CNS Drugs

, Volume 23, Supplement 1, pp 21–31 | Cite as

Efficacy and Safety Limitations of Attention-Deficit Hyperactivity Disorder Pharmacotherapy in Children and Adults

  • Sharon B. Wigal
Review Article

Abstract

There have been major advances in the treatment and understanding of attention-deficit hyperactivity disorder (ADHD) in the last decade. Among these are the availability of newer stimulant formulations, an appreciation of the combined effects of medication and behavioural therapies, and a better understanding of the neurobiology of the disorder in children (aged 6–12 years), adolescents and adults. This article focuses on the evaluation of the efficacy and safety profiles of medications used for the management of ADHD.

In assessing the various medical treatments for ADHD, certain issues and analyses have become important to address. The diagnosis, characterization and quantification of ADHD symptoms are crucial to assessing treatment effectiveness. A standardized setting for measuring the severity of ADHD symptoms is the laboratory school protocol, which simulates a school environment with tightly controlled timing of measurements. This method has been adapted successfully to the adult workplace environment to help with the evaluation of adult ADHD symptoms.

Statistical analyses, such as effect size and number needed to treat, may aid in the comparison and interpretation of ADHD study results. Although an objective approach to evaluating the efficacy and safety profiles of the available medications provides necessary details about the medical options, typical clinical decisions are often based on trial and error and may be individualized based on a patient’s daily routine, comorbidities and risk factors.

Stimulants remain the US FDA-approved medical treatment of choice for patients with ADHD and are associated with an exceptional response rate. Findings of the Multimodal Treatment of Children With ADHD study suggest that the combination of behavioural and medical therapy may benefit most patients. Nonstimulant agents, such as atomoxetine (FDA-approved), and several non-approved agents, bupropion, guanfacine and clonidine, may offer necessary alternatives to the stimulants. This is especially important for patients who have comorbidities that are contraindicated for stimulant use based on medical issues and/or risk for stimulant abuse. Typical psychiatric comorbidities in patients with ADHD include oppositional defiant disorder, conduct disorder, major depressive disorder, bipolar disorder, anxiety, substance abuse disorder, tic disorder, and Tourette’s syndrome.

Although relatively safe, both stimulants and atomoxetine have class-related warnings and contraindications and are associated with adverse effects that require consideration when prescribing. Polypharmacy is a common psychiatric approach to address multiple symptoms or emergent adverse effects of necessary treatments. Future research may provide an improved understanding of polypharmacy and better characterization of the factors that influence the diagnosis and successful treatment of patients with ADHD.

References

  1. 1.
    Bradley C. The behaviour of children receiving benzedrine. Am J Psychiatry 1937; 94: 577–85Google Scholar
  2. 2.
    Pelham WE, Aronoff HR, Midlam JK, et al. A comparison of Ritalin and Adderall: efficacy and time-course in children with attention-deficit/hyperactivity disorder. Pediatrics 1999; 103: e43PubMedCrossRefGoogle Scholar
  3. 3.
    Stein MA. Innovations in attention-deficit/hyperactivity disorder pharmacotherapy: long-acting stimulant and nonstimulant treatments. Am J Manag Care 2004; 10: S89–98PubMedGoogle Scholar
  4. 4.
    Weisler RH. Review of long-acting stimulants in the treatment of attention deficit hyperactivity disorder. Expert Opin Pharmacother 2007; 8: 745–58PubMedCrossRefGoogle Scholar
  5. 5.
    Wigal SB, Wigal TL. The laboratory school protocol: its origin, use, and new applications. J Atten Disord 2006; 10: 92–111PubMedCrossRefGoogle Scholar
  6. 6.
    Swanson JM, Lerner M, Wigal T, et al. The use of a laboratory school protocol to evaluate concepts about efficacy and side effects of new formulations of stimulant medications. J Atten Disord 2002; 6Suppl. 1: S73–88PubMedGoogle Scholar
  7. 7.
    Wigal SB, Gupta S, Guinta D, et al. Reliability and validity of the SKAMP rating scale in a laboratory school setting. Psychopharmacol Bull 1998; 34: 47–53PubMedGoogle Scholar
  8. 8.
    Wigal T, Wigal S, Steinhoff K, et al. Establishing a clinical diagnosis of ADHD in adults: the QUEST method. Advances in ADHD 2007; 2: 17–24Google Scholar
  9. 9.
    Becker LA. Effect size [online]. Available from URL: http://web.uccs.edu/lbecker/Psy590/es.htm [Accessed 2009 Feb 9]
  10. 10.
    Faraone SV, Sergeant J, Gillberg C, et al. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2003; 2: 104–13PubMedGoogle Scholar
  11. 11.
    Owens EB, Hinshaw SP, Kraemer HC, et al. Which treatment for whom for ADHD? Moderators of treatment response in the MTA. J Consult Clin Psychol 2003; 71: 540–52PubMedCrossRefGoogle Scholar
  12. 12.
    Stein MA, McGough JJ. The pharmacogenomic era: promise for personalizing attention deficit hyperactivity disorder therapy. Child Adolesc Psychiatr Clin N Am 2008; 17: 475–90PubMedCrossRefGoogle Scholar
  13. 13.
    Van der Oord S, Prins PJ, Oosterlaan J, et al. Treatment of attention deficit hyperactivity disorder in children: predictors of treatment outcome. Eur Child Adolesc Psychiatry 2008; 17: 73–81PubMedCrossRefGoogle Scholar
  14. 14.
    Biederman J, Krishnan S, Zhang Y, et al. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther 2007; 29: 450–63PubMedCrossRefGoogle Scholar
  15. 15.
    Greenhill LL, Findling RL, Swanson JM. A double-blind, placebo-controlled study of modified-release methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics 2002; 109: e39PubMedCrossRefGoogle Scholar
  16. 16.
    Greenhill LL, Muniz R, Ball RR, et al. Efficacy and safety of dexmethylphenidate extended-release capsules in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006; 45: 817–23PubMedCrossRefGoogle Scholar
  17. 17.
    Markowitz JS, Straughn AB, Patrick KS. Advances in the pharmacotherapy of attention-deficit-hyperactivity disorder: focus on methylphenidate formulations. Pharmacotherapy 2003; 23: 1281–99PubMedCrossRefGoogle Scholar
  18. 18.
    McCracken JT, Biederman J, Greenhill LL, et al. Analog classroom assessment of a once-daily mixed amphetamine formulation, SLI381 (Adderall XR), in children with ADHD. J Am Acad Child Adolesc Psychiatry 2003; 42: 673–83PubMedCrossRefGoogle Scholar
  19. 19.
    McGough JJ, 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
  20. 20.
    Michelson D, Faries 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: e83PubMedCrossRefGoogle Scholar
  21. 21.
    Wolraich ML, 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: 883–92PubMedCrossRefGoogle Scholar
  22. 22.
    Elia J, Borcherding BG, Rapoport JL, et al. Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true nonresponders? Psychiatry Res 1991; 36: 141–55PubMedCrossRefGoogle Scholar
  23. 23.
    Scottish Intercollegiate Guidelines Network. Attention deficit and hyperkinetic disorders in children and young people: a national clinical guideline. Edinburgh, Scotland: SIGN Executive, 2001Google Scholar
  24. 24.
    Spencer T, Biederman J, Wilens T, et al. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry 1996; 35: 409–32PubMedCrossRefGoogle Scholar
  25. 25.
    Swanson J, Wigal S, Wigal T, et al. A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (The COMACS Study). Pediatrics 2004; 113: 206–16CrossRefGoogle Scholar
  26. 26.
    Wigal SB, Wigal TL, Kollins SH. Advances in methylphenidate drug delivery systems for ADHD therapy. Advances in ADHD 2006; 1: 4–7Google Scholar
  27. 27.
    Spencer TJ, Wilens TE, Biederman J, et al. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attention-deficit/ hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006; 28: 266–79PubMedCrossRefGoogle Scholar
  28. 28.
    Faraone SV. Understanding the effect size of ADHD medications: implications for clinical care [online]. Available from URL: http://www.medscape.com/viewarticle/461543 [Accessed 2009 Feb 9]
  29. 29.
    The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/ hyperactivity disorder. Arch Gen Psychiatry 1999; 56: 1073–86CrossRefGoogle Scholar
  30. 30.
    Jensen PS, Garcia JA, Glied S, et al. Cost-effectiveness of ADHD treatments: findings from the multimodal treatment study of children with ADHD. Am J Psychiatry 2005; 162: 1628–36PubMedCrossRefGoogle Scholar
  31. 31.
    Swanson JM, Kraemer HC, Hinshaw SP, et al. Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry 2001; 40: 168–79PubMedCrossRefGoogle Scholar
  32. 32.
    The MTA Cooperative Group. Moderators and mediators of treatment response for children with attention-deficit/ hyperactivity disorder: the multimodal treatment study of children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999; 56: 1088–96CrossRefGoogle Scholar
  33. 33.
    Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry 2007; 46: 989–1002PubMedCrossRefGoogle Scholar
  34. 34.
    Mohammadi MR, Akhondzadeh S. Pharmacotherapy of attention-deficit/hyperactivity disorder: nonstimulant medication approaches. Expert Rev Neurother 2007; 7: 195–201PubMedCrossRefGoogle Scholar
  35. 35.
    Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366: 237–48PubMedCrossRefGoogle Scholar
  36. 36.
    Banaschewski T, Roessner V, Dittmann RW, et al. Non-stimulant medications in the treatment of ADHD. Eur Child Adolesc Psychiatry 2004; 13Suppl. 1: I102–16PubMedGoogle Scholar
  37. 37.
    Wigal SB, McGough JJ, McCracken JT, et al. A laboratory school comparison of mixed amphetamine salts extended release (Adderall XR) and atomoxetine (Strattera) in school-aged children with attention deficit/hyperactivity disorder. J Atten Disord 2005; 9: 275–89PubMedCrossRefGoogle Scholar
  38. 38.
    Greenhill LL, Newcorn JH, Gao H, et al. Effect of two different methods of initiating atomoxetine on the adverse event profile of atomoxetine. J Am Acad Child Adolesc Psychiatry 2007; 46: 566–72PubMedCrossRefGoogle Scholar
  39. 39.
    Biederman J, Melmed RD, Patel A, et al. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics 2008; 121: e73–84PubMedCrossRefGoogle Scholar
  40. 40.
    Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1999; 38: 1551–9PubMedCrossRefGoogle Scholar
  41. 41.
    Daviss WB, Bentivoglio P, Racusin R, et al. Bupropion sustained release in adolescents with comorbid attention-deficit/hyperactivity disorder and depression. J Am Acad Child Adolesc Psychiatry 2001; 40: 307–14PubMedCrossRefGoogle Scholar
  42. 42.
    Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry 2001; 158: 1067–74PubMedCrossRefGoogle Scholar
  43. 43.
    Wigal SB, Biederman J, Swanson JM, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with or without prior stimulant treatment for attention-deficit/hyperactivity disorder: pooled analysis of 3 randomized, double-blind, placebo-controlled studies. Prim Care Companion J Clin Psychiatry 2006; 8: 352–60PubMedGoogle Scholar
  44. 44.
    Palumbo DR, Sallee FR, Pelham Jr WE, et al. Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes. J Am Acad Child Adolesc Psychiatry 2008; 47: 180–8PubMedCrossRefGoogle Scholar
  45. 45.
    Arnsten AFT. Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs 2009; 23Suppl. 1: 33–41PubMedCrossRefGoogle Scholar
  46. 46.
    Scahill L. Alpha-2 Adrenergic agonists in children with inattention, hyperactivity and impulsiveness. CNS Drugs 2009; 23Suppl. 1: 43–49PubMedCrossRefGoogle Scholar
  47. 47.
    Biederman J, Swanson JM, Wigal SB, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study. Pediatrics 2005; 116: e777–84PubMedCrossRefGoogle Scholar
  48. 48.
    Faraone SV, Biederman J, Monuteaux M, et al. Long-term effects of extended-release mixed amphetamine salts treatment of attention-deficit/hyperactivity disorder on growth. J Child Adolesc Psychopharmacol 2005; 15: 191–202PubMedCrossRefGoogle Scholar
  49. 49.
    Gale C, Oakley-Browne M. Generalised anxiety disorder. Clin Evid 2002; 8: 974–90PubMedGoogle Scholar
  50. 50.
    Geddes JR, Butler R. Depressive disorders. Am Fam Physician 2002; 65: 1395–7PubMedGoogle Scholar
  51. 51.
    Pitschel-Walz G, Leucht S, Bauml J, et al. The effect of family interventions on relapse and rehospitalization in schizophrenia — a meta-analysis. Schizophr Bull 2001; 27: 73–92PubMedCrossRefGoogle Scholar
  52. 52.
    Biederman J, Spencer TJ, Newcorn JH, et al. Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data. Psychopharmacology (Berl) 2007; 190: 31–41CrossRefGoogle Scholar
  53. 53.
    Bangs ME, Emslie GJ, Spencer TJ, et al. Efficacy and safety of atomoxetine in adolescents with attention-deficit/ hyperactivity disorder and major depression. J Child Adolesc Psychopharmacol 2007; 17: 407–20PubMedCrossRefGoogle Scholar
  54. 54.
    Ghaemi SN, Martin A. Defining the boundaries of childhood bipolar disorder. Am J Psychiatry 2007; 164: 185–8PubMedCrossRefGoogle Scholar
  55. 55.
    Scheffer RE, Kowatch RA, Carmody T, et al. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Am J Psychiatry 2005; 162: 58–64PubMedCrossRefGoogle Scholar
  56. 56.
    Scahill L, Pachler M. Treatment of hyperactivity in children with pervasive developmental disorders. J Child Adolesc Psychiatr Nurs 2007; 20: 59–62PubMedCrossRefGoogle Scholar
  57. 57.
    Research Units on Pediatric Psychopharmacology Autism Network. Randomized, controlled, crossover trial of methyphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005; 62: 1266–74CrossRefGoogle Scholar
  58. 58.
    Spencer TJ, Sallee FR, Gilbert DL, et al. Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome. J Atten Disord 2008; 11: 470–81PubMedCrossRefGoogle Scholar
  59. 59.
    Wilens TE, Adamson J, Sgambati S, et al. Do individuals with ADHD self-medicate with cigarettes and substances of abuse? Results from a controlled family study of ADHD. Am J Addict 2007; 16Suppl. 1: 14–21PubMedCrossRefGoogle Scholar
  60. 60.
    Wilson JJ. ADHD and substance use disorders: developmental aspects and the impact of stimulant treatment. Am J Addict 2007; 16Suppl. 1: 5–11PubMedCrossRefGoogle Scholar
  61. 61.
    Biederman J, Monuteaux MC, Spencer T, et al. Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled10-year follow-up study. Am J Psychiatry 2008; 165: 597–603PubMedCrossRefGoogle Scholar
  62. 62.
    US Food and Drug Administration. FDA asks attention-deficit hyperactivity disorder (ADHD) drug manufacturers to develop patient medication guides [online]. Available from URL: http://www.fda.gov/cder/drug/infopage/ADHD/default.htm [Accessed 2009 Feb 9]
  63. 63.
    US Food and Drug Administration. FDA directs ADHD drug manufacturers to notify patients about cardiovascular adverse events and psychiatric adverse events [online]. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01568.html [Accessed 2009 Feb 9]
  64. 64.
    Eli Lilly and Company. Strattera PI. 2007 (Data on file)Google Scholar
  65. 65.
    Stein MA. Unravelling sleep problems in treated and untreated children with ADHD. J Child Adolesc Psycho-pharmacol 1999; 9: 157–68CrossRefGoogle Scholar
  66. 66.
    Findling RL, Bukstein OG, Melmed RD, et al. A randomized, double-blind, placebo-controlled, parallel-group study of methylphenidate transdermal system in pediatric patients with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2008; e1-11Google Scholar
  67. 67.
    Kratochvil CJ, Wilens TE, Greenhill LL, et al. Effects of long-term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006; 45: 919–27PubMedCrossRefGoogle Scholar
  68. 68.
    Faraone S, Biederman J, Morley C, et al. Effects of stimulants on height and weight: a review of literature. J Am Acad Child Adolesc Psychiatry 2008; 47: 1–16PubMedGoogle Scholar
  69. 69.
    Swanson JM, Elliott GR, Greenhill LL, et al. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry 2007; 46: 1015–27PubMedCrossRefGoogle Scholar
  70. 70.
    Swanson J, Arnold LE, Kraemer H, et al. Evidence, interpretation, and qualification from multiple reports of long-term outcomes in the Multimodal Treatment Study of Children With ADHD (MTA): part I: executive summary. J Atten Disord 2008; 12: 4–14PubMedCrossRefGoogle Scholar
  71. 71.
    Swanson J, Arnold LE, Kraemer H, et al. Evidence, interpretation, and qualification from multiple reports of long-term outcomes in the Multimodal Treatment Study of children With ADHD (MTA): part II: supporting details. J Atten Disord 2008; 12: 15–43PubMedCrossRefGoogle Scholar
  72. 72.
    Spencer TJ, Newcorn JH, Kratochvil CJ, et al. Effects of atomoxetine on growth after 2-year treatment among pediatric patients with attention-deficit/hyperactivity disorder. Pediatrics 2005; 116: e74–80PubMedCrossRefGoogle Scholar
  73. 73.
    Baptista-Neto L, Dodds A, Rao S, et al. An expert opinion on methylphenidate treatment for attention deficit hyperactivity disorder in pediatric patients with epilepsy. Expert Opin Investig Drugs 2008; 17: 77–84PubMedCrossRefGoogle Scholar
  74. 74.
    Torres AR, Whitney J, Gonzalez-Heydrich J. Attention-deficit/hyperactivity disorder in pediatric patients with epilepsy: review of pharmacological treatment. Epilepsy Behav 2008; 12: 217–33PubMedCrossRefGoogle Scholar
  75. 75.
    Wernicke JF, Holdridge KC, Jin L, et al. Seizure risk in patients with attention-deficit-hyperactivity disorder treated with atomoxetine. Dev Med Child Neurol 2007; 49: 498–502PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Sharon B. Wigal
    • 1
  1. 1.Child Development CenterUniversity of California IrvineIrvineUSA

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