Methylphenidate for attention deficit hyperactivity disorder (ADHD)

616 Pages·2015·4.29 MB·English

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Methylphenidate for attention deficit hyperactivity disorder
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in children and adolescents. A Cochrane systematic review
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with meta-analyses and trial sequential analyses of
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Journnal: BMJ
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Manuscript ID: BMJ.2015.027217
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Article Type: Research
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BMJ Journal: BMJ
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Date Submitted by the Author: 28-May-20 15
Complete List of Authors: Storebø, Ole Jakob; Psychiatric Research Unit, Psychiatric Department
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Krogh, Helle; Psychiatric Research Unit, Psychiatric Department
Ramstad, Erica Linda; Psychiatric Research Unit, Psychiatric Department
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Maia, Carlos; Federal University of Rio,
Holmskov, Mathilde;r Psychiatric Research Unit, Psychiatric Department
Skoog, Maria; Copenha gen Trial Unit, Centre for Clinical Intervention
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Nilausen, Trine; Psychiatric Research Unit, Psychiatric Department
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Magnusson, Frederik; Psychiatric Research Unit, Psychiatric Department
Zwi, Morris; Islington CAMHS, Whittington Health
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Gillies, Donna; Western Sydney Local Health District, Mental Health
Rosendal, Susanne; Psychiatric Centre North Zealand,
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Groth, Camilla; Pediatric Department,, Herlev University Hospital
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Rasmussen, Kirsten; Psychiatric Research Unit, Psychiatric Department
Gauci, Dorothy; Department of Health Information and Research,
Kirubakaran, Richard; South Asian Cocherane Network & Center, Prof. BV
Moses Center for Evidence-Informed Health Care and Health Policy
Forsbøl, Bente; Child Psychiatric Clinic, Child and Adolescent Psychiatric
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Department

Simonsen, Erik; Psychiatric Research Unit, Psychiatric Department
Gluud, Christian; Rigshospitalet, Copenhagen University Hospital, The
Copenhagen Trial Unit, Centre for Clinical Intervention Research
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Attention Deficit Hyperactivity Disorder, Methylpheniate , Ritalin, ADHD,
Keywords: Pharmacological treatment n
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10 Methylphenidate for attention deficit hyperactivity disorder in
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children and adolescents. A Cochrane systematic review with meta-
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19 Ole Jakob Storebø senior researcher1,2,4, Helle B. Krogh medical student1,2, Erica Ramstad medical
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21 student1,2. Carlos R Moreira Maia psychiatrist5, Mathilde Holmskov medical student1, Maria Skoog
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23 research fellow3, Trine Danvad Nilausen physician 1, Frederik L. Magnusson medical student1,
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25 Morris Zwi, child & adolescent psychiatrist and cllinical director6, Donna Gillies, senior
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27 researcher7, Susanne Rosendal, psychiatrist8, Camilla G roth Ph.D. student9, Kirsten Buch
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Rasmussen, librarian1, Dorothy Gauci, physican10, Richard Kirubakaran physican11, Bente Forsbøl,
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child and adolescent psychiatrist2, Erik Simonsen, professor and head of department1,12, Christian
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32 Gluud, head of department3,13 r
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36 1Psychiatric Research Unit, Region Zealand Psychiatry, Roskilde, Denmark; 2Child and Adolescent
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38 Psychiatric Department, Region Zealand, Denmark; 3Copenhagen Trial Unit, Centre for Clinical
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40 Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, iDenmark;
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42 4Psychological Institute, Faculty of Health Science, South Danish University, Odense, Deenmark;
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44 5Federal University of Rio Grande do Sul, Porto Alegre, Brazil; 6Islington CAMHS, Whittingwton
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Health, UK; 7Western Sydney Local Health District; Mental Health, Parramatta, Australia;
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8Psychiatric Centre North Zealand, The Capital Region of Denmark, Denmark; 9Pediatric O
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8 Research, G’Mangia, Malta; 11 South Asian Cochrane Network & Center, Prof. BV Moses Center
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10 for Evidence-Informed Health Care and Health Policy, Christian Medical College, Vellore, India;
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12 12Institute of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University,
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Copenhagen, Denmarkf; 13The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for
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Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital,
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Copenhagen, Denmark.
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Erica Ramstad and Helle B. Krogh are cot-second authors on this review.
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27 * This article is based on a Cochrane Review published in the Cochrane Database of Systematic
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29 Reviews (CDSR) YYYY, Issue X, DOI: 10.1002/1465185F8.CD00xxxx
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31 (see www.thecochranelibrary.com for information). Cochrane oReviews are regularly updated as
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new evidence emerges and in response to feedback, and the CDSR should be consulted for the most
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42 Correspondence to: Ole Jakob Storebø, Psychiatric Research Unit, Psychiatric Department, Region
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44 Zealand, Denmark. [email protected]. Phone nr: [phone] wField Code Changed
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10 Abstract
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12 Objective To assess the benefits and harms of methylphenidate in children and adolescents with
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17 Design Systematic review dof randomised clinical trials with meta-analyses and trial sequential
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Data sources We searched CENTRAL,t Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, ISI
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Conference Proceedings Citation Index, WHO's trials registry portal (ICTRP) and 'Clinical Trials
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registry´ up to March 2015. We also screened reference lists of identified reviews, meta-analyses
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and a selection of included trials for additional relevant articles. Furthermore, we contacted
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31 unpublished data. o
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34 Review methods Using The Cochrane Collaboration methodology, we reviewed randomised
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36 clinical trials comparing methylphenidate versus placebo or no intervention. Outcomes assessed
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were ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and
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40 quality of life. Meta-analyses and trial sequential analyses were conducted. We used thie Grading of
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Recommendations Assessment, Development and Evaluation to assess quality. e
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11 Results We oincluded 185 randomised clinical trials, 38 parallel (5111 participants) and 147 cross-
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13 over trials (7134 pnarticipants). The quality of evidence was very low for efficacy outcomes and low
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for safety outcomes. We fiound small benefits for methylphenidate on ADHD symptoms (SMD -
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0.77, 95% CI -0.90 to -0.64d, 19 trials, 1698 participants) corresponding to an average change of 9.6
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points on the ADHD rating scalee, 3 points over the minimal clinical relevant difference of 6.6.,
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general behaviour (SMD -0.87, 95%n CI -1.04 to -0.71, 5 trials, 668 participants) and quality of life
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(SMD 0.61, 95% CI 0.42 to 0.80, 3 trials, 51i4 participants). Methylphenidate does not appear to
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24 increase the risk of serious adverse events (relaative risk (RR) 0.98, 95% CI 0.44 to 2.22, 9 trials,
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26 1532 participants) but increases the risk of non-serio:us adverse events overall (RR 1.29, 95% CI
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28 1.10 to 1.51, 21 trials, 3132 participants) as well as several specific adverse events.
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Conclusion Methylphenidate appears to have a small beneficial effect on ADHD symptoms,
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general behaviour and quality of life, seems without an increased risk of serious adverse events, but
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it is associated with a relatively high risk of non-serious adverse events overall. Due to lack of
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blinding, outcome reporting bias, vested interests, and heterogeneity, the quality of the evidence is
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38 very low to low for all outcomes. Accordingly, based on evidence from all identifiable trials we are
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40 unable to recommend or refute methylphendiate for the treatment of ADHD in childreni and
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Introduction
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14 Attention deficit hyperfactivity disorder (ADHD) is one of the most commonly diagnosed and
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treated childhood psychiatric disorders1 with a prevalence of 3% to 5%,2 depending on the
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classification system used. ADHD is increasingly seen as a developmental disorder, which has high
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comorbidity with other psychiatric disorders.3 Diagnosis is made through recognition of excessive
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inattention, hyperactivity and impulsivityt in a child, before 12 years of age, that impairs his or her
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27 Methylphenidate has been used for the treatment of AD HD for over 50 years and is now globally
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29 the most common treatment for ADHD.6 7 Despite the widFespread use of methylphenidate there has
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31 not been a comprehensive systematic review of both benefits aond harms. Fifteen reviews of the
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effect of methylphenidate on the symptoms of ADHD in children and adolescents have been
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published.8-22 None of them were conducted using Cochrane methodology and none pre-published a
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peer-reviewed protocol. Twelve did not undertake subgroup analyses regarding comorbidity
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38 influencing treatment9-11 13-19 22 nor did they control for the effect of ADHD subtypes on treatment.8-
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40 11 15-22 Twelve did not consider dosage 8 9 11-14 16-20 22 and four did not undertake meta-ianalyses.9 10
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42 14 16 Seven meta-analyses combined outcome data across raters and observers8-10 15-17 20 and nine did
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44 not separate outcomes for inattention and hyperactivity/impulsivity. 8 10-13 15 17 20 22 Ten failed wto
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46 present spontaneous adverse events8 10-16 18 22 and 11 did not report adverse events measured by
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48 rating scales.8-13 15 16 18 20 22 Nine reviews8 9 11-14 17 21 22 did not follow ‘gold standard’ guidelines, i.e., O
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The Cochrane Handbook23 or the Preferred Reporting Items for Systematic Reviews and Meta- n
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Analyses (PRISMA guidelines).8 24 Risk of random errors, risk of bias and trial quality were not
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8 systematically assessed in 11 reviews.8-17 22 Language bias (exclusion of non-English publications)
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10 in 13 reviews,8-14 16-20 22 and narrow or unreported search strategies (in six reviews8 11 15 16 20 22) may
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To avoid these flaws, we conducted a systematic review of the benefits and harms of
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methylphenidate in children and adolescents with ADHD using The Cochrane Handbook23 and the
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21 the benefits and harms of methylphenidatte in randomised clinical trials.26 A second systematic
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27 Methods
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placebo or no intervention for children and adolescents with ADHD. Trials were included
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irrespective of language, publication year, publication type, or publication status. After the
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exclusion of duplicates and studies clearly not meeting the inclusion criteria, full-text articles were
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46 The ADHD diagnosis used in a trial had to be made according to the Diagnostic and Statistical
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50 and DSM-IV, DSM-IV-TR, DSM-5)4 5, or according to the International Classification of Diseases n
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version 9 and version 10 (ICD-9, ICD-10).5 At least 75% of participants had to be <19 years and the
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8 mean age of the study population had to be <19 years. We included trials in which participants had
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10 comorbidities; however, at least 75% of the participants were required to have a normal intellectual
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Search strategy and seilection criteria
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We searched the Cochrane dCentral Register of Controlled Trials (The Cochrane Library 2014, Issue
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2), MEDLINE, EMBASE, CINAeHL, PsycINFO, ISI Conference Proceedings Citation Index-
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24 March 2015 using two different search strategaies, one for efficacy and one for adverse events. The
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26 complete search strategy is available in the Cochrane: review.26 We screened reference lists of
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28 identified reviews, meta-analyses and a selection of included trials for additional relevant articles.
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Furthermore, we contacted pharmaceutical companies, including Shire, Medice (represented in
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Denmark by HB Pharma), Janssen-Cilag and Novartis, for published and unpublished data. Emails
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were also sent to experts in the field requesting data on unpublished or ongoing studies.
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36 Outcomes
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39 Primary outcomes v
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long-term (>six months).
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44 • Serious adverse events: Defined as any event that led to death, was life-threatening, rewquired
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46 inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or
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48 significant disability and any important medical event that may have jeopardized the
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8 Secondary outcomes
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• Non-serious adverse events: We assessed all adverse events, including growth, cardiologic,
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neurologic, gastrointestinal, appetite, and sleep events.29
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• General behavifour at school and home was rated with psychometric validated instruments
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and classified according to length of assessment as short (≤six months) or long-term (>six
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months).
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22 Data extraction and synthesis
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24 Seventeen reviewers extracted the data indepeandently in the first of a two-phase process.26 In the
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26 second phase, a different reviewer checked the extrac:ted data and disparities were resolved through
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discussion between extractors, or consultation with the first author (OJS) where consensus was not
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reached. 26 If data were missing, we contacted authors for missing data. Mendely and Google Drive
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online software were used for data exchange and storage. Six authors entered the data into Review
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33 Manager 5.3 (RevMan).26
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37 Dichotomous data was summarised as risk ratios (RR) with 95% confidence inetervals (CI).
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39 Continuous data was used to calculate the mean difference (MD) between groups (vwith 95% CI) if
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41 the same measure was used in all trials or we calculated the standardised mean difference (SMD)
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43 where different outcome measures were used for the same construct in different trials. To assess the
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minimal clinical relevant difference (MIREDIF), we transformed the SMD into MD using scales
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with published MIREDIF. To our knowledge, the only published MIREDIF on scales measuring
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our outcomes are 6.6 points for the ADHD-RS (ADHD symptoms)30 and 7.0 points for the Child
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11 Because crosos-over trials are more prone to bias due to carry-over effects, period effects and unit of
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data from cross-over trialis (where available) were analysed with data from parallel trials. Our
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original intent was to adjustd for the effect of the unit of analysis error in cross-over trials by
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conducting a covariate analysis, ebut there were insufficient data for this. We tested for the
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possibility of a carry-over effect andn period effect and found similar treatment effects in the
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26 subgroup analyses. We therefore present the analyses: separately.
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29 The treatment effect was defined as an improvement in AFDHD symptoms, general behaviour or
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31 quality of life. ADHD symptoms and general behaviour were moeasured by teachers, observers or
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parents. We considered these data as different outcomes and teacher-rated measures as the primary
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outcome because symptoms of ADHD are more readily detectable in the school setting. 33
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