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

Conclusions

Multinutrients combining 4 or more ingredients, mindfulness, and polyunsaturated fatty acids showed replicated, consistent moderate effects and can be encouraged as secondary treatments in combination with primary treatments or if a primary treatment is not a fit for the participant and their family.

Summary

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.

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

Sibley MH, Bruton AM, Zhao X, Johnstone JM, Mitchell J, Hatsu I, Arnold LE, Basu HH, Levy L, Vyas P, Macphee F, Gonzalez ES, Kelley M, Jusko ML, Bolden CR, Zulauf-McCurdy C, Manzano M, Torres G. Non-pharmacological interventions for attention-deficit hyperactivity disorder in children and adolescents. Lancet Child Adolesc Health. 2023 Mar 9:S2352-4642(22)00381-9.

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

ABSTRACT
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; p¼.03) 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.

CMRO

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

Brenda M. Y. Leung, Priya Srikanth, Barbara Gracious, Irene E. Hatsu, Gabriella Tost, Valerie Conrad, Jeanette M. Johnstone & L. Eugene Arnold (2022) Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study, Current Medical Research and Opinion, 2022 Sep;38:9, 1595-1602.

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.

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

Abstract

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.

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

Jeanette M Johnstone, Andrew Hughes, Joshua Z Goldenberg, Amy R Romijn, Julia J Rucklidge. Nutrients. 2020 Nov 4;12(11):3394.

†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®.