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

Abstract

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.

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

Tost G, Srikanth P, Bruton A, Hatsu IE, Leung BM, Ast HK, Eiterman LP, Robinette LM, Williams C, Gracious B, Eugene Arnold L, Johnstone JM. Eur Child Adolesc Psychiatry. 2024 May 31.

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

Abstract

Objective: To evaluate whether micronutrients (vitamins/minerals) benefit attention-deficit/hyperactivity disorder (ADHD) and irritability in a North American pediatric sample.

Method: A three-site 8-week placebo-controlled randomized clinical trial of micronutrients was conducted in unmedicated children ages 6-12 with ADHD and at least one 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 (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<0.001). CASI-5 composite scores improved significantly for both groups (p<0.01) 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. But the between group difference was not significant (mean change = -0.02; 97.5% CI: -0.16, 0.12, ES = 0.07, p=0.70). The micronutrient group grew six millimeters more than the placebo group (p=0.002). No serious adverse events nor 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 adhered to the number of capsules prescribed. This RCT replicates safety and efficacy reported for ADHD in two 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.

Journal of the American Academy of Child & Adolescent Psychiatry

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

Johnstone JM, Hatsu I, Tost G, Srikanth P, Eiterman LP, Bruton A, Ast HK, Robinette LM, Stern MM, Millington EG, Gracious B, Hughes AJ, Leung BM, Arnold LE. Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth: A Placebo-Controlled Randomized Clinical Trial. J Am Acad Child Adolesc Psychiatry. 2021 Jul 21:S0890-8567(21)00473-1.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce

The 'Micronutrient Formula' rated by this international taskforce was Daily Essential Nutrients, and was given an 'Evidence Grade' of 'A', due to a statistically significant meta-analysis (k = 2, n = 173) with statistically significant RCTs in adult and child samples. They gave the following supporting statements for Daily Essential Nutrients:

  • Meta-analytic level results have shown supportive evidence for efficacy in ADHD as a monotherapy

  • More replicated evidence required (in both adults and children)

  • This particular micronutrient formula’s efficacy cannot necessarily be extended to other multi-nutrient formulas

  • Dosing may need to be supervised (and titrated) via a health profession

  • Cost and compliance may be an issue due to a recommended dosage of 8–12 capsules per day

  • Acceptable safety data

Abstract

Objectives: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations.

Methods: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed.

Conclusions: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce

Sarris J, Ravindran A, Yatham LN, Marx W, Rucklidge JJ, McIntyre RS, Akhondzadeh S, Benedetti F, Caneo C, Cramer H, Cribb L, de Manincor M, Dean O, Deslandes AC, Freeman MP, Gangadhar B, Harvey BH, Kasper S, Lake J, Lopresti A, Lu L, Metri NJ, Mischoulon D, Ng CH, Nishi D, Rahimi R, Seedat S, Sinclair J, Su KP, Zhang ZJ, Berk M. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry. 2022 Jul;23(6):424-455.

†The micronutrient formulation studied was a pre-2013 version of Truehope EMPowerplus which was co-formulated by David Hardy and Anthony Stephan. Truehope EMPowerplus is a registered trademark of The Synergy Group of Canada Inc., which was co-founded by David Hardy and Anthony Stephan in 1999. David Hardy officially resigned as a shareholder of The Synergy Group of Canada Inc. and director of Truehope Nutritional Support Ltd. in 2013 to focus his efforts exclusively on Hardy Nutritionals®.