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Risk of Serious Cardiovascular Problems with Medications for Attention-Deficit Hyperactivity Disorder

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Abstract

Attention-deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterized by persistent symptoms of inattention, hyperactivity and/or impulsivity. The proportion of patients diagnosed with ADHD receiving pharmacological treatments has increased enormously in recent years. Despite the well established efficacy and the good safety and tolerability profile, there is concern about the potential for rare but serious cardiovascular adverse events, as well as sudden cardiac death, with pharmacotherapies used for treating ADHD in children, adolescents and adults. The present paper aims to comprehensively and critically review the published evidence on the controversial association between medications approved for treating patients with ADHD and the risk of serious cardiovascular problems, specifically the risk of corrected QT interval (QTc) prolongation, and the risk of sudden cardiac death. A comprehensive search of relevant databases (PubMed, EMBASE and PsychINFO) was conducted to identify studies published in peer-reviewed journals until 21 July 2012. Clinical reports, as well as retrospective or prospective population-based studies with children, adolescents or adults as participants, of pharmacotherapies for ADHD reporting cardiovascular adverse events were included. Stimulant medications for ADHD, including methylphenidate and amphetamine derivatives, are generally safe and well tolerated. Small but statistically significant increases in blood pressure (BP) and heart rate (HR) are among the adverse events of stimulant treatment in all age groups. Similarly, the non-stimulant medication atomoxetine has also been associated with increased HR and BP, although as is the case with stimulants, these are generally minor, time limited and of minor clinical significance in children, adolescents or adults. Growing evidence suggests that these medications do not cause sudden and unexpected cardiac death or serious cardiovascular problems including statistically or clinically significant increases in QTc, at therapeutic doses in ADHD patients across the lifespan. Small decreases in mean systolic BP, diastolic BP and HR have been observed in studies with guanfacine-extended release (-XR) or clonidine-XR, two α2-adrenergic receptor agonists, administered alone or in combination with psychostimulants to children and adolescents with ADHD. There are also no statistically or clinically significant increases in QTc associated with clonidine or guanfacine. There are no reports of torsades de pointes clearly and directly related to medications used for treating ADHD in patients of all age groups. The risk for serious cardiovascular adverse events, including statistically or clinically significant increases in QTc, and sudden cardiac death associated with stimulants, atomoxetine or α2-adrenergic agonists prescribed for ADHD is extremely low and the benefits of treating individual patients with ADHD, after an adequate assessment, outweigh the risks. However, great caution is advised when considering stimulant and non-stimulant medications for patients of any age with a diagnosis of ADHD and a personal or family history or other known risk factors for cardiovascular disease.

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References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.

  2. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366:237–48.

    Article  PubMed  Google Scholar 

  3. Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol Med. 2006;36:159–65.

    Article  PubMed  Google Scholar 

  4. Kooij SJ, Bejerot S, Blackwell A, et al. European consensus statement on diagnosis and treatment of adult ADHD: the European Network Adult ADHD. BMC Psychiatry. 2010;10:67.

    Article  PubMed  Google Scholar 

  5. Stein MA. Impairment associated with adult ADHD. CNS Spectr. 2008;13(Suppl. 12):9–11.

    PubMed  Google Scholar 

  6. Sala M, Lazzaretti M, De Vidovich G, et al. Electrophysiological changes of cardiac function during antidepressant treatment. Ther Adv Cardiovasc Dis. 2009;3:29–43.

    Article  PubMed  Google Scholar 

  7. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013–22.

    Article  PubMed  CAS  Google Scholar 

  8. Bradley C. The behavior of children receiving Benzedrine. Am J Psychiatry. 1937;94:577–85.

    Google Scholar 

  9. Banaschewski T, Coghill D, Santosh P, et al. Long-acting medications for the hyperkinetic disorders: a systematic review and European treatment guideline. Eur Child Adolesc Psychiatry. 2006;15:476–95.

    Article  PubMed  Google Scholar 

  10. Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult ADHD using meta-analysis of effect sizes. J Clin Psychiatry. 2010;71:754–63.

    Article  PubMed  Google Scholar 

  11. National Collaborating Centre for Mental Health. Attention deficit hyperactivity disorder: the NICE guideline on diagnosis and management of ADHD in children, young people and adults. National clinical practice guideline number 72. London: Alden Press; 2009.

  12. National Institute of Mental Health. 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.

    Article  Google Scholar 

  13. Volkow ND, Wang GJ, Fowler JS, et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry. 1998;155:1325–31.

    PubMed  CAS  Google Scholar 

  14. Volkow ND, Wang GJ, Fowler JS, et al. Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry. 2004;161:1173–80.

    Article  PubMed  Google Scholar 

  15. Aagaard L, Hansen EH. The occurrence of adverse drug reactions reported for attention deficit hyperactivity disorder (ADHD) medications in the pediatric population: a qualitative review of empirical studies. Neuropsychiatr Dis Treat. 2011;7:729–44.

    Article  PubMed  CAS  Google Scholar 

  16. Graham J, Coghill D. Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management. CNS Drugs. 2008;22:213–37.

    Article  PubMed  CAS  Google Scholar 

  17. Findling RL, Biederman J, Wilens TE, et al. Short- and long-term cardiovascular effects of mixed amphetamine salts extended release in children. J Pediatr. 2005;147:348–54.

    Article  PubMed  CAS  Google Scholar 

  18. Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol (epub 2012 Jul 13).

  19. Vitiello B. Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function. Child Adolesc Psychiatr Clin N Am. 2008;17:459–74.

    Article  PubMed  Google Scholar 

  20. Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2005;66:253–9.

    Article  PubMed  Google Scholar 

  21. Wilens T, McBurnett K, Stein M, et al. ADHD treatment with once-daily OROS methylphenidate: final results from a long-term open-label study. J Am Acad Child Adolesc Psychiatry. 2005;44:1015–23.

    Article  PubMed  Google Scholar 

  22. Ballard JE, Boileau RA, Sleator EK, et al. Cardiovascular responses of hyperactive children to methylphenidate. JAMA. 1976;236:2870–4.

    Article  PubMed  CAS  Google Scholar 

  23. Volkow ND, Wang GJ, Fowler JS, et al. Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma. Psychopharmacology (Berl). 2003;166:264–70.

    CAS  Google Scholar 

  24. Gould MS, Walsh BT, Munfakh JL, et al. Sudden death and use of stimulant medications in youths. Am J Psychiatry. 2009;166:992–1001.

    Article  PubMed  Google Scholar 

  25. Pilgrim JL, Gerostamoulos D, Drummer OH, et al. Involvement of amphetamines in sudden and unexpected death. J Forensic Sci. 2009;54:478–85.

    Article  PubMed  CAS  Google Scholar 

  26. Moen MD, Keam SJ. Dexmethylphenidate extended release: a review of its use in the treatment of attention-deficit hyperactivity disorder. CNS Drugs. 2009;23:1057–83.

    Article  PubMed  CAS  Google Scholar 

  27. Santosh PJ, Sattar S, Canagaratnam M. Efficacy and tolerability of pharmacotherapies for attention-deficit hyperactivity disorder in adults. CNS Drugs. 2011;25:737–63.

    Article  PubMed  CAS  Google Scholar 

  28. Wilens TE, Biederman J, Lerner M, et al. Effects of once-daily osmotic-release methylphenidate on blood pressure and heart rate in children with attention-deficit/hyperactivity disorder: results from a one-year follow-up study. J Clin Psychopharmacol. 2004;24:36–41.

    Article  PubMed  CAS  Google Scholar 

  29. Biederman J, Mick E, Surman C, et al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2006;59:829–35.

    Article  PubMed  CAS  Google Scholar 

  30. Rösler M, Fischer R, Ammer R, Ose C, et al. A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder. Eur Arch Psychiatry Clin Neurosci. 2009;259:120–9.

    Article  PubMed  Google Scholar 

  31. Adler LA, Zimmerman B, Starr HL, et al. Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose-escalation study. J Clin Psychopharmacol. 2009;29:239–47.

    Article  PubMed  CAS  Google Scholar 

  32. Adler LA, Orman C, Starr HL, et al. Long-term safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: an open-label, dose-titration, 1-year study. J Clin Psychopharmacol. 2011;31:108–14.

    Article  PubMed  CAS  Google Scholar 

  33. Lucas PB, Gardner DL, Wolkowitz OM, et al. Methylphenidate-induced cardiac arrhythmias [letter]. N Engl J Med. 1986;315:1485.

    Article  PubMed  CAS  Google Scholar 

  34. Deshmankar BS, Lewis JA. Ventricular tachycardia associated with the administration of methylphenidate during guanethidine therapy. Can Med Assoc J. 1967;97:1166–7.

    PubMed  CAS  Google Scholar 

  35. Fernández-Fernández MA, Rufo-Campos M, Mateos-Checa R, et al. Cardiovascular side effects secondary to treatment with methylphenidate [in Spanish]. Rev Neurol. 2010;50:573–4.

    PubMed  Google Scholar 

  36. Nahshoni E, Sclarovsky S, Spitzer S, et al. Early repolarization in young children with attention-deficit/hyperactivity disorder versus normal controls: a retrospective preliminary chart review study. J Child Adolesc Psychopharmacol. 2009;19:731–5.

    Article  PubMed  Google Scholar 

  37. Hill SL, El-Khayat RH, Sandilands EA, et al. Electrocardiographic effects of methylphenidate overdose. Clin Toxicol (Phila). 2010;48:342–6.

    Article  CAS  Google Scholar 

  38. Klampfl K, Quattländer A, Burger R, et al. Case report: intoxication with high dose of long-acting methylphenidate (Concerta®) in a suicidal 14-year-old girl. Atten Defic Hyperact Disord. 2010;2:221–4.

    Article  PubMed  CAS  Google Scholar 

  39. Ozdemir E, Karaman MG, Yurteri N, et al. A case of suicide attempt with long-acting methylphenidate (Concerta). Atten Defic Hyperact Disord. 2010;2:103–5.

    Article  PubMed  Google Scholar 

  40. Hammerness P, Wilens T, Mick E, et al. Cardiovascular effects of longer-term, high-dose OROS methylphenidate in adolescents with attention deficit hyperactivity disorder. J Pediatr. 2009;155:84–9.

    Article  PubMed  CAS  Google Scholar 

  41. Ruwald MH, Ruwald AC, Tønder N. Methylphenidate induced ST elevation acute myocardial infarction [in Danish]. Ugeskr Laeger. 2012;174:647–8.

    PubMed  Google Scholar 

  42. Stiefel G, Besag FM. Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attention-deficit hyperactivity disorder. Drug Saf. 2010;33:821–42.

    Article  PubMed  CAS  Google Scholar 

  43. Kalant H, Kalant OJ. Death in amphetamine users: causes and rates. Can Med Assoc J. 1975;112:299–304.

    PubMed  CAS  Google Scholar 

  44. Lora-Tamayo C, Tena T, Rodríguez A. Amphetamine derivative related deaths. Forensic Sci Int. 1997;85:149–57.

    Article  PubMed  CAS  Google Scholar 

  45. Barr AM, Panenka WJ, MacEwan GW, et al. The need for speed: an update on methamphetamine addiction. J Psychiatry Neurosci. 2006;31:301–13.

    PubMed  Google Scholar 

  46. Sylvester AL, Agarwala B. Acute myocardial infarction in a teenager due to Adderall XR. Pediatr Cardiol. 2012;33:155–7.

    Article  PubMed  Google Scholar 

  47. Wilens TE, Spencer TJ, Biederman J. Short- and long-term cardiovascular effects of mixed amphetamine salts extended-release in adolescents with ADHD. CNS Spectr. 2005;10(Suppl. 15):22–30.

    PubMed  Google Scholar 

  48. Donner R, Michaels MA, Ambrosini PJ. Cardiovascular effects of mixed amphetamine salts extended release in the treatment of school-aged children with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61:706–12.

    Article  PubMed  CAS  Google Scholar 

  49. Weisler RH, Biederman J, Spencer TJ, et al. Long-term cardiovascular effects of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr. 2005;10:35–43.

    PubMed  Google Scholar 

  50. Cowles BJ. Lisdexamfetamine for treatment of attention-deficit/hyperactivity disorder. Ann Pharmacother. 2009;43:669–76.

    Article  PubMed  CAS  Google Scholar 

  51. Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010;6:317–27.

    Article  PubMed  CAS  Google Scholar 

  52. Elbe D, Macbride A, Reddy D. Focus on lisdexamfetamine: a review of its use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry. 2010;19:303–14.

    PubMed  Google Scholar 

  53. Findling R, Childress A, Cutler A, et al. Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50:395–405.

    Article  PubMed  Google Scholar 

  54. Adler LA, Weisler RH, Goodman DW, et al. Short-term effects of lisdexamfetamine dimesylate on cardiovascular parameters in a 4-week clinical trial in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2009;70:1652–61.

    Article  PubMed  CAS  Google Scholar 

  55. Hammerness P, Zusman R, Systrom D, et al. A cardiopulmonary study of lisdexamfetamine in adults with attention-deficit/hyperactivity disorder. World J Biol Psychiatry (epub 2012 May 6).

  56. Garnock-Jones KP, Keating GM. Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. Pediatr Drugs. 2009;11:203–26.

    Article  Google Scholar 

  57. Zerbe RL, Rowe H, Enas GG, et al. Clinical pharmacology of tomoxetine, a potential antidepressant. J Pharmacol Exp Ther. 1985;232:139–43.

    PubMed  CAS  Google Scholar 

  58. 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:E83–91.

    Article  PubMed  CAS  Google Scholar 

  59. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003;53:112–20.

    Article  PubMed  CAS  Google Scholar 

  60. Spencer TJ, Biederman J, Wilens TE, et al. Novel treatments for attention-deficit/hyperactivity disorder in children. J Clin Psychiatry. 2002;63(Suppl. 12):16–22.

    PubMed  CAS  Google Scholar 

  61. Kratochvil CJ, Milton DR, Vaughan BS, et al. Acute atomoxetine treatment of younger and older children with ADHD: a meta-analysis of tolerability and efficacy. Child Adolesc Psychiatry Ment Health. 2008;2:25.

    Article  PubMed  Google Scholar 

  62. Simpson D, Plosker GL. Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder. Drugs. 2004;64:205–22.

    Article  PubMed  CAS  Google Scholar 

  63. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry. 2002;63(Suppl. 12):50–5.

    PubMed  CAS  Google Scholar 

  64. Wolraich ML, McGuinn L, Doffing M. Treatment of attention deficit hyperactivity disorder in children and adolescents: safety considerations. Drug Saf. 2007;30:17–26.

    Article  PubMed  CAS  Google Scholar 

  65. Trzepacz PT, Williams DW, Feldman PD, et al. CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. Eur Neuropsychopharmacol. 2008;18:79–86.

    Article  PubMed  CAS  Google Scholar 

  66. Michelson D, Read HA, Ruff DD, et al. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry. 2007;46:242–51.

    Article  PubMed  Google Scholar 

  67. Loghin C, Haber H, Beasley CM, et al. Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers. Br J Clin Pharmacol (epub 2012 Jul 16).

  68. Jefferson JW. A review of the cardiovascular effects and toxicity of tricyclic antidepressants. Psychosom Med. 1975;37:160–79.

    PubMed  CAS  Google Scholar 

  69. Wilens TE, Biederman J, Baldessarini RJ, et al. Cardiovascular effects of therapeutic doses of tricyclic antidepressants in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1996;35:1491–501.

    Article  PubMed  CAS  Google Scholar 

  70. Wernicke JF, Faries D, Girod D, et al. Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf. 2003;26:729–40.

    Article  PubMed  CAS  Google Scholar 

  71. Stratteran® (atomoxetine tablets): US prescribing information. Indianapolis: Eli Lilly and Company; 2011.

  72. Peterson K, McDonagh MS, Fu R. Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis. Psychopharmacology. 2008;197:1–11.

    Article  PubMed  CAS  Google Scholar 

  73. Wilens TE, Newcorn JH, Kratochvil CJ, et al. Long-term atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder. J Pediatr. 2006;149:112–9.

    Article  PubMed  CAS  Google Scholar 

  74. McCarthy S, Cranswick N, Potts L, et al. Mortality associated with attention-deficit hyperactivity disorder (ADHD) drug treatment: a retrospective cohort study of children, adolescents and young adults using the general practice research database. Drug Saf. 2009;32:1089–96.

    Article  PubMed  Google Scholar 

  75. Dovies M, Cornelius V, Fogg C, et al. A study to examine cardiac events in patients prescribed atomoxetine in England: results of an interim modified prescription event monitoring study. Drug Saf. 2009;32:976–7.

    Google Scholar 

  76. Sert A, Gokcen C, Aypar E, et al. Effects of atomoxetine on cardiovascular functions and on QT dispersion in children with attention deficit hyperactivity disorder. Cardiol Young. 2012;22:158–61.

    Article  PubMed  Google Scholar 

  77. Lovecchio F, Kashani J. Isolated atomoxetine (Strattera) ingestions commonly result in toxicity. J Emerg Med. 2006;31:267–8.

    Article  PubMed  Google Scholar 

  78. Spiller HA, Lintner CP, Winter ML. Atomoxetine ingestions in children: a report from poison centers. Ann Pharmacother. 2005;39:1045–8.

    Article  PubMed  CAS  Google Scholar 

  79. Stojanovski SD, Robinson RF, Baker SD, et al. Children and adolescent exposures to atomoxetine hydrochloride reported to a poison control center. Clin Toxicol (Philadelphia). 2006;44:243–7.

    Article  Google Scholar 

  80. Barker MJ, Benitez JG, Ternullo S, et al. Acute oxcarbazepine and atomoxetine overdose with quetiapine. Vet Hum Toxicol. 2004;46:130–2.

    PubMed  Google Scholar 

  81. Sawant S, Daviss SR. Seizures and prolonged QTc with atomoxetine overdose [letter]. Am J Psychiatry. 2004;161:757.

    Article  PubMed  Google Scholar 

  82. Kashani J, Ruha AM. Isolated atomoxetine overdose resulting in seizure. J Emerg Med. 2007;32:175–8.

    Article  PubMed  Google Scholar 

  83. Scherer D, Hassel D, Bloehs R, et al. Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents. Br J Pharmacol. 2009;156:226–36.

    Article  PubMed  CAS  Google Scholar 

  84. Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: hERG mutations cause long QT syndrome. Cell. 1995;80:795–803.

    Article  PubMed  CAS  Google Scholar 

  85. Wang Q, Chen Q, Towbin JA. Genetics, molecular mechanisms and management of long QT syndrome. Ann Med. 1998;30:58–65.

    Article  PubMed  CAS  Google Scholar 

  86. Cohen DJ, Young JG, Nathanson JA, et al. Clonidine in Tourette’s syndrome. Lancet. 1979;2(8142):551–3.

    Article  PubMed  CAS  Google Scholar 

  87. 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;38:1551–9.

    Article  PubMed  CAS  Google Scholar 

  88. Gourlay S, Forbes A, Marriner T, et al. A placebo-controlled study of three clonidine doses for smoking cessation. Clin Pharmacol Ther. 1994;55:64–9.

    Article  PubMed  CAS  Google Scholar 

  89. Gowing LR, Farrell M, Ali RL, et al. α2-Adrenergic agonists in opioid withdrawal. Addiction. 2002;97:49–58.

    Article  PubMed  Google Scholar 

  90. Arnsten AF, Scahill L, Findling RL. Alpha-2 adrenergic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: emerging concepts from new data. J Child Adolesc Psychopharmacol. 2007;17:393–406.

    Article  PubMed  Google Scholar 

  91. Connor DF, Findling RL, Kollins SH, et al. Effects of guanfacine extended release on oppositional symptoms in children aged 6–12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial. CNS Drugs. 2010;24:755–68.

    PubMed  CAS  Google Scholar 

  92. Ming X, Mulvey M, Mohanty S, et al. Safety and efficacy of clonidine and clonidine extended-release in the treatment of children and adolescents with attention deficit and hyperactivity disorders. AHMT. 2011;2:105–12.

    Article  CAS  Google Scholar 

  93. Scahill L. Alpha-2 adrenergic agonists in children with inattention, hyperactivity and impulsiveness. CNS Drugs. 2009;23(Suppl. 1):43–9.

    Article  PubMed  CAS  Google Scholar 

  94. Cinnamon Bidwell L, Dew RE, Kollins SH. Alpha-2 adrenergic receptors and attention-deficit/hyperactivity disorder. Curr Psychiatry Rep. 2010;12:366–73.

    Article  PubMed  CAS  Google Scholar 

  95. Jain AK, Hiremath A, Michael R, et al. Clonidine and guanfacine in hypertension. Clin Pharmacol Ther. 1985;37:271–6.

    Article  PubMed  CAS  Google Scholar 

  96. Childress AC, Sallee FR. Revisiting clonidine: an innovative add-on option for attention-deficit/hyperactivity disorder. Drugs Today (Barc). 2012;48:207–17.

    CAS  Google Scholar 

  97. Jain R, Segal S, Kollins SH, et al. Clonidine extended-release tablets for pediatric patients with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50:171–9.

    Article  PubMed  Google Scholar 

  98. Kollins SH, Jain R, Brams M, et al. Clonidine extended-release tablets as add-on therapy to psychostimulants in children and adolescents with ADHD. Pediatrics. 2011;127:e1406–13.

    Article  PubMed  Google Scholar 

  99. Daviss WB, Patel NC, Robb AS, et al. Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis. J Am Acad Child Adolesc Psychiatry. 2008;47:189–98.

    Article  PubMed  Google Scholar 

  100. Fenichel RR. Combining methylphenidate and clonidine: the role of post-marketing surveillance. J Child Adolesc Psychopharmacol. 1995;5:155–6.

    Article  Google Scholar 

  101. Maloney MJ, Schwam JS. Clonidine and sudden death. Pediatrics. 1995;96:1176–7.

    PubMed  CAS  Google Scholar 

  102. Cantwell DP, Swanson J, Connor DF. Case study: adverse response to clonidine. J Am Acad Child Adolesc Psychiatry. 1997;36:539–44.

    Article  PubMed  CAS  Google Scholar 

  103. Schmittner J, Schroeder JR, Epstein DH, et al. QT interval increased after single dose of lofexidine. BMJ. 2004;329:1075.

    Article  PubMed  Google Scholar 

  104. Kofoed L, Tadepalli G, Oesterheld JR, et al. Case series: clonidine has no systematic effects on PR or QTc intervals in children. J Am Acad Child Adolesc Psychiatry. 1999;38:1193–6.

    Article  PubMed  CAS  Google Scholar 

  105. Catelli M, Feldman J, Bousquet P, et al. Protective effects of centrally acting sympathomodulatory drugs on myocardial ischemia induced by sympathetic overactivity in rabbits. Braz J Med Biol Res. 2003;36:85–95.

    Article  PubMed  CAS  Google Scholar 

  106. Girgis I, Chakko S, de Marchena E, et al. Effect of clonidine on heart rate variability in congestive heart failure. Am J Cardiol. 1998;82:335–7.

    Article  PubMed  CAS  Google Scholar 

  107. 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:e73–84.

    Article  PubMed  Google Scholar 

  108. Sallee F, McGough J, Wigal T, et al. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2009;48:155–65.

    Article  PubMed  Google Scholar 

  109. Biederman J, Melmed RD, Patel A, et al. Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD. CNS Spectr. 2008;13:1047–55.

    PubMed  CAS  Google Scholar 

  110. Spencer TJ, Greenbaum M, Ginsberg LD. Safety and effectiveness of coadministration of guanfacine extended release and psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19:501–10.

    Article  PubMed  Google Scholar 

  111. Wilens TE, Bukstein O, Brams M, et al. A controlled trial of extended-release guanfacine and psychostimulants for attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51:74–85.

    Article  PubMed  Google Scholar 

  112. Bélanger S, Warren A, Hamilton R, et al. Cardiac risk assessment before the use of stimulant medications in children and youth. Paediatr Child Health. 2009;14:579–92.

    PubMed  Google Scholar 

  113. Knight M. Stimulant drug therapy for attention deficit disorder (with or without hyperactivity) and sudden cardiac death. Pediatrics. 2007;119:154–5.

    Article  PubMed  Google Scholar 

  114. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006;354:1445–8.

    Article  PubMed  CAS  Google Scholar 

  115. Villalba L. Follow up review of AERS search identifying cases of sudden death occurring with drugs used for the treatment of attention deficit hyperactivity disorder (ADHD), February 28, 2006 (online). http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210b_07_01_safetyreview.pdf. Accessed 30 May 2011.

  116. Berger S, Utech L, Hazinski MF. Sudden death in children and adolescents. Pediatr Clin North Am. 2004;51:1653–77.

    Article  PubMed  Google Scholar 

  117. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365:1896–904.

    Article  PubMed  CAS  Google Scholar 

  118. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306:2673–83.

    Article  PubMed  CAS  Google Scholar 

  119. Schelleman H, Bilker WB, Strom BL, et al. Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics. 2011;127:1102–10.

    Article  PubMed  Google Scholar 

  120. Winterstein AG, Gerhard T, Shuster J, et al. Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2007;120:e1494–501.

    Article  PubMed  Google Scholar 

  121. Winterstein AG, Gerhard T, Shuster J, et al. Cardiac safety of methylphenidate versus amphetamine salts in the treatment of ADHD. Pediatrics. 2009;124:e75–80.

    Article  PubMed  Google Scholar 

  122. Olfson M, Huang C, Gerhard T, et al. Stimulants and cardiovascular events in youth with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51:147–56.

    Article  PubMed  Google Scholar 

  123. Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169:178–85.

    Article  PubMed  Google Scholar 

  124. Elia J, Vetter VL. Cardiovascular effects of medications for the treatment of attention-deficit hyperactivity disorder: what is known and how should it influence prescribing in children? Pediatr Drugs. 2010;12:165–75.

    Article  Google Scholar 

  125. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Elements recommended for inclusion in summaries of product characteristics for methylphenidate-containing medicinal products authorised for the treatment of ADHD in children aged six years and above and adolescents. Wording recommended by the CHMP on 22 January 2009 (online). http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Methylphenidate_31/WC500011184.pdf. Accessed 18 Mar 2011.

  126. Vitiello B, Towbin K. Stimulant treatment of ADHD and risk of sudden death in children. Am J Psychiatry. 2009;166:955–7.

    Article  PubMed  Google Scholar 

  127. Warren AE, Hamilton RM, Bélanger SA, et al. Cardiac risk assessment before the use of stimulant medications in children and youth: a joint position statement by the Canadian Paediatric Society, the Canadian Cardiovascular Society, and the Canadian Academy of Child and Adolescent Psychiatry. Can J Cardiol. 2009;25:625–30.

    Article  PubMed  CAS  Google Scholar 

  128. Hamilton R, Gray C, Bélanger SA, et al. Cardiac risk assessment before the use of stimulant medications in children and youth: a joint position statement by the Canadian Paediatric Society, the Canadian Cardiovascular Society and the Canadian Academy of Child and Adolescent Psychiatry. J Can Acad Child Adolesc Psychiatry. 2009;18:349–55.

    PubMed  CAS  Google Scholar 

  129. Swanson J, Gupta S, Lam A, et al. Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies. Arch Gen Psychiatry. 2003;60:204–11.

    Article  PubMed  CAS  Google Scholar 

  130. Silva RR, Skimming JW, Muniz R. Cardiovascular safety of stimulant medications for pediatric attention-deficit hyperactivity disorder. Clin Pediatr (Phila). 2010;49:840–51.

    Google Scholar 

  131. Kuehn BM. Stimulant use linked to sudden death in children without heart problems. JAMA. 2009;302:613–4.

    Article  PubMed  CAS  Google Scholar 

  132. Hayden GF, Kramer MS, Horwitz RI. The case–control study: a practical review for the clinician. JAMA. 1982;247:326–31.

    Article  PubMed  CAS  Google Scholar 

  133. The U.S. Food and Drug Administration. Communication about an ongoing safety review of stimulant medications used in children with attention-deficit/hyperactivity disorder (ADHD), last updated 04/20/2011 (online). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm165858.htm. Accessed 25 Mar 2011.

  134. Westover AN, Halm EA. Do prescription stimulants increase the risk of adverse cardiovascular events? A systematic review. BMC Cardiovasc Disord. 2012;12:41.

    Article  PubMed  Google Scholar 

  135. Vitiello B, Glen R, Elliott GR, et al. Blood pressure and heart rate over 10 years in the Multimodal Treatment Study of children with ADHD. Am J Psychiatry. 2012;169:167–77.

    Article  PubMed  Google Scholar 

  136. Perrin JM, Friedman RA, Knilans TK, et al. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics. 2008;122:451–3.

    Article  PubMed  Google Scholar 

  137. Hamilton RM, Rosenthal E, Hulpke-Wette M, et al. Cardiovascular considerations of attention deficit hyperactivity disorder medications: a report of the European Network on Hyperactivity Disorders work group, European Attention Deficit Hyperactivity Disorder Guidelines Group on attention deficit hyperactivity disorder drug safety meeting. Cardiol Young. 2012;22:63–70.

    Article  PubMed  Google Scholar 

  138. Mahle WT, Hebson C, Strieper MJ. Electrocardiographic screening in children with attention-deficit hyperactivity disorder. Am J Cardiol. 2009;104:1296–9.

    Article  PubMed  Google Scholar 

  139. Denchev P, Kaltman JR, Schoenbaum M, et al. Modeled economic evaluation of alternative strategies to reduce sudden cardiac death among children treated for attention deficit/hyperactivity disorder. Circulation. 2010;121:1329–37.

    Article  PubMed  Google Scholar 

  140. Graham J, Banaschewski T, Buitelaar J, et al. European guidelines on managing adverse effects of medication for ADHD. Eur Child Adolesc Psychiatry. 2011;20:17–37.

    Article  PubMed  CAS  Google Scholar 

  141. Charach A, Dashti B, Carson P, et al. Attention deficit hyperactivity disorder: effectiveness of treatment in at-risk preschoolers; long-term effectiveness in all ages; and variability in prevalence, diagnosis, and treatment. Comparative effectiveness review no. 44 (prepared by the McMaster University Evidence-based Practice Center under Contract No. MME2202 290-02-0020). AHRQ publication no. 12-EHC003-EF. Rockville (MD): Agency for Healthcare Research and Quality, October 2011 (online). http://www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed 29 Oct 2012.

  142. Gerhard T, Winterstein AG, Olfson M, et al. Pre-existing cardiovascular conditions and pharmacological treatment of adult ADHD. Pharmacoepidemiol Drug Saf. 2010;19:457–64.

    PubMed  CAS  Google Scholar 

  143. Keltikangas-Jarvinen L, Pulkki-Raback L, Puttonen S, et al. Childhood hyperactivity as a predictor of carotid artery intima media thickness over a period of 21 years: the cardiovascular risk in young Finns study. Psychosom Med. 2006;68:509–16.

    Article  PubMed  Google Scholar 

  144. Buchhorn R, Müller C, Willaschek C, et al. How to predict the impact of methylphenidate on cardiovascular risk in children with attention deficit disorder: methylphenidate improves autonomic dysfunction in children with ADHD. ISRN Pharmacol (epub 5 Mar 2012).

  145. Mick E, McGough JJ, Middleton FA, et al. Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:466–72.

    Article  PubMed  CAS  Google Scholar 

  146. Pliszka SR. Pharmacologic treatment of attention-deficit/hyperactivity disorder: efficacy, safety and mechanisms of action. Neuropsychol Rev. 2007;17:61–72.

    Article  PubMed  Google Scholar 

  147. Prasad S, Furr AJ, Zhang S, et al. Baseline values from the electrocardiograms of children and adolescents with ADHD. Child Adolesc Psychiatry Ment Health. 2007;1:11.

    Article  PubMed  Google Scholar 

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Acknowledgements

Dr. Jose Martinez-Raga and Dr. Nestor Szerman have received honoraria for being speakers and on advisory boards for Janssen Pharmaceuticals. Dr. Carlos Knecht and Dr. Isabel Martinez report no conflicts of interest that are directly relevant to the content of this manuscript. No sources of funding were used in the preparation, review or approval of this manuscript.

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Authors and Affiliations

  1. Teaching Unit of Psychiatry and Psychological Medicine, Medicine Department, University of Valencia, Valencia, Spain

    Jose Martinez-Raga

  2. Servicio de Psiquiatría, Hospital Universitario Dr. Peset, Avda. Gaspar Aguilar 90, 46017, Valencia, Spain

    Jose Martinez-Raga

  3. Pharmacy Department, Universidad CEU Cardenal Herrera, Valencia, Spain

    Jose Martinez-Raga & María I. Martinez

  4. Unidad de Salud Mental de Vila-Real, Departamento de Salud de La Plana, Agencia Valenciana de Salut, Castellon, Spain

    Carlos Knecht

  5. Servicio Salud Mental Retiro, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Nestor Szerman

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  1. Jose Martinez-Raga
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Correspondence to Jose Martinez-Raga.

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Martinez-Raga, J., Knecht, C., Szerman, N. et al. Risk of Serious Cardiovascular Problems with Medications for Attention-Deficit Hyperactivity Disorder. CNS Drugs 27, 15–30 (2013). https://doi.org/10.1007/s40263-012-0019-9

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