title: Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.
abstract: OBJECTIVE
  Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents?
  
  
  METHODS
  Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour.
  
  
  CONCLUSIONS
  The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) -0.77, n=1698), corresponding to a mean difference of -9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD -0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE.
  
  
  CONCLUSIONS
  The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events.
  
  
  BACKGROUND
  Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library.
authors.affiliation: Psychiatric Research Unit, Region Zealand Psychiatry, Denmark Child and Adolescent Psychiatric Department, Region Zealand, Denmark Department of Psychology, Faculty of Health Science, University of Southern Denmark ojst@regionsjaelland.dk.
authors.forename: Ole Jakob
authors.initials: OJ
authors.lastname: Storebø
authors.affiliation: Psychiatric Research Unit, Region Zealand Psychiatry, Denmark Child and Adolescent Psychiatric Department, Region Zealand, Denmark.
authors.forename: Helle B
authors.initials: HB
authors.lastname: Krogh
authors.affiliation: Psychiatric Research Unit, Region Zealand Psychiatry, Denmark Child and Adolescent Psychiatric Department, Region Zealand, Denmark.
authors.forename: Erica
authors.initials: E
authors.lastname: Ramstad
authors.affiliation: Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Moreira-Maia
authors.affiliation: Psychiatric Research Unit, Region Zealand Psychiatry, Denmark.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Holmskov
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Skoog
authors.affiliation: Psychiatric Research Unit, Region Zealand Psychiatry, Denmark.
authors.forename: Trine Danvad
authors.initials: TD
authors.lastname: Nilausen
authors.affiliation: Psychiatric Research Unit, Region Zealand Psychiatry, Denmark.
authors.forename: Frederik L
authors.initials: FL
authors.lastname: Magnusson
authors.affiliation: Islington CAMHS, Whittington Health, London, UK.
authors.forename: Morris
authors.initials: M
authors.lastname: Zwi
authors.affiliation: Western Sydney Local Health District; Mental Health, Parramatta, Australia.
authors.forename: Donna
authors.initials: D
authors.lastname: Gillies
authors.affiliation: Psychiatric Centre North Zealand, The Capital Region of Denmark, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosendal
authors.affiliation: Pediatric Department, Herlev University Hospital, Herlev, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Groth
authors.affiliation: Psychiatric Research Unit, Region Zealand Psychiatry, Denmark.
authors.forename: Kirsten Buch
authors.initials: KB
authors.lastname: Rasmussen
authors.affiliation: Directorate for Health Information and Research, Department of Health, G'Mangia, Malta.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Gauci
authors.affiliation: South Asian Cochrane Network & Center, Prof BV Moses Center for Evidence-Informed Health Care and Health Policy, Christian Medical College, Vellore, India.
authors.forename: Richard
authors.initials: R
authors.lastname: Kirubakaran
authors.affiliation: Child and Adolescent Psychiatric Department, Region Zealand, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Forsbøl
authors.affiliation: Psychiatric Research Unit, Region Zealand Psychiatry, Denmark Institute of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
authors.forename: Erik
authors.initials: E
authors.lastname: Simonsen
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D002648:Child; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D006801:Humans; D008774:Methylphenidate / Q000627:therapeutic use*; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate