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Research Article
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Published Online: 19 August 2014

Cardiovascular Safety of Stimulants in Children with Attention-Deficit/Hyperactivity Disorder: A Nationwide Prospective Cohort Study

Publication: Journal of Child and Adolescent Psychopharmacology
Volume 24, Issue Number 6

Abstract

Objective: The purpose of this study was to determine whether stimulant users are at higher risk of a later cardiovascular event than are non-users, examining this association in both a national cohort and a population-based sample of children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD). We also aim to examine a possible dose-response relationship in such an association.
Methods: We conducted a longitudinal, prospective cohort study of all children born in Denmark between 1990 and 1999. Within this cohort, children with ADHD were identified. Data from national health registers on psychiatric and somatic diagnoses, stimulant prescriptions, cardiovascular risk factors, pre- and perinatal and sociodemographic covariates in all children and their parents were merged, using the unique personal identification number. Hazard ratios (HR) for cardiovascular events were estimated using Cox regression, adjusted for other known risk factors.
Results: In the total population (n=714,258 contributing a total of 6,767,982 person-years) use of stimulants increased the risk of a cardiovascular event; adjusted HR=1.83 (1.10–3.04). In children with ADHD (n=8300) stimulant treatment also increased the risk of a cardiovascular event (adjusted HR=2.20 [2.15–2.24]), with a complex time-dependent dose-response relationship.
Conclusions: This is the first nationwide cohort study of the cardiovascular safety of stimulants in children and adolescents, and it represents, to our knowledge, the longest prospective follow-up study. Cardiovascular events were rare but twice as likely in stimulant users as in non-users, both in the total national population and in children with ADHD. We found a complex, time- and dose-dependent interrelationship between cardiovascular adverse events and stimulant treatment in children and adolescents. Our results suggest a safety signal with an increased risk of cardiovascular disease associated with stimulant treatment in children and adolescents, even after adjusting for a number of potential confounders.

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References

Aileru AA, Carpentier RG: Mechanisms of the in vitro effects of amphetamine on rat sinus node automaticity and membrane potentials of atrial fibers. J Electrocardiol 29:123–130, 1996.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision. Washington, DC; American Psychiatric Association, 2000.
Arcieri R, Germinario EAP, Bonati M, Masi G, Zuddas A, Vella S, Chiarotti F, Panei, Italian Attention-Deficit/Hyperactivity Disorder Regional Reference Centers: Cardiovascular measures in children and adolescents with attention-deficit/hyperactivity disorder who are new users of methylphenidate and atomoxetine. J Child Adolesc Psychopharmacol 22:423–431, 2012.
Bahcelioglu M, Gozil R, Take G, Elmas C, Oktem H, Kadioglu D, Calguner E, Erdogan D, Sargon MF, Yazici AC, Tas M, Bardakci Y, Senol S: Dose-related immunohistochemical and ultrastructural changes after oral methylphenidate administration in cerebrum and cerebellum of the rat. World J Biol Psychiatry 10:531–543, 2009.
Buchhorn R, Conzelmann A, Willaschek C, Stork D, Taurines R, Renner TJ: Heart rate variability and methylphenidate in children with ADHD. Atten Defic Hyperact Disord 4:85–91, 2012a.
Buchhorn R, Muller C, Willaschek C, Norozi K.: 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 Pharm 2012:170935, 2012b.
Casis O, Espiña L, Gallego M: Effects of amphetamine on calcium and potassium currents in rat heart. J Cardiovasc Pharmacol 36:390–395, 2000.
Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA: ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med 365:1896–1904, 2011.
Dalsgaard S, Leckman JF, Nielsen HS, Simonsen M: Gender and injuries predict stimulant medication J Child Adolesc Psychopharmacol. 2014 [Epub ahead of print].
Dalsgaard S, Mortensen PB, Frydenberg M, Thomsen PH: Conduct problems, gender and adult psychiatric outcome of children with attention-deficit hyperactivity disorder. Br J Psychiatry 181:416–421, 2002.
Dalsgaard S, Nielsen HS, Simonsen M: Five-fold increase in national prevalence rates of attention-deficit/hyperactivity disorder medications for children and adolescents with autism spectrum disorder, attention-deficit/hyperactivity disorder, and other psychiatric disorders: A Danish register-based study. J Child Adolesc Psychopharmacol 23:432–439, 2013a.
Dalsgaard S, Humlum MK, Nielsen HS, Simonsen M. Common Danish standards in prescribing medication for children and adolescents with ADHD. Eur Child Adolesc Psychiatry, 2013b.
Dresel S, Krause J, Krause KH, LaFougere C, Brinkbaumer K, Kung HF, Hahn K, Tatsch K: Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med 27:1518–1524, 2000.
Findling RL, Short EJ, Manos MJ: Short-term cardiovascular effects of methylphenidate and Adderall. J Am Acad Child Adolesc Psychiatry 40:525–529, 2001.
Fusar–Poli P, Rubia K, Rossi G, Sartori G, Balottin U: Striatal dopamine transporter alterations in ADHD: Pathophysiology or adaptation to psychostimulants? A meta-analysis. Am J Psychiatry 169:264–272, 2012.
Graham J, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Dittmann RW, Dopfner M, Hamilton R, Hollis C, Holtmann M, Hulpke–Wette M, Lecendreux M, Rosenthal E, Rothenberger A, Santosh P, Sergeant J, Simonoff E, Sonuga–Barke E, Wong IC, Zuddas A, Steinhausen HC, Taylor E: European guidelines on managing adverse effects of medication for ADHD. Eur Child Adolesc Psychiatry 20:17–37, 2011.
Graham J, Coghill D: Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management. CNS Drugs 22:213–237, 2008.
Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen–Huynh MN, Ray WA, Selby JV: ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 306:2673–2683, 2011.
Hamilton RM, Rosenthal E, Hulpke–Wette M, Graham JG, Sergeant J: 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 22:63–70, 2012.
Henderson TA, Fischer VW: Effects of methylphenidate (Ritalin) on mammalian myocardial ultrastructure. Am J Cardiovasc Pathol 5:68–78, 1995.
Holick CN, Turnbull BR, Jones ME, Chaudhry S, Bangs ME, Seeger JD: Atomoxetine and cerebrovascular outcomes in adults. J Clin Psychopharmacol 29:453–460, 2009.
Huang YS, Tsai MH: Long-term outcomes with medications for attention-deficit hyperactivity disorder: Current status of knowledge. CNS Drugs 25:539–554, 2011.
Imeraj L, Antrop I, Roeyers H, Deschepper E, Bal S, Deboutte D: Diurnal variations in arousal: a naturalistic heart rate study in children with ADHD. Eur Child Adolesc Psychiatry 20:381–392, 2011.
Jiao X, Velez S, Ringstad J, Eyma V, Miller D, Bleiberg M: Myocardial infarction associated with adderall XR and alcohol use in a young man. J Am Board Fam Med 22:197–201, 2009.
Kauppila E, Vanninen E, Kuusela T, Kaurijoki S, Karhunen L, Pietilainen KH, Rissanen A, Kaprio J, Tiihonen J, Kuikka J: Cardiac repolarization and striatal dopamine transporter function are interrelated. Nucl Med Commun 30:713–717, 2009.
Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K: Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: Effects of methylphenidate as measured by single photon emission computed tomography. Neurosci Lett 285:107–110, 2000.
Kraut AA, Langner I, Lindemann C, Banaschewski T, Petermann U, Petermann F, Mikolajczyk RT, Garbe E: Comorbidities in ADHD children treated with methylphenidate: a database study. BMC Psychiatry 13:11, 2013.
Lang HC, Scheffler RM, Hu TW: The discrepancy in attention deficit hyperactivity disorder (ADHD) medications diffusion: 1994–2003: A global pharmaceutical data analysis. Health Policy 97:71–78, 2010.
Linnet KM, Dalsgaard S, Obel C, Wisborg K, Henriksen TB, Rodriguez A, Kotimaa A, Moilanen I, Thomsen PH, Olsen J, Jarvelin MR: Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: Review of the current evidence. Am J Psychiatry 160:1028–1040, 2003.
Linnet KM, Wisborg K, Secher NJ, Hove Thomsen P, Obel C, Dalsgaard S, Henriksen TB: Coffee consumption during pregnancy and the risk of hyperkinetic disorder and ADHD: A prospective cohort study. Acta Paediatr 98:173–179, 2009.
Martinez–Raga J, Knecht C, Szerman N, Martinez MI: Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs 27:15–30, 2013.
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 23:534–541, 2013.
Olfson M, Huang C, Gerhard T, Winterstein AG, Crystal S, Allison PD, Marcus SC: Stimulants and cardiovascular events in youth with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 51:147–156, 2012.
Palomar AR, Larios BN, De Sanchez VC, Perez LM, Lopez Fde L, Flores G, Gomez–Villalobos Mde J: Expression and distribution of dopamine transporter in cardiac tissues of the guinea pig. Neurochem Res 36:399–405, 2011.
Pedersen CB, Gøtzsche H, Møller JØ, Mortensen PB: The Danish Civil Registration System – A cohort of eight million persons. Dan Med Bull 53:441–449, 2006.
Ruwald MH, Ruwald AC, Tonder N: Methylphenidate induced ST elevation acute myocardial infarction [in Danish]. Ugeskr Laeger 174:647–648, 2012.
Samuels JA, Franco K, Wan F, Sorof JM: Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: A double-blind, randomized, cross-over trial. Pediatr Nephrol 21:92–95, 2006.
SAS Institute Inc.: SAS (release 9.2). Cary, NC: SAS Institute Inc.; 2000.
Schelleman H, Bilker WB, Kimmel SE, Daniel GW, Newcomb C, Guevara JP, Cziraky MJ, Strom BL, Hennessy S: Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry 169:178–185, 2012.
Schelleman H, Bilker WB, Strom BL, Kimmel SE, Newcomb C, Guevara JP, Daniel GW, Cziraky MJ, Hennessy S: Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics 127:1102–1110, 2011.
Schimpf R, Borggrefe M, Wolpert C. Clinical and molecular genetics of the short QT syndrome. Curr Opin Cardiol 23:192–198, 2008.
Tsuji H, Larson MG, Venditti FJ Jr., Manders ES, Evans JC, Feldman CL, Levy D: Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 94:2850–2855, 1996.
Vetter VL, Elia J, Erickson C, Berger S, Blum N, Uzark K, Webb CL: Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder [corrected]: A scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation 117:2407–2423, 2008.
Vitiello B, Elliott GR, Swanson JM, Arnold LE, Hechtman L, Abikoff H, Molina BS, Wells K, Wigal T, Jensen PS, Greenhill LL, Kaltman JR, Severe JB, Odbert C, Hur K, Gibbons R: Blood pressure and heart rate over 10 years in the multimodal treatment study of children with ADHD. Am J Psychiatry 169:167–177, 2012.
Westover AN, Halm EA: Do prescription stimulants increase the risk of adverse cardiovascular events? A systematic review. BMC Cardiovasc Disord 12:41, 2012.
Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A: Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics 120:e1494–e1501, 2007.
Winterstein AG, Gerhard T, Shuster J, Saidi A: Cardiac safety of methylphenidate versus amphetamine salts in the treatment of ADHD. Pediatrics 124:e75–80, 2009.
World Health Organization: The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: World Health Organization; 1993.

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cover image Journal of Child and Adolescent Psychopharmacology
Journal of Child and Adolescent Psychopharmacology
Volume 24Issue Number 6August 2014
Pages: 302 - 310
PubMed: 24956171

History

Published online: 19 August 2014
Published in print: August 2014
Published ahead of print: 23 June 2014

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Søren Dalsgaard, MD, PhD
National Centre for Register-based Research, School of Business and Social Sciences, Department of Economics and Business, Aarhus University, Aarhus, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark.
Department of Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway.
Department of Child and Adolescent Mental Health Odense, Research Unit, Mental Health Services in the Region of Southern Denmark, University of Southern Denmark, Denmark.
Anette Primdal Kvist, MSc
Department of Economics and Business, Aarhus University, Aarhus, Denmark.
James F. Leckman, MD
Child Study Center, Yale University School of Medicine, New Haven, Connecticut.
Helena Skyt Nielsen, PhD
Department of Economics and Business, Aarhus University, Aarhus, Denmark.
Marianne Simonsen, PhD
Department of Economics and Business, Aarhus University, Aarhus, Denmark.

Notes

Funding: The study was funded by grants from the Lundbeck Foundation, the Danish Council for Independent Research (Sapere Aude Starting Grant, 10-079597), Centre For Integrated Register-Based Research at Aarhus University (CIRRAU), The Foundation for Psychiatric Research in the Region of Southern Denmark, and Slagtermester Max Wørzner and Inger Wørzners Foundation.
Address correspondence to:Søren Dalsgaard, MD, PhDNational Centre for Register-Based ResearchAarhus UniversityFuglesangs Allé 4, Building K8210 Aarhus VDenmark
E-mail: [email protected]

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No competing financial interests exist.

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