Abstract
Objective
The aim of this study was to assess the type and frequency of adverse events (AEs) in children with attention-deficit/hyperactivity disorder (ADHD) treated with methylphenidate or atomoxetine over a 5-year period in a large naturalistic study.
Methods
We draw on data from the Italian ADHD Registry, a national database for postmarketing phase IV pharmacovigilance of ADHD medications across 90 centers. AEs were defined as severe or mild as per the classification of the Italian Medicines Agency. AE frequency in the two treatment groups was compared using incidence rates per 100 person-years (IR100PY) and incidence rate ratios (IRRs). Mantel–Haenszel adjusted IRRs were calculated to control for psychiatric comorbidity.
Results
A total of 1350 and 753 participants (aged 6–18 years, mean age 10.7 ± 2.8) were treated with methylphenidate and atomoxetine, respectively, from 2007 to 2012. Ninety participants (7 %) were switched from methylphenidate to atomoxetine, and 138 (18 %) from atomoxetine to methylphenidate. Thirty-seven children treated with atomoxetine and 12 with methylphenidate had their medication withdrawn. Overall, 645 patients (26.8 %) experienced at least one mild AE (including decreased appetite and irritability, for both drugs) and 95 patients (3.9 %) experienced at least one severe AE (including severe gastrointestinal events). IR100PY were significantly higher in the atomoxetine-treated group compared with the methylphenidate-treated group for a number of mild and severe AEs and for any severe or mild AEs. After controlling for comorbidities, IRR was still significantly higher in the atomoxetine group compared with the methylphenidate group for a number of mild (decreased appetite, weight loss, abdominal pain, dyspepsia, stomach ache, irritability, mood disorder and dizziness) and severe (gastrointestinal, neuropsychiatric, and cardiovascular) AEs.
Conclusions
In this naturalistic study, methylphenidate had a better safety profile than atomoxetine.
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References
Polanczyk GV, Willcutt EG, Salum GA, Kieling C, Rohde LA. ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol. 2014;43(2):434–42.
Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164(6):942–8.
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(2):159–65.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366(9481):237–48.
Cortese S, Lecendreux M, Mouren MC, Konofal E. ADHD and insomnia. J Am Acad Child Adolesc Psychiatry. 2006;45(4):384–5.
Speranza M, Revah-Levy A, Cortese S, Falissard B, Pham-Scottez A, Corcos M. ADHD in adolescents with borderline personality disorder. BMC Psychiatry. 2011;11:158.
Pliszka S. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894–921.
NICE. National Institute for Health and Care Excellence. Attention deficit hyperactivity disorder: diagnosis and management of ADHD in children, young people and adults. Clinical Guidance 72 (CG72). 2008. Available at: http://www.nice.org.uk/CG72. Accessed 10 July 2015.
Taylor E, Dopfner M, Sergeant J, et al. European clinical guidelines for hyperkinetic disorder: first upgrade. Eur Child Adolesc Psychiatry. 2004;13(Suppl 1):17–30.
Schneider BN, Enenbach M. Managing the risks of ADHD treatments. Curr Psychiatry Rep. 2014;16(10):479.
Cortese S, Holtmann M, Banaschewski T, et al. Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry. 2013;54(3):227–46.
Hanwella R, Senanayake M, de Silva V. Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis. BMC Psychiatry. 2011;11:176.
Bushe CJ, Savill NC. Suicide related events and attention deficit hyperactivity disorder treatments in children and adolescents: a meta-analysis of atomoxetine and methylphenidate comparator clinical trials. Child Adolesc Psychiatry Ment Health. 2013;7:19.
Sangal RB, Owens J, Allen AJ, Sutton V, Schuh K, Kelsey D. Effects of atomoxetine and methylphenidate on sleep in children with ADHD. Sleep. 2006;29(12):1573–85.
Garg J, Arun P, Chavan BS. Comparative short term efficacy and tolerability of methylphenidate and atomoxetine in attention deficit hyperactivity disorder. Indian Pediatr. 2014;51(7):550–4.
Wang Y, Zheng Y, Du Y, et al. Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Aust N Z J Psychiatry. 2007;41(3):222–30.
Purgato M, Barbui C, Stroup S, Adams C. Pragmatic design in randomized controlled trials. Psychol Med. 2014;2:1–6.
Panei P, Arcieri R, Vella S, Bonati M, Martini N, Zuddas A. Italian attention-deficit/hyperactivity disorder registry. Pediatrics. 2004;114(2):514.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.
Panei P, Arcieri R, et al. Italian Register of ADHD (attention deficit hyperactivity disorder): first year report (2007–2008) [in Italian]. 2008. Rapporti ISTISAN 08/35: p. 31.
Ruggiero S, Rafaniello C, Bravaccio C, et al. Safety of attention-deficit/hyperactivity disorder medications in children: an intensive pharmacosurveillance monitoring study. J Child Adolesc Psychopharmacology. 2012;22(6):415–22.
Italian Medicines Agency. Available at: http://www.agenziafarmaco.gov.it/wscs_render_attachment_by_id/111.18359.11338317741280417.pdf?id=111.18364.1133831774289. Accessed 10 July 2015.
Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology. 1990;1:43–6.
Vitiello B, Elliott GR, Swanson JM, 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.
US FDA. Drug safety warning. Available at: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm110235.htm#AtomoxetineMarketedasStrattera:SeriousLiverInjury. Accessed 10 July 2015.
US FDA. Drug safety warning. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm051733.htm. Accessed 10 July 2015.
Italian Medicines Agency. Available at: http://www.agenziafarmaco.gov.it/it/content/nota-39. Accessed 10 July 2015.
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;45:919–27.
Acknowledgments
The authors would like to thank Profs. Rossi and Pascotto and Dr. Bravaccio for their contribution to a previous version of this manuscript, as well as all participating Regional Reference Centres: Region Liguria (Dr. Edvige Veneselli, Dr. Maria Josè Baldizzone, Dr. Gianni De Nobili); region Lazio (Dr. Marco Marcelli, Prof. Maria Giulia Torrioli, Dr. Stefano Vicari, Dr. Sandro Bartolomeo, Prof. Paolo Curatolo, Prof. Roberta Penge, Prof. Antonio Persico, Dr. Maria Grazia Melegari, Dr. Renato Donfrancesco); region Emilia-Romagna (Dr. Stefano Palazzi, Dr. Antonella Squarcia, Dr. Stefano Trebbi, Dr Roberto Parisi, Dr. Nicoletta Modena, Dr. Flaviana Murru, Dr. Andrea Tullini, Dr. Simona Chiodo); region Veneto (Dr. Ettore Morbin, Prof. Bernardo Dalla Bernardina, Dr. Dino Maschietto, Dr.ssa Cristina Mambelli, Prof. Antonio Condini, Dr. Maurizio Brighenti, Dr. Piergiorgio Miottello, Dr. Roberto Tombolato, Dr Lenio Rizzo, Dr. Maria Rondinone, Dr. Alberto Angarano); region Sicilia (Dr. Sebastiano Musumeci, Dr. Giancarlo Costanza, Dr. Donatella Ragusa, Dr. Giuseppe Santangelo, Gaetano Tortorella, Dr. Renata Rizzo); region Friuli Venezia Giulia (Dr. Antonella Merlo, Dr. Marco Carrozzi, Dr. Giuseppe Zappulla); region Lombardia (Dr. Alberto Ottolini, Dr. Daniele Arisi, Prof. Alessandra Tiberti, Dr. Maria L. Terragni, Dr. Paola Morosini, Dr. Corrado Meraviglia, Prof. Carlo Lenti, Dr. Marco Pezzani, Prof. Umberto Balottin, Prof. Paolo Piccinelli, Dr. Simonetta Oriani, Dr. Emilio Brunati, Dr. Massimo Molteni, Dr. Francesco Rinaldi, Dr. Giorgio Rossi, Dr. Roberto Segala, Dr. Ottaviano Martinelli, Dr. Antonella Costantino, Dr. Francesco Bossi); region Piemonte (Dr. Flavio Guccione, Dr. Paolo Bailo, Dr. Bianca Bassi, Dr. Marco Rolando, Dr. Francesca Ragazzo, Prof. Orazio Pirro, Dr. Giovanni Galloni, Dr. Ilaria Maraucci); region Sardegna (Prof. Alessandro Zuddas, Prof. Massimo Tondi); province Bolzano (Prof. Andreas Conca, Dr. Gianni de Polo, Dr. Donatella Arcangeli, Dr. Ingo Stermann); province Trento (Dr. Costanza Giannelli); region Val D’Aosta (Dr. Giovanni Voltolin); region Abruzzo (Dr. Maria Pia Legge, Prof. Enzo Sechi, Dr. Elena Gennaro); region Calabria (Dr. Antonio La Vitola, Dr. Antonia Zavettieri, Dr. Daniela Mallamaci); region Puglia (Dr. Angelo Spina, Prof. Lucia Margari, Dr. Angelo Massagli); region Campania (Prof. Antonio Pascotto, Dr.ssa Carmela Bravaccio, Prof. Francesco Rossi, Dr.ssa Annalisa Capuano, Dr. Rosario Granato, Dott.ssa Giampina Grimaldi); region Umbria (Prof. Giovanni Mazzotta); region Toscana (Dr. Gabriele Masi, Prof. Giovanni Cioni); region Marche (Dr. Maurizio Pincherle, Dr. Vera Stoppioni, Dr. Rosolino Tasca, Dr. Maria Antonietta Tavoni).
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Prof. Curatolo has received honoraria from Shire for participation in Advisory Board Meetings. Drs. Cortese, Panei, Arcieri, Germinaro, Capuano, Margari, and Chiarotti declare no competing interests.
Research involving human participants
The study was approved by the Ethic Committee of the Italian National Institute of Health in 2005. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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No funding was used to assist with the conduct of the study or the preparation of this manuscript.
Informed consent
Informed consent was obtained from all individual patients whose data was extracted from the Italian ADHD Registry and used in the analysis presented in this manuscript.
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Cortese, S., Panei, P., Arcieri, R. et al. Safety of Methylphenidate and Atomoxetine in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): Data from the Italian National ADHD Registry. CNS Drugs 29, 865–877 (2015). https://doi.org/10.1007/s40263-015-0266-7
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DOI: https://doi.org/10.1007/s40263-015-0266-7