BMJ Confidential: For Review Only Methylph enidate for attention deficit hyperactivity disorder in children and adolescents. A Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials Journal: BMJ Manuscript ID: BMJ.2015.027217 Article Type: Research BMJ Journal: BMJ Date Submitted by the Author: 28-May-2015 Complete List of Authors: Storebø, Ole Jakob; Psychiatric Research Unit, Psychiatric Department Krogh, Helle; Psychiatric Research Unit, Psychiatric Department Ramstad, Erica Linda; Psychiatric Research Unit, Psychiatric Department Maia, Carlos; Federal University of Rio, Holmskov, Mathilde; Psychiatric Research Unit, Psychiatric Department Skoog, Maria; Copenhagen Trial Unit, Centre for Clinical Intervention Research Nilausen, Trine; Psychiatric Research Unit, Psychiatric Department Magnusson, Frederik; Psychiatric Research Unit, Psychiatric Department Zwi, Morris; Islington CAMHS, Whittington Health Gillies, Donna; Western Sydney Local Health District, Mental Health Rosendal, Susanne; Psychiatric Centre North Zealand, Groth, Camilla; Pediatric Department,, Herlev University Hospital Rasmussen, Kirsten; Psychiatric Research Unit, Psychiatric Department Gauci, Dorothy; Department of Health Information and Research, Kirubakaran, Richard; South Asian Cochrane Network & Center, Prof. BV Moses Center for Evidence-Informed Health Care and Health Policy Forsbøl, Bente; Child Psychiatric Clinic, Child and Adolescent Psychiatric Department Simonsen, Erik; Psychiatric Research Unit, Psychiatric Department Gluud, Christian; Rigshospitalet, Copenhagen University Hospital, The Copenhagen Trial Unit, Centre for Clinical Intervention Research Attention Deficit Hyperactivity Disorder, Methylpheniate , Ritalin, ADHD, Keywords: Pharmacological treatment https://mc.manuscriptcentral.com/bmj Page 1 of 615 BMJ 1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 Methylphenidate for attention deficit hyperactivity disorder in 11 12 children and adolescents. A Cochrane systematic review with meta- 13 14 15 analyses and trial sequential analyses of randomised clinical trials* 16 17 18 19 Ole Jakob Storebø senior researcher1,2,4 , Helle B. Krogh medical student 1,2 , Erica Ramstad medical 20 21 student 1,2 . Carlos R Moreira Maia psychiatrist 5, Mathilde Holmskov medical student 1, Maria Skoog 22 23 research fellow 3, Trine Danvad Nilausen physician 1, Frederik L. Magnusson medical student 1, 24 6 25 Morris Zwi, child & adolescent psychiatrist and clinical director , Donna Gillies, senior 26 7 8 9 27 researcher , Susanne Rosendal, psychiatrist , Camilla Groth Ph.D. student , Kirsten Buch 28 1 10 11 29 Rasmussen, librarian , Dorothy Gauci, physican , Richard Kirubakaran physican , Bente Forsbøl, 30 child and adolescent psychiatrist 2, Erik Simonsen, professor and head of department 1,12 , Christian 31 32 Gluud, head of department 3,13 33 34 35 36 1Psychiatric Research Unit, Region Zealand Psychiatry, Roskilde, Denmark; 2Child and Adolescent 37 38 Psychiatric Department, Region Zealand, Denmark; 3Copenhagen Trial Unit, Centre for Clinical 39 40 Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 41 4 42 Psychological Institute, Faculty of Health Science, South Danish University, Odense, Denmark ; 43 5 6 44 Federal University of Rio Grande do Sul, Porto Alegre, Brazil; Islington CAMHS, Whittington 45 7 46 Health, UK; Western Sydney Local Health District; Mental Health, Parramatta, Australia; 47 8Psychiatric Centre North Zealand, The Capital Region of Denmark, Denmark; 9Pediatric 48 49 Department, Herlev University Hospital, Herlev, Denmark; 10 Department of Health Information and 50 51 52 53 54 55 56 1 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 2 of 615 1 2 3 4 5 6 7 8 Research,Confidential: G’Mangia, Malta; 11 South Asian Cochrane Network For & Center, Prof.Review BV Moses Center Only 9 10 for Evidence-Informed Health Care and Health Policy, Christian Medical College, Vellore, India; 11 12 12 Institute of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, 13 13 14 Copenhagen, Denmark; The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for 15 16 Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, 17 Copenhagen, Denmark. 18 19 20 21 Erica Ramstad and Helle B. Krogh are co-second authors on this review. 22 23 24 25 26 27 * This article is based on a Cochrane Review published in the Cochrane Database of Systematic 28 29 Reviews (CDSR) YYYY, Issue X, DOI: 10.1002/14651858.CD00xxxx 30 31 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as 32 33 new evidence emerges and in response to feedback, and the CDSR should be consulted for the most 34 recent version of the review. 35 36 37 38 39 40 41 42 Correspondence to: Ole Jakob Storebø, Psychiatric Research Unit, Psychiatric Department, Region 43 44 Zealand, Denmark. [email protected] . Phone nr: +45 25 11 99 01 Field Code Changed 45 46 47 48 49 50 51 52 53 54 55 56 2 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 3 of 615 BMJ 1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 Abstract 11 12 Objective To assess the benefits and harms of methylphenidate in children and adolescents with 13 14 attention deficit hyperactivity disorder (ADHD). 15 16 17 Design Systematic review of randomised clinical trials with meta-analyses and trial sequential 18 19 analyses. 20 21 22 Data sources We searched CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, ISI 23 Conference Proceedings Citation Index, WHO's trials registry portal (ICTRP) and 'Clinical Trials 24 25 registry´ up to March 2015. We also screened reference lists of identified reviews, meta-analyses 26 27 and a selection of included trials for additional relevant articles. Furthermore, we contacted 28 29 pharmaceutical companies manufacturing methylphenidate for additional published as well as 30 31 unpublished data. 32 33 34 Review methods Using The Cochrane Collaboration methodology, we reviewed randomised 35 36 clinical trials comparing methylphenidate versus placebo or no intervention. Outcomes assessed 37 38 were ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and 39 40 quality of life. Meta-analyses and trial sequential analyses were conducted. We used the Grading of 41 Recommendations Assessment, Development and Evaluation to assess quality. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 3 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 4 of 615 1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 Results We included 185 randomised clinical trials, 38 parallel (5111 participants) and 147 cross- 12 13 over trials (7134 participants). The quality of evidence was very low for efficacy outcomes and low 14 15 for safety outcomes. We found small benefits for methylphenidate on ADHD symptoms (SMD - 16 17 0.77, 95% CI -0.90 to -0.64, 19 trials, 1698 participants) corresponding to an average change of 9.6 18 points on the ADHD rating scale, 3 points over the minimal clinical relevant difference of 6.6., 19 20 general behaviour (SMD -0.87, 95% CI -1.04 to -0.71, 5 trials, 668 participants) and quality of life 21 22 (SMD 0.61, 95% CI 0.42 to 0.80, 3 trials, 514 participants). Methylphenidate does not appear to 23 24 increase the risk of serious adverse events (relative risk (RR) 0.98, 95% CI 0.44 to 2.22, 9 trials, 25 26 1532 participants) but increases the risk of non-serious adverse events overall (RR 1.29, 95% CI 27 28 1.10 to 1.51, 21 trials, 3132 participants) as well as several specific adverse events. 29 30 Conclusion Methylphenidate appears to have a small beneficial effect on ADHD symptoms, 31 32 general behaviour and quality of life, seems without an increased risk of serious adverse events, but 33 34 it is associated with a relatively high risk of non-serious adverse events overall. Due to lack of 35 36 blinding, outcome reporting bias, vested interests, and heterogeneity, the quality of the evidence is 37 38 very low to low for all outcomes. Accordingly, based on evidence from all identifiable trials we are 39 40 unable to recommend or refute methylphendiate for the treatment of ADHD in children and 41 42 adolescents. 43 44 45 Word count: 374. 46 47 48 49 50 51 52 53 54 55 56 4 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 5 of 615 BMJ 1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 Introduction 13 14 Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and 15 1 2 16 treated childhood psychiatric disorders with a prevalence of 3% to 5%, depending on the 17 18 classification system used. ADHD is increasingly seen as a developmental disorder, which has high 19 comorbidity with other psychiatric disorders.3 Diagnosis is made through recognition of excessive 20 21 inattention, hyperactivity and impulsivity in a child, before 12 years of age, that impairs his or her 22 23 functioning or development.4 5 24 25 26 27 Methylphenidate has been used for the treatment of ADHD for over 50 years and is now globally 28 29 the most common treatment for ADHD. 6 7 Despite the widespread use of methylphenidate there has 30 31 not been a comprehensive systematic review of both benefits and harms. Fifteen reviews of the 32 33 effect of methylphenidate on the symptoms of ADHD in children and adolescents have been 34 8-22 35 published. None of them were conducted using Cochrane methodology and none pre-published a 36 peer-reviewed protocol. Twelve did not undertake subgroup analyses regarding comorbidity 37 38 influencing treatment 9-11 13-19 22 nor did they control for the effect of ADHD subtypes on treatment. 8- 39 40 11 15-22 Twelve did not consider dosage 8 9 11-14 16-20 22 and four did not undertake meta-analyses.9 10 41 42 14 16 Seven meta-analyses combined outcome data across raters and observers 8-10 15-17 20 and nine did 43 44 not separate outcomes for inattention and hyperactivity/impulsivity.