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.
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Notes
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References
Wolraich M. Attention deficit hyperactivity disorder: the most studied yet most controversial diagnosis. Ment Retard Dev Disabil Res Rev 1999: 5: 163–8
Bradley C. The behavior of children receiving benzedrine. A J of Psychiatry 1937; 94: 577–85
Clements SD. Minimal brain dysfunction in children: terminology and identification. Washington, DC: US Department of Health, Education and Welfare, 1966
Conners CK. The effects of dexedrine on rapid discrimination and motor control of hyperkinetic children under mild stress. J Nerv Ment Dis 1966; 142: 420–33
Wolraich ML. Stimulant drug therapy in hyperactive children: research and clinical implications. Pediatrics 1977; 60: 512–8
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, 1998
Swanson JM, McBurnett K, Wigal T, et al. Effect of stimulant medication on children with ADD: a “Review of Reviews”. Exceptional Children. 1993; 60: 154–62
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: 1475–88
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: 785–90
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): e83
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: e75
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: 249–57
Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 2003, 20
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: 1896–901
Pliszka SR. Non-stimulant treatment of attention-deficit/hyperactivity disorder. CNS Spectrums 2003 Apr; 8(4): 253–8
Wolraich M. The use of psychotropic medications in children: an American view. J Child Psychol Psychiatry 2003; 44: 159–68
Varley C, McClellan J. Case study: additional sudden deaths with tricyclic antidepressants. J Am Acad Child Adolesc Psychiatry 1997; 36: 390–4
Greenhill LL, Halperin JM, Abikoff H. Stimulant medications. J Am Acad Child Adolesc Psychiatry 1999; 38(5): 503–12
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: 517–24
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: 857–64
Charach A, Ickowicz A, Schachar R. Stimulant treatment over five years: adherence, effectiveness, and adverse effects. J Am Acad Child Adolesc Psychiatry 2004; 43: 559–67
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: 754–61
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, D030403
El-Zein R, Abdel-Rahman SZ, Hay MJ, et al. Cytogenetic effects in children treated with methylphenidate. Cancer Lett 2005; 230: 284–91
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: 1107–31
Safer DJ, Krager JM. A survey of medication treatment for hyperactive/inattentive students. JAMA 1988; 260: 2256–8
Safer DJ, Krager JM. Effect of a media blitz and a threatened lawsuit on stimulant treatment. JAMA 1992; 268: 1004–7
Safer DJ, Zito JM, Fine EM. Increased methylphenidate usage for attention deficit disorder in the 1990’s. Pediatrics 1996; 98: 1084–8
US Drug Enforcement Agency. Yearly aggregate production quotas. Washington, DC: Drug Enforcement Administration Office of Public Affairs, 1995
Zito JM, Safer DJ, dosReis S, et al. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000; 283(8): 1025–30
Anonymous. Another long-acting methylphenidate (Metadate CD). Med Lett Drugs Ther 2001 43: 83–4
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: 833–41
McGough J, Pataki CS, R. S. Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder. Expert Rev Neurother 2005 5: 437–41
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): 883–92
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): 491–501
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: 542–54
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: 476–85
Transdermal methylphenidate (Daytrana) for ADHD. Med Lett Drugs Ther 2006 Jun 19; 48 (1237): 49–51.
Kvale K. The efficacy of stimulant drug treatment for hyperactivity: a meta-analysis. J Learn Disabil 1982; 15: 280
Ottenbacher KJ, Cooper HM. Drug treatment of hyperactivity in children. Dev Med Child Neurol 1983; 25: 358–66
Thurber S, Walker CE. Medication and hyperactivity: a meta-analysis. J Gen Psychol 1983; 108: 79–86
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: 762–9
Klein-Schwartz W. Abuse and toxicity of methylphenidate. Curr Opin in Pediatrics 2002; 14: 219–23
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: 184–92
Swanson JM. Measures of cognitive functioning appropriate for use in pediatric psychopharmacological research studies. Psychopharmacol Bull 1985; 21: 887–90
Poulton A, Cowell CT. Slowing of growth in height and weight on stimulants: a characteristic pattern. J Paediatr Child Health 2003; 39(3): 180–5
Lewis BR, Aoun SL, Bernstein GA, et al. Pharmacokinetic interactions between cyclosporin and bupropion or methylphenidate. J Child Adolesc Psychopharmacol 2001; 11: 193–8
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: 614–9
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: 589–96
Feldman H, Crumrine P, Handen BL, et al. Methylphenidate in children with seizures and attention deficit disorder. Am J Dis Child 1989; 143: 1081–6
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: 670–4
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: 1–10
Teo S, San RH, Wayne VO, et al. D-methylphenidate is non-genotoxic in in vitro and in vitro assays. Mutat Res 2003; 537: 67–79
Dunnick J, Hailey JR. Experimental studies on the long-term effects of methylphenidate hydrochloride. Toxicology 1995; 103: 77–84
Selby J, Friedman GD, Fireman BH. Screening precription drugs for possible carcinogenicity: eleven to fifteen years of follow-up. Cancer Res 1989; 49: 5736–47
Berger S, Kugler JD, Thomas JA, et al. Sudden cardiac death in children and adolescents: introduction and overview. Pediatr Clin North Am 2004; 51: 1201–9
Physicians’ Desk Reference. Montvale, NJ: Thomson Healthcare, 2006
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: 1284–93
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: 292–301
Stevenson R, Wolraich ML. Stimulant medication therapy in the treatment of children with attention deficit hyperactivity disorder. Pediatr Clin North Am 1989; 36: 1183–97
Markowitz J, Patrick KS. Pharmacokinetics and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet 2001; 40: 753–72
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): 1304–13
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: 662–6
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: 61–5
Simpson D, Perry CM. Atomoxetine. Pediatric Drugs 2003; 5: 407–15
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: 179–85
Low K, Gendaszek AE. Illicit use of psychostimulents among college students: a preliminary study. Psychol Health Med 2002; 7: 283–7
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.
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Wolraich, M.L., McGuinn, L. & Doffing, M. Treatment of Attention Deficit Hyperactivity Disorder in Children and Adolescents. Drug-Safety 30, 17–26 (2007). https://doi.org/10.2165/00002018-200730010-00003
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DOI: https://doi.org/10.2165/00002018-200730010-00003