title: Cardiovascular Effects of Stimulant and Non-Stimulant Medication for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis of Trials of Methylphenidate, Amphetamines and Atomoxetine.
abstract: BACKGROUND
  Many children and adolescents with attention deficit/hyperactivity disorder (ADHD) are treated with stimulant and non-stimulant medication. ADHD medication may be associated with cardiovascular effects. It is important to identify whether mean group effects translate into clinically relevant increases for some individual patients, and/or increase the risk for serious cardiovascular adverse events such as stroke or sudden death.
  
  
  OBJECTIVE
  To evaluate potential cardiovascular effects of these treatments, we conducted a systematic review and meta-analysis of the effects of methylphenidate (MPH), amphetamines (AMP), and atomoxetine (ATX) on diastolic and systolic blood pressure (DBP, SBP) and heart rate (HR) in children and adolescents with ADHD.
  
  
  METHODS
  We conducted systematic searches in electronic databases (PsychINFO, EMBASE and Medline) to identify published trials which involved individuals who were (i) diagnosed with ADHD and were aged between 0-18 years; (ii) treated with MPH, AMP or ATX and (iii) had their DBP and SBP and/or HR measured at baseline (pre) and the endpoint (post) of the study treatment. Studies with an open-label design or a double-blind randomised control design of any duration were included. Statistical analysis involved calculating differences between pre- and post-treatment measurements for the various cardiovascular parameters divided by the pooled standard deviation. Further, we assessed the percentage of clinically relevant increased BP or HR, or documented arrhythmias.
  
  
  RESULTS
  Eighteen clinical trials met the inclusion criteria (10 for MPH, 5 for AMP, and 7 for ATX) with data from 5837 participants (80.7% boys) and average duration of 28.7 weeks (range 4-96 weeks). All three medications were associated with a small, but statistically significant pre-post increase of SBP (MPH: standard mean difference [SMD] 0.25, 95% confidence interval [CI] 0.08-0.42, p < 0.01; AMP: SMD 0.09, 95% CI 0.03-0.15, p < 0.01; ATX: SMD 0.16, 95% CI 0.04-0.27, p = 0.01). MPH did not have a pre-post effect on DBP and HR. AMP treatment was associated with a small but statistically significant pre-post increase of DBP (SMD 0.16, CI 0.03-0.29, p = 0.02), as was ATX treatment (SMD 0.22, CI 0.10-0.34, p < 0.01). AMP and ATX were associated with a small to medium statistically significant pre-post increase of HR (AMP: SMD 0.37, CI 0.13-0.60, p < 0.01; ATX: SMD 0.43, CI 0.26-0.60, p < 0.01). The head-to-head comparison of the three medications did not reveal significant differences. Sensitivity analyses revealed that AMP studies of <18 weeks reported higher effect sizes on DBP compared with longer duration studies (F(1) = 19.55, p = 0.05). Further, MPH studies published before 2007 reported higher effect sizes on SBP than studies after 2007 (F(1) = 5.346, p = 0.05). There was no effect of the following moderators: type of medication, doses, sample size, age, gender, type of ADHD, comorbidity or dropout rate. Participants on medication reported 737 (12.6%) other cardiovascular effects. Notably, 2% of patients discontinued their medication treatment due to any cardiovascular effect. However, in the majority of patients, the cardiovascular effects resolved spontaneously, medication doses were changed or the effects were not considered clinically relevant. There were no statistically significant differences between the medication treatments in terms of the severity of cardiovascular effects.
  
  
  CONCLUSIONS
  Statistically significant pre-post increases of SBP, DBP and HR were associated with AMP and ATX treatment in children and adolescents with ADHD, while MPH treatment had a statistically significant effect only on SBP in these patients. These increases may be clinically significant for a significant minority of individuals that experience larger increases. Since increased BP and HR in general are considered risk factors for cardiovascular morbidity and mortality during adult life, paediatric patients using ADHD medication should be monitored closely and regularly for HR and BP.
authors.affiliation: Department of Cognitive Neuroscience (204), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 9100 HB, Nijmegen, The Netherlands.
authors.forename: Leonie
authors.identifier: http://orcid.org/0000-0002-6563-9820
authors.initials: L
authors.lastname: Hennissen
authors.affiliation: Department of Cognitive Neuroscience (204), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 9100 HB, Nijmegen, The Netherlands.
authors.forename: Mireille J
authors.initials: MJ
authors.lastname: Bakker
authors.affiliation: Paediatric Psychopharmacology, Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.affiliation: Child and Adolescent Neuropsychiatric Unit, Department of Biomedical Sciences, University of Cagliari and "A. Cao" Microcitemico Paediatric Hospital, Cagliari, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Carucci
authors.affiliation: Division of Neuroscience, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.|Departments of Paediatrics and Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Coghill
authors.affiliation: Child and Adolescent Psychiatry, Department of Neurosciences, KU Leuven, Louvain, Belgium.
authors.forename: Marina
authors.initials: M
authors.lastname: Danckaerts
authors.affiliation: Paediatric Psychopharmacology, Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Ralf W
authors.initials: RW
authors.lastname: Dittmann
authors.affiliation: Division of Psychiatry and Applied Psychology, University of Nottingham, Nottingham, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Hollis
authors.affiliation: Department of Psychology, University of Southampton, Highfield, Southampton, UK.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kovshoff
authors.affiliation: School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Suzanne
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Nagy
authors.affiliation: Department of Psychology, University of Southampton, Highfield, Southampton, UK.
authors.forename: Edmund
authors.initials: E
authors.lastname: Sonuga-Barke
authors.affiliation: Research Department of Practice and Policy, UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1 N 1AX, UK.|Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.
authors.forename: Ian C K
authors.initials: IC
authors.lastname: Wong
authors.affiliation: Child and Adolescent Neuropsychiatric Unit, Department of Biomedical Sciences, University of Cagliari and "A. Cao" Microcitemico Paediatric Hospital, Cagliari, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zuddas
authors.affiliation: Department of Paediatric Cardiology, Evelina London Children's Hospital, St Thomas' Hospital, London, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Rosenthal
authors.affiliation: Department of Cognitive Neuroscience (204), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 9100 HB, Nijmegen, The Netherlands. Jan.Buitelaar@radboudumc.nl.|Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, The Netherlands. Jan.Buitelaar@radboudumc.nl.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
mesh_terms: D000293:Adolescent; D000662:Amphetamines / Q000009:adverse effects / Q000627:therapeutic use; D000069445:Atomoxetine Hydrochloride / Q000009:adverse effects / Q000627:therapeutic use; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007223:Infant; D008774:Methylphenidate / Q000009:adverse effects / Q000627:therapeutic use; D011619:Psychotropic Drugs / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000662:Amphetamines; D000697:Central Nervous System Stimulants; D011619:Psychotropic Drugs; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride