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Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials

BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h5203 (Published 25 November 2015) Cite this as: BMJ 2015;351:h5203
  1. Ole Jakob Storebø, senior researcher123,
  2. Helle B Krogh, medical student12,
  3. Erica Ramstad, medical student12,
  4. Carlos R Moreira-Maia, psychiatrist4,
  5. Mathilde Holmskov, medical student1,
  6. Maria Skoog, research fellow5,
  7. Trine Danvad Nilausen, physician1,
  8. Frederik L Magnusson, medical student1,
  9. Morris Zwi, child and adolescent psychiatrist and clinical director6,
  10. Donna Gillies, senior researcher7,
  11. Susanne Rosendal, psychiatrist8,
  12. Camilla Groth, PhD student9,
  13. Kirsten Buch Rasmussen, librarian1,
  14. Dorothy Gauci, physician10,
  15. Richard Kirubakaran, physician11,
  16. Bente Forsbøl, child and adolescent psychiatrist2,
  17. Erik Simonsen, professor and head of department112,
  18. Christian Gluud, head of department513
  1. 1Psychiatric Research Unit, Region Zealand Psychiatry, Denmark
  2. 2Child and Adolescent Psychiatric Department, Region Zealand, Denmark
  3. 3Department of Psychology, Faculty of Health Science, University of Southern Denmark
  4. 4Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
  5. 5Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  6. 6Islington CAMHS, Whittington Health, London, UK
  7. 7Western Sydney Local Health District; Mental Health, Parramatta, Australia
  8. 8Psychiatric Centre North Zealand, The Capital Region of Denmark, Denmark
  9. 9Pediatric Department, Herlev University Hospital, Herlev, Denmark
  10. 10Directorate for Health Information and Research, Department of Health, G’Mangia, Malta
  11. 11South Asian Cochrane Network & Center, Prof BV Moses Center for Evidence-Informed Health Care and Health Policy, Christian Medical College, Vellore, India
  12. 12Institute of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark
  13. 13The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  1. Correspondence to: O J Storebø ojst{at}regionsjaelland.dk
  • Accepted 13 September 2015

Abstract

Study question 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.

Study answer and limitations 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.

What this study adds 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.

Funding, competing interests, data sharing 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.

Footnotes

  • We thank Janus Christian Jacobsen (Copenhagen Trial Unit) for elaborating the idea of conducting this review; Trine Lacoppidan Kæstel (research librarian, Psychiatric Research Unit, Region Zealand, Denmark) for her help with the search of studies and description of the measurement scales; Lise Aagaard (University of Southern Denmark) for the advice given during the work of this review; Jesper Pedersen (Department of Childrens and Youths Psychiatry, Region Zealand, Denmark) for backing up this project; Torben Bille (Pediatric Department, Holbaek Hospital, Copenhagen, Denmark) for helping to write the protocol and for performing the selection of studies; Maria Gaardahl, Kim Boesen, Farhad Shokraneh, and Rene Spijker for helping with the translation of articles in Japanese, Italian, Turkish, Farsi and Dutch; Nadia Pedersen (Psychiatric Research Unit) for helping with finalising the review; Martina Riegl (senior medical assessor, Medicine and Healthcare products Regulatory Agency, Special Populations Unit (Paediatrics), London) for helping with data extraction and assessment of risk of bias; Jacob Riis (user experience lead, the Nordic Cochrane Centre, Copenhagen, Denmark) and Rasmus Moustgaard (senior systems architect, the Nordic Cochrane Centre, Copenhagen, Denmark) for help on issues regarding Review Manager. We thank Geraldine McDonald (coordinating editor), Joanne Wilson (managing editor), Gemma O’Loughlin (assistant managing editor), and Margaret Anderson (trials search coordinator) of the Cochrane Developmental, Psychosocial and Learning Problems Group for providing help and support. We are grateful for the advice and support of Toby Lasserson (senior editor) and David Tovey (editor in chief) of the Cochrane Central Editorial Unit.

  • We also thank the many authors who responded to our requests for further information on their trials, and the editors and peer reviewers of the Cochrane Group and the BMJ for helpful comments on our Cochrane review, which also influenced the wording of the present version.

  • ER and HBK are co-second authors on this review. This review is an abridged version of a Cochrane systematic review: Storebø OJ, Ramstad E, Krogh HB, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev 2015 (In press).

  • Contributors: OJS, CGl, MS,SR, CGr, KBR, and ES wrote the protocol. KBR developed the search strategy. OJS, ER, HK,TDN, MS, MH, FLM, SR, and KBR carried out the study selection. OJS, ER, HK, TDN, MS, SR, MH, CGJ, FLM, CMM, DG, KBR, DG, MZ, RK, and ES carried out the data extraction and evaluation of bias. OJS and CGl developed the analytical strategy. OJS, ER, HBK, MH, FLM, and CRMM entered data into RevMan. OJS, ER, HBK, MH, FLM, and CRMM conducted the statistical analysis. All authors participated in the discussion and writing of the final review. OJS is the guarantor.

  • Funding: This study received funding from Region Zealand Research Foundation, Psychiatric Research Unit, Region Zealand Psychiatry, Roskilde, Denmark and the Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark.

  • Competing interests: All authors have completed the ICMJE uniform disclosure for at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: CRMM receives financial research support from the government agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); has served as speaker to Novartis, developed educational material for Novartis; received travel awards from the Health Technology Assessment Institute (IATS), Universidade Federal do Rio Grande do Sul (UFRGS), and travel and registration support to the 4th World Congress on ADHD from the World Federation of ADHD; MZ sits on the Paediatric Medicines Expert Advisory Group at the Medicines and Healthcare Regulatory Agency, which considers applications regarding the licensing of paediatric medicines. Payment for MZ’s attendance at this meeting goes to his NHS organization. RK is currently employed by South Asian Cochrane Centre, funded by Indian Council for Medical Research, India and Effective Healthcare Research Consortium (DFID), UK. CG received funds from the Lundbeck Foundation to finance part of her Ph.D in the paediatric field on Tourette Syndrome. CG confirms that none of these funds were used to work on this review.

  • Ethical approval: Not required.

  • Data sharing: Full data are available in the version of this Cochrane review published by The Cochrane Library (www.cochrane library.com).

  • Transparency: The lead author (OJS) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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