatric symptoms and lifetime mental health services use, respectively. An expert consensus approach informed by published treatment guidelines was used to determine the adequacy of children's psychotropic medication treatment. RESULTS: Black children (compared with White children; OR=1.84, 95% CI=1.53-2.23) and those with anxiety disorders (vs. no anxiety disorder; OR=1.55, 95% CI=1.08-2.20) were more likely to receive inadequate pharmacotherapy; those whose caregivers had a bachelor's degree or more education (vs. those who had a high school education, general equivalency diploma, or less than high school education; OR=0.74, 95% CI=0.61-0.89) were less likely to receive inadequate pharmacotherapy. CONCLUSIONS: The consensus rater approach permitted use of published treatment efficacy data and patient characteristics (e.g., age, diagnoses, history of recent hospitalizations, and psychotherapy) to assess adequacy of pharmacotherapy. These results replicate findings of racial disparities reported in previous research using traditional methods to determine treatment adequacy (e.g., with a minimum number of treatment sessions) and highlight the continued need for research on racial disparities and strategies to improve access to high-quality care.

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.

Complementary and Integrative Treatments for Attention-Deficit/Hyperactivity Disorder in Youth.

First-line psychopharmacologic and psychosocial treatments for attention-deficit/hyperactivity disorder in children are effective but limited by tolerability and accessibility problems. Many complementary and integrative strategies have been investigated as alternative or adjunctive treatments for the disorder, and the literature has progressed to meta-analyses for several. Although heterogeneity of study methods and risk of bias pervades the literature, we conclude that Omega-3 supplementation, dietary restriction of artificial food colorings, and physical activity can be considered evidence-based. Additionally, meditation, yoga, and sleep hygiene are safe, partially effective, cost effective and sensible adjunctive treatment strategies.

Mood Disorders in Youth: Complementary and Integrative Medicine.

Omega-3 polyunsaturated fatty acids, probiotics, vitamin C, vitamin D, folic acid and L-methyl folate, broad-spectrum micronutrients, N-acetylcysteine, physical activity, herbs, bright light therapy, melatonin, saffron, meditation, school-based interventions, and transcranial photobiomodulation are reviewed, with a focus on their use for treating mood disorders in children and adolescents. For each treatment, all published randomized controlled trials are summarized.

Autism Spectrum Disorder and Complementary-Integrative Medicine.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects 0.6%-1.7% of children. The etiology of autism is hypothesized to include both biological and environmental factors (Watts, 2008). In addition to the core symptoms of social-communication delay and restricted, repetitive interests, co-occurring irritability/aggression, hyperactivity, and insomnia negatively impact adaptive functioning and quality of life of patients and families. Despite years of effort, no pharmacologic agent has been found that targets the core symptoms of ASD. The only FDA-approved agents are risperidone and aripiprazole for agitation and irritability in ASD, not for core symptoms. Though they effectively reduce irritability/violence, they do so at the expense of problematic side effects: metabolic syndrome, elevated liver enzymes, and extrapyramidal side effects. Thus, it is not surprising that many families of children with ASD turn to nonallopathic treatment, including dietary interventions, vitamins, and immunomodulatory agents subsumed under complementary-integrative medicine (CIM). Per recent studies, 27% to 88% of families report using a CIM treatment. In an extensive population-based survey of CIM, families of children with more severe ASD, comorbid irritability, GI symptoms, food allergies, seizures, and higher parental education tend to use CIM at higher rates. The perceived safety of CIM treatments as "natural treatment" over allopathic medication increases parental comfort in using these agents. The most frequently used CIM treatments include multivitamins, an elimination diet, and Methyl B12 injections. Those perceived most effective are sensory integration, melatonin, and antifungals. Practitioners working with these families should improve their knowledge about CIM as parents currently perceive little interest in and poor knowledge of CIM by physicians. This article reviews the most popular complementary treatments preferred by families with children with autism. With many of them having limited or poor quality data, clinical recommendations about the efficacy and safety of each treatment are discussed using the SECS versus RUDE criteria.

Systematic Review and Meta-Analyses: Safety and Efficacy of Complementary and Alternative Treatments for Pediatric Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Complementary and alternative treatments (CATs) for ADHD have proliferated over the past decade; however, their safety and efficacy remain uncertain. We completed a systematic review and meta-analyses across CAT domains. METHODS: Systematic search and data extraction identified randomized controlled trials for pediatric ADHD (ages 3-19 years) that included probably blind ADHD symptom outcome measures. We evaluated basic (RCT of a CAT compared with sham/placebo, attention/active control, treatment as usual, and waitlist control), complementary (RCTs comparing an evidence-based treatment with a CAT and the same evidence-based treatment), and alternative (evidence-based treatment to CAT) efficacy. Random-effect meta-analyses were conducted when at least 3 blinded studies were identified for a specific CAT domain. RESULTS: Eighty-seven of 2253 nonduplicate screened manuscripts met inclusion criteria. No study reported significantly greater adverse effects for CATs than controls; naturopathy reported fewer adverse effects than evidence-based treatments but did not demonstrate basic efficacy. In the systematic review of basic efficacy, evidence of effectiveness was mixed but replicated previous evidence for the possible efficacy of cognitive training, neurofeedback, and essential fatty acid supplementation for certain patients. With respect to alternative and complementary efficacy, no CAT outperformed or enhanced evidence-based treatments (stimulant medications and behavioral therapy) when replication was required. Individual meta-analyses indicated that cognitive training was the only CAT that demonstrated overall basic efficacy ( SMD = 0.216; p = 0.032). CONCLUSION: Clinicians may cautiously recommend (but monitor) cognitive training when evidence-based treatments are not feasible or effective for a patient. Additional studies are needed to further understand the potential of CAT domains.

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.

For Which Children with ADHD is TBR Neurofeedback Effective? Comorbidity as a Moderator.

We examined psychiatric comorbidities moderation of a 2-site double-blind randomized clinical trial of theta/beta-ratio (TBR) neurofeedback (NF) for attention deficit hyperactivity disorder (ADHD). Seven-to-ten-year-olds with ADHD received either NF (n = 84) or Control (n = 58) for 38 treatments. Outcome was change in parent-/teacher-rated inattention from baseline to end-of-treatment (acute effect), and 13-month-follow-up. Seventy percent had at least one comorbidity: oppositional defiant disorder (ODD) (50%), specific phobias (27%), generalized anxiety (23%), separation anxiety (16%). Comorbidities were grouped into anxiety alone (20%), ODD alone (23%), neither (30%), or both (27%). Comorbidity (p = 0.043) moderated acute effect; those with anxiety-alone responded better to Control than to TBR NF (d = - 0.79, CI - 1.55- - 0.04), and the other groups showed a slightly better response to TBR NF than to Control (d = 0.22 ~ 0.31, CI - 0.3-0.98). At 13-months, ODD-alone group responded better to NF than Control (d = 0.74, CI 0.05-1.43). TBR NF is not indicated for ADHD with comorbid anxiety but may benefit ADHD with ODD.Clinical Trials Identifier: NCT02251743, date of registration: 09/17/2014.

Diagnostic accuracy of the Child and Adolescent Symptom Inventory (CASI-4R) substance use subscale in detecting substance use disorders in youth.

Identifying substance use disorders (SUDs) early and accurately improves case formulation and treatment. Previous studies have investigated validity and reliability of the Child and Adolescent Symptom Inventory (CASI) for anxiety, mood, and behavior problems. The present study's aim was to test if the embedded CASI Substance Use (SU) subscale can discriminate adolescents and young adults (AYA) with and without a SUD diagnosis accurately enough to justify clinical application within an evidence-based assessment framework. N = 479 outpatient AYA (age 14-21) and their caregivers completed K-SADS-PLW semistructured diagnostic interviews; caregivers completed the CASI and adolescents completed a parallel version, the Youth (self-report) Inventory (YI). K-SADS-PLW indicated that 33 youth met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for SUDs. Receiver Operating Characteristic (ROC) analyses found that both CASI and YI Substance Use subscale scores significantly identified K-SADS-diagnosed SUDs in AYA: Caregiver area under curve (AUC) = .91, p < .0005; YI(AUC) = .90, p < .0005. There was no significant difference in diagnostic accuracy between informants. Both subscales showed diagnostic and clinical utility in identifying AYA SUDs in outpatient mental health settings. Findings suggest that the CASI-4R subscale could be a helpful screening instrument for AYA SUDs. A case vignette illustrates the clinical application of study findings. Future research should examine rapport as a moderator of reporting accuracy, and replicate use of these measures under varying clinical scenarios. (PsycInfo Database Record (c) 2023 APA, all rights reserved).