Drug Safety

, Volume 30, Issue 1, pp 17–26 | Cite as

Treatment of Attention Deficit Hyperactivity Disorder in Children and Adolescents

Safety Considerations
  • Mark L. Wolraich
  • Laura McGuinn
  • Melissa Doffing
Review Article

Abstract

Despite a large body of evidence for both the validity of the diagnosis of attention deficit hyperactivity disorder (ADHD) and the efficacy of its treatment with medication, there is an equally long history of controversy. This article focuses on presenting safety information for medications approved by the US FDA for the treatment of individuals with ADHD.

Stimulant medications are generally safe and effective. The common adverse effects of stimulant medications, including appetite suppression and insomnia, are usually of mild severity and manageable without stopping the medication. The more severe adverse effects such as tics or bizarre behaviours occur with low frequency and usually resolve when the medication is stopped. The possible impact on growth requires careful monitoring. Several rare but potentially severe adverse effects including sudden cardiac death and cancer following long-term treatment have been reported; however, these effects have not been adequately demonstrated to be of significant concern at this time. Atomoxetine also has a mild adverse effect profile in terms of severity and frequency although the numbers of studies and years of clinical experience is considerably less with this drug than for the stimulant medications.

When the risks are juxtaposed to the clear efficacy in significantly reducing dysfunctional symptoms of ADHD, benefit-risk analyses support the continued use of these pharmacological treatments for patients with ADHD.

Keywords

Attention Deficit Hyperactivity Disorder Sudden Cardiac Death Methylphenidate Attention Deficit Hyperactivity Disorder Atomoxetine 

Notes

Acknowledgements

No sources of funding were used in the preparation of this review. Laura McGuinn and Melissa Doffing have no conflicts of interest relevant to the content of this review. Mark Wolraich is a consultant to Shire and Eli Lilly and has received research support from Eli Lilly. He has also acted as a consultant to McNeil.

References

  1. 1.
    Wolraich M. Attention deficit hyperactivity disorder: the most studied yet most controversial diagnosis. Ment Retard Dev Disabil Res Rev 1999: 5: 163–8CrossRefGoogle Scholar
  2. 2.
    Bradley C. The behavior of children receiving benzedrine. A J of Psychiatry 1937; 94: 577–85Google Scholar
  3. 3.
    Clements SD. Minimal brain dysfunction in children: terminology and identification. Washington, DC: US Department of Health, Education and Welfare, 1966Google Scholar
  4. 4.
    Conners CK. The effects of dexedrine on rapid discrimination and motor control of hyperkinetic children under mild stress. J Nerv Ment Dis 1966; 142: 420–33CrossRefGoogle Scholar
  5. 5.
    Wolraich ML. Stimulant drug therapy in hyperactive children: research and clinical implications. Pediatrics 1977; 60: 512–8PubMedGoogle Scholar
  6. 6.
    Miller A, Lee SK, Raina P, et al. A review of therapies for attention deficit/hyperactivity disorder. Vancouver: Research Institute for Chilldren’s and Women’s Health and University of British Columbia, 1998Google Scholar
  7. 7.
    Swanson JM, McBurnett K, Wigal T, et al. Effect of stimulant medication on children with ADD: a “Review of Reviews”. Exceptional Children. 1993; 60: 154–62Google Scholar
  8. 8.
    Schachter H, Pham B, King J, et al. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolesents? A meta-analysis. CMAJ 2001; 165: 1475–88PubMedGoogle Scholar
  9. 9.
    Willy M, Manda B, Shatin D, et al. A study of compliance with FDA precommendations for pemoline (Cylert). J Am Acad Child Adolesc Psychiatry 2002; 41: 785–90PubMedCrossRefGoogle Scholar
  10. 10.
    Michelson D, Fares D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics 2001; 108(5): e83PubMedCrossRefGoogle Scholar
  11. 11.
    Biederman J, Heiligenstein JH, Faries DE, et al. Atomoxetine ADHD Study Group. Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder. Pediatrics 2002; 110: e75PubMedCrossRefGoogle Scholar
  12. 12.
    Buitelaar J, Danckaerts M, Gillberg C. A prospective, multicenter, open-label assessment of atomoxetine in non-North American children and adolescents with ADHD. Eur Child Adolesc Psychiatry 2004; 13: 249–57PubMedGoogle Scholar
  13. 13.
    Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 2003, 20Google Scholar
  14. 14.
    Michelson D, Allen A, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 2002; 159: 1896–901PubMedCrossRefGoogle Scholar
  15. 15.
    Pliszka SR. Non-stimulant treatment of attention-deficit/hyperactivity disorder. CNS Spectrums 2003 Apr; 8(4): 253–8PubMedGoogle Scholar
  16. 16.
    Wolraich M. The use of psychotropic medications in children: an American view. J Child Psychol Psychiatry 2003; 44: 159–68PubMedCrossRefGoogle Scholar
  17. 17.
    Varley C, McClellan J. Case study: additional sudden deaths with tricyclic antidepressants. J Am Acad Child Adolesc Psychiatry 1997; 36: 390–4PubMedCrossRefGoogle Scholar
  18. 18.
    Greenhill LL, Halperin JM, Abikoff H. Stimulant medications. J Am Acad Child Adolesc Psychiatry 1999; 38(5): 503–12PubMedCrossRefGoogle Scholar
  19. 19.
    Kramer JR, Loney J, Ponto LB, et al. Predictors of adult height and weight in boys treated with methylphenidate for childhood behavior problems. J Am Acad Child Adolesc Psychiatry 2000; 39: 517–24PubMedCrossRefGoogle Scholar
  20. 20.
    Gillberg C, Melander H, von Knorring A, et al. Long-term stimulant treatment of children with Attention-Deficit Hyperactivity Disorder symptoms: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 1997 1997; 54: 857–64CrossRefGoogle Scholar
  21. 21.
    Charach A, Ickowicz A, Schachar R. Stimulant treatment over five years: adherence, effectiveness, and adverse effects. J Am Acad Child Adolesc Psychiatry 2004; 43: 559–67PubMedCrossRefGoogle Scholar
  22. 22.
    MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-month outcomes of treatment strategies for attention-deficit/hyperactivity disorder. Pediatrics 2004 113: 754–61Google Scholar
  23. 23.
    Avigan M. Review of AERS data from marketed safety experience during stimulant therapy: death, sudden death, cardiovascular SAEs (including stroke): Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research; April 27, 2004, D030403Google Scholar
  24. 24.
    El-Zein R, Abdel-Rahman SZ, Hay MJ, et al. Cytogenetic effects in children treated with methylphenidate. Cancer Lett 2005; 230: 284–91PubMedCrossRefGoogle Scholar
  25. 25.
    Rapport M, Moffitt C. Attention deficit/hyperactivity disorder and methylphenidate: A review of height/weight, cardiovascular, and somatic complaint side effects. Clin Psychol Rev 2002; 22: 1107–31PubMedCrossRefGoogle Scholar
  26. 26.
    Safer DJ, Krager JM. A survey of medication treatment for hyperactive/inattentive students. JAMA 1988; 260: 2256–8PubMedCrossRefGoogle Scholar
  27. 27.
    Safer DJ, Krager JM. Effect of a media blitz and a threatened lawsuit on stimulant treatment. JAMA 1992; 268: 1004–7PubMedCrossRefGoogle Scholar
  28. 28.
    Safer DJ, Zito JM, Fine EM. Increased methylphenidate usage for attention deficit disorder in the 1990’s. Pediatrics 1996; 98: 1084–8PubMedGoogle Scholar
  29. 29.
    US Drug Enforcement Agency. Yearly aggregate production quotas. Washington, DC: Drug Enforcement Administration Office of Public Affairs, 1995Google Scholar
  30. 30.
    Zito JM, Safer DJ, dosReis S, et al. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000; 283(8): 1025–30PubMedCrossRefGoogle Scholar
  31. 31.
    Anonymous. Another long-acting methylphenidate (Metadate CD). Med Lett Drugs Ther 2001 43: 83–4Google Scholar
  32. 32.
    Biederman J, Quinn D, Weiss M, et al. Efficacy and safety of Ritalin LA, a new, once daily, extended-release dosage form of methylphenidate, in children with attention deficit hyperactivity disorder. Paediatric Drugs 2003; 5: 833–41PubMedCrossRefGoogle Scholar
  33. 33.
    McGough J, Pataki CS, R. S. Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder. Expert Rev Neurother 2005 5: 437–41PubMedCrossRefGoogle Scholar
  34. 34.
    Wolraich M, Greenhill LL, Pelham W, et al. Randomized controlled trial of OROS methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics 2001; 108(4): 883–92PubMedCrossRefGoogle Scholar
  35. 35.
    Pelham WE J, Sturges J, Hoza J, et al. Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Pediatrics 1987 Oct; 80(4): 491–501PubMedGoogle Scholar
  36. 36.
    Arnold L, Lindsay RL, Conners CK, et al. A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2004; 14: 542–54PubMedCrossRefGoogle Scholar
  37. 37.
    McGough J, Wigal SB, Abikoff H, et al. A randomized, double-blind, placebo-controlled, laboratory classroom assessment of methylphenidate transdermal system in children with ADHD. J Atten Disord 2006; 9: 476–85PubMedCrossRefGoogle Scholar
  38. 38.
    Transdermal methylphenidate (Daytrana) for ADHD. Med Lett Drugs Ther 2006 Jun 19; 48 (1237): 49–51.Google Scholar
  39. 39.
    Kvale K. The efficacy of stimulant drug treatment for hyperactivity: a meta-analysis. J Learn Disabil 1982; 15: 280CrossRefGoogle Scholar
  40. 40.
    Ottenbacher KJ, Cooper HM. Drug treatment of hyperactivity in children. Dev Med Child Neurol 1983; 25: 358–66PubMedCrossRefGoogle Scholar
  41. 41.
    Thurber S, Walker CE. Medication and hyperactivity: a meta-analysis. J Gen Psychol 1983; 108: 79–86PubMedCrossRefGoogle Scholar
  42. 42.
    MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics 2004 113: 762–9Google Scholar
  43. 43.
    Klein-Schwartz W. Abuse and toxicity of methylphenidate. Curr Opin in Pediatrics 2002; 14: 219–23CrossRefGoogle Scholar
  44. 44.
    Barkley RA, McMurray MB, Edelbrook CS, et al. Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation. Pediatrics 1990; 86: 184–92PubMedGoogle Scholar
  45. 45.
    Swanson JM. Measures of cognitive functioning appropriate for use in pediatric psychopharmacological research studies. Psychopharmacol Bull 1985; 21: 887–90PubMedGoogle Scholar
  46. 46.
    Poulton A, Cowell CT. Slowing of growth in height and weight on stimulants: a characteristic pattern. J Paediatr Child Health 2003; 39(3): 180–5PubMedCrossRefGoogle Scholar
  47. 47.
    Lewis BR, Aoun SL, Bernstein GA, et al. Pharmacokinetic interactions between cyclosporin and bupropion or methylphenidate. J Child Adolesc Psychopharmacol 2001; 11: 193–8PubMedCrossRefGoogle Scholar
  48. 48.
    Wilens TE, Spencer TJ, Swanson JM, et al. Combining methylphenidate and clonidine: a clinically sound medication option. J Am Acad Child Adolesc Psychiatry 1999; 38: 614–9PubMedCrossRefGoogle Scholar
  49. 49.
    Castellanos F, Giedd JN, Elia J, et al. Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: effects of stimulant and dose. J Am Acad Child Adolesc Psychiatry 1997; 36: 589–96PubMedCrossRefGoogle Scholar
  50. 50.
    Feldman H, Crumrine P, Handen BL, et al. Methylphenidate in children with seizures and attention deficit disorder. Am J Dis Child 1989; 143: 1081–6PubMedGoogle Scholar
  51. 51.
    Gross-Tsur V, Manor O, van der Meere J, et al. Epilepsy and attention deficit hyperactivity disorder: Is mehtylphenidate safe and effective? Journal of Pediatrics 1997; 130: 670–4PubMedCrossRefGoogle Scholar
  52. 52.
    Barbaresi W, Katusic SK, Colligan RC, et al. Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study. J Dev Behav Pediatr 2006; 27: 1–10PubMedCrossRefGoogle Scholar
  53. 53.
    Teo S, San RH, Wayne VO, et al. D-methylphenidate is non-genotoxic in in vitro and in vitro assays. Mutat Res 2003; 537: 67–79PubMedCrossRefGoogle Scholar
  54. 54.
    Dunnick J, Hailey JR. Experimental studies on the long-term effects of methylphenidate hydrochloride. Toxicology 1995; 103: 77–84PubMedCrossRefGoogle Scholar
  55. 55.
    Selby J, Friedman GD, Fireman BH. Screening precription drugs for possible carcinogenicity: eleven to fifteen years of follow-up. Cancer Res 1989; 49: 5736–47PubMedGoogle Scholar
  56. 56.
    Berger S, Kugler JD, Thomas JA, et al. Sudden cardiac death in children and adolescents: introduction and overview. Pediatr Clin North Am 2004; 51: 1201–9PubMedCrossRefGoogle Scholar
  57. 57.
    Physicians’ Desk Reference. Montvale, NJ: Thomson Healthcare, 2006Google Scholar
  58. 58.
    Greenhill LL, Kollins S, Abikoff H, et al. Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry 2006; 45: 1284–93PubMedCrossRefGoogle Scholar
  59. 59.
    Arnold L, Huestis RD, Smeltzer DJ, et al. Levoamphetamine vs dextroamfetamine in minimal brain dysfunction: replication, time response, and differential effect by diagnostic group and family rating. Arch Gen Psychiatry 1976; 33: 292–301PubMedCrossRefGoogle Scholar
  60. 60.
    Stevenson R, Wolraich ML. Stimulant medication therapy in the treatment of children with attention deficit hyperactivity disorder. Pediatr Clin North Am 1989; 36: 1183–97PubMedGoogle Scholar
  61. 61.
    Markowitz J, Patrick KS. Pharmacokinetics and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet 2001; 40: 753–72PubMedCrossRefGoogle Scholar
  62. 62.
    Greenhill LL, Abikoff HB, Aanold E, et al. Medication treatment strategies in the MTA study: relevance to clinicians and researchers. J Am Acad Child Adolesc Psychiatry 1996; 34(10): 1304–13CrossRefGoogle Scholar
  63. 63.
    Efron D, Jarman F, Barker M. Side effects of methylphenidate and dextroamfetamine in children with attention deficit hyperactivity disorder: a double-blind crossover trial. Pediatrics 1997; 100: 662–6PubMedCrossRefGoogle Scholar
  64. 64.
    Wong DT, Threlkeld PG, Best KL, et al. A new inibitor of norepinehrine uptake devoid of affinity for receptors in rat brain. J Pharmacolog Exp Ther 1982; 222: 61–5Google Scholar
  65. 65.
    Simpson D, Perry CM. Atomoxetine. Pediatric Drugs 2003; 5: 407–15PubMedGoogle Scholar
  66. 66.
    Wilens T, Faraone S, Biederman J, et al. Does stimulant therapy of ADHD beget later substance abuse: a metanalytic review of the literature. Pediatrics 2003; 11: 179–85CrossRefGoogle Scholar
  67. 67.
    Low K, Gendaszek AE. Illicit use of psychostimulents among college students: a preliminary study. Psychol Health Med 2002; 7: 283–7CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Mark L. Wolraich
    • 1
  • Laura McGuinn
    • 1
  • Melissa Doffing
    • 1
  1. 1.Department of Pediatrics, Section of Developmental and Behavioral PediatricsUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations