Understanding the Risk of Using Medications for Attention Deficit Hyperactivity Disorder with Respect to Physical Growth and Cardiovascular Function

      The effects of stimulant medications and atomoxetine on physical growth and on cardiovascular function are reviewed in light of the most recent data, with attention to clinical implications and research needs. Although these medications have a favorable benefit/risk profile and do not induce clinically significant changes in growth or cardiovascular function in the majority of cases, careful patient monitoring is needed to identify individuals at risk for negative outcomes. More research is needed to elucidate the mechanism of growth suppression to estimate better the risk for rare but life-threatening events and test the effectiveness of monitoring procedures.
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      References

        • Greenhill L.L.
        • Swanson J.M.
        • Vitiello B.
        • et al.
        Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial.
        J Am Acad Child Adolesc Psychiatry. 2001; 40: 180-187
        • Wigal T.
        • Greenhill L.L.
        • Chuang S.
        • et al.
        Safety and tolerability of methylphenidate in preschool children with ADHD.
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 1294-1303
        • Efron D.
        • Jarman F.
        • Barker M.
        Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial.
        Pediatrics. 1997; 100: 662-666
        • Research Units on Pediatric Psychopharmacology (RUPP)
        Autism network. A randomized controlled crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity.
        Arch Gen Psychiatry. 2005; 62: 1266-1274
        • Zuvekas S.H.
        • Vitiello B.
        • Norquist N.S.
        Recent trends in stimulant medication use among U.S. children.
        Am J Psychiatry. 2006; 163: 579-585
        • Scheffler R.M.
        • Hinshaw S.P.
        • Modrek S.
        • et al.
        The global market for ADHD medications.
        Health Aff. 2007; 26: 450-457
        • Ross R.G.
        Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder.
        Am J Psychiatry. 2006; 163: 1149-1152
        • Wilens T.E.
        • Faraone S.V.
        • Biederman J.
        • et al.
        Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature.
        Pediatrics. 2003; 111: 179-185
        • Safer D.J.
        • Allen R.P.
        • Barr E.
        Depression of growth in hyperactive children with stimulant drugs.
        N Engl J Med. 1972; 287: 217-220
        • Safer D.J.
        • Allen R.P.
        • Barr E.
        Growth rebound after termination of stimulant drugs.
        J Pediatr. 1975; 86: 113-116
        • Mattes J.A.
        • Gittelman R.
        Growth of hyperactive children on maintenance regimen of methylphenidate.
        Arch Gen Psychiatry. 1983; 40: 317-321
        • Klein R.G.
        • Landa B.
        • Mattes J.A.
        • et al.
        Methylphenidate and growth in hyperactive children. A controlled withdrawal study.
        Arch Gen Psychiatry. 1988; 45: 1127-1130
        • Klein R.G.
        • Mannuzza S.
        Hyperactive boys almost grown up. III. Methylphenidate effects on ultimate height.
        Arch Gen Psychiatry. 1988; 45: 1131-1134
        • Gualtieri C.T.
        • Hicks R.E.
        • Patrick K.
        • et al.
        Growth hormone and prolactin secretion in adults and hyperactive children: relation to methylphenidate serum levels.
        Psychoneuroendocrinology. 1981; 6: 331-339
        • Greenhill L.L.
        • Puig-Antich J.
        • Novacenko H.
        • et al.
        Prolactin, growth hormone and growth responses in boys with attention deficit disorder and hyperactivity treated with methylphenidate.
        J Am Acad Child Psychiatry. 1984; 23: 58-67
        • Greenhill L.L.
        • Puig-Antich J.
        • Chambers W.
        • et al.
        Growth hormone, prolactin, and growth responses in hyperkinetic males treated with d-amphetamine.
        J Am Acad Child Psychiatry. 1981; 20: 84-103
        • American Academy of Pediatrics
        Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder.
        Pediatrics. 2001; 108: 1033-1044
        • Greenhill L.L.
        • Pliszka S.
        • Dulcan M.K.
        • et al.
        Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.
        J Am Acad Child Adolesc Psychiatry. 2002; 41: 26S-49S
        • Spencer T.
        • Biederman J.
        • Harding M.
        • et al.
        Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays?.
        J Am Acad Child Adolesc Psychiatry. 1996; 35: 1460-1469
        • Swanson J.
        • Greenhill L.
        • Wigal T.
        • et al.
        Stimulant-related reductions of growth rates in the PATS.
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 1304-1313
        • Swanson J.M.
        • Elliott G.R.
        • Greenhill L.L.
        • 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: 1014-1026
        • Kramer J.R.
        • Loney J.
        • Ponto L.B.
        • 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: 517-524
        • Sund A.N.
        • Zeiner P.
        Does extended medication with amphetamine or methylphenidate reduce growth in hyperactive children?.
        Nord J Psychiatry. 2002; 56: 53-57
        • Lisska M.C.
        • Rivkees S.A.
        Daily methylphenidate use slows the growth of children: a community based study.
        J Pediatr Endocrinol Metab. 2005; 16: 711-718
        • Poulton A.
        • Cowell C.T.
        Slowing of growth in height and weight on stimulants: a characteristic pattern.
        J Paediatr Child Health. 2003; 39: 180-185
        • Biederman J.
        • Faraone S.V.
        • Monuteaux M.C.
        • et al.
        Growth deficits and attention-deficit/hyperactivity disorder revisited: impact of gender, development, and treatment.
        Pediatrics. 2003; 111: 1010-1016
        • 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: 762-769
        • Faraone S.V.
        • 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: 191-202
        • Spencer T.J.
        • Faraone S.V.
        • Biederman J.
        • et al.
        Does prolonged therapy with a long-acting stimulant suppress growth in children with ADHD?.
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 527-537
        • Pliszka S.R.
        • Matthews T.L.
        • Braslow K.J.
        • et al.
        Comparative effects of methylphenidate and mixed salts amphetamine on height and weight in children with attention-deficit/hyperactivity disorder.
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 520-526
        • Charach A.
        • Figueroa M.
        • Chen S.
        • et al.
        Stimulant treatment over 5 years: effect on growth.
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 415-421
        • Zachor D.A.
        • Roberts A.W.
        • Hodgens J.B.
        • et al.
        Effects of long-term psychostimulant medication on growth of children wth ADHD.
        Res Dev Disabil. 2006; 27: 162-174
        • Farietta-Murray T.
        • Castellanos D.
        • Katsikas S.
        Effects of stimulants on Hispanic boys' height and weight.
        J Am Acad Child Adolesc Psychiatry. 2007; 46: 150-151
        • Poulton A.
        Growth on stimulant medication; clarifying the confusion: a review.
        Arch Dis Child. 2005; 90: 801-806
        • MTA Cooperative Group
        A 14-Month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder (ADHD).
        Arch Gen Psychiatry. 1999; 56: 1073-1086
        • Vitiello B.
        • Severe J.B.
        • Greenhill L.L.
        • et al.
        Methylphenidate dosage for children with ADHD over time under controlled conditions: lessons from the MTA.
        J Am Acad Child Adolesc Psychiatry. 2001; 40: 188-196
        • Holtkamp K.
        • Peters-Wallraf B.
        • Wueller S.
        • et al.
        Methyphenidate-related growth impairment.
        J Child Adolesc Psychopharmacol. 2002; 12: 55-61
        • Satterfield J.H.
        • Cantwell D.P.
        • Schell A.
        • et al.
        Growth of hyperactive children with methylphenidate.
        Arch Gen Psychiatry. 1979; 36: 212-217
        • Batterson K.D.
        • Southard K.A.
        • Dawson D.V.
        • et al.
        The effect of chronic methylphenidate administration on tooth maturation in a sample of Caucasian children.
        Pediatr Dent. 2005; 27 (292–7)
        • Wolraich M.L.
        • Greenhill L.L.
        • Pelham W.
        • et al.
        Randomized, controlled trial of OROS methylphenidate once a day in children with attention-deficit/hyperactivity disorder.
        Pediatrics. 2001; 108: 883-892
        • Vitiello B.
        • Abikoff H.B.
        • Chuang S.Z.
        • et al.
        Effectiveness of methylphenidate in the 10-month continuation phase of the Preschoolers with ADHD Treatment Study (PATS).
        J Child Adolesc Psychopharmacol. 2007; 17: 593-603
        • Bosse R.
        • Fumagalli F.
        • Jaber M.
        • et al.
        Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter.
        Neuron. 1997; 19: 127-138
        • Dunbar F.
        • Kusumakar V.
        • Daneman D.
        • et al.
        Growth and sexual maturation during long-term treatment with risperidone.
        Am J Psychiatry. 2004; 161: 918-920
        • Bereket A.
        • Turan S.
        • Karaman M.G.
        • et al.
        Height, weight, IGF-1, IGFBP-3 and thyroid functions in prepubertal children with attention deficit hyperactivity disorder: effect of methylphenidate.
        Horm Res. 2005; 63: 159-164
        • Cheng J.Y.
        • Chen R.Y.
        • Ko J.S.
        • et al.
        Efficacy and safety of atomoxetine for attention-deficit hyperactivity disorder in children and adolescents—meta-analysis and meta-regression analysis.
        Psychopharmacol. 2007; 194: 197-209
        • Kratochvil C.J.
        • Wilens T.E.
        • Greenhill L.L.
        • et al.
        Effects of long-term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder.
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 919-927
        • Spencer T.J.
        • Newcorn J.H.
        • Kratochvil C.J.
        • et al.
        Effects of atomoxetine on growth after 2-year treatment among pediatric patients with attention-deficit/hyperactivity disorder.
        Pediatrics. 2005; 116: e74-e80
        • Volkow N.D.
        • Wang G.J.
        • Fowler J.
        • et al.
        Cardiovascular effects of methylpenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma.
        Psychopharmacol. 2003; 166: 264-270
        • Klein-Schwartz W.
        Abuse and toxicity of methylphenidate.
        Curr Opin Pediatr. 2002; 14: 219-223
        • Findling R.L.
        • Short E.J.
        • Manos M.J.
        Short-term cardiovascular effects of methylphenidate and Adderall.
        J Am Acad Child Adolesc Psychiatry. 2001; 40: 525-529
        • Wilens T.
        • Biederman J.
        • Lerner M.
        Effects of once-daily osmotic-release methylphenidate on blood pressure and hear rate in children with attention-deficit/hyperactivity disorder.
        J Clin Psychopharmacol. 2004; 24: 36-41
        • Wilens T.
        • Spencer T.
        • Biederman J.
        Short- and long-term cardiovascular effects of mixed amphetamine salts extended-release in adolescents with ADHD.
        CNS Spectr. 2005; 10: 22-30
        • 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: 829-835
        • Wilens T.E.
        • Hammerness P.G.
        • Biederman J.
        • et al.
        Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder.
        J Clin Psychiatry. 2005; 66: 253-259
        • Samuels J.A.
        • Franco K.
        • Wan F.
        • et al.
        Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross over trial.
        Pediatr Nephrol. 2006; 21: 92-95
        • Findling R.L.
        • Biederman J.
        • Wilens T.E.
        • et al.
        Short- and long-term cardiovascular effects of mixed amphetamine salts extended release in children.
        J Pediatr. 2005; 57: 147-154
        • Spencer T.
        • Biederman J.
        • Wilens T.
        • et al.
        A large, double-blind, randomized clincial trial of methylphenidate in the treatment of adults with ADHD.
        Biol Psychiatry. 2005; 57: 456-463
        • Donner R.
        • Michaels M.A.
        • Ambrosini P.J.
        Cardiovascular effects of mixed amphetamine salts extended release in the treatment of school-aged children with attention-deficit/hyperactivity disorder.
        Biol Psychiatry. 2007; 61: 706-712
        • Weisler R.H.
        • Biederman J.
        • Spencer T.J.
        • et al.
        Long-term cardiovascular effects of mixed amphetamine salts extended release in adults with ADHD.
        CNS Spectr. 2005; 10: 35-43
        • Nissen S.E.
        ADHD drugs and cardiovascular risk.
        N Engl J Med. 2006; 354: 1445-1448
        • Wilens T.E.
        • Prince J.B.
        • Spencer T.J.
        • et al.
        Stimulants and sudden death: what is a physician to do?.
        Pediatrics. 2006; 118: 1215-1219
        • Roberts W.C.
        Sudden cardiac death: definitions and causes.
        Am J Cardiology. 1986; 57: 1410-1413
        • Liberthson R.R.
        Sudden death from cardiac causes in children and young adults.
        N Engl J Med. 1996; 334: 1039-1044
        • Villalba L.
        • Racoosin J.
        Postmarketing safety review of sudden death during treatment with drugs used to treat ADHD.
        Food and Drug Administration. 2006; (Available at:) (Accessed September 5, 2007)
      1. Mc Neil Pharmaceuticals. Product label for concerta. 2007. Available at: http://www.fda.gov/cder/foi/label/2007/021121s014lbl.pdf. Accessed September 5, 2007.

        • Gutgesell H.
        • Atkins D.
        • Barst R.
        • et al.
        AHA scientific statement: cardiovascular monitoring of children and adolescents receiving psychotropic drugs.
        J Am Acad Child Adolesc Psychiatry. 1999; 38: 1047-1050
        • Wilens T.
        • Spencer T.J.
        Combining methylphenidate and clonidine: a clinically sound medication option.
        J Am Acad Child Adolesc Psychiatry. 1999; 38: 614-616
        • Swanson J.
        • Flockhart D.
        • Udrea D.
        • et al.
        Clonidine in the treatment of ADHD: questions about safety and efficacy.
        J Child Adolesc Psychopharmacol. 1995; 5: 301-304
        • Wernicke J.F.
        • Faries D.
        • Girod D.
        • et al.
        Cardiovascular effects of atomoxetine in children, adolescents, and adults.
        Drug Saf. 2003; 26: 729-740
        • Spiller H.A.
        • Lintner C.P.
        • Winter M.L.
        Atomoxetine ingestions in children: a report from poison centers.
        Ann Pharmacother. 2005; 39: 1045-1048
        • Pliszka S.R.
        • Crimson M.L.
        • Hughes C.W.
        • et al.
        The Texas children's medication algorithm project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder.
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 642-657
        • Biederman J.
        • Thisted R.A.
        • Greenhill L.L.
        • et al.
        Estimation of the association between desipramine and the risk for sudden death in 5 to 14 year old children.
        J Clin Psychiatry. 1995; 56: 87-93