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

Jeanette M Johnstone, Brenda Leung, Barbara Gracious, Leanna Perez, Gabriella Tost, Andrew Savoy, Irene Hatsu, Andrew Hughes, Alisha Bruton, L Eugene Arnold, Jeanette M Johnstone, Brenda Leung, Barbara Gracious, Leanna Perez, Gabriella Tost, Andrew Savoy, Irene Hatsu, Andrew Hughes, Alisha Bruton, L Eugene Arnold

Abstract

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.

Keywords: ADHD; Irritability; Micronutrients; Minerals; Vitamins.

Conflict of interest statement

Dr. Arnold has received research funding from Forest, Lilly, Noven, Shire, Supernus, Roche, and YoungLiving (as well as NIH and Autism Speaks); has consulted with Pfizer, Tris Pharma, and Waypoint; and been on advisory boards for Arbor, Ironshore, Otsuka, Pfizer, Roche, Seaside Therapeutics, Shire. Dr. Gracious has been or is a consultant to: AstraZeneca, Otsuka, and NovoNordisc. The other authors declare that they have no competing interests.

© 2019 The Authors.

Figures

Fig. 1
Fig. 1
Study flow diagram.

References

    1. American Psychiatric Association . fourth ed. American Psychiatric Association; Washington, DC: 1994. Diagnostic and Statistical Manual of Mental Disorders.
    1. Danielson M.L., Bitsko R.H., Ghandour R.M., Holbrook J.R., Kogan M.D., Blumberg S.J. Prevalence of parent-reported ADHD diagnosis and associated treatment among U.S. Children and adolescents, 2016. J. Clin. Child Adolesc. Psychol. 2018;47(2):199–212.
    1. Lenzi F., Cortese S., Harris J., Masi G. Pharmacotherapy of emotional dysregulation in adults with ADHD: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 2017
    1. Dickstein D.P. Mechanisms distinguishing irritability in children and adolescents. Am. J. Psychiatr. 2016;173:653–654.
    1. Aman M.G., Bukstein O.G., Gadow K.D., Arnold L.E., Molina B.S., McNamara N.K., Rundberg-Rivera E.V., Li X., Kipp H., Schneider J. What does risperidone add to parent training and stimulant for severe aggression in child attention-deficit/hyperactivity disorder? J. Am. Acad. Child Adolesc. Psychiatry. 2014;53(1):47–60. e41.
    1. Barkley R.A., editor. Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. third ed. The Guilford Press; New York, NY: 2006.
    1. Klein R.G., Mannuzza S., OMA R., Roizen E., Hutchison J.A., Lashau E.C., Castellanos X. Clinical and functional outcome of childhood attention-deficit/hyperactivity disorder 33 years later. Arch. Gen. Psychiatr. 2012:1–9.
    1. Mannuzza S., Klein R.G., Bessler A., Malloy P., LaPadula M. Adult outcome of hyperactive boys - educational-achievement, occupational rank, and psychiatric status. Arch. Gen. Psychiatr. 1993;50:565–576.
    1. Molina B.S.G., Hinshaw S.P., Swanson J.M., Arnold L.E., Vitiello B., Jensen P.S., al e. The MTA at 8 Years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J. Am. Acad. Child Adolesc. Psychiatry. 2009;48(5):484–500.
    1. Baumgaertel A. Alternative and controversial treatments for attention-deficit/hyperactivity disorder. Pediatr. Clin. N. Am. 1999;46(5):977–992.
    1. Sonuga-Barke E.J., Brandeis D., Cortese S., Daley D., Ferrin M., Holtmann M., Stevenson J., Danckaerts M., Van der Oord S., Döpfner M. Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments. Am. J. Psychiatry. 2013;170(3):275–289.
    1. Nigg J., Lewis K., Edinger T., Falk M. Meta-analysis of attention-deficit/hyperactivity disorder or attention-deficit/hyperactivity disorder symptoms, restriction diet, and synthetic food color additives. J. Am. Acad. Child Adolesc. Psychiatry. 2012;51(1):86–97 e88.
    1. Konikowska K., Regulska-Ilow B., Rozanska D. The influence of components of diet on the symptoms of ADHD in children. Rocz. Panstw. Zakl. Hig. 2012;63(2)
    1. Galler J.R., Bryce C.P., Zichlin M.L., Fitzmaurice G., Eaglesfield G.D., Waber D.P. Infant malnutrition is associated with persisting attention deficits in middle adulthood. J. Nutr. 2012;142(4):788–794.
    1. Ríos-Hernández A., Alda J.A., Farran-Codina A., Ferreira-García E., Izquierdo-Pulido M. The Mediterranean diet and ADHD in children and adolescents. Pediatrics. 2017;139(2) e20162027.
    1. Howard A.L., Robinson M., Smith G.J., Ambrosini G.L., Piek J.P., Oddy W.H. ADHD is associated with a “Western” dietary pattern in adolescents. J. Atten. Disord. 2011;15(5):403–411.
    1. McCann D., Barrett A., Cooper A., Crumpler D., Dalen L., Grimshaw K., Kitchin E., Lok K., Porteous L., Prince E. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. The Lancet. 2007;370(9598):1560–1567.
    1. Sinha D., Efron D. Complementary and alternative medicine use in children with attention deficit hyperactivity disorder. J. Paediatr. Child Health. 2005;41(1–2):23–26.
    1. Bussing R., Zima B.T., Gary F.A., Garvan C.W. Use of complementary and alternative medicine for symptoms of attention-deficit hyperactivity disorder. Psychiatr. Serv. 2002;53(9):1096–1102.
    1. Wilson K., Dowson C., Mangin D. Prevalence of complementary and alternative medicine use in Christchurch, New Zealand: children attending general practice versus paediatric outpatients. N. Z. Med. J. 2007;120(1251):1–9.
    1. Chan E. The role of complementary and alternative medicine in attention-deficit hyperactivity disorder. J. Dev. Behav. Pediatr. 2002;23(Suppl1):S37–S45.
    1. Stubberfield T.G., Wray T.A., Parry T.S. Utilization of alternative therapies in attention-deficit hyperactivity disorder. J. Paediatr. Child Health. 1999;35:450–453.
    1. Rucklidge J.J., Johnstone J., Kaplan B.J. Nutrient supplementation approaches in the treatment of ADHD. Expert Rev. Neurother. 2009;9(4):461–476.
    1. Bloch M.H. Mulqueen J: nutritional supplements for the treatment of ADHD. Child Adolesc. Psychiatr. Clin. 2014;23(4):883–897.
    1. Popper C.W. Single-micronutrient and broad-spectrum micronutrient approaches for treating mood disorders in youth and adults. Child Adolesc. Psychiatr. Clin. N. Am. 2014;23(3):591–672.
    1. Palego L., Betti L., Rossi A., Giannaccini G. Tryptophan biochemistry: structural, nutritional, metabolic, and medical aspects in humans. J. Amino Acids. 2016 2016.
    1. Gostner J.M., Geisler S., Stonig M., Mair L., Sperner-Unterweger B., Fuchs D. Tryptophan metabolism and related pathways in psychoneuroimmunology: the impact of nutrition and lifestyle. Neuropsychobiology. 2019:1–11.
    1. Kaur A. A review on synergistic relationship between nutrition and exercise in treating depression. Indian J. Health WellBeing. 2018;9(4)
    1. Leung C.W., Laraia B.A., Coleman-Phox K., Bush N.R., Lin J., Blackburn E.H., Adler N.E., Epel E.S. Sugary beverage and food consumption, and leukocyte telomere length maintenance in pregnant women. Eur. J. Clin. Nutr. 2016;70(9):1086–1088.
    1. Mertz W. A balanced approach to nutrition for health: the need for biologically essential minerals and vitamins. J. Am. Diet. Assoc. 1994;94:1259–1262.
    1. Kaplan B.J., Fisher J.E., Crawford S.G., Field C.J., Kolb B. Improved mood and behavior during treatment with a mineral-vitamin supplement: an open-label case series of children. J. Child Adolesc. Psychopharmacol. 2004;14(1):115–122.
    1. Rucklidge J.J., Taylor M., Whitehead K. Effect of micronutrients on behavior and mood in adults with ADHD: evidence from an 8-week open label trial with natural extension. J. Atten. Disord. 2011;15(1):79–91.
    1. Rucklidge J.J., Gately D., Kaplan B.J. Database analysis of children and adolescents with bipolar disorder consuming a multinutrient formula. BMC Psychiatry. 2010;74(10)
    1. Rucklidge J.J., Harrison R. Successful treatment of Bipolar Disorder II and ADHD with a micronutrient formula: a case study. CNS Spectr. 2010;15(5):289–295.
    1. Harding K.L., Judah R.D., Gant C. Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD. Altern. Med. Rev. 2003;8(3):319–330.
    1. Patel K., Curtis L.T. Comprehensive approach to treating autism and attention-deficit hyperactivity disorder: a prepilot study. J. Altern. Complement. Med. 2007;13(10):1091–1097.
    1. Rucklidge J.J., Frampton C.M., Gorman B., Boggis A. Vitamin-mineral treatment of ADHD in adults. J. Atten. Disord. 2017;21(6):522–532.
    1. Gordon H.A., Rucklidge J.J., Blampied N.M., Johnstone J.M. Clinically significant symptom reduction in children with attention-deficit/hyperactivity disorder treated with micronutrients: an open-label reversal design study. J. Child Adolesc. Psychopharmacol. 2015;25(10):783–798.
    1. Dietary reference intakes (DRIs) Recommended dietary allowance.
    1. Benton D. To establish the parameters of optimal nutrition do we need to consider psychological in addition to physiological parameters? Mol. Nutr. Food Res. 2013;57(1):6–19.
    1. Rucklidge J.J.E.M., Johnstone J.M., Darling K., Frampton C. Vitamin-mineral treatment improves aggression and emotional control in children with ADHD: a fully blinded, randomized, placebo-controlled trial. JCPP (J. Child Psychol. Psychiatry) 2018;59(3):232–246.
    1. Gadow K.S. Checkmate Plus; NY: 2015. J: Child and Adolescent Symptoms Inventory-5. Stony Brook.
    1. American Psychiatric Association . fifth ed. American Psychiatric Association; Washington, DC: 2013. Diagnostic and Statistical Manual of Mental Disorders.
    1. Harris P.A., Taylor R., Thielke R., Payne J., Gonzalez N., Conde J.G. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 2009;42(2):377–381.
    1. Kaplan B.J., Steiger R.A., Pope J., Marsh A., Sharp M., Crawford S.G. Successful treatment of pill-swallowing difficulties with head posture practice. Paediatr. Child Health. 2010;15(5):e1–5.
    1. Rucklidge J., Taylor M., Whitehead K. Effect of micronutrients on behavior and mood in adults with ADHD: evidence from an 8-week open label trial with natural extension. J. Atten. Disord. 2011;15(1):79–91.
    1. Rucklidge J.J., Frampton C.M., Gorman B., Boggis A. Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial. Br. J. Psychiatry. 2014;204(4):306–315.
    1. Rucklidge J.J., Frampton C.M., Gorman B., Boggis A. Vitamin–mineral treatment of ADHD in adults a 1-year naturalistic follow-up of a randomized controlled trial. J. Atten. Disord. 2014 1087054714530557.
    1. Hathcock J.N. Safety limits for nutrients. J. Nutr. 1996;126(Suppl-9) 238S236-2389S.
    1. Rucklidge J.J., Eggleston M.J., Ealam B., Beaglehole B., Mulder R.T. An observational preliminary study on the safety of long-term consumption of micronutrients for the treatment of psychiatric symptoms. J. Altern. Complement. Med. 2019;25(6):613–622.
    1. Gipson D.S., Kirkendall E.S., Gumbs-Petty B., Quinn T., Steen A., Hicks A., McMahon A., Nicholas S., Zhao-Wong A., Taylor-Zapata P. Development of a pediatric adverse events terminology. Pediatrics. 2017;139(1) e20160985.
    1. Rucklidge J.J., Johnstone J., Gorman B., Boggis A., Frampton C.M. Moderators of treatment response in adults with ADHD treated with a vitamin–mineral supplement. Prog. Neuro Psychopharmacol. Biol. Psychiatry. 2014;50:163–171.
    1. Frazier E.A., Gracious B., Arnold L.E., Failla M., Chitchumroonchokchai C., Habash D., Fristad M.A. Nutritional and safety outcomes from an open-label micronutrient intervention for pediatric bipolar spectrum disorders. J. Child Adolesc. Psychopharmacol. 2013;23(8):558–567.
    1. Fernández de la Cruz L., Simonoff E., McGough J.J., Halperin J.M., Arnold L.E., Stringaris A. Treatment of children with attention-deficit/hyperactivity disorder (ADHD) and irritability: results from the multimodal treatment study of children with ADHD (MTA) J. Am. Acad. Child Adolesc. Psychiatry. 2015;54(1):62–70. e63.
    1. Karalunas S.L., Fair D., Musser E.D., Aykes K., Iyer S.P., Nigg J.T. Subtyping attention-deficit/hyperactivity disorder using temperament dimensions: toward biologically based nosologic criteria. JAMA Psychiatr. 2014;71(9):1015–1024.
    1. Karalunas S.L., Gustafsson H.C., Fair D., Musser E.D., Nigg J.T. Do we need an irritable subtype of ADHD? Replication and extension of a promising temperament profile approach to ADHD subtyping. Psychol. Assess. 2019;31(2):236.
    1. Beattie V., Breuer K., O'connell N., Sneddon I., Mercer J., Rance K., Sutcliffe M., Edwards S. Factors identifying pigs predisposed to tail biting. Anim. Sci. 2005;80(3):307–312.
    1. Fraser D. Mineral-deficient diets and the pig's attraction to blood: implications for tail-biting. Can. J. Anim. Sci. 1987;67(4):909–918.
    1. Wurtman R.J., Fernstrom J.D. Control of brain neurotransmitter synthesis by precursor availability and nutritional state. Biochem. Pharmacol. 1976;25(15):1691–1696.
    1. Prehn-Kristensen A., Zimmermann A., Tittmann L., Lieb W., Schreiber S., Baving L., Fischer A. Reduced microbiome alpha diversity in young patients with ADHD. PLoS One. 2018;13(7) e0200728.
    1. Aarts E., Ederveen T.H., Naaijen J., Zwiers M.P., Boekhorst J., Timmerman H.M., Smeekens S.P., Netea M.G., Buitelaar J.K., Franke B. Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One. 2017;12(9) e0183509.
    1. Mitchell R.H., Goldstein B.I. Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J. Am. Acad. Child Adolesc. Psychiatry. 2014;53(3):274–296.
    1. Krajmalnik‐Brown R., Ilhan Z.E., Kang D.W., DiBaise J.K. Effects of gut microbes on nutrient absorption and energy regulation. Nutr. Clin. Pract. 2012;27(2):201–214.
    1. Jumpertz R., Le D.S., Turnbaugh P.J., Trinidad C., Bogardus C., Gordon J.I., Krakoff J. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans–. Am. J. Clin. Nutr. 2011;94(1):58–65.
    1. Sole E., Blampied N., Rucklidge J. Anxiety and stress in children following an earthquake: Clinically beneficial effects of treatment with micronutrients. Journal of Child and Family Studies. 2017;26(5):1422–1431.
    1. Kaplan B.J., Rucklidge J.J., Romijn A.R., Dolph M. A randomised trial of nutrient supplements to minimise psychiatric illness after a natural disaster. Psychiatry Research. 2015;228:373–379.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa