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
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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. 8 10 13 15 17 20 22 Ten failed to 45 46 present spontaneous adverse events 8 10 16 18 22 and 11 did not report adverse events measured by 47 8 13 15 16 18 20 22 8 9 11 14 17 21 22 48 rating scales. Nine reviews did not follow ‘gold standard’ guidelines, i.e.,
49 23 50 The Cochrane Handbook or the Preferred Reporting Items for Systematic Reviews and Meta
51 8 24 52 Analyses (PRISMA guidelines). Risk of random errors, risk of bias and trial quality were not 53 54 55 56 5 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 6 of 615
1 2 3 4 5 6 7 8 systematicallyConfidential: assessed in 11 reviews.8 17 22 Language bias For(exclusion of non EnglishReview publications) Only 9 10 in 13 reviews,8 14 16 20 22 and narrow or unreported search strategies (in six reviews 8 11 15 16 20 22 ) may 11
12 have compromised data collection and ultimately, the meta analyses. 13 14 15 16 To avoid these flaws, we conducted a systematic review of the benefits and harms of 17 methylphenidate in children and adolescents with ADHD using The Cochrane Handbook 23 and the 18 19 PRISMA guidelines.24 25 This article presents the results of the first systematic review focusing on 20 21 the benefits and harms of methylphenidate in randomised clinical trials.26 A second systematic 22 23 review will focus on harms in non randomised studies. 27 24 25 26 27 Methods 28 29 We used The Cochrane systematic review methodology 23 following our published protocol.28 30 31 32 Study selection 33 34 We included both parallel and cross over RCTs comparing all types of methylphenidate versus 35 36 placebo or no intervention for children and adolescents with ADHD. Trials were included 37 38 irrespective of language, publication year, publication type, or publication status. After the 39 exclusion of duplicates and studies clearly not meeting the inclusion criteria, full text articles were 40 41 obtained as per protocol (Figure 1). 28 42 43 44 Inclusion criteria 45 46 The ADHD diagnosis used in a trial had to be made according to the Diagnostic and Statistical 47 48 Manual of Mental Disorders version III, version III revised and version IV (DSM III, DSM III R 49 4 5 50 and DSM IV, DSM IV TR, DSM 5) , or according to the International Classification of Diseases
51 5 52 version 9 and version 10 (ICD 9, ICD 10). At least 75% of participants had to be <19 years and the 53 54 55 56 6 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 7 of 615 BMJ
1 2 3 4 5 6 7 8 mean ageConfidential: of the study population had to be <19 years. We includedFor trials inReview which participants had Only 9 10 comorbidities; however, at least 75% of the participants were required to have a normal intellectual 11 12 quotient (IQ >70). 13 14 Search strategy and selection criteria 15 16 We searched the Cochrane Central Register of Controlled Trials ( The Cochrane Library 2014, Issue 17 18 2), MEDLINE, EMBASE, CINAHL, PsycINFO, ISI Conference Proceedings Citation Index 19 20 Science and Conference Proceedings Citation Index Social Science & Humanities (Web of 21 22 Science), ClincalTrials.gov and International Clinical Trials Registry Platform (ICTRP) up to 23 24 March 2015 using two different search strategies, one for efficacy and one for adverse events. The 25 26 complete search strategy is available in the Cochrane review.26 We screened reference lists of 27 28 identified reviews, meta analyses and a selection of included trials for additional relevant articles. 29 30 Furthermore, we contacted pharmaceutical companies, including Shire, Medice (represented in 31 Denmark by HB Pharma), Janssen Cilag and Novartis, for published and unpublished data. Emails 32 33 were also sent to experts in the field requesting data on unpublished or ongoing studies. 34 35 36 Outcomes 37 38 39 Primary outcomes 40 • ADHD symptoms (inattention, hyperactivity and impulsivity), both short (≤six months) and 41 42 long term (>six months). 43 44 • Serious adverse events: Defined as any event that led to death, was life threatening, required 45 46 inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or 47 48 significant disability and any important medical event that may have jeopardized the 49 50 patient’s life or required intervention to prevent it. All other adverse events were considered 51 29 52 non serious. 53 54 55 56 7 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 8 of 615
1 2 3 4 5 6 7 8 Secondary Confidential:outcomes For Review Only 9 10 • Non serious adverse events: We assessed all adverse events, including growth, cardiologic, 11 neurologic, gastrointestinal, appetite, and sleep events.29 12 13 • General behaviour at school and home was rated with psychometric validated instruments 14 15 and classified according to length of assessment as short (≤six months) or long term (>six 16 17 months). 18 19 • Quality of life measured by psychometric validated instruments. 20 21 22 Data extraction and synthesis 23 26 24 Seventeen reviewers extracted the data independently in the first of a two phase process. In the 25 26 second phase, a different reviewer checked the extracted data and disparities were resolved through 27 28 discussion between extractors, or consultation with the first author (OJS) where consensus was not 29 reached. 26 If data were missing, we contacted authors for missing data. Mendely and Google Drive 30 31 online software were used for data exchange and storage. Six authors entered the data into Review 32 33 Manager 5.3 (RevMan).26 34 35 36 37 Dichotomous data was summarised as risk ratios (RR) with 95% confidence intervals (CI). 38 39 Continuous data was used to calculate the mean difference (MD) between groups (with 95% CI) if 40 41 the same measure was used in all trials or we calculated the standardised mean difference (SMD) 42 43 where different outcome measures were used for the same construct in different trials. To assess the 44 45 minimal clinical relevant difference (MIREDIF), we transformed the SMD into MD using scales 46 with published MIREDIF. To our knowledge, the only published MIREDIF on scales measuring 47 48 our outcomes are 6.6 points for the ADHD RS (ADHD symptoms)30 and 7.0 points for the Child 49 50 Health Questionnaire (quality of life).31 Fixed effect and random effects models were applied and 51 52 discrepancies between the results investigated. 53 54 55 56 8 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 9 of 615 BMJ
1 2 3 4 5 6 7 8 . Confidential: For Review Only 9 10 11 Because cross over trials are more prone to bias due to carry over effects, period effects and unit of 12 32 13 analysis errors, we conducted a subgroup analysis to compare two analysis groups. First period 14 15 data from cross over trials (where available) were analysed with data from parallel trials. Our 16 original intent was to adjust for the effect of the unit of analysis error in cross over trials by 17 18 conducting a covariate analysis, but there were insufficient data for this. We tested for the 19 20 possibility of a carry over effect and period effect and found similar treatment effects in the 21 22 parallel/first period cross over trials group and the second period cross over trials. Furthermore, we 23 24 found no significant subgroup differences between the two groups, but high heterogeneity in the 25 26 subgroup analyses. We therefore present the analyses separately. 27 28 29 The treatment effect was defined as an improvement in ADHD symptoms, general behaviour or 30 31 quality of life. ADHD symptoms and general behaviour were measured by teachers, observers or 32 33 parents. We considered these data as different outcomes and teacher rated measures as the primary 34 outcome because symptoms of ADHD are more readily detectable in the school setting. 33 35 36 37 We used the parallel group or first period of cross over trials teacher rated ADHD symptoms as our 38 39 primary analysis to give test the robustness of this estimate with several subgroup analyses: 40 41 42 • Type of scale. 43 44 • Dose of methylphenidate (low dose: ≤20 mg/day or ≤0.6 mg/kg/day compared to 45 46 moderate/high dose: >20 mg/day or >0.6 mg/kg/day). 47 48 • Design (parallel trial compared to first phase and end of trial cross over trials). 49 50 51 52 53 54 55 56 9 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 10 of 615
1 2 3 4 5 6 7 8 • MedicationConfidential: status before randomisation, i.e., ‘medi cationFor naive’ (comprisingReview 80% of Only 9 10 participants) compared to ‘previously exposed’ to medication (fewer than 20% of 11 12 participants). 13 14 • Risk of bias (trials with low risk of bias compared to trials with high risk of bias). 15 16 • Age ̶ comparing trials with participants of two to six years, to those with participants of 7 17 to 11 years and to those with participants of 12 to 18 years. 18 19 • Sex ̶ boys compared to girls. 20 21 • Comorbidity ̶ children with comorbid disorders compared to children without comorbid 22 23 disorders. 24 25 • Type of ADHD ̶ predominantly participants with inattentive type compared to participants 26 27 with combined type. 28 29 30 Sensitivity analyses 31 32 33 We conducted sensitivity analyses to ascertain whether our findings were sensitive to: 34 35 36 1. Decisions during the review, e.g., our assessment of clinical heterogeneity. 37 38 2. The combination of both ’change scores’ and ’end of trial’ scores in one meta analysis. 39 40 41 3. Inclusion of studies whose participants had IQ’s <70 or ages >18 years. 42 43 44 Consequently, we undertook sensitivity analyses excluding trials using change scores, trials with 45 46 participants with IQ <70, and trials with participants >18 years. The following studies were 47 48 excluded from the analysis in sensitivity analysis: change scores 38 42 ; IQ <70 34 37 ; age >18 years. 43 49 50 44 51 52 53 54 55 56 10 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 11 of 615 BMJ
1 2 3 4 5 6 7 8 There is noConfidential: valid method for combining the results of trials Forrated ‘high risk’ Review and ’low risk’ of bias.23 Only 9 10 We performed sensitivity analyses grouping together the trials with similar classifications of bias 11 12 and investigated the impact on intervention effects. 13 14 15 Trial sequential analysis 16 17 18 Comparable to the a priori sample size estimation in a single randomised trial, a meta analysis 19 20 should include a required information size (RIS) estimation at least as large as the sample size of an 21 adequately powered single trial to reduce the risk of random error. 22 23 24 Trial sequential analysis (TSA) is a methodology combining the required information size for a 25 26 meta analysis with the threshold for statistical significance 45 48 to quantify the statistical reliability 27 28 of the data in a cumulative meta analysis, controlling the P value thresholds for sparse data and 29 30 repetitive testing of accumulating data.45 48 31 32 33 TSA calculates the RIS in a meta analysis and provides trial sequential monitoring boundaries to 34 48 49 35 adjust the significance level for sparse data and repetitive testing on accumulating data. 36 37 Thereby, the risk of random error can be assessed. 38 39 For the calculations with the Trial Sequential Analysis program we included zero event trials by 40 41 substituting zero with 0.5.48 49 42 43 44 When new trials emerge, multiple analyses of accumulating data leads to repeated significance 45 46 testing and introduction of multiplicity. Thus, use of conventional P value criterion exacerbate the 47 48 risks of random error.50 51 Meta analyses not reaching the RIS are analysed with trial sequential 49 50 monitoring boundaries analogous to interim monitoring boundaries in a single trial.48 If a TSA does 51 52 not result in significant findings (no Z curve crossing of the trial sequential monitoring boundaries) 53 54 55 56 11 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 12 of 615
1 2 3 4 5 6 7 8 before theConfidential: required information size has been reached, the conclusionFor should Review either be that more Only 9 10 trials are needed to accept or reject an intervention effect used for calculating the required sample 11 12 size or in case the cumulated Z curve enters the futility area, the anticipated intervention effect can 13 14 be rejected. 15 16 For the outcomes, 'total serious adverse events' and 'total non serious adverse events', we calculated 17 18 the a priori diversity adjusted required information size (DARIS) (i.e., number of patients required 19 20 to detect or reject a specific intervention effect in the meta analysis) and performed a TSA for the 21 22 outcomes based on the following assumptions:45 48 52 the proportion of patients in the control group 23 24 with adverse events; a relative risk reduction or increase of 20%; a type I error of 5%; a type II error 25 26 of 20%; and the observed diversity of the meta analysis. 27 28 29 Quality of evidence 30 31 32 For each included trial, data extractors independently evaluated all risk of bias domains listed 33 34 below, resolving any disagreements by discussion. We assigned each bias domain to one of three 35 36 categories: low risk of bias, uncertain risk of bias or high risk of bias, according to the Cochrane
37 23 38 Handbook for Systematic Reviews of Interventions guidelines. Due to the risk of overestimation of 39 beneficial intervention effects and underestimation of harmful intervention effects in randomised 40 41 53 59 clinical trials with unclear or inadequate methodological quality, we assessed the influence of 42 43 the risk of bias on our results (see subgroup analyses). We use the following domains to assess the 44 45 risk of bias in the included trials:23 60 generation of allocation sequence, allocation of concealment, 46 47 blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, 48 49 selective outcome reporting and vested interest. Low risk of bias trials were defined as trials having 50 51 low risk of bias in all domains. We considered trials with one or more unclear or inadequate 52 53 component as trials with high risk of bias. We noted a specific type section bias, occurring prior to 54 55 56 12 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 13 of 615 BMJ
1 2 3 4 5 6 7 8 randomizationConfidential: for 32% (59 of 185) of the included trials. MethylphenidateFor Review non responders, placebo Only 9 10 responders and/or patients that had adverse events due to the medication were excluded as a 11 12 consequence of exclusion criteria or after a titration phase. Such trials have limited external validity 13 14 and, to identify whether this 'cohort selection bias of all participants' had an effect on estimates of 15 16 effectiveness, subgroup analyses was conducted. 17 18 We assessed and graded the evidence according to the Grading of Recommendations Assessment, 19 20 Development and Evaluation (GRADE) for high risk of bias, imprecision, indirectness, 21 22 heterogeneity and publication bias.61 The analyses were performed with Review Manager 5.3 23 24 (Review Manager 2014 ). 25 26 27 Results 28 29 We identified 14,431 records. After removal of duplicates and irrelevant references we retrieved 30 31 1,460 publications in full text for assessment of eligibility. 689 publications were excluded for not 32 33 meeting inclusion criteria and eight were classified as either awaiting classification or as ongoing 34 studies. The remaining 761 publications (69 of which in non English languages) describing 185 35 36 RCTs and 243 non randomised studies (NRS) were included in the review (Figure 1).62 When there 37 38 was missing information to assess eligibility or bias, or missing or unclear data the authors of the 39 40 RCTs were contacted. Authors of 161 RCTs were contacted up to twice times and answers were 41 42 received for 92 trials. 43 44 Of the 185 RCTs, 38 were parallel group (n = 5111) and 147 cross over (n =7134) trials, with a 45 46 total of 12,245 participants. Participants of both sexes were included. All participants were aged 47 48 between three and 21 years with an average age of 9.7 years. The majority of these trials were 49 50 conducted in high income countries. The duration of methylphenidate treatment ranged from one to 51 425 days with an average of 74.8 days. No parallel group trials and only six cross over trials (3.2%, 52 53 54 55 56 13 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 14 of 615
1 2 3 4 5 6 7 8 285 participants)Confidential: had low risk of bias in all domains and 179 For (96.8%) were Review considered high risk of Only 9 10 bias trials. By using GRADE, we rated the quality of evidence as being very low for the efficacy 11 12 outcomes and low for the safety outcomes. 13 14 ADHD symptoms Formatted: Font: Bold 15 16 We could only include 25 parallel trials and 73 cross over trials reporting ADHD symptoms in our 17 analyses. The results showed a small effect of methylphenidate on teacher rated ADHD symptoms 18 19 in the parallel trials (SMD 0.77, 95% CI 0·90 to 0.64; 1,698 participants; 19 trials; very low 20 21 quality, Figure 2). This corresponds to a mean difference of 9·6 points (95% CI 11.25 to 8.00) on 22 23 the ADHD RS which was larger than the MIREDIF of 6.6 points. There was no publication bias 24 25 (Egger’s test P=0.81). All the trials had high risk of bias, primarily due to vested interest, lack of 26 27 blinding of participants, lack of outcome assessor blinding, incomplete outcome data and selection 28 29 bias. The GRADE assessment was 'very low quality' due to high risk of bias, heterogeneity, and 30 31 selective outcome reporting. The intervention effect was significantly influenced by choice of scale 32 33 (test for subgroup differences, P=0.006). Long term trials had a smaller effect (SMD 0.47; 95% CI 34 0·72 to 0.22; 253 participants, 1 trial) compared to short term trials (SMD 0.81; 95% , CI 0.94 to 35 36 0·68; 1445 participants,18 trials; test of subgroup difference, P=0.02). Prior exposure to 37 38 medication before randomisation resulted in a larger effect (SMD 1.06, 95% CI 1.33 to 0,79, 286 39 40 participants, 2 trials) compared to trials with medication naive patients (SMD 0.79, 95% CI 1.08 41 42 to 0.50, 431 participants,4 trials; test for subgroup difference, P=0.04). However, dose trial design 43 44 and cohort selection bias did not seem to be of significant influences. One trial included in the meta 45 41 46 analysis reported change from baselines scores rather than endpoint data. Removing this trial did 47 48 not change the estimate significantly. 49 50 The post cross over trials also showed a significant treatment effect with a SMD of 0.93 (95% CI 51 52 1.06 to 0.80; 5145 participants, 59 trials) which was not significantly influenced by risk of bias. 53 54 55 56 14 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 15 of 615 BMJ
1 2 3 4 5 6 7 8 The benefit,Confidential: however, was significantly greater with higher Fordoses of methylphenidate Review dose (SMD Only 9 10 0.98; 95% CI 1.13 to 0.84; 4941 participants, 55 trials) compared to low dose (SMD 0.73; 95% 11 12 CI 0.89 to 0.57; 204 participants, 4 trials; test for subgroup difference, P=0.02). Three trials
13 35 37 14 included participants with IQ <70 but removing these did not change the estimate significantly. 15 16 Additional subgroup analyses Formatted: Font: Not Bold 17 18 19 Additional subgroup analyses on ADHD symptoms in parallel group trials and first period cross 20 21 over trials showed that neither age, nor comorbidity significantly influenced the intervention effect. 22 23 The intervention effect was significantly influenced by ADHD subtype, with a higher intervention 24 25 effect for the inattentive subtype (SMD 1.31, 95% CI 1.61 to 1.01, 1 trial, n = 204) compared to 26 27 the combined type (SMD 0.65, 95% CI 1.30 to 2.60, 2 trials, n = 559; test for subgroup differences, 28 29 P=0.05), but this difference rested upon one single trial. We found no evidence of a 'carry over 30 31 effect' in the cross over trials in a subgroup analysis between first period and second period data 32 33 from four cross over trials (n=372). First period (SMD 0.64, 95% CI 0.85 to 0.44, 372 34 participants, 4 trials, second period (SMD 0.91, 95% CI 1.18 to 0.65, 372 participants, 4 trials; 35 36 test for subgroup difference (P=0.1). 37 38 39 Serious adverse events 40 41 We could only include nine parallel group trials reporting serious adverse event. For these trials 42 43 methylphenidate was not associated with an overall increase in total serious adverse events (RR 44 45 0.98, 95% CI 0.44 to 2·22; 1,532 participants; low quality, Figure 3). All the trials had high risk of 46 47 bias due to vested interest, incomplete outcome data and lack of blinding. The GRADE assessment 48 49 was 'low quality' due to high risk of bias due to lack of blinding and selective outcome reporting. 50 51 Eight cross over trials reported serious adverse events at the end of the second period. These trials 52 53 54 55 56 15 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 16 of 615
1 2 3 4 5 6 7 8 did not differConfidential: between intervention groups in cross over trials For (RR 1.62, 95%Review CI 0.34 to 7.71; 1,648 Only 9 10 participants; I 2 = 0%). 11 12 13 14 15 We conducted TSA on the ‘total serious adverse events’ outcome including nine parallel group 16 17 trials. Trials with zero serious adverse events were included by substituting zero with a constant of 18 19 0.5. 63 The diversity adjusted required information size (DARIS) was calculated based on serious 20 21 adverse events in the control group of 2%; relative risk reduction or increase of 20% in the 22 23 experimental group; type I error of 5%; type II error of 20% (80% power); and a diversity (D 24 25 square) of 0%. The DARIS was 43,685 participants. The cumulative Z curve did not cross the 26 27 conventional or trial sequential monitoring boundaries for benefit, harm, or futility (data not 28 shown). As only less than 4% of the DARIS was accrued, risks of random error cannot be excluded. 29 30 Therefore, the total sample size in the meta analysis severe adverse events of 1532 participants was 31 32 considerably under powered to identify a difference in severe adverse events. 33 34 35 36 37 Non-serious adverse events 38 39 We could only include 25 parallel reporting non serious adverse events. Methylphenidate increased 40 41 the overall risk of total non serious adverse events by 29% (RR 1.29, 95% CI 1.10 to 1.51, 21 trials, 42 43 3,132 participants; low quality, Figure 4). All trials had high risk of bias due to lack of blinding of 44 participants, lack of outcome assessor blinding, vested interest, and incomplete outcome data. The 45 46 GRADE assessment was 'low quality' due to high risk of bias, heterogeneity, and selective outcome 47 48 reporting. There was substantial heterogeneity between trials (Tau² = 0.08; Chi² = 61·94, df = 12 49 50 (P<0.00001); I² = 81%) which did not appear to be related to dose (test for subgroup differences 51 52 between low and high dose methylphenidate, P=0.56). The adverse events reported over all trials 53 54 55 56 16 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 17 of 615 BMJ
1 2 3 4 5 6 7 8 included neurological,Confidential: digestive, urinary, circulatory, respiratory, For reproductive, Review skeletal, muscular Only 9 10 and immunological adverse events as well as physical measures such as difference in height, 11 12 weight, body mass index and vital signs among others. The most common non serious adverse
13 2 14 events were decreased appetite (RR 1.33, 95% CI 1.11 to 1.58; 2,072 participants; 21 trials; I =
15 2 16 18%) and sleep problems (RR 1.60, 95% CI 1.15 to 2.23, I = 0%, 13 trials, n = 2416). 17
18 19 65 cross over trials reported serious adverse events at the end of second period. For these trials 20 21 methylphenidate was not associated with an overall increase in total serious adverse events (RR 22 23 1.29, 95% CI 1.10 to 1.51, I2=21 trials). The most common specific non serious adverse events 24 25 which were more likely in the methylphenidate group were decreased appetite (RR 3.04, 95% CI 26 27 2.35 to 3.94, I 2 = 40%, 35 trials, n=3862) and sleep problems (RR 1.57, 95% CI 1.20 to 2.06, I 2 = 28 29 47%, 31 trials, n = 3270). 30 31 32 33 34 We conducted TSA on the ‘total non serious adverse events’ outcome including 21 parallel groups 35 36 and end of first period in cross over trials (Figure 5). One trial with zero non serious adverse events 37 38 was included by substituting zero with a constant of 0.5. 63 The diversity adjusted required 39 40 information size (DARIS) was calculated based on adverse events in the control group of 47%; 41 42 relative risk reduction or increase of 20% in the experimental group; type I error of 5%; type II error 43 44 of 20% (80% power); and a diversity (D square) of 79%. The DARIS was 4,133 participants. The 45 cumulative Z curve (blue line) crossed the trial sequential monitoring boundaries for harm (red 46 47 inward sloping line) after the 7th trial and again after the 17th trial. Accordingly, the risk of random 48 49 error in the finding can be excluded according to the Lan DeMetz O’Brien Fleming stopping rule. 50 51 52 53 54 55 56 17 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 18 of 615
1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 General behaviour 11 12 We could only include seven parallel and 18 cross over trials reporting general behaviour. The 13 14 analysis of teacher rated general behaviour in parallel trials showed a SMD of 0.87 (95% CI 1.04 15 16 to 0.71; 668 participants, five trials; very low quality; Figure 5). It was not possible to transform 17 18 this estimate to a widely used validated scale. All the trials were high risk of bias due lack of 19 20 blinding of participants, vested interest, incomplete outcome data, and selective reporting. The 21 22 GRADE assessment was 'very low quality' due to high risk of bias due to lack of blinding, 23 24 indirectness, and selective outcome reporting. Neither the type of scales nor dose did significantly 25 influence the intervention effect. The cross over trial analysis also showed a beneficial treatment 26 27 effect with a SMD of 0.69 (95% CI 0.78 to 0.60; 2014 participants, 16 trials). The intervention 28 29 effect was not influenced by dose of methylphenidate. All crossover trials were at considered a high 30 31 risk of bias. 32 33 34 35 36 Quality of life 37 38 Only three parallel trials reported quality of life. No cross over trials had usable data. There was a 39 40 small beneficial effect on quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 514 participants; three 41 trials; very low quality; Figure 6), which corresponds to a mean difference of 8.0 points (95% CI: 42 43 5.49 to 10.46) on the Child Health Questionnaire scale, which is larger than the MIREDIF of 7.0.31 44 45 However, the estimate relies on only three trials and all three had high risk of bias, primarily due to 46 47 lack of blinding of participants and vested interest. The GRADE assessment was 'very low quality' 48 49 due to high risk of bias, indirectness, and selective outcome reporting. 50 51 52 53 54 55 56 18 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 19 of 615 BMJ
1 2 3 4 5 6 7 8 DiscussionConfidential: For Review Only 9 10 11 To the best of our knowledge, this is the most comprehensive systematic review and meta analyses 12 13 of ADHD treatment with methylphenidate for children and adolescents. We included 185 RCTs of 14 15 published studies available in any language until now, resulting in a total of 12,245 participants. In 16 17 addition, this review demonstrates the first successful attempt to meta analyse adverse events for 18 19 the same intervention. There is a limitation of this review that we did not search the FDA homepage 20 21 or the European Medicines Agency for studies and data. The results suggest a small effect of 22 23 methylphenidate on reducing ADHD symptoms, corresponding to a mean difference of 9.6 points 24 25 on ADHD Rating Scale (ADHD RS). We also observed a small beneficial effect on quality of life 26 27 (8.0 points on the CHQ) and on general behaviour (but are unable to convert this to a measure on a 28 validated scale). The apparent effects of methylphenidate on both the ADHD RS and the CHQ 29 30 should be considered clinically relevant based on our predefined minimal relevant differences: a 31 32 difference of 6.6 points on the ADHD Rating Scale, ranging from 0 to 72 points based on a trial by 33 34 Zang et al. 30 and a difference of 7.0 points on the CHQ, ranging from 0 to 100 points based on a 35 36 trial by Rentz et al. 31 . However, our present results are based on trials which by GRADE is 37 38 considered 'very low quality'. 39 40 41 The use of methylphenidate does not seem to cause an increased risk of serious adverse events, but 42 43 is associated with a relatively high risk of non serious adverse events in general. Although 44 methylphenidate has been reported to cause: “rare but serious cardiac events as well as sudden 45 46 cardiac death” ,64 it did not appear to cause an increase in serious adverse events in the short term in 47 48 our meta analysis. However, the data on serious adverse events was underpowered as demonstrated 49 50 by the TSA analysis and there was no data available from RCTs on the long term incidence of 51 52 severe adverse events. Because these data are not available from RCTs we are currently working 53 54 55 56 19 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 20 of 615
1 2 3 4 5 6 7 8 on a secondConfidential: systematic review, assessing harms of methylphenidate For in observational Review studies, which Only 9 10 is expected to be published later in 2015. 27 This review investigates the long term harms of 11 12 methylphenidate based on non randomised studies with a duration up to 36 months. The 13 14 preliminary results from this review show that the proportion of serious adverse events following 15 16 treatment with methylphenidate is low but one case control study highlighted the risk of sudden 17 death in adolescents. Just over a quarter of children appear to experience non serious adverse events 18 19 following methylphenidate treatment. Formatted: Font: 12 pt, English 20 (U.S.) 21 22 23 Our findings should be seen in the context of the low quality of the included trials due to avoidable 24 25 methodological limitations, e.g., inadequate sequence generation and allocation concealment, 26 27 blinding, performance bias, detection bias, selection bias, attrition bias, reporting bias and possible 28 66 67 29 bias caused by vested interest. Only six trials of 185 with a total of 285 participants appeared at 30 31 low risk of bias in all domains. Even the trials showing a low risk of bias may in fact be trials with 32 33 high risk of bias due to lack of blinding in spite of placebo use, as methylphenidate gives rise to a 34 number of easily recognisable adverse events which can lead to loss of blinding and influence the 35 36 rating of symptoms and adverse events. We found no trials employing nocebo tablets ('active 37 38 placebo') in the controls, thus the extent of this bias cannot be assessed. Furthermore, heterogeneity 39 40 might have influenced the results. 41 42 43 44 We cannot demonstrate that methylphenidate offers more benefits than harms. Accordingly, we are 45 46 unable to either recommend or refute the use of methylphenidate for ADHD in children and 47 48 adolescents. More long term randomised nocebo controlled clinical trials without risks of 49 50 systematic errors are necessary to allow firm decisions on methylphenidate treatment in children 51 and adolescents with ADHD. Such trials ought first to be conducted in adults with ADHD. 52 53 54 55 56 20 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 21 of 615 BMJ
1 2 3 4 5 6 7 8 AgreementsConfidential: and disagreements with other studies For or reviews Review Only 9 10 11 During the last 15 years, several reviews investigating the efficacy of methylphenidate for ADHD 12 13 (with or without meta analysis) have been published. 15 reviews have pooled results of ADHD 14 15 rating scales on the efficacy of methylphenidate treatment for children and adolescents with 16 8 22 17 ADHD. These reviews have several shortcomings, which we have described in detail in the in 18 19 the introduction. Most did not assess the risk of bias of the included studies or adverse events. 20 Moreover, none of these reviews considered the risks of random errors. Therefore, one does not 21 22 know the true estimate of the medication and information about adverse events from a number of 23 24 randomised clinical trials is missing. All of these reviews and meta analyses report a large effect of 25 26 methylphenidate. 27 28 29 We have carefully assessed the risks of bias and random errors in our review and due to the low 30 31 quality of almost all of the included trials, we do not know the true intervention effect, if any. Also, 32 33 we found an overall large risk of outcome reporting bias in the outcomes for both serious and non 34 35 serious adverse events with many non serious adverse events. Without high quality trials that 36 37 include systematic recording of adverse effects alongside symptom reduction, the value of 38 methylphenidate, positive or negative, remains unknown. 39 40 41 There seems to be a general tendency for many meta analyses and reviews to over estimate the 42 43 efficacy of methylphenidiate both in children, adolescents and adults. In a recent Cochrane review 44 45 investigating the efficacy of methylphenidate for adults with ADHD, the evidence apparently 46 47 showed a benefit of methylphenidate with few adverse events.68 All the studies in this review were 48 49 considered to be of high quality. We do not agree with this assessment. On the contrary, we judge 50 51 the studies in that particular review to be at high risk of bias; the meta analyses show high
52 69 53 inconsistency between studies and the estimates are highly imprecise. 54 55 56 21 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 22 of 615
1 2 3 4 5 6 7 8 ImplicationsConfidential: for practice For Review Only 9 10 11 This review suggests a potential small effect for methylphenidate on the outcomes: ADHD 12 13 symptoms, general behaviour and quality of life. However, methylphenidate also causes a number 14 15 of adverse effects. Moreover, all the evidence in this review (as in all other studies investigating the 16 17 effects of methylphenidate) is limited by serious risks of bias. The risk of serious adverse effects 18 19 seems low, but these data come from only 9/185 trials which are considerably underpowered. It is 20 21 also problematic for fair assessment that only half of all the trials (90/185) trials reported non 22 serious adverse events. Accordingly, we cannot recommend or refute methylphenidate for children 23 24 and adolescents with ADHD. 25 26 27 If methylphenidate is used for treatment, clinicians should consider to use it for short periods, with 28 29 careful monitoring of both benefits and harms, and cease its use if there is no evidence of clear 30 31 improvement or if harmful effects overpowering benefits appear. 32 33 34 35 Conclusions 36 37 Methylphenidate used in children and adolescents appears to have at best small beneficial effects on 38 39 ADHD symptoms, general behaviour and quality of life. It does not seem to cause an increased risk 40 41 of serious adverse events in the short term but it is associated with a relatively high risk of non 42 43 serious adverse events. These findings should be interpreted in the light of a number of limitations, 44 45 including the lack of blinding, outcome reporting bias, heterogeneity and the consequent very low 46 47 to low quality of evidence for all outcomes. Accordingly, we are unable to recommend or refute 48 49 methylphendiate for the treatment of ADHD in children and adolescents. More long term 50 randomised nocebo tablet ('active placebo') controlled clinical trials without risks of bias are 51 52 53 54 55 56 22 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 23 of 615 BMJ
1 2 3 4 5 6 7 8 necessaryConfidential: to allow firm decisions on methylphenidate treatment For in children Review and adolescents with Only 9 10 ADHD. Such nocebo controlled trials ought to be conducted first in adults with ADHD. 11 12 13 Word count main text: 5134 words 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 23 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 24 of 615
1 2 3 4 5 6 7 8 We thank JanusConfidential: Christian Jacobsen, Ph.D., the Copenhagen Trial For Unit, for elaborating Review the idea of conducting Only 9 10 this review; Trine Lacoppidan Kæstel, research librarian, Psychiatric Research Unit, Region Zealand, 11 12 Denmark, for her help with the search of studies and description of the measurement scales; Lise Aagaard, 13 14 Ph.D. (pharm), University of Southern Denmark, for the advice given during the work of this review; Jesper 15 16 Pedersen, Ph.D., M.D., Department of Childrens and Youths Psychiatry, Region Zealand, Denmark for 17 backing up this project; Torben Bille, M.D., Pediatric Department, Holbaek Hospital, Copenhagen, Denmark for 18 19 helping to write the protocol and for performing the selection of studies; Maria Gaardahl, Kim Boesen, Farhad 20 21 Shokraneh and Rene Spijker for helping with the translation of articles in Japanese, Italian, Turkish, Farsi and 22 23 Dutch; Nadia Pedersen, stud.scient.san.publ., Psychiatric Research Unit, for helping with finalizing the review; 24 25 Dr. Martina Riegl, Senior Medical Assessor, MHRA, Special Populations Unit (Paediatrics), London for helping 26 27 with data extraction and assessment of risk of bias; Jacob Riis, User Experience Lead, the Nordic Cochrane 28 29 Centre, Copenhagen, Denmark for his help on issues regarding Review Manager; Rasmus Moustgaard, 30 31 Senior Systems Architect, the Nordic Cochrane Centre, Copenhagen, Denmark for his help on issues 32 regarding Review Manager. 33 34 35 36 We are grateful to the many authors who kindly responded to our requests for further information on the trials 37 38 in which they were involved. We wish to thank the Cochrane Developmental, Psychosocial and Learning 39 40 Problems Group for their help and support and the editors and peer reviewers of the Cochrane Group for 41 42 helpful comments to our Cochrane review, which also influenced the wording of the present version of the 43 44 review. 45 46 . 47 48 49 50 51 52 53 54 55 56 24 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 25 of 615 BMJ
1 2 3 4 5 6 7 8 Funding: ThisConfidential: study received funding from Region Zealand Research For Foundation, ReviewPsychiatric Research Unit, Only 9 10 Region Zealand Psychiatry, Roskilde, Denmark and the Copenhagen Trial Unit, Centre for Clinical Intervention 11 12 Research, Copenhagen University Hospital, Copenhagen, Denmark. 13 14 15 16 Contributions of authors: OJS, CGl, MS,SR, CGr, KBR and ES contributed to writing the protocol; KBR 17 developed the search strategy; OJS, ER, HK,TDN, MS, MH, FLM, SR and KBR performed the selection of the 18 19 studies; OJS, ER, HK, TDN, MS, SR, MH, CGJ, FLM, CMM, DG, KBR, DG, MZ, RK and ES carried out the 20 21 data extraction and evaluation of bias; OJS and CG lL developed the analytic strategy; OJS, ER, HBK, MH, 22 23 FLM and CRMM, entered data into RevMan; OJS, ER, HBK, MH, FLM and CRMM conducted the statistical 24 25 analysis. All authors participated in the discussion and writing of the final review. 26 27 28 29 Competing interest: All authors have completed the ICMJE uniform disclosure for at 30 31 www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: Carlos Field Code Changed 32 Renato M. Maia ̶- receives financial research support from the Government Agencies: Coordenação de 33 34 Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento 35 36 Científico e Tecnológico (CNPq); has served as speaker to Novartis, developed educational material to 37 38 Novartis; received travel awards from the Health Technology Assessment Institute (IATS), Universidade 39 40 Federal do Rio Grande do Sul (UFRGS) and travel and registration support to the 4th World Congress on 41 42 ADHD from the World Federation of ADHD; Morris Zwi sits on the Paediatric Medicines Expert Advisory Group 43 44 at the Medicines and Healthcare Regulatory Agency, which considers applications regarding the licensing of 45 46 paediatric medicines. Payment for MZ's attendance at this meeting goes to his NHS organization; Richard 47 48 Kirubakaran - is currently employed by South Asian Cochrane Centre, funded by Indian Council for Medical 49 Research, India and Effective Healthcare Research Consortium (DFID), UK. All the other authors have no 50 51 conflict of interest to declare. 52 53 54 55 56 25 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 26 of 615
1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 Ethical approval: Not needed . 11 12 13 14 Data sharing: Full data are available in the version of this Cochrane review published by The Cochrane 15 16 Library. 17 18 This review is an abridged version of a Cochrane systematic review: Ole Jakob Storebø, Erica Ramstad, Helle 19 20 B. Krogh, Trine Danvad Nilausen, Maria Skoog, Mathilde Holmskov et al. Methylphenidate for attention deficit 21 22 hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev 2015 (In press). 23 24 25 26 27 28 Formatted: Don't hyphenate 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 26 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 27 of 615 BMJ
1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 What is already known on this topic 12 13 14 • Methylphenidate has been used for the treatment of write out (ADHD) for over 50 years and is globally 15 the most common treatment for ADHD. 16 17 • Despite the widespread use of methylphenidate, there have not been a comprehensive systematic 18 19 reviews of both benefits and harms. 20 21 22 23 24 25 What this study adds 26 27 • To the best of our knowledge, this is the most comprehensive systematic review and meta-analyses 28 29 on ADHD treatment with methylphenidate for children and adolescents. We included 185 randomised 30 31 clinical trials of all published studies available in any language until now, including a total of 12,245 32 33 participants. 34 35 • We cannot demonstrate that methylphenidate offers more benefits than harms. Accordingly, we are 36 37 unable to recommend or refute the use of methylphenidate for ADHD in children and adolescents. 38 • Long-term randomised nocebo-controlled clinical trials without risks of systematic errors and random 39 40 errors are necessary to allow firm decisions on methylphenidate treatment in children and adolescents 41 42 with ADHD. 43 44 • Such trials ought to be conducted first in adults with ADHD. 45 46 47 48 49 50 51 52 53 54 55 56 27 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 28 of 615
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1 2 3 4 5 6 7 8 38 CarlsonConfidential: GA, Dunn D, Kelsey D, Ruff D, Ball S, Ahrbecker For L, et al.Review A pilot study for Only 9 augmenting atomoxetine with methylphenidate: safety of concomitant therapy in children 10 with attention deficit/hyperactivity disorder. Child and Adolescent Psychiatry and Mental 11 Health 2007;1(1):10. 12 13 39 Findling RL, Short EJ, McNamara NK, Demeter CA, Stansbrey RJ, Gracious BL, et al. 14 Methylphenidate in the treatment of children and adolescents with bipolar disorder and attention deficit/hyperactivity disorder. Journal of the American Academy of Child and 15 Adolescent Psychiatry 2007;46(11):1445 53. 16 17 40 Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore RJ, et al. Atomoxetine 18 and osmotically released methylphenidate for the treatment of attention deficit hyperactivity 19 disorder: acute comparison and differential response. American Journal of Psychiatry 20 2008;165(6):721 30. 21 22 41 Palumbo DR, Sallee FR, Pelham WE, Bukstein OG, Daviss WB, McDermott MP. Clonidine 23 for attention deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes. Journal of 24 the American Academy of Child and Adolescent Psychiatry 2008;47(2):180 8. 25 42 Tucker JD, Suter W, Petibone DM, Thomas RA, Bailey NL, Zhou Y, et al. Cytogenetic 26 assessment of methylphenidate treatment in pediatric patients treated for attention deficit 27 hyperactivity disorder. Mutation Research 2009;677(1 2):53 8. 28 29 43 Green T, Weinberger R, Diamond A, Berant M, Hirschfeld L, Frisch A, et al. The effect of 30 methylphenidate on prefrontal cognitive functioning, inattention, and hyperactivity in 31 velocardiofacial syndrome. Journal of Child and Adolescent Psychopharmacology 32 2011;21(6):589 95. 33 34 44 Szobot CM, Rohde LA, Katz B, Ruaro P, Schaefer T, Walcher M, et al. A randomized 35 crossover clinical study showing that methylphenidate SODAS improves attention 36 deficit/hyperactivity disorder symptoms in adolescents with substance use disorder. Brazilian Journal of Medical and Biological Research 2008;41(3):250 7. 37 38 45 Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient 39 information size and potentially false positive results in many meta analyses. J Clin 40 Epidemiol 2008 Aug;61(8):763 9. 41 42 46 Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta analysis may be 43 inconclusive trial sequential analysis adjustment of random error risk due to repetitive 44 testing of accumulating data in apparently conclusive neonatal meta analysis. International 45 Journal of Epidemiology 2009;38(1):287 98. 46 47 47 Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta analysis? 48 International Journal of Epidemiology 2009;38(1):276 86. 49 50 48 Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when 51 firm evidence is reached in cumulative meta analysis. J Clin Epidemiol 2008 Jan;61(1):64 52 75. 53 54 55 56 31 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 32 of 615
1 2 3 4 5 6 7 8 49 CopenhagenConfidential: Trial Unit. TSA Trial Sequential Analysis. For 2011. Review Only 9 Ref Type: Online Source 10 11 50 Bental B, Tirosh E. The effects of methylphenidate on word decoding accuracy in boys with 12 attention deficit/hyperactivity disorder. Journal of Clinical Psychopharmacology 13 2008;28(1):89 92. 14 51 Lau J, Schmid CH, Chalmers TC. Cumulative meta analysis of clinical trials builds 15 evidence for exemplary medical care. Journal of Clinical Epidemiology 1995;48(1):45 57. 16 17 52 Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by 18 quantifying diversity in random effects model meta analyses. BMC Medical Research 19 Methodology 2009;9:86. 20 21 53 Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies 22 between large and small randomized trials in meta analyses. Annals of Internal Medicine 23 2001;135(11):982 9. 24 54 Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research 25 outcome. Cochrane Database of Systematic Reviews 2012;(12). 26 27 55 Moher D, Pham B, Jones A, Cook DJ, Jadad A, Moher M, et al. Does quality of reports of 28 randomised trials affect estimates of intervention efficacy reported in meta analysis? Lancet 29 1998;352(9128):609 13. 30 31 56 Savovic´ J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported 32 study design characteristics on intervention effect estimates from randomized, controlled 33 trials. Annals of Internal Medicine 2012;157(6):429–38. 34 57 Savovic´ J, Jones H, Altman D, Harris R, Jüni P, Pildal J, et al. Influence of reported 35 study design characteristics on intervention effect estimates from randomised controlled 36 trials: combined analysis of meta epidemiological studies. Health Technology Assessment 37 2012;16(35):1 82. 38 39 58 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of 40 methodological quality associated with estimates of treatment effects in controlled trials. 41 JAMA 1995;273(5):408 12. 42 43 59 Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of 44 bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta epidemiological study. BMJ 2008;336(7644):601–5. 45 46 60 Gluud C NDKSL. Cochrane Hepato BilliaryAbout the Cochrane Collaboration (Cochrane 47 Review Groups (CRGs). About the Cochrane Collaboration (Cochrane Review Groups 48 (CRGs). Cochrane Review Groups 2015;1(Art.No:LIVER). 49 50 61 Andrews J, Guyatt G, Oxman AD, Alderson P, Dahm P, Falck Ytter Y, et al. GRADE 51 guidelines: 14. Going from evidence to recommendations: the significance and presentation 52 of recommendations. J Clin Epidemiol 2013;66(7):719 25. 53 54 55 56 32 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 33 of 615 BMJ
1 2 3 4 5 6 7 8 62 MoherConfidential: D, Liberati A, Tetzlaff J, Altman DG. Preferred For reporting itemsReview for systematic Only 9 reviews and meta analyses: the PRISMA Statement. Open Med 2009;3(3):e123 e130. 10 11 63 Jacobi Polishook T, Shorer Z, Melzer I. The effect of methylphenidate on postural stability 12 under single and dual task conditions in children with attention deficit hyperactivity disorder 13 a double blind randomized control trial. J Neurol Sci 2009;280(1 2):15 21. 14 64 Martinez Raga J, Knecht C, Szerman N, Martinez MI. Risk of serious cardiovascular 15 problems with medications for attention deficit hyperactivity disorder. CNS Drugs 2013 16 Jan;27(1):15 30. 17 18 65 Gould MS, Walsh BT, Munfakh JL, Kleinman M, Duan N, Olfson M, et al. Sudden death 19 and use of stimulant medications in youths. Am J Psychiatry 2009;166(9):992 1001. 20 21 66 Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research 22 outcome. Cochrane Database Syst Rev 2012;12:MR000033. 23 67 Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, ildal J, et al. Influence of Reported 24 Study Design Characteristics on Intervention Effect Estimates From Randomized, 25 Controlled Trials. Annals of Internal Medicine 2012;157(6):429 38. 26 27 68 Epstein T, Patsopoulos NA, Weiser M. Immediate release methylphenidate for attention 28 deficit hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 29 2014;(9). 30 31 69 Storebø O, Gluud C. Criticism to "Immediate release methylphenidate for attention deficit 32 hyperactivity disorder (ADHD) in adults" [personal communication]. Email to: T Epstein 33 via Wiley Online Feedback form. 12 5 2015. 34 Ref Type: Generic
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1 2 3 4 5 6 7 8 Confidential:Figure 1: Prisma flow Forchart Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Figure 2: Teacher-rated ADHD symptoms - parallel group 41 42
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1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Figure 3: Serious adverse events – parallel trials 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 35 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 36 of 615
1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Figure 4: Non-serious adverse events - parallel group 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 36 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 37 of 615 BMJ
1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 5: TSA analysis on total of non-serious adverse events 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 37 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 38 of 615
1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Figure 6: Teacher-rated general behavior - parallel trials 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 38 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 39 of 615 BMJ
1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Figure 7: Quality of life – parallel trials 26
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1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
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1 2 3 4 Methylphenidate for attention deficit hyperactivity disorder 5 6 (ADHD) in children and adolescents (Review) 7 8 Confidential: For Review Only 9 10 Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, Rosendal S, Groth 11 C, Magnusson FL, Moreira-Maia CR, Gillies D, Buch Rasmussen K, Gauci D, Zwi M, 12 13 Kirubakaran R, Forsbøl B, Simonsen E, Gluud C 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 45 2015, Issue 5 46 http://www.thecochranelibrary.com 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 42 of 615
1 2 3 4 TABLEOFCONTENTS 5 6 HEADER...... 1 7 ABSTRACT ...... 1 8 Confidential:PLAINLANGUAGESUMMARY ...... For ...... Review ...... Only ...... 3 9 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON ...... 4 10 BACKGROUND ...... 6 11 OBJECTIVES ...... 8 12 METHODS...... 8 13 Figure1...... 10 14 RESULTS...... 14 15 Figure2...... 16 16 Figure3...... 22 17 Figure4...... 23 18 Figure5...... 32 19 Figure6...... 34 20 DISCUSSION ...... 34 21 AUTHORS’CONCLUSIONS ...... 38 22 ACKNOWLEDGEMENTS ...... 39 23 REFERENCES ...... 39 24 CHARACTERISTICSOFSTUDIES ...... 106 25 DATAANDANALYSES...... 584 26 Analysis 1.1. Comparison 1 Teacher-rated ADHD symptoms, Outcome 1 All parallel group trials and 1st period cross-over 27 trials...... 598 28 Analysis 1.2. Comparison 1 Teacher-rated ADHD symptoms, Outcome 2 Subgroup analysis: types of scales. . . . 599 29 Analysis 1.3. Comparison 1 Teacher-rated ADHD symptoms, Outcome 3 Subgroup analysis: duration of treatment. 602 30 Analysis 1.4. Comparison 1 Teacher-rated ADHD symptoms, Outcome 4 Subgroup analysis: dose...... 603 31 Analysis 1.5. Comparison 1 Teacher-rated ADHD symptoms, Outcome 5 Subgroup analysis: parallel group trials compared 32 with 1st period cross-over trials...... 605 33 Analysis 1.6. Comparison 1 Teacher-rated ADHD symptoms, Outcome 6 Subgroup analysis: trials with cohort selection 34 bias of all participants compared with trials without cohort selection bias of all participants...... 606 35 Analysis 1.7. Comparison 1 Teacher-rated ADHD symptoms, Outcome 7 ADHD symptoms, cross over trial (end of 36 trial)...... 608 37 Analysis 1.8. Comparison 1 Teacher-rated ADHD symptoms, Outcome 8 ADHD symptoms, cross-over trials (end of 38 trial). Subgroup analysis: dose...... 611 39 Analysis 1.9. Comparison 1 Teacher-rated ADHD symptoms, Outcome 9 Subgroup analysis: all parallel group trials and 40 1st period cross-over trials (teacher rated) compared with cross-over trials (end of trial)...... 614 41 Analysis 1.10. Comparison 1 Teacher-rated ADHD symptoms, Outcome 10 All parallel group trials and cross-over trials: riskofbias...... 618 42 Analysis 1.11. Comparison 1 Teacher-rated ADHD symptoms, Outcome 11 Medication naive vs not medication naive. 621 43 Analysis 2.1. Comparison 2 Observer-rated ADHD symptoms, Outcome 1 All parallel group trials and 1st period cross- 44 overtrials...... 622 45 Analysis 2.2. Comparison 2 Observer-rated ADHD symptoms, Outcome 2 Subgroup analysis: types of scales. . . . 623 46 Analysis 2.3. Comparison 2 Observer-rated ADHD symptoms, Outcome 3 Subgroup analysis: duration of treatment. 624 47 Analysis 2.4. Comparison 2 Observer-rated ADHD symptoms, Outcome 4 Subgroup analysis: dose...... 625 48 Analysis 2.5. Comparison 2 Observer-rated ADHD symptoms, Outcome 5 Subgroup analysis: parallel group trials 49 comparedFor with 1st period cross-overPreview trials...... Only ...... 626 50 Analysis 2.6. Comparison 2 Observer-rated ADHD symptoms, Outcome 6 Subgroup analysis: trials with cohort selection 51 bias of all participants compared with trials without cohort selection bias of all participants...... 627 52 Analysis 2.7. Comparison 2 Observer-rated ADHD symptoms, Outcome 7 ADHD symptoms, cross-over trials (end of 53 trial)subgroup analysis:risk of bias...... 628 54 Analysis 2.8. Comparison 2 Observer-rated ADHD symptoms, Outcome 8 ADHD symptoms, cross-over trials (end of 55 trial). Subgroup analysis: dose...... 629 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) i Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 43 of 615 BMJ
1 2 3 4 Analysis 2.9. Comparison 2 Observer-rated ADHD symptoms, Outcome 9 Subgroup analysis: all parallel group trials and 5 1st period cross-over trials (observer rated) compared with cross-over trials (end of trial)...... 631 6 Analysis 3.1. Comparison 3 Parent-rated ADHD symptoms, Outcome 1 All parallel group trials and 1st period cross-over 7 trials...... 633 8 Confidential:Analysis 3.2. Comparison 3 Parent-rated ADHD For symptoms, Outco Reviewme 2 Subgroup analysis: types Only of scales. . . . . 634 9 Analysis 3.3. Comparison 3 Parent-rated ADHD symptoms, Outcome 3 Subgroup analysis: duration of treatment. . 637 10 Analysis 3.4. Comparison 3 Parent-rated ADHD symptoms, Outcome 4 Subgroup analysis: dose...... 638 11 Analysis 3.5. Comparison 3 Parent-rated ADHD symptoms, Outcome 5 Subgroup analysis: parallel group trials compared 12 with 1st period cross-over trials...... 640 13 Analysis 3.6. Comparison 3 Parent-rated ADHD symptoms, Outcome 6 Subgroup analysis: trials with cohort selection 14 bias of all participants compared with trials without cohort selection bias of all participants...... 641 15 Analysis 3.7. Comparison 3 Parent-rated ADHD symptoms, Outcome 7 ADHD symptoms, cross-over trials (end of 16 trial)...... 643 17 Analysis 3.8. Comparison 3 Parent-rated ADHD symptoms, Outcome 8 ADHD symptoms, cross-over trials (end of trial), 18 Subgroupanalysis:dose...... 645 19 Analysis 3.9. Comparison 3 Parent-rated ADHD symptoms, Outcome 9 Subgroup analysis: all parallel group studies and 20 1st period cross-over trials (parent rated) compared with cross-over trials (end of trial)...... 648 21 Analysis 3.10. Comparison 3 Parent-rated ADHD symptoms, Outcome 10 Medication naive vs not medication naive. 651 22 Analysis 4.1. Comparison 4 Additional subgroup analyses of ADHD symptoms parallel group trials and 1st period cross- 23 overtrials,Outcome1Age...... 652 24 Analysis 4.2. Comparison 4 Additional subgroup analyses of ADHD symptoms parallel group trials and 1st period cross- 25 over trials, Outcome 2 Comorbidity vs no comorbidity...... 653 26 Analysis 4.3. Comparison 4 Additional subgroup analyses of ADHD symptoms parallel group trials and 1st period cross- 27 over trials, Outcome 3 Comparision of raters...... 654 28 Analysis 4.4. Comparison 4 Additional subgroup analyses of ADHD symptoms parallel group trials and 1st period cross- 29 over trials, Outcome 4 Subtypes ADHD: ADHD-Rating Scale (parent-, teacher- or observer-rated). . . . . 657 30 Analysis 4.5. Comparison 4 Additional subgroup analyses of ADHD symptoms parallel group trials and 1st period cross- 31 over trials, Outcome 5 Cross-over trials: 1st period data vs end of trial data (parent, observer, and teacher rated). 658 32 Analysis 5.1. Comparison 5 Number of serious adverse events, parallel group trials and 1st period cross-over trials, Outcome 33 1Numberofseriousadverseevents(SAE)...... 659 34 Analysis 5.2. Comparison 5 Number of serious adverse events, parallel group trials and 1st period cross-over trials, Outcome 35 2Nervoussystem...... 660 36 Analysis 5.3. Comparison 5 Number of serious adverse events, parallel group trials and 1st period cross-over trials, Outcome 37 3Digestivesystem...... 661 38 Analysis 5.4. Comparison 5 Number of serious adverse events, parallel group trials and 1st period cross-over trials, Outcome 39 4Urinarysystem...... 662 40 Analysis 5.5. Comparison 5 Number of serious adverse events, parallel group trials and 1st period cross-over trials, Outcome 41 5 Circulatory and respiratory system...... 662 Analysis 5.6. Comparison 5 Number of serious adverse events, parallel group trials and 1st period cross-over trials, Outcome 42 6Immunesystem...... 663 43 Analysis 5.7. Comparison 5 Number of serious adverse events, parallel group trials and 1st period cross-over trials, Outcome 44 7Other...... 664 45 Analysis 6.1. Comparison 6 Number of serious adverse events, cross-over trials (end of trial), Outcome 1 Number of serious 46 adverseevents(SAE)...... 665 47 Analysis 6.2. Comparison 6 Number of serious adverse events, cross-over trials (end of trial), Outcome 2 48 Hallucinations/psychosis...... 666 49 Analysis 7.1. ComparisonFor 7 Number Preview of non-serious adverse events, parallel group Only trials and 1st period cross-over trials, 50 Outcome 1 Total number of non-serious adverse events...... 667 51 Analysis 7.2. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 52 Outcome 2 Subgroup analysis: total number of non-serious adverse events according to dose...... 668 53 Analysis 7.3. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 54 Outcome3Nervoussystem...... 670 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) ii Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 44 of 615
1 2 3 4 Analysis 7.4. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 5 Outcome4Digestivesystem...... 675 6 Analysis 7.5. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 7 Outcome 5 Circulatory and respiratory system...... 679 8 Confidential:Analysis 7.6. Comparison 7 Number of non-serious For adverse eve nts,Review parallel group trials and 1st periodOnly cross-over trials, 9 Outcome 6 Skeletal and muscular system...... 681 10 Analysis 7.7. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 11 Outcome7Immunesystem...... 682 12 Analysis 7.8. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 13 Outcome8Height...... 684 14 Analysis 7.9. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 15 Outcome9Weigth...... 685 16 Analysis 7.10. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 17 Outcome10BMI...... 685 18 Analysis 7.11. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 19 Outcome11Vitalsigns...... 686 20 Analysis 7.12. Comparison 7 Number of non-serious adverse events, parallel group trials and 1st period cross-over trials, 21 Outcome12Other...... 688 22 Analysis 8.1. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 1 Total number 23 ofnon-seriousadverseevents...... 690 24 Analysis 8.2. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 2 Subgroup 25 analysis: total number of non-serious adverse events accordingtodose...... 691 26 Analysis 8.3. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 3 Nervous 27 system...... 693 28 Analysis 8.4. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 4 Digestive 29 system...... 704 30 Analysis 8.5. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 5 Urinary 31 system...... 708 32 Analysis 8.6. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 6 Skeletal and 33 muscularsystem...... 708 34 Analysis 8.7. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 7 Immune 35 system...... 709 36 Analysis 8.8. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 8 Skin. . 711 37 Analysis 8.9. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 9 Vital signs. 712 38 Analysis 8.10. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 10 Height 39 (cm)...... 714 40 Analysis 8.11. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 11 Weight. 714 41 Analysis 8.12. Comparison 8 Number of non-serious adverse events, cross-over trials (end of trial), Outcome 12 Subgroup analysis: cross-over (end of trial) - dichotomous versus continuous data (decreased appetite)...... 715 42 Analysis 9.1. Comparison 9 Teacher-rated general behaviour, Outcome 1 All parallel group trials and 1st period cross-over 43 trials-riskofbias...... 717 44 Analysis 9.2. Comparison 9 Teacher-rated general behaviour, Outcome 2 Subgroup analysis: types of scales. . . . 718 45 Analysis 9.3. Comparison 9 Teacher-rated general behaviour, Outcome 3 Subgroup analysis: duration of treatment. . 719 46 Analysis 9.4. Comparison 9 Teacher-rated general behaviour, Outcome 4 Subgroup analysis: dose...... 720 47 Analysis 9.5. Comparison 9 Teacher-rated general behaviour, Outcome 5 Subgroup analysis: parallel group trials compared 48 with 1st period cross-over trials...... 721 49 Analysis 9.6. ComparisonFor 9 Teacher-rated Preview general behaviour, Outcome 6 General Only behaviour, cross-over trials (end of 50 trial)...... 722 51 Analysis 9.7. Comparison 9 Teacher-rated general behaviour, Outcome 7 Subgroup analysis: general behaviour, cross-over 52 trials(endoftrial):riskofbias...... 724 53 Analysis 9.8. Comparison 9 Teacher-rated general behaviour, Outcome 8 Subgroup analysis: all parallel group trials and 1st 54 period cross-over trials (teacher rated) compared with cross-over trials (end of trial)...... 725 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) iii Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 45 of 615 BMJ
1 2 3 4 Analysis 9.9. Comparison 9 Teacher-rated general behaviour, Outcome 9 All parallel group trials and cross-over trials: risk 5 ofbias...... 727 6 Analysis 10.1. Comparison 10 Observer-rated general behaviour, Outcome 1 General behaviour, cross-over trials (end of 7 trial)...... 728 8 Confidential:Analysis 10.2. Comparison 10 Observer-rated generalFor behaviour, Review Outcome 2 Subgroup analysis: generalOnly behaviour, cross- 9 over trials (end of trial): risk of bias...... 730 10 Analysis 10.3. Comparison 10 Observer-rated general behaviour, Outcome 3 Subgroup analysis: all parallel group trials and 11 1st period cross-over trials (observer rated) compared with cross-over trials (end of trial)...... 731 12 Analysis 11.1. Comparison 11 Parent-rated general behaviour, Outcome 1 All parallel group trials and 1st period cross-over 13 trials...... 732 14 Analysis 11.2. Comparison 11 Parent-rated general behaviour, Outcome 2 Subgroup analysis: risk of bias. . . . . 733 15 Analysis 11.3. Comparison 11 Parent-rated general behaviour, Outcome 3 Subgroup analysis: types of scales. . . . 734 16 Analysis 11.4. Comparison 11 Parent-rated general behaviour, Outcome 4 Subgroup analysis: duration of treatment. 735 17 Analysis 11.5. Comparison 11 Parent-rated general behaviour, Outcome 5 Subgroup analysis: dose...... 736 18 Analysis 11.6. Comparison 11 Parent-rated general behaviour, Outcome 6 Subgroup analysis: parallel group trials compared 19 with 1st period cross-over trials...... 737 20 Analysis 11.7. Comparison 11 Parent-rated general behaviour, Outcome 7 General behaviour, cross-over trials (end of 21 trial)...... 738 22 Analysis 11.8. Comparison 11 Parent-rated general behaviour, Outcome 8 Subgroup analysis: general behavior, cross-over 23 trials(endoftrial):riskofbias...... 739 24 Analysis 11.9. Comparison 11 Parent-rated general behaviour, Outcome 9 Subgroup analysis: all parallel group trials and 25 1st period cross-over trials (parent rated) compared with cross-over trials (end of trial)...... 740 26 Analysis 12.1. Comparison 12 General behaviour, comparision of raters, parallel group trials and 1st period cross-over 27 trials, Outcome 1 Comparisions of raters...... 741 28 Analysis 13.1. Comparison 13 Additional subgroup analyses of general behaviour, parallel trials and 1st period cross-over, 29 Outcome 1 Comorbidity vs no comorbidity...... 742 30 Analysis 13.2. Comparison 13 Additional subgroup analyses of general behaviour, parallel trials and 1st period cross-over, 31 Outcome 2 Cross-over trials: 1st period data vs end of trial data (teacher, parent, and observer rated). . . . 743 32 Analysis 14.1. Comparison 14 Quality of life, parallel group trials and 1st period cross-over trials, Outcome 1 Child Health 33 Questionnaire(CHQ)...... 743 34 Analysis 14.2. Comparison 14 Quality of life, parallel group trials and 1st period cross-over trials, Outcome 2 Children‘s 35 GlobalAssessmentScale(CGAS)...... 744 36 Analysis 14.3. Comparison 14 Quality of life, parallel group trials and 1st period cross-over trials, Outcome 3 Child Health 37 and Illness Profile, Child Edition: Parent Report Form (CHIP-CE:PRF)...... 744 38 Analysis 14.4. Comparison 14 Quality of life, parallel group trials and 1st period cross-over trials, Outcome 4 Subgroup 39 analysis:typesofscales...... 745 40 ADDITIONALTABLES...... 745 41 APPENDICES ...... 753 CONTRIBUTIONSOFAUTHORS ...... 776 42 DECLARATIONSOFINTEREST ...... 776 43 SOURCESOFSUPPORT ...... 777 44 DIFFERENCES BETWEEN PROTOCOL AND REVIEW ...... 777 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) iv Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 46 of 615
1 2 3 4 [Intervention Review] 5 6 Methylphenidate for attention deficit hyperactivity disorder 7 8 Confidential:(ADHD) in children and adolescentsFor Review Only 9 10 11 Ole Jakob Storebø1,2,3, Erica Ramstad1,2, Helle B. Krogh1,2a, Trine Danvad Nilausen2, Maria Skoog4, Mathilde Holmskov2, Susanne 12 Rosendal5, Camilla Groth6, Frederik L Magnusson2 , Carlos R Moreira-Maia7, Donna Gillies8, Kirsten Buch Rasmussen2, Dorothy 13 Gauci9, Morris Zwi10, Richard Kirubakaran11, Bente Forsbøl1, Erik Simonsen2,12, Christian Gluud4,13 14 15 1Child Psychiatric Clinic, Psychiatric Department, Region Zealand, Holbaek, Denmark. 2Psychiatric Research Unit, Region Zealand 16 Psychiatry, Roskilde, Denmark. 3Psychological Institute, Faculty of Health Science, South Danish University, Odense, Denmark. 17 4Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark. 18 5Psychiatric Centre North Zealand, The Capital Region of Denmark, Denmark. 6Pediatric Department, Herlev University Hospital, 19 Herlev, Denmark. 7Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 8Western Sydney Local Health District 20 - Mental Health, Parramatta, Australia. 9Directorate for Health Information and Research, Department of Health, G’Mangia, Malta. 21 10Islington Child & Adolescent Mental Health Service, Whittington Health, London, UK. 11 South Asian Cochrane Network & Center, 22 Prof. BV Moses Center for Evidence-Informed Health Care and Health Policy, Christian Medical College, Vellore, India. 12Institute of 23 Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark. 13The Cochrane Hepato- 24 Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen 25 University Hospital, Copenhagen, Denmark 26 27 aHelle B. Krogh is a co-second author with Erica Ramstad on this review 28 29 Contact address: Ole Jakob Storebø, Child Psychiatric Clinic, Psychiatric Department, Region Zealand, Birkevaenget 3, Holbaek, 30 4300, Denmark. [email protected]. 31 32 Editorial group: Cochrane Developmental, Psychosocial and Learning Problems Group. 33 Publication status and date: New, published in Issue 5, 2015. 34 Review content assessed as up-to-date: 27 April 2015. 35 36 Citation: Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, Rosendal S, Groth C, Magnusson FL, Moreira- 37 Maia CR, Gillies D, Buch Rasmussen K, Gauci D, Zwi M, Kirubakaran R, Forsbøl B, Simonsen E, Gluud C. Methylphenidate for 38 attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database of Systematic Reviews 2015, Issue 5. 39 Art. No.: CD009885. DOI: 10.1002/14651858.CD009885.pub2. 40 41 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 42 43 44 45 ABSTRACT 46 47 Background 48 Despite widespread use of methylphenidate for the treatment of ADHD in children and adolescents, a comprehensive systematic review 49 of its benefits and harmsFor has not yet beenPreview conducted. Only 50 51 Objectives 52 53 To assess the beneficial and harmful effects of methylphenidate in children and adolescents with ADHD. 54 This systematic review is the first of two systematic reviews. A second review focusing on harms in non-randomised studies will be 55 published later in 2015. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 1 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 47 of 615 BMJ
1 2 3 4 Search methods 5 6 In March 2015 we searched CENTRAL, Ovid MEDLINE, Embase, CINAHL, PsycINFO, ISI Conference Proceedings Citation Indexes, and two trials registers . We also screened reference lists of identified reviews, meta-analyses, and a selection of included trials 7 for additional relevant articles. Furthermore, we contacted pharmaceutical companies manufacturing methylphenidate for published 8 Confidential: For Review Only as well as unpublished data. 9 10 Selection criteria 11 We included all randomised trials comparing methylphenidate versus placebo or no intervention in children and adolescents aged up to 12 and including 18 years of age, with an intelligence quotient (IQ) greater than 70, who were diagnosed with ADHD. Assessed outcomes 13 were ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour, and quality of life. 14 15 Data collection and analysis 16 Seventeen review authors participated in data extraction and risk of bias assessment, and all tasks were independently performed by two 17 authors. We contacted the authors of included trials for any missing data. Data from parallel trials and the first period data available 18 from cross-over trials, formed our first analysis group. A second group comprised post-crossover data from cross-over trials. Random- 19 effects and fixed-effect models were applied. Subgroup and sensitivity analyses were used to test the robustness of the estimates. Risk 20 of bias domains were assessed to identify potential causes of systematic errors. Trial Sequential Analyses was used to control random 21 errors of type I (5%) and type II (20%). We assessed and downgraded the evidence according to the Grades of Recommendation 22 Assessment, Development and Evalutation (GRADE) recommendations for high risk of bias, imprecision, indirectness, heterogeneity, 23 and publication bias. 24 25 Main results 26 We included 185 randomised trials - 38 parallel group trials (5111 participants) and 147 cross-over trials (7134 participants). Most 27 participants were from high income countries. Participants of both sexes were included, with a boys-girls ratio of 5:1. All participants 28 were aged between 3 and 21 years with an average age of 9.7 years. The duration of methylphenidate treatment ranged from one to 29 425 days with an average of 74.8 days. Only six trials with 285 participants appeared at low risk of bias in all domains. 30 31 The results indicate a small beneficial effect for methylphenidate on teacher-rated ADHD symptoms (SMD -0.77, 95% confidence 32 intervals (CI) -0.90 to -0.64; 19 trials, 1698 participants; very low quality). This corresponds to a mean difference of -9.6 points (95% 33 CI -13.75 to -6.38) on the ADHD-Rating Scale, (ranges 0 to 72). Methylphenidate was not associated with an overall increase in 34 serious adverse events (with a relative risk (RR) of 0.98,95% CI 0.44 to 2.22, 9 trials, 1532 participants; low quality evidence), but 35 this estimate is based on only 9/185 randomised clinical trials, with very few events. However, methylphenidate increased the overall 36 risk of any non-serious adverse events by 29% (RR 1.29, 95% CI 1.10 to 1.51, 21 trials, 3132 participants; low quality evidence). The 37 most common non-serious adverse events were sleep problems, which were increased by 60% (RR 1.60, 95% CI 1.15 to 2.23, 13 trials, 38 2416 participants) and decrease in appetite which increased by 280% (RR 3.80, 95% CI 2.58 to 5.59, 16 trials, 2962 participants). 39 Teacher-rated general behaviour improved with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71, 5 trials, 668 participants; very 40 low quality evidence) though It was not possible to transform this estimate to a well known scale. There was a small beneficial effect 41 of methylphenidate on quality of life (SMD 0.61, 95% CI 0.42 to 0.80, 3 studies, 514 participants; very low quality evidence) which corresponds to a mean difference of 8.0 points (95% CI 5.49 to 10.46) on the Child Health Questionaire (CHQ) scale (range 0 to 42 100).The apparent effects of methylphenidate on both the ADHD-RS and the CHQ should be considered clinically relevant based on 43 our predefined minimal relevant differences of 6.6 points on the ADHD-Rating Scale, and 7.0 points on the CHQ. However, these 44 results are based on trials which,according to our GRADE assessments, are considered ’very low quality’. Furthermore, the observed 45 effects could be biased due to lack of effective blinding as a result of identifiable adverse effects of methylphenidate. 46 47 Authors’ conclusions 48 Methylphenidate appears to have small beneficial effects on ADHD symptoms, general behaviour and quality of life amongst children 49 and adolescents withFor ADHD. It does notPreview seem to cause an increased risk of serious adverseOnly events in the short-term but it is associated 50 with a relatively high risk of non-serious adverse events in general. These findings should be interpreted in the light of a number 51 of limitations, including the lack of blinding, outcome reporting bias, heterogeneity, and the consequent very low to low quality of 52 evidence for all outcomes. Accordingly, we are unable to recommend or refute methylphendiate for the treatment of ADHD in children 53 and adolescents. More long-term randomised nocebo tablet (’active-placebo’) controlled clinical trials without risks of bias are necessary 54 to allow firm decisions on methylphenidate treatment in children and adolescents with ADHD. Such nocebo-controlled trials ought 55 to be conducted first in adults with ADHD. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 2 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 48 of 615
1 2 3 4 PLAINLANGUAGESUMMARY 5 6 The benefits and harms of methylphenidate in children and adolescents with ADHD 7 Review question: This review assessed the effectiveness of methylphenidate on hyperactivity, attention and impulsivity in children and 8 Confidential:adolescents with attention deficit hyperactivity disorder For (ADHD). Review Only 9 Background: ADHD is one of the most commonly diagnosed and treated childhood psychiatric disorders. Methylphenidate (MPH) 10 is the drug most often prescribed to treat children and adolescents with ADHD. We found 185 randomised clinical trials. 11 12 Search date: The evidence is current to March 2015. 13 Study characteristics The 185 randomised trials in this review included 12,245 children or adolescents. All the trials compared 14 methylphenidate with a placebo - something designed to look and taste the same as methylphenidate but which has no active ingredient. 15 Most trials were small and treatment duration only lasted an average of 75 days (ranging from 1 day to 425 days), making it impossible 16 to assess the long-term effects of methylphenidate. Most of the trials had other weaknesses that meant they were likely to overestimate 17 the benefits of methylphenidate and to underestimate the harmful effects of methylphenidate. Forty-four percent of the trials were 18 funded by industry. 19 20 Key results: The findings suggest that methylphenidate might help to improve some of the core symptoms of ADHD - reducing 21 hyperactivity and impulsivity and helping children to concentrate. Methylphenidate might also help to improve their general behaviour 22 and quality of life. There is no evidence from randomised trials that methylphenidate increases the risk of serious harms when used for 23 up to six months, but MPH is associated with a high risk of non-serious harms like problems sleeping, decreased appetite, decreased 24 weight, excoriation etc. 25 Quality of the evidence: The quality of evidence was very low for efficacy outcomes (e.g., ADHD symptoms), and low for the safety 26 outcomes (e.g., adverse events). 27 28 Conclusion: At present it is not possible to say whether methylphenidate should, or should not, be recommended for the treatment 29 of ADHD symptoms in children and adolescents. Better designed randomised trials with long-term follow-up are needed. Because 30 methylphenidate is associated with non-serious harms (such as problems with sleeping and decreased appetite) trials need to use 31 comparisons that also produce such unwanted adverse effects, in order to accurately assess the benefits of methylphenidate. For ethical 32 reasons, such trials - known as ‘nocebo trials’ - shouldfirst be conducted in adults before being considered for children. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 3 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 49 of 615 BMJ
1 2 3 4 J by Published Collaboration. Cochrane The 2015 © disor Copyright hyperactivity deficit attention for Methylphenidate SUMMARYOFFINDINGSFORTHEMAINCOMPARISON [Explanation] 5 Confidential: For Review Only 6 7 8 Methylphenidate compared with placebo or no intervention for ADHD 9 10 Patient or population: patients with ADHD 11 Settings: All 12 Intervention: Methylphenidate 13 Comparison: Placebo or no intervention 14 15 Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments 16 (95% CI) (studies) (GRADE) 17 18 Assumed risk Corresponding risk 19 e AH)i hlrnadaoecns(Review) adolescents and children in (ADHD) der 20 Placebo or no interven- Methylphenidate
21 Ltd. Sons, & Wiley ohn tion 22 23 ADHD symptoms-paral- The mean ADHD symp- SMD 1698 ⊕ Quality very low due to , , 24 lel and 1st period cross- toms-parallel and 1st pe- -0.77 (-0.64 to -0.90) (19 studies) very low1 2 3 high risks of bias due to 25 over riod cross-over in the lack of blinding; bias due 26 ADHD rating scales intervention groups was to selective outcome re- 27 (Teacher-rated) corresponding to a mean porting; and heterogene- 28 difference of 9.6 (95% CI: ity 29 11.25 to 8.00) on ADHD- 30 Rating Scale (ADHD-RS) 31 32 Total number of serious trialpopulation RR 0.98 1532 ⊕⊕ Quality low due to high , 33 adverse events (0.44 to 2.22) (9 studies) low1 3 risks of bias due to lack For16 perPreview 1000 16 per 1000 Only of blinding and bias due 34 35 (7 to 36) to selective outcome re- 36 porting 37 38 Total number of non-se- trialpopulation RR 1.29 3132 ⊕⊕ Quality low due to high 39 rious adverse event (1.10 to 1.51) (21 studies) low1,3 risks of bias due to lack 40 of blinding; and bias due 41 to selective outcome re- 42 porting 43 4 44 45 46 https://mc.manuscriptcentral.com/bmj 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 50 of 615
1 2 3 4 J by Published Collaboration. Cochrane The 2015 © disor Copyright hyperactivity deficit attention for Methylphenidate 5 Confidential: For Review Only 6 7 408 per 1000 526 per 1000 8 (448 to 615) 9 10 11 12 General behavior- paral- The mean general behav- SMD 668 ⊕ Quality very low due to , , 13 lel and 1st period cross- ior- parallel and 1st pe- -0.87 (-0.71 to -1.04) (5 studies) very low1 3 4 high risks of bias due to 14 over riod cross-over in the in- lack of blinding; bias due 15 General behavior ratings tervention groups was to selective outcome re- 16 scales (Teacher-rated) 0.87 standard mean de- porting; and directness 17 viations lower 18 (1.04 to 0.71 lower) 19 e AH)i hlrnadaoecns(Review) adolescents and children in (ADHD) der 20 Quality of life The mean quality of life SMD 0.61 514 ⊕ Quality very low due to (Parents-rated) in the intervention groups (0.42 to 0.8 higher) (3 studies) very low1,3,4 high risks of bias due to 21 Ltd. Sons, & Wiley ohn 22 was lack of blinding; bias due 23 coorosponding to a mean to selective outcome re- 24 difference of 8.0 (95% CI: porting; and directness 25 5.49 to 10.46) on the 26 Child Health Questionaire 27 scale 28 *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the 29 assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 30 CI: Confidence interval; RR: Risk ratio; 31 32 GRADE Working Group grades of evidence 33 High quality:ForFurther research isPreview very unlikely to change our confidence in theOnly estimate of effect. 34 Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. 35 Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. 36 Very low quality: We are very uncertain about the estimate. 37 38 1 Many studies in the meta-analysis with high risk of bias 39 2 High hetereogenity 40 3 Selective outcome reporting bias 41 4 Indirection 42
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1 2 3 4 BACKGROUND the age of six (ICD-10) or 12 years (DSM-5), and that some im- 5 pairment from the symptoms is present in two or more settings. 6 There must also be clinically significant impairment in social, aca- 7 Description of the condition demic, or occupational functioning (APA 1994; APA 2000; WHO 8 Confidential: For1992 Review). ADHD is increasingly seen Only as a developmental psychiatric Attention deficit hyperactivity disorder (ADHD) is one of the 9 disorder that extends into adulthood, with high heterogeneity and most commonly diagnosed and treated childhood psychiatric dis- 10 comorbidity with other psychiatric disorders (Schmidt 2009). orders (Scahill 2000). 11 Comorbid disorders are common in ADHD. The Multimodal It is rarely out of the news as the absence of a validated diagnostic 12 Treatment of Attention Deficit Hyperactivity Disorder (MTA) test to confirm the clinical diagnosis of ADHD has given rise to 13 trial identified one or more comorbid disorders in almost 40% of debate about its validity as a diagnosis (Timimi 2004). For some 14 the participants (MTA 1999). These included oppositional defi- time there have been concerns about rising rates of ADHD di- 15 ant disorder, conduct disorder, depression, anxiety, tics, learning agnoses and possible harms of drug treatment in children (Zito 16 dificulties and cognitive deficits (Jensen 2001; Kadesjö 2001). 2000) as well as variations in prevalence estimates (Moffit 2007; 17 Polanczyk 2014) Professional and national bodies have developed 18 guidelines on the assessment, diagnosis and treatment of ADHD 19 in an attempt to ensure the maintenance of high standards of diag- Description of the intervention 20 nostic and therapeutic practice (American Academy of Pediatrics The stimulant medications methylphenidate, dexamphetamine, 21 2011; CADDRA 2011; NICE 2009; Pliszka 2007a; SIGN 2009). 22 and atomoxetine (a nonstimulant selective noradrenaline reup- Psychosocial interventions such as parent management training take inhibitor) are considered treatments of choice for children 23 are recommended in the first instance for younger children and 24 and adolescents with ADHD (Greenhill 2006b; NICE 2009). for those with mild to moderate symptoms (American Academy of Globally, methylphenidate is the most commonly used drug in 25 Pediatrics 2011; NICE 2009; Pliszka 2007a) and stimulants (alone 26 the treatment of ADHD and it has been used for more than 50 or in combination with psychosocial interventions) are recom- years (Kadesjö 2002; NICE 2009). Some research suggests that 27 mended for more severe ADHD ( American Academy of Pediatrics the combination of behavioural therapy (e.g., behavioural par- 28 2011; CADDRA 2011; NICE 2009). ent training, school consultation, and direct contingency manage- 29 The prevalence of ADHD in children and adolescents is estimated ment) and pharmacotherapy might benefit children with ADHD 30 to be 3% to 5% (Polanczyk 2007), depending on the classification (Gilmore 2001; MTA 1999). 31 system used, with boys two to four times more likely to be diag- Methylphenidate is approved for the treatment of ADHD and nar- 32 nosed than girls (Schmidt 2009). Individuals with ADHD show colepsy (Kanjwal 2012). Pharmacological treatment of children 33 difficulties in attentional and cognitive functions such as prob- and adolescents with ADHD is reported to have a beneficial effect 34 lem-solving, planning, orienting, flexibility, sustained attention, on the major symptoms of hyperactivity, impulsivity, and atten- 35 response inhibition, and working memory (Pasini 2007; Sergeant tion. The dosage of the intervention can vary quite significantly 36 2003). Other problems include affective components such as mo- between children and therefore, needs to be titrated individually to 37 tivational delay and mood dysregulation (Castellanos 2006; Nigg an optimal dosage that maximises benefits and minimises adverse 38 2005; Schmidt 2009). effects (Stevenson 1989). This variety in therapeutic dosage ranges 39 Diagnosis is made through recognition of excessive inattention, from anything between 5 mg to 60 mg methylphenidate admin- 40 hyperactivity, and impulsivity in a child, before 12 years of age, istered two to three times daily (Pliszka 2007a). It has been sug- 41 that impairs his or her functioning or development (APA 2013; gested that treatment with methylphenidate should include med- 42 WHO 1992). The ADHD construct compromises 18 signs re- ication-free periods to reassess effects on symptoms (Kidd 2000; 43 flecting inattention, hyperactivity and impulsivity described in the NICE 2009). 44 principal diagnostic classification systems, the International Clas- There is debate as to whether it is valid to diagnose preschool 45 sification of Diseases, Tenth Revision (ICD-10; WHO 1992) and children with ADHD and whether methylphenidate is efficacious 46 the Diagnostic and Statistical Manual of Mental Disorders, Fifth and safe for them to use (Greenhill 2006b). 47 Edition (DSM-5; APA 2013). 48 In the DSM-IV, there are different subtypes, which identify and 49 classify particular symptoms. The subtypes are ’predominantly For PreviewHow the intervention Only might work 50 inattentive type’, ’predominantly hyperactive-impulsive type’, and 51 ’combined type’, which presents with both hyperactive-impulsive It is presumed that the effects of methylphenidate on ADHD 52 and inattentive symptoms (Willcut 2012). symptoms are related to its effects on dopaminergic and no- 53 The criteria of the DSM-5 and the ICD-10 require that inatten- radrenergic neurotransmissions in the central nervous system 54 tion, hyperactivity, and impulsivity are pervasive, i.e. seen in a (CNS) (Engert 2008). Methylphenidate acts by inhibiting the 55 range of situations, for at least six months, and are present before catecholamine reuptake, primarily as a dopamine-norepinephrine 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 6 Copyright © 2015 The Cochrane Collaboration. 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1 2 3 4 reuptake inhibitor modulating the levels of dopamine and to a King 2006; Maia 2014; Punja 2013; Reichow 2013; Schachter 5 lesser extent the levels of norepinephrine. Methylphenidate binds 2001; Van der Oord 2008a). Also, many did not meta-analyse 6 to and blocks dopamine and norepinephrine transporters (Heal the data (Charach 2011; Charach 2013; Faraone 2010; Kambeitz 7 2006; Iversen 2006). The increased concentrations of dopamine 2014), while others did not consider the effect according to dose 8 Confidential:and norepinephrine in the synaptic cleft leads to increased For neuro- of Review methylphenidate (Bloch 2009 ; CharachOnly 2011; Faraone 2002; 9 transmission. The bioavailability of oral methylphenidate is 11% Faraone 2006; Faraone 2009; Faraone 2010; Kambeitz 2014; King 10 to 52% and has a duration of action for instant release of around 2006; Maia 2014; Punja 2013; Reichow 2013; Van der Oord 11 two to four hours, for sustained release of three to eight hours, 2008a), 12 and for extended release of eight to 12 hours (Kimko 1999). Regarding the outcomes, most meta-analyses pooled data across 13 Methylphenidate is believed to activate self-regulation control pro- parent- and teacher-raters and observers (Bloch 2009; Charach 14 cesses thereby ameliorating what is believed to be the core neu- 2011; Charach 2013; Hanwella 2011; Kambeitz 2014; King 15 rofunctional problems of ADHD (Barkley 1977a; Schulz 2012a; 2006; Reichow 2013), and did not separate outcome measures for 16 Solanto 1998). Symptom control is found to be strongly related to inattention and hyperactivity/impulsivity (Bloch 2009; Charach 17 functional improvement (Biederman 2003b; Cox 2004; Swanson 2013; Faraone 2002; Faraone 2006; Faraone 2009; Hanwella 18 2004a). 2011; King 2006; Reichow 2013; Van der Oord 2008a). Most 19 Studies indicate that methylphenidate is effective for both core studies did not present data on spontaneous adverse events (Bloch 20 symptoms of ADHD (inattention, hyperactivity, and impul- 2009; Charach 2013; Faraone 2002; Faraone 2006; Faraone 2009; 21 sivity) and aggression (Connor 2002). Children become more Faraone 2010; Hanwella 2011; Kambeitz 2014; Maia 2014; 22 able to manage their impulsivity (Barkley 1981; Barkley 1989a; Van der Oord 2008a), on adverse events measured by rating 23 Shaw 2012). However, there may be factors which result in a scales (Bloch 2009; Charach 2011; Charach 2013; Faraone 2002; 24 child or adolescent becoming less responsive to methylphenidate. Faraone 2006;;Faraone 2009; Hanwella 2011; Kambeitz 2014; 25 In a supplementary analysis of the trial ’A Comparison of Maia 2014; Reichow 2013; Van der Oord 2008a); or reasons for 26 Methylphenidates in an Analog Classroom Setting’ (COMACS), the lack of such information. 27 the investigators found girls to have a superior response to Most of the studies (Bloch 2009; Charach 2011; Faraone 2002; 28 methylphenidate than boys (Sonuga-Barke 2007; Swanson Faraone 2006; Faraone 2009; Faraone 2010; King 2006; Schachter 29 2004a). In addition, Barkley 1991b found differences in response 2001; Van der Oord 2008a) did not follow the guidelines of the 30 to methylphenidate between the ADHD inattentive and com- Cochrane Handbook (Higgins 2011) or the Preferred Report- 31 bined subtypes. Children with the inattentive subtype were judged ing Items for Systematic Reviews and Meta-Analyses (PRISMA) 32 to have a less positive response to methylphenidate than those di- guidelines (Bloch 2009; Moher 2015). In addition, the risk of ran- 33 agnosed with the combined type. dom errors, risk of bias, and trial quality were not systematically as- 34 sessed (Bloch 2009; Charach 2011; Charach 2013; Faraone 2002; 35 Faraone 2006; Faraone 2009; Faraone 2010; Hanwella 2011; 36 Why it is important to do this review Kambeitz 2014; King 2006; Van der Oord 2008a; Higgins 2011; Wetterslev 2008). These shortcomings plus other methodological 37 During the last 15 years, several systematic reviews investigating shortcomings, including potential biases in excluding non-English 38 the efficacy of methylphenidate for ADHD (with or without meta- publications (Bloch 2009; Charach 2011; Charach 2013; Faraone 39 analysis) have been published. Most only investigated the effects 2002; Faraone 2006; Faraone 2009; Faraone 2010; Kambeitz 40 of methylphenidate on symptoms of ADHD and not the potential 2014; King 2006; Maia 2014; Punja 2013; Reichow 2013; Van 41 harms. Over 15 reviews have pooled results of methylphenidate der Oord 2008a), and not searching the principal major interna- 42 treatment for children and adolescents with ADHD (Bloch 2009; tional databases or reporting the search terms clearly (Bloch 2009; 43 Charach 2011; Charach 2013; Faraone 2002; Faraone 2006;; Faraone 2002; Hanwella 2011; Kambeitz 2014; Reichow 2013; 44 Faraone 2009; Faraone 2010; Hanwella 2011; Kambeitz 2014; Van der Oord 2008a) can compromise the data collection and 45 King 2006; Maia 2014; Punja 2013; Reichow 2013; Schachter consequently the results reliability of previous meta-analyses. 46 2001; Van der Oord 2008a). None of them were conducted as The increasing use of methylphenidate in children has raised con- 47 Cochrane systematic reviews, and none seem to have had a peer- cerns. Although stimulant medications may have a favourable risk- 48 reviewed protocol published before the conduct of the analyses. benefit profile they might carry potential risks of both serious 49 Many of the reviews did not conduct subgroup analyses exam- For Previewand non-serious adverseOnly effects. The most common adverse ef- ining the effect of comorbidities on treatment effects (Charach 50 fects associated with methylphenidate are headache, sleep prob- 2011; Charach 2013; Faraone 2002;Faraone 2006; Faraone 2009; 51 lems, tiredness, and problems of decreased appetite. Serious ad- Faraone 2010; Hanwella 2011; Kambeitz 2014; King 2006; Maia 52 verse reactions, such as psychotic symptoms and mood disorders, 2014; Punja 2013; Van der Oord 2008a), nor controlled for treat- 53 affect about 3% of the children treated with methylphenidate ment effect of ADHD subtypes (Bloch 2009; Charach 2011; 54 (Block 1998; Cherland 1999; MTA 1999; NICE 2009; Pliszka 55 Charach 2013; Faraone 2002; Hanwella 2011; Kambeitz 2014; 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 7 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 53 of 615 BMJ
1 2 3 4 1998). Some studies indicate that methylphenidate can decrease METHODS 5 children’s height and weight (Schachar 1997a; Swanson 2004a; 6 Swanson 2009). In addition, there have been reports of sudden 7 death during methylphenidate treatment, and it is still unclear as Criteria for considering studies for this review 8 Confidential:to whether these deaths were directly related to the drugFor treat- Review Only 9 ment (Vitiello 2008). Therefore, further research on the link be- 10 tween sudden death and methylphenidate treatment is currently Types of studies 11 being conducted (U.S. FDA 2011). In addition, as the use of Randomised clinical trials (RCT) of methylphenidate in the treat- 12 methylphenidate in children under six years of age is increasing so ment of children and adolescents with attention deficit hyperactiv- 13 it is vital to explore the risk versus benefit in this younger popula- ity disorder (ADHD). We included trials irrespective of language, 14 tion (U.S. FDA 2011). publication year, publication type, or publication status. 15 A Cochrane systematic review on methylphenidate for adults with ADHD concluded that immediate-release methylphenidate 16 Types of participants 17 is efficacious for treating symptoms of hyperactivity, impulsivity 18 and inattentiveness, and improves the overall clinical condition Children and adolescents up to and including 18 years of age 19 (Epstein 2014). This review, and the reviews cited above, indicated diagnosed with ADHD according to the Diagnostic and Sta- 20 moderate to large SMD effects on ADHD core symptoms. Epstein tistical Manual of Mental Disorders, Third Edition (DSM-III; 21 2014 further concluded that adverse effects from immediate-re- APA 1980), Third Edition Revised (DSM-III-R; APA 1987), and 22 lease methylphenidate for adults with ADHD are probably not of Fourth Edition (DSM-IV; APA 1994), and Fifth Edition (DSM- 23 serious clinical significance, although this conclusion is limited by 5: APA 2013) or diagnosed with hyperkinetic disorders according 24 the short duration of trials(Epstein 2014). All of these reviews may to the International Statistical Classification of Diseases Related Health Problems, Ninth Revision (ICD-9) and Tenth Revision 25 be overestimating the effects sizes due to low quality of the included (ICD-10) (WHO 1992). We included participants with ADHD, 26 studies or methodological shortcomings. In this respect, our assess- with or without comorbid conditions such as conduct or opposi- 27 ment of the quality of included studies in Epstein 2014 is at odds tional disorders, tics, depression, attachment disorders, or anxiety 28 with those of the author team and we have submitted a criticism disorders. At least 75% of the participants in a trial were required 29 of this (Storebø 2015b [pers comm]). The present systematic re- to be 18 years of age or younger, and the mean age of the trial pop- 30 view of the benefits and harms of methylphenidate in children and ulation had to be 18 years of age or younger. At least 75% of the 31 adolescents with ADHD, undertaken in accordance with the stan- participants in a trial were required to have a normal intellectual 32 dards operated by The Cochrane Collaboration (http://editorial- quotient (IQ > 70). 33 unit.cochrane.org/sites/editorialunit.cochrane.org/files/uploads/ 34 MECIR_conduct_standards%202.3%2002122013.pdf) and the 35 PRISMA guidelines (Liberati 2009;Moher 2015) addresses the Types of interventions 36 weaknesses that previous reviews seem to have missed. Methylphenidate administered at any dosage or formulation, as 37 Because of the limitations of existing reviews, we conducted our part of any medical treatment regimen, compared with placebo or 38 systematic review of the benefits and harms of methylphenidate in no intervention. 39 children and adolescents with ADHD according to The Cochrane Co-interventions were allowed if the intervention groups received 40 Collaboration recommendations (Higgins 2011) and PRISMA the co-interventions similarly. Polypharmacy as co-intervention in 41 guidelines (Liberati 2009; Moher 2015). one of the groups are therefore not allowed. 42 43 Types of outcome measures 44 45 46 OBJECTIVES Primary outcomes 47 To assess the beneficial and harmful effects of methylphenidate 1. ADHD symptoms (attention, hyperactivity, and 48 in children and adolescents with attention deficit hyperactivity impulsivity), measured over the short (≤ six months) and long 49 disorder (ADHD).For Previewterm (> six months), Only by psychometric instruments or by 50 observation of behaviour using, for example, the Conners’ 51 This systematic review focuses on both beneficial and harmful teacher’s rating scales (Conners 1998;Conners 2008). The raters 52 effects of methylphenidate in randomised clinical trials, and is the could be teachers, other observers (independent assessors), or 53 first of two systematic reviews. A second review focusing on harms parents. 54 in non-randomised studies will be published later in 2015 (Storebø 2. Serious adverse events. A serious adverse event was defined 55 in press). as any event that led to death, was life-threatening, required 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 8 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 54 of 615
1 2 3 4 inpatient hospitalisation or prolongation of existing 1. Cochrane Central Register of Controlled Trials 2015, Issue 5 hospitalisation, resulted in persistent or significant disability, and 2 part of The Cochrane Library, searched ? March 2015 6 any important medical event that may have jeopardized the 2. Ovid MEDLINE,1948 to current, searched 10 March 7 patient’s life or required intervention to prevent it. All other 2015, 8 Confidential:adverse events were considered non-serious (ICH 1996 For). 3.Review EMBASE (Ovid), 1980 to current,Only searched 10 March, 9 2015, 10 4. CINAHL (EBSCOhost), 1980 to current, searched 10 11 Secondary outcomes March 2015, 12 1. Non-serious adverse events. We assessed all adverse events 5. PsycINFO (Ovid), 1806 to current, searched 10 March 13 including, for example, growth retardation, cardiological, 2015, 14 neurological, and gastrointestinal events according to the 6. Conference Proceedings Citation Index -Science and 15 International Committee of Harmonization guidelines (ICH Conference Proceedings Citation Index -Social Science & 16 1996). Humanities (Web of Science ) 1990 to 17 March 2015, searched 17 2. General behaviour in school and at home were rated on 19 March 2015, 18 psychometric instruments such as the Achenbach Child 7. ClinicalTrials.gov 1999 to current, searched 26 February 19 Behaviour Checklist (CBCL) (Achenbach 1991), measured over 2015, 20 the short (≤ six months) and long term (> six months).The 8. International Clinical Trials Registry Platform (ICTRP) 21 raters could be teachers, other observers (independent assessors), 1999 to current, searched 26 February 2015. 22 or parents. We chose to use the teacher-rated outcome as the The search strategy for each database is shown in Appendix 23 primary analysis. 1. We searched CENTRAL, Ovid MEDLINE, Embase and 24 3. Quality of life, measured by psychometric instruments such PsycINFO using two different search strategies (one for efficacy of 25 as the Child Health Questionnaire (CHQ) (Landgraf 1998).The methylphenidate and one for adverse events of methylphenidate). 26 raters could be teachers, other observers (independent assessors), For the remaining databases we used one broad strategy. In order 27 or parents. to overcome poor indexing and abstracting, we listed individual 28 We chose to use teacher-rated outcomes for our primary analyses, brand names in the search strategies. The literature searches were 29 for both ADHD symptoms and general behaviour outcomes. The not limited by language, year of publication, or type or status of 30 observers were independent assessors. GM I don’t understand publication. We sought translation of the relevant sections of non- 31 this sentence. English language articles. 32 33 Searching other resources 34 Search methods for identification of studies In order to find additional relevant trials not identified by the 35 electronic searches, we checked the bibliographic references of 36 identified review articles, meta-analyses, and a selection of in- 37 Electronic searches cluded trials. Furthermore, we sent requests for published as well 38 We ran the first literature searches in October 2011 and updated as unpublished data to pharmaceutical companies manufacturing 39 them in November 2012, March 2014, and most recently March methylphenidate, including Shire, Medice (represented in Den- 40 2015. We searched the following sources: mark by HB Pharma), Janssen-Cilag, and Novartis (Figure 1). We 41 also requested unpublished studies from experts in the field. 42 43 44 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 9 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 55 of 615 BMJ
1 2 3 4 Figure 1. Letter for medical companies 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Data extraction and management 34 Data collection and analysis Seventeen reviewers extracted data (CGr, CRMM, DGa, DGi, 35 We conducted the review according to the Cochrane Handbook ER, ES, FLM, HK, KBR, MH, MJR, MS, MZ, OJS, RK, SR, 36 for Systematic Reviews of Interventions (Higgins 2011). We per- and TDN). The seventeen authors worked together in groups of 37 formed the analyses using Review Manager 5.3 (RevMan) (Review two. We resolved disagreements by discussion or used an arbiter 38 Manager 2014). if required. In those cases where there were incomplete data or 39 Selection of studies data were unclear in the published trial reports we contacted the 40 authors, requesting them to clarify the missing information. We 41 also contacted the authors of all cross-over trials to get first period Eleven reviewers (ER, FLM, HBK, KBR, MH, MS, OJS, TDN, 42 data on ADHD symptoms. SR, TK, and TB) worked together in groups of two and inde- 43 Data extraction forms were developed a priori and, following data pendently screened titles and abstracts of all publications obtained 44 extraction pilots, were updated to accommodate more detailed from the literature searches; uncertainty or disagreements were re- 45 extraction and to facilitate standardised approaches to data extract solved by consensus or by consulting a third review author. We 46 among the authors. These extraction forms were used by all data obtained full-text articles of studies presenting data potentially rel- 47 extractors (see Appendix 2; Appendix 3). evant for the review. We then assessed the full-text articles accord- 48 CRMM, FLM, MH, HK, ER, and OJS entered data into the ing to our listed inclusion criteria. Disagreements were discussed, 49 Cochrane Collaboration’s statistical software Review Manager and if agreement orFor consensus could notPreview be reached, a third re- Only 50 (RevMan) (Review Manager 2014). 51 view author was consulted (OJS). We listed randomised clinical 52 trials pre-included on abstract assessment, but excluded after read- ing the full-text with reasons for exclusion (see Characteristics of 53 Assessment of risk of bias in included studies 54 excluded studies). 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 10 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 56 of 615
1 2 3 4 For each included trial, data extractors independently evaluated Incomplete outcome data 5 all risk of bias domains listed below, resolving any disagreements • Low risk of bias. The underlying reasons for the missing 6 by discussion. For each domain of bias we assigned each study to data would probably not affect the outcome measurement 7 one of the following three categories: low risk of bias, uncertain regarding the effect of methylphenidate,as all the missing data 8 Confidential:risk of bias, and high risk of bias, according to the guidelines Forin the can Review be considered as missing at random Only or all data were reported. 9 Cochrane Handbook for Systematic Reviews of Interventions (Higgins • Uncertain risk of bias. There was not enough information 10 2011). Due to the risk of overestimation of beneficial intervention to assess whether the missing data or the method used to handle 11 effects and underestimation of harmful intervention effects in ran- missing data would create bias on the estimate of effect of 12 domised clinical trials with unclear or inadequate methodological methylphenidate. 13 quality (Schulz 1995; Kjaergard 2001; Lundh 2012; Moher 1998; • High risk of bias. The crude estimate of effects could be 14 Savovi 2012a; Savovi 2012b; Wood 2008), we assessed the in- biased due to the underlying reasons for the absence of data. 15 fluence of the risk of bias on our results (See subgroup analyses). 16 We will use the domains with definitions provided below to assess 17 the risk of bias in the included trials (Higgins 2011; Gluud 2015) Selective outcome reporting The risk of bias components were as follows. 18 • Low risk of bias. The trial protocol was available, and all 19 prespecified outcomes of interest were reported.. 20 • Uncertain risk of bias. Incomplete information to assess Generation of the allocation sequence 21 whether there was selective outcome reporting. 22 • Low risk of bias. The method used was either adequate • High risk of bias. Not all of the primary outcomes 23 (e.g., computer generated random numbers or table of random specified beforehand were reported. Selection bias (exclusion of 24 numbers) or was unlikely to introduce selection bias. participants after randomisation). 25 • Uncertain risk of bias. There was not enough information 26 to assess whether the method used could cause bias. 27 • High risk of bias. The method used was likely to introduce Vested interest bias 28 bias. • Low risk of bias. The trial’s source(s) of funding did not 29 come from any parties that might have had a conflict of interest 30 (e.g., a manufacturer of methylphenidate). 31 Allocation concealment • Uncertain risk of bias. The source of funding was not clear. 32 • Low risk of bias. The method used (e.g., central • High risk of bias. The trial was funded by parties that 33 allocation) was unlikely to bias allocation to groups. might have had a conflict of interest (e.g., a manufacturer of 34 • Uncertain risk of bias. There was not enough information methylphenidate). Potential conflicts of interests among the 35 to assess whether the method used could cause bias in allocation. authors. 36 • High risk of bias. The method used (e.g., open random 37 allocation schedule) could bias allocation to groups. 38 Other sources of bias 39 • Low risk of bias. The trial appeared to be free of other 40 Blinding of participants and personnel sources of bias. 41 • • Uncertain risk of bias. There was inadequate information 42 Low risk of bias. The method of blinding was described sufficiently and conducted in a satisfactory way. and therefore it was not possible to assess other possible sources 43 • Uncertain risk of bias. There was insufficient information to bias. 44 to assess whether adequate blinding used. • High risk of bias. There was other sources of bias 45 • High risk of bias. No blinding or incomplete blinding. 46 Low risk of bias trials were defined as trials having low risk of bias 47 in all domains. We considered trials with one ore more unclear or 48 inadequate component as trials with high risk of bias. Blinding of outcome assessors 49 Some of the trials excluded methylphenidate non responders, • Low risk of bias.ForThe method of blindingPreview was described placebo responders, Only and/or patients that had adverse events due 50 51 and blinding was done in a satisfactory way. to the medication before randomisation. These were not consid- 52 • Uncertain risk of bias. There was insufficient information ered as a risk bias as this was done before the randomisation of 53 to assess whether the type of blinding used was likely to induce patients. However, to identify whether this ’cohort selection bias 54 bias on the estimate of effect. of all participants’ had an effect on estimates of effectiveness, we 55 • High risk of bias. No blinding or incomplete blinding. conducted subgroup analyses based on these criteria. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 11 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 57 of 615 BMJ
1 2 3 4 Measures of treatment effect effect and period effect (Subgroup analysis and investigation of 5 The treatment effect was defined as an improvement in ADHD heterogeneity). We found similar treatment effects in the parallel/ 6 symptoms, general behaviour, and quality of life. GM I have to first period cross over trials group and the second period cross- 7 say that I don’t think parents would necessarily concur with over trials and no significant subgroup differences between the 8 Confidential:this. (OJ: Read Hartmann et al 2007. This is moved For to “data two Review groups. There was considerable Only heterogeneity, however, so we 9 synthesis” as suggested) present the analyses separately. 10 We used endpoint data where these were reported or obtained 11 from authors but data from trials reporting only ’change scores’ 12 Dichotomous data were pooled with ’end point scores’ in meta-analyses. We checked 13 We summarised dichotomous data as risk ratios (RR) with 95% whether the inclusion of change data affected outcomes by per- 14 confidence intervals (CI). We calculated the risk difference (RD). forming sensitivity analyses (see Sensitivity analysis). 15 16 Dealing with missing data 17 Continuous data 18 We obtained missing data through contacting authors but if data If the same measure was used in all trials in a meta-analysis of remained unavailable, we used the incomplete data in the analysis. 19 a given continuous outcome we calculated the mean difference 20 Despite some trials reporting that intention-to-treat (ITT) analy- (MD) with 95% CI. If different measures were used we calculated ses were used, many had missing primary outcomes data (Hollis 21 the standardised mean difference (SMD) with 95% CI. If the trials 1999). 22 did not report means and standard deviations but other values 23 W We discussed the methods used to handle the missing data and (like t-tests and P values), we transformed these into standard to what extent it was likely that the missing data would influence 24 deviations. 25 the results of the trial.GM where do you report this/indicate it? For the primary analyses of teacher-rated ADHD symptoms, Please add. (I delete this sentence) 26 teacher-rated general behaviour, and quality of life, we transformed 27 the SMD into a MD on the following scales to assess whether 28 the result exceeded the minimum clinical important differences: Assessment of heterogeneity 29 ADHD-Rating Scale (ADHD-RS), Conners Global Index (CGI), Overall there are three types of heterogeneity: clinical, method- 30 and Child Health Questionnaire (CHQ). We identifieda mini- ological, and statistical. Variability in the participants, interven- 31 mal clinical relevant difference (MIREDIF) of 6.6 points on the tions, and outcomes of trials is clinical heterogeneity. Variability 32 ADHD-RS ranging from 0 to 72 points based on a trial by Zhang in the design of the trials is methodological heterogeneity and 33 et al. (Zhang 2005), a MIREDIF of 7.0 points on the CHQ rang- the difference in the effects estimates between trials is statistical 34 ing from 0 to 100 points based on a trial by Rentz et al. (Rentz heterogeneity . We assessed clinical heterogeneity by comparing 35 2005) but wewere not able to find any references describing a differences in the trial population, interventions, and outcomes 36 MIREDIF on the CGI (range 0 to 30 points). and methodological heterogeneity by comparing the design of the 37 trials. We identified potential reasons for the clinical and method- 38 ological heterogeneity by examining individual trial characteristics Unit of analysis issues 39 and subgroups. Furthermore, we observed statistical heterogeneity 40 We used data from the randomised comparison groups in parallel in the trials both by visual inspection of a forest plot and by using 41 group trials and in cross-over trials. GM Perhaps lose this sen- a standard Chi2 value with a significance level of α = 0.1 and used 42 tence - or rewrite. It isn’t clear what you are trying to say. (OJ: I2 for quantifying the inconsistency, where I2 values between 30% 43 I have now tried to make it clearer!!) to 60% indicate a moderate level of heterogeneity (Higgins 2011). 44 Many ADHD trials use cross-over methodology. We aimed to 45 obtain data from the first period of these and pool it with parallel 46 trial data, as they are similar (Curtin 2002). We requested this Assessment of reporting biases 47 from authors if it was not available in the published paper. We We followed the Cochrane Handbook for Systematic Reviews of 48 established a second analysis group of cross-over trial data, where Interventions (Higgins 2011) for reporting bias, including pub- 49 first period data wasFor not available. Our originalPreview intent was to adjust lication bias and Only outcome reporting bias. We drew funnel plots 50 for the effect of the unit of analysis error in cross-over trials by (estimated differences in treatment effects against their standard 51 conducting a covariate analysis, but there was not enough data error) and performed the Eggers’ statistical test for small-study 52 to do this. Because cross-over trials are more prone to bias from effects. We did not visually inspect the funnel plot if there were 53 carry-over effects, period effects and unit of analysis errors (Curtin fewer than ten studies in the meta-analysis, in accordance with 54 2002), we conducted a subgroup analysis to compare the two the Cochrane Handbook for Systematic Reviews of Interventions 55 analysis groups. We also tested for the possibility of a carry-over (Higgins 2011). Asymmetry could be due to publication bias, but 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 12 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 58 of 615
1 2 3 4 could also be due to genuine heterogeneity between small and analyses and sensitivity analyses investigating the hetereogen- 5 large trials (Higgins 2011). ity: eg.; age, sex, type of ADHD, comorbidity etc) 6 GM: Isn’t here the place to deal with different perspectives 7 (teachers, parents etc)? (OJ: Yes! Thank you!) 8 Confidential:Data synthesis For Review Only 9 We performed statistical analyses according to the recommenda- 10 Heterogeneity-adjusted required information size tions in the Cochrane Handbook for Systematic Reviews of Interven- 11 and trial sequential analysis (Higgins 2011). We synthesised data statistically, assuming 12 tions that clinical heterogeneity was not excessive (e.g. there was not too Trial sequential analysis (TSA) is a methodology combining the 13 much variability in participants’ characteristics). Furthermore, we required information size for a meta-analysis with the threshold for 14 included and analysed trials undertaken in any configuration or statistical significance (Brok 2008; Brok 2009; Thorlund 2009; 15 setting (e.g., in groups, at home, at a centre). Wetterslev 2008) in order to quantify the statistical reliability of 16 We used the inverse variance method, giving large studies more the data in a cumulative meta-analysis, controlling the P value 17 weight, to enable more precise estimates. Data was synthesised by thresholds for sparse data, and repetitive testing of accumulating 18 using final values or change from baseline scores. If data was avail- data (Brok 2008; Brok 2009; Thorlund 2009; Wetterslev 2008). 19 able for a number of intervals, we used the longest period assessed. Comparable to the a priori sample size estimation in a single ran- 20 We used the random-effects models as the primary method for domised trial, a meta-analysis should include a required informa- 21 all meta-analyses and the fixed-effect model for sensitivity anal- tion size (RIS) at least as large as the sample size of an adequately 22 yses (Jakobsen 2014). We performed separate meta-analyses for powered single trial to reduce the risk of random error. TSA cal- 23 three types of raters (teachers; observers; parents), for pooled par- culates the RIS in a meta-analysis and provides trial sequential 24 allel group trials/first period cross-over trials and for end of trial monitoring boundaries to adjust the significance level for sparse 25 crossover data. data and repetitive testing on accumulating data (Wetterslev 2008; 26 The ADHD symptom scales describe the severity of inatten- CTU 2011). Thereby, the risk of random error can be assessed. 27 tion, hyperactivity and impulsivity at home and at school. Severe For the calcualtions with the Tral Sequential Analysis program we 28 ADHD achieved high scores. We judged that in spite of the di- included zero event trials by substituting zero with 0.5 (CTU 29 versity of psychometric instruments, they could be used for our 2011; Thorlund 2011). 30 outcomes and we integrated the different types of scales in the When new trials emerge, multiple analyses of accumulating data 31 analyses. Three scales focused on specific attentional measures. If leads to repeated significant testing and hence introduces multi- 32 the same measure was used in all trials or we used the mean differ- plicity. Thus, use of conventional P value criterion is prone to exac- 33 ence (MD) but used standardised mean difference (SMD) where erbating the risk of random error (Lau 1995; Berkey 1996). Meta- 34 different outcome measures were used for the same construct in analyses not reaching the RIS are analysed with trial sequential 35 different trials. monitoring boundaries analogous to interim monitoring bound- 36 When separate measures of hyperactivity, impulsivity, and inat- aries in a single trial (Wetterslev 2008). This approach will also be 37 tention were available we preferred to use combined scores. When crucial in coming updates of the review. 38 symptoms were measured and reported at different time points If a TSA does not result in any significant findings (no Z-curve 39 during the day (after the ingestion of the medication or placebo), crossing of the trial sequential monitoring boundaries) before the 40 we chose to use the time point closest to noon. required information size has been reached, then the conclusion 41 The ADHD symptoms and general behaviour were measured by should either be that more trials are needed to reject or accept an 42 three types of raters: teachers, observers, or parents. We considered intervention effect that was used for calculation of the required 43 these data as different outcomes and teacher-rated measures as the sample size or in case the cumulated Z-curve enters the futility 44 primary outcome because symptoms of ADHD are more readily 45 detectable in the school setting (Hartman 2007). area the anticipated intervention effect can be rejected. 46 When studies reported data for different doses, we used data for For the outcomes, ’total serious adverse events’ and ’total non-seri- 47 the dose we defined as moderate/high dose (> 20 mg/day) in our ous adverse events’, we calculated the a priori diversity adjusted re- 48 primary analyses. quired information size (DARIS) (i.e. number of patients required 49 We summarised adverseFor event data as RRPreview with 95% CI. for di- to detect or reject Only a specific intervention effect in the meta-analy- 50 chotomous outcomes. For the purpose of this review, we only used sis) and performed a TSA for the outcomes based on the following 51 dichotomous outcomes reflecting the number of participants af- assumptions (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 52 fected by the event per the total number of participants. 2009;Wetterslev 2009 ). 53 GM do you mean that this is an assumption you made, OR 1. The proportion of patients in the control group with 54 that you only did this WHEN this appeared to be the case? (OJ adverse events. 55 always assuming that was the case. we did a lot of subgroup 2. A relative risk reduction of 20%. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 13 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 59 of 615 BMJ
1 2 3 4 3. A type I error of 5% The following studies were excluded from the analysis in sensitivity 5 4. A type II error of 20%. analysis: 6 5. The observed diversity of the meta-analysis. IQ<70: Pearson 2013; Smith 1998; Taylor 1987; Oesterheld 1998 7 Change scores: Carlson 2007; Findling 2007; Newcorn 2008; 8 Confidential: ForPalumbo Review 2008;Tucker 2009 Only Subgroup analysis and investigation of heterogeneity 9 Age>18 years: Green 2011; Szobot 2008 10 We used the parallel group/first period cross-over trials of teacher- 11 rated ADHD symptoms as our primary analyses to test the ro- 12 bustness of this estimate through several subgroup analyses. GM Summary of findings tables 13 something wrong here? Several of these were not identified a We used GRADE (GRADEpro 2014) to construct a ’Summary 14 priori in the protocol and are therefore listed below as post hoc of findings’ table for all of the review outcomes. The GRADE ap- 15 analyses. These subgroup analyses were added because it were ap- proach appraises the quality of a body of evidence based on the ex- 16 parent before data extraction commenced, that further subgroup tent to which one can be confident that an estimate of effect or asso- 17 analyses might be important to undertake GM can you say whey ciation reflects the item being assessed. Considerations are due to: 18 you added these post hoc? (OJ: Done) within-trial risk of bias; the directness of the evidence; heterogene- 19 • Dose of methylphenidate (low dose: ≤20 mg/day or ≤0.6 ity of the data; precision of effect estimates; and risk of publication 20 mg/kg/day compared to moderate/high dose: >20 mg/day or bias (Andrews 2013a; Andrews 2013b; Balshem 2011; Brunetti 21 >0.6 mg/kg/day: post hoc subgroup analysis); 2013; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; 22 • Design (parallel trial compared to first phase and end-of- Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h; 23 trial cross-over trials: post hoc subgroup analysis); Guyatt 2013a; Guyatt 2013b; Guyatt 2013c; Mustafa 2013). 24 • Medication status before randomisation (medication naive When possible, that is, when mean difference or relative risk were 25 (more than 80% of the included participant were medication available, we used results obtained with the TSA for the rating 26 naïve) compared to not medication naive (less than 20% of the for imprecision (Jakobsen 2014). We reported the two primary 27 included participants were medication naïve): post hoc subgroup and the three secondary outcomes in the SOF table; teacher-rated 28 analysis); ADHD symptoms, serious adverse events, non-serious adverse • 29 Risk of bias (trials with low risk of bias compared to trials events, teacher-rated general behavior and quality of life. 30 with high risk of bias); 31 • Age comparing trials with participants of two to six 32 years, to those with participants of 7 to 11 years, and to those 33 with participants of 12 to 18 years; RESULTS 34 35 • Sex boys compared to girls; 36 • Comorbidity children with comorbid disorders Description of studies 37 compared to children without comorbid disorders; and 38 All evaluated studies not fulfilling the inclusion criteria for this 39 • Type of ADHD predominantly participants with review are listed in Characteristics of excluded studies with rea- 40 inattentive type compared to participants with combined type. sons. Studies awaiting classification as well as ongoing studies are 41 also listed (see Characteristics of studies awaiting classification; 42 Sensitivity analysis Characteristics of ongoing studies). The main reasons for exclu- 43 sion of studies in this review were: no acceptable ADHD diag- We conducted sensitivity analyses to determine whether findings 44 nosis, no methylphenidate treatment, or polypharmacy, no assess- were sensitive to: 45 ment of ADHD symptoms, general behaviour, quality of life or • Decisions made during the review process such as our 46 adverse events. The typical reasons for exclusion in the included assessment on level of clinical heterogeneity which are listed 47 trials were: children with autism, substance abuse, epilepsy, med- below. 48 ical or neurological diseases, and a history of seizures, mental re- • Combining ’change-scores’ and ’end-of-trial’ scores in the 49 tardation, Tourette’s syndrome. meta-analyses. For Preview Only 50 Results of the searches 51 There is no sufficiently well-designed method to combine the re- We carried out electronic searches over four time periods. Searches 52 sults of trials with high risk and low risk of bias (Higgins 2011). up to October 2011 produced 6358 records after duplicates were 53 We performed sensitivity analyses grouping together the trials with removed (10,249 initial records). Searches up to November 2012 54 similar classifications of bias, as described above, and investigated produced an additional 713 records after duplicates were removed 55 the impact on intervention effects. (1,080 initial records). Searches up to March 2014 produced an 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 14 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 60 of 615
1 2 3 4 additional 654 records after duplicates were removed (1,274 ini- English, including Danish, Norwegian, German, Dutch, French, 5 tial records). Searches up to February 2015 (ClinicalTrials.org and Italian, Spanish, Portuguese, Czech, Turkish, Farsi, Japanese, and 6 ICTRP) and March 2015 (the rest of the databases) produced an Chinese. These were all translated. We included 761 publications 7 additional 1178 records after duplicates were removed (1,460 ini- describing 185 randomised clinical trials and 243 non-randomised 8 Confidential:tial records). We further identified 368 publications through For refer- studies. Review A total of 138 publications Only described 38 parallel group 9 ence list reading of 298 reviews and correspondence with authors trials and 311 publications described 147 cross-over trials (Figure 10 of relevant literature as well as pharmaceutical companies. Of a 2;Moher 2009). The 243 non-randomised studies described in 11 total of 9271 screened records, we excluded 7811 clearly irrelevant 312 publications, will be assessed and synthesised in the forth- 12 publications through title and abstract reading. We retrieved the coming review on adverse events in observational studies (Storebø 13 full text of 1460 reports, which we assessed for eligibility. Of the in press). 14 retrieved publications, 69 were written in languages other than 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 15 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 61 of 615 BMJ
1 2 3 4 Figure 2. Flow chart 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 16 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 62 of 615
1 2 3 4 5 We contacted the authors of 161 trials twice for supplemental 6 information and data, and received answers from 92 (Abikoff 2002; Lin 2014; Martins 2004; Newcorn 2008; Palumbo 2008; 7 2009; Armstrong 2012; Arnold 2004; Barkley 1989; Barkley Perez-Alvarez 2009; Pliszka 2000; Riggs 2011; Schachar 1997; 8 Confidential:1991; Barkley 2000; Bedard 2008; Brams 2008; Brown For 1984a; Szobot Review 2004; Tourette’s-Syndrome-Study-Group Only 2002; Tucker 9 Brown 1988a; Carlson 1995; Carlson 2007; Castellanos 1997; 2009; Van der Meere 1999; Wigal 2004; Wilens 2006; Wolraich 10 Chacko 2005; Chronis 2003; Connor 2000; Cook 1993; Corkum 2001). The majority (34 trials) were short-term trials under six 11 2008; Cox 2006; Douglas 1986; DuPaul 1996; Duric 2012; months duration, and three were long-term trials conducted for 12 Epstein 2011; Fabiano 2007; Fine 1993; Flapper 2008; Froehlich more than six months (Perez-Alvarez 2009; Schachar 1997; Jensen 13 2011; Gadow 1990; Gadow 1995; Gadow 2007; Garfinkel 1983; 1999 (MTA)); in one trial the duration of the trial was unclear 14 Gonzalez-Heydrich 2010; Gorman 2006; Green 2011; Grizenko (Tucker 2009). The average duration was 74.8 days, and the range 15 2012; Hicks 1985; Horn 1991; Ialongo 1994; Jensen 1999 of duration was one to 425 days. 16 (MTA); Kelly 1989; Kent 1999; Klorman 1990; Kolko 1999; 17 Kollins 2006 (PATS); Leddy 2009; Lopez 2003; Lufi 1997; 18 Lufi 2007; Manos 1999; McGough 2006; Moshe 2012; Murray Location 19 2011; Musten 1997; Newcorn 2008; Nikles 2006; Palumbo 2008; Twenty-one of the 38 trials were conducted in the USA (Arnold 20 Pelham 2005; Pliszka 1990; Pliszka 2000; Pliszka 2007; Ramtvedt 2004; Brown 1985; Carlson 2007; Childress 2009; Connor 2000; 21 2013; Rapport 1985a; Rapport 1987; Rapport 2008; Riggs 2011; Findling 2008; Findling 2010; Greenhill 2002; Greenhill 2006; 22 Schachar 1997; Sharp 1999; Silva 2008; Smith 2004; Smithee Horn 1991; Ialongo 1994; Kollins 2006 (PATS); Newcorn 2008; 23 1998; Solanto 2009; Stein 1996; Stein 2003; Stein 2011; Swanson Palumbo 2008; Perez-Alvarez 2009; Pliszka 2000; Riggs 2011; 24 2004; Szobot 2004; Szobot 2008; Tannock 1992; Tannock 1993; Tucker 2009; Wigal 2004; Wilens 2006; Wolraich 2001), two 25 Tannock 1995; Taylor 1987; Tervo 2002; Tirosh 1993; Tirosh were conducted in the USA and Canada (Biederman 2003; Jensen 26 1993a; Van der Meere 1999; Wallander 1987; Waxmonsky 2008; 1999 (MTA)),one was conducted in the USA, Canada, and Aus- 27 Wigal 2014; Wilkison 1995; Wodrich 1998; Wolraich 2001; Zeni tralia (Findling 2006), and one was conducted in USA, Canada, 28 2009). Taiwan, Mexico, and Puerto Rico (Lin 2014). Two trials each were 29 Responses were not received from authors of 69 trials (Ashare conducted in Brazil (Martins 2004; Szobot 2004), Canada (Butter 30 2010; Ben 2002; Biederman 2003; Bliznakova 2007; Blum 2011; 1983; Schachar 1997), Israel (Green 2011; Jacobi-Polishook 31 Brams 2012; Buitelaar 1995; Childress 2009; Coghill 2007; 2009), and Germany (Coghill 2013; Lehmkuhl 2002) though 32 Douglas 1995; Döpfner 2004a; Findling 2006; Findling 2007; Coghill 2013 also included participants in Sweden. Single trials 33 Findling 2008; Findling 2010; Firestone 1981; Forness 1992; were conducted in New Zealand (Heriot 2008), Norway (Duric 34 Gadow 2011; Greenhill 2002; Gruber 2007; Hale 2011; Heriot 2012), and the Netherlands (Van der Meere 1999). The coun- 35 2008; Hoeppner 1997; Johnston 1988; Kaplan 1990; Kent 1995; try was not clear in two trials (Tourette’s-Syndrome-Study-Group 36 Konrad 2004; Konrad 2005; Lehmkuhl 2002; Lijffijt 2006; 2002; Firestone 1981). 37 Lin 2014; Martins 2004; Muniz 2008; Pelham 1989; Pelham 38 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham 2002; Pelham 2011a; Pelham 2014; Perez-Alvarez 2009; Quinn 2004; 39 Setting 40 Rubinsten 2008; Samuels 2006; Schachar 2008; Schwartz 2004; All of the trials were carried out in an out clinic setting except for 41 Shiels 2009; Silva 2005a; Silva 2006; Smith 1998; Stoner 1994; one trial, which was carried out in a naturalistic classroom setting 42 Sumner 2010; Sunohara 1999; Swanson 1998; Swanson 1999; (Greenhill 2006), and one trial carried out at a research unit at a 43 Swanson 2002a; Swanson 2002b; Symons 2007; Tannock 1989; Tannock 1995a; Taylor 1993; Tucker 2009; Whalen 1990; Wigal hospital (Schachar 1997). One trial had no information on setting 44 (Brown 1985). 45 2003; Wigal 2013; Wilens 2008; Wilens 2010; Zeiner 1999). 46 Included parallel group randomised clinical trials 47 Participants 48 We included 38 randomised parallel group trials described in 138 49 publications (Arnold 2004; Biederman 2003; Brown 1985; Butter The 38 randomised trials included a total of 5111 participants; 1983; Carlson 2007For; Childress 2009 ;PreviewCoghill 2013; Connor 3517 boys and 1057Only girls with the percentage of girls ranging 50 51 2000; Duric 2012; Findling 2006; Findling 2008; Findling from 0% to 50% (average 20.7%, equal to a boys-girls-ratio of 52 2010; Firestone 1981; Green 2011; Greenhill 2002; Greenhill 5:1). All participants were aged between 3 and 20 years with an 53 2006; Heriot 2008; Horn 1991; Ialongo 1994; Jacobi-Polishook average age of 9.7 years. Twenty-six trials described the percentage 54 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); Lehmkuhl of methylphenidate naïve participants with an average of 58.2% 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 17 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 63 of 615 BMJ
1 2 3 4 (range 0% to 100%). The proportion of participants with com- Included cross-over randomised clinical trials 5 bined subtype ADHD was described in 23 trials with an aver- We included 147 cross-over trials described in 311 publica- 6 age of 72% (range 25% to 100%); the proportion of participants tions (Abikoff 2009; Ahmann 1993; Armstrong 2012; Ashare 7 with hyperactive subtype was 5.0% (19 trials, range 0% to 56%), 2010; Barkley 1989; Barkley 1991; Barkley 2000; Bedard 2008; 8 Confidential:and the proportion with inattentive subtype was 24% For (20 tri- Review Only Ben 2002; Bliznakova 2007; Blum 2011; Borcherding 1990; 9 als, 0% to 72.4%). Although only five trials excluded children Brams 2008; Brams 2012; Brown 1984a; Brown 1988a; Brown 10 and adolescents with a comorbidity (Findling 2010; Greenhill 1991, Buitelaar 1995; Bukstein 1998, Carlson 1995; Castellanos 11 2002; Perez-Alvarez 2009; Tucker 2009; Wigal 2004), it was 1997; Chacko 2005, Chronis 2003; Coghill 2007; Cook 1993; 12 unclear if such participants were included in 11 trials (Arnold Corkum 2008; Cox 2006; Douglas 1986; Douglas 1995; DuPaul 13 2004; Biederman 2003; Brown 1985; Butter 1983; Duric 2012; 1996; Döpfner 2004a, Epstein 2011; Fabiano 2007; Findling 14 Findling 2006; Findling 2008; Firestone 1981; Greenhill 2006; 2007; Fine 1993; Fitzpatrick 1992; Flapper 2008; Forness 1992; 15 Jacobi-Polishook 2009; Wilens 2006). Oppositional defiant dis- Froehlich 2011; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 16 order was the most common comorbidity ranging from 8% to 2011; Garfinkel 1983; Gonzalez-Heydrich 2010; Gorman 2006; 17 53% of participants (average 36.3%), followed by conduct disor- Grizenko 2012; Gruber 2007; Hale 2011; Hicks 1985; Hoeppner 18 der, which ranged from 2% to 32% (average 11.6%). 1997; Johnston 1988; Kaplan 1990; Kelly 1989; Kent 1995; Kent 19 Participants taking other medications were specifically excluded 1999; Klorman 1990; Kolko 1999; Kollins 2006 (PATS); Konrad 20 in ten trials (Green 2011; Heriot 2008; Ialongo 1994; Jacobi- 2004; Konrad 2005; Leddy 2009; Lijffijt 2006; Lopez 2003; Lufi Polishook 2009; Kollins 2006 (PATS); Martins 2004; Palumbo 21 1997; Lufi 2007; Manos 1999; McBride 1988a; McGough 2006; 2008; Perez-Alvarez 2009; Schachar 1997; Wigal 2004) and al- 22 McInnes 2007; Moshe 2012; Muniz 2008; Murray 2011; Musten lowed in two trials (Lehmkuhl 2002; Van der Meere 1999), while 23 1997; Nikles 2006; Oesterheld 1998; Overtoom 2003; Pearson Riggs 2011 allowed drug and alcohol use (Riggs 2011). 24 2013; Pelham 1989; Pelham 1990a; Pelham 1993a; Pelham 25 1999; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 2011a; 26 Pelham 2014; Pliszka 1990; Pliszka 2007; Quinn 2004; Ramtvedt 27 Interventions 2013; Rapport 1985a; Rapport 1987; Rapport 2008; Rubinsten 28 Extended-release and modified-release methylphenidate was used 2008; Samuels 2006; Schachar 2008; Schulz 2010a; Schwartz 29 in 12 trials (Biederman 2003; Childress 2009; Coghill 2013; 2004; Sharp 1999; Shiels 2009; Silva 2005a; Silva 2006; Silva 30 Green 2011; Greenhill 2002; Greenhill 2006; Lehmkuhl 2002; 2008; Smith 1998; Smith 2004; Smithee 1998; Solanto 2009; 31 Lin 2014; Newcorn 2008; Riggs 2011; Tucker 2009; Wilens Stein 1996; Stein 2003; Stein 2011; Stoner 1994; Sumner 2010; 32 2006); both immediate- and extended-release methylphenidate Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; 33 were used in two trials (Findling 2006; Wolraich 2001), and trans- Swanson 2002b; Swanson 2004; Symons 2007; Szobot 2008; 34 dermal methylphenidate patches were used in two trials (Findling Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995; 35 2008; Findling 2010). Immediate-release methylphenidate was Tannock 1995a; Taylor 1987; Taylor 1993; Tervo 2002; Tirosh 36 used in all other trials. The method of reporting the dosage of 1993; Tirosh 1993a; Ullmann 1985; Ullmann 1986; Urman 37 methylphenidate varied considerably between trials but the overall 1995; Wallace 1994; Wallander 1987; Waxmonsky 2008; Whalen 38 daily dose ranged from 5 mg to 60 mg with a mean reported total 1990; Wigal 2003; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 39 daily dose of 28.2 mg/day or 0.73 mg/kg/day. The average dose 2010; Wilkison 1995; Wodrich 1998; Zeiner 1999; Zeni 2009 40 of any kind of modified and extended release of methylphenidate (Figure 2). 41 was 41.0 mg and the average dose of immediate release was 23.1 Eighty-three trials were described in a single publication and 42 mg. ten trials had five or more publications (Brams 2012; Döpfner 43 Twenty-eight of the trials used placebo as control and ten trials 2004a; Gadow 1995; Grizenko 2012; Kollins 2006 (PATS); 44 used no intervention as control (Brown 1985; Connor 2000; Rapport 1987; Sharp 1999; Swanson 2002a; Swanson 2002b; 45 Duric 2012; Firestone 1981; Heriot 2008; Jensen 1999 (MTA); Swanson 2004). The PATS trial had the highest number of pub- 46 Perez-Alvarez 2009; Riggs 2011; Schachar 1997; Tucker 2009). lications per trial with 23 publications (Kollins 2006 (PATS). 47 Four trials used clonidine (Connor 2000; Palumbo 2008; All of the 147 cross-over trials were short-term trials with a du- 48 Tourette’s-Syndrome-Study-Group 2002) or atomoxetine ( ration of less than six months. Three trials did not report the 49 Carlson 2007) as cointerventionsFor in bothPreview intervention and con- duration (Kelly 1989Only; Sunohara 1999; Tannock 1993). Of the 50 trol groups. Three trials also used parent training (Firestone 1981; 144 trials, 103 were carried out in the USA (Abikoff 2009; 51 Heriot 2008; Schachar 1997), two used cognitive behavioural Ahmann 1993; Armstrong 2012; Ashare 2010; Barkley 1989; 52 therapy (Brown 1985; Riggs 2011), and five used other be- Barkley 1991; Barkley 2000; Blum 2011; Borcherding 1990; 53 havioural therapies (Duric 2012; Horn 1991; Jensen 1999 (MTA); Brams 2008; Brams 2012; Brown 1984a; Brown 1988a; Brown 54 Perez-Alvarez 2009; Tucker 2009) as cointerventions in the inter- 1991; Bukstein 1998; Carlson 1995; Castellanos 1997; Chacko 55 vention and control groups. 2005; Chronis 2003; Cook 1993; Cox 2006; DuPaul 1996; 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 18 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 64 of 615
1 2 3 4 Epstein 2011; Fabiano 2007; Findling 2007; Fitzpatrick 1992; 2003; Oesterheld 1998; Schachar 2008; Sharp 1999; Silva 2006; 5 Forness 1992; Froehlich 2011; Gadow 1990; Gadow 1995; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; 6 Gadow 2007; Gadow 2011; Garfinkel 1983; Gonzalez-Heydrich Wigal 2003; Wigal 2014). Eight trials did not report the setting 7 2010; Gorman 2006; Hale 2011; Hoeppner 1997; Johnston 1988; (Ben 2002; Bliznakova 2007; Froehlich 2011; Pliszka 2007; Stoner 8 Confidential:Kaplan 1990; Kelly 1989; Kent 1995; Klorman 1990 For; Kolko 1994 Review; Tervo 2002; Ullmann 1985 ;OnlyUrman 1995). 9 1999; Kollins 2006 (PATS); Leddy 2009; Lopez 2003; Manos 10 1999; McBride 1988a; McGough 2006; Muniz 2008; Murray 11 2011; Oesterheld 1998; Pearson 2013; Pelham 1989; Pelham Participants 12 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham The 147 randomised trials included a total of 7134 participants 13 2002; Pelham 2005; Pelham 2011a; Pelham 2014; Pliszka 1990; (range 1 to 430 per trial; mean 48.5). In 131 of these trials a total of 14 Pliszka 2007; Rapport 1985a; Rapport 1987; Rapport 2008; 6597 participants were randomised of which 6018 were followed 15 Samuels 2006; Schachar 2008; Sharp 1999; Shiels 2009; Silva up in the analyses; in 13 trials 537 participants were randomised 16 2005a; Silva 2006; Silva 2008; Smith 1998; Smith 2004; Smithee but it was unclear how many participants that were followed up. 17 1998; Solanto 2009; Stein 1996; Stein 2003; Stein 2011; Stoner In two of the trials it was unclear how many participants who 18 1994; Sumner 2010; Swanson 1998; Swanson 1999; Swanson were included, but 191 were followed up in the analyses (Epstein 19 2002a; Swanson 2002b; Swanson 2004; Symons 2007; Tervo 2011; Sharp 1999). In one of the 147 trials it was unclear how 20 2002; Ullmann 1985; Ullmann 1986; Wallace 1994; Wallander many that was included as well as followed up (Rapport 1987). 1987; Waxmonsky 2008; Whalen 1990; Wigal 2003; Wigal 2013; 21 In nine trials the ratio of boys to girls was not stated (Epstein Wigal 2014; Wilens 2008; Wilens 2010; Wilkison 1995; Wodrich 22 2011; Fine 1993; Leddy 2009; Pliszka 1990; Rapport 1987; 1998) and 21 in Canada (Bedard 2008; Ben 2002; Corkum 2008; 23 Samuels 2006; Solanto 2009; Sumner 2010; Wallace 1994) and Douglas 1986; Douglas 1995; Fine 1993; Grizenko 2012; Gruber 24 30 trials specifically did not comprise girls (Ben 2002; Bliznakova 2007; Kent 1999; McInnes 2007; Musten 1997; Rubinsten 2008; 25 2007; Borcherding 1990; Brown 1984a; Brown 1988a; Brown Schwartz 2004; Sunohara 1999; Tannock 1989; Tannock 1992; 26 1991; Carlson 1995; Castellanos 1997; Coghill 2007; Cook 1993; Tannock 1993; Tannock 1995; Tannock 1995a; Taylor 1993; 27 Forness 1992; Gadow 1990; Garfinkel 1983; Johnston 1988; Urman 1995). 28 Kaplan 1990; Kolko 1999; Moshe 2012; Overtoom 2003; Pelham 29 1990a; Pelham 1993a; Pelham 2002; Pelham 2011a; Quinn 2004; 30 Smith 2004; Stein 1996; Stoner 1994; Szobot 2008; Taylor 1987; Location 31 Wilkison 1995; Zeiner 1999). In the 108 trials that included par- 32 One trial was carried out in both the USA and Canada (Quinn ticipants of both sexes and reported the proportions, the percent- 33 2004). Five trials were carried out in Israel (Lufi 1997; Lufi age of girls ranged from 4% to 50%, with a mean of 21.8%. Par- 34 2007; Moshe 2012; Tirosh 1993; Tirosh 1993a); five in Germany ticipants were aged between four and 21 years with an average age 35 (Bliznakova 2007; Döpfner 2004a; Konrad 2004; Konrad 2005; of 9.7 years (17 trials did not report average age; however, all of 36 Schulz 2010a); four in the Netherlands (Buitelaar 1995; Flapper these trials reported age range). 37 2008; Lijffijt 2006; Overtoom 2003); two each in the UK (Coghill A total of 98 trials described the percentage of methylphenidate 38 2007; Taylor 1987), Norway (Ramtvedt 2013; Zeiner 1999) and naïve participants with an average of 51% (range 0% to 100%). 39 Brazil (Szobot 2008; Zeni 2009); and one in Australia (Nikles In 26 trials all participants were methylphenidate naïve (Abikoff 40 2006). One trial did not specify country of origin (Hicks 1985). 2009; Buitelaar 1995; Coghill 2007; Cook 1993; Corkum 2008; 41 Epstein 2011; Fine 1993; Flapper 2008; Forness 1992; Froehlich 42 2011; Kelly 1989; Kollins 2006 (PATS); Konrad 2004; Lufi 1997; 43 Setting Moshe 2012; Oesterheld 1998; Ramtvedt 2013; Rapport 1987; 44 All of the trials were carried out in an out clinic setting ex- Stoner 1994; Szobot 2008; Taylor 1987; Tirosh 1993; Tirosh 45 cept for 17 trials, which were carried out as part of summer 1993a; Urman 1995; Wallander 1987; Zeiner 1999). In 30 trials 46 treatment programs or summer schools (Bukstein 1998; Chacko only participants previously treated with methylphenidate were 47 2005; Chronis 2003; Fabiano 2007; Johnston 1988; Kolko 1999; included (Bliznakova 2007; Brams 2008; Brams 2012; Castellanos 48 Leddy 2009; Pelham 1989; Pelham 1990a; Pelham 1993a; Pelham 1997; Döpfner 2004a; Lijffijt 2006; Lopez 2003; Lufi 2007; 49 2001a; Pelham 2002For; Pelham 2014; ShielsPreview 2009; Smith 1998; Muniz 2008; NiklesOnly 2006; Overtoom 2003; Pelham 2001a; 50 Waxmonsky 2008; Whalen 1990). Five trials were carried out Pelham 2011a; Quinn 2004; Rubinsten 2008; Schulz 2010a; 51 in an in patient ward (Carlson 1995; Gonzalez-Heydrich 2010; Silva 2005a; Silva 2006; Silva 2008; Smith 2004; Sunohara 1999; 52 Kent 1995; Konrad 2005; Solanto 2009), five trials were carried Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; 53 out both out clinic and in ward (Garfinkel 1983; Hicks 1985; Swanson 2004; Whalen 1990; Wigal 2013; Wigal 2014; Wilkison 54 Kaplan 1990; Konrad 2004; Wallander 1987), and 12 trials were 1995). 55 carried out in a laboratory classroom setting (Brams 2008; Lopez The proportion of participants with combined subtype ADHD 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 19 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 65 of 615 BMJ
1 2 3 4 was described in 64 trials with an average of 69.1% (range 0% 2007; Nikles 2006; Wallace 1994). The overall daily dose ranged 5 to 100%); hyperactive subtype was 12.3% (63 trials, range 0% to from 4 mg to 77 mg with a mean reported total daily dose of 24.5 6 100%) and inattentive subtype was 20.2% (63 trials, 0% to 72%). mg or 0.6 mg/kg. Dose for immediate-release methylphenidate 7 ranged from 4 mg to 54 mg with a mean reported total daily dose of 8 Confidential:In 14 trials the participants did not have any comorbidityFor25 Review mg or 0.7 mg/kg. Dose for extended-release Only methylphenidate 9 (Borcherding 1990; Brams 2012; Garfinkel 1983; Lufi 1997; ranged from 15 mg to 77 mg with a mean reported total daily dose 10 Moshe 2012; Quinn 2004; Schachar 2008; Sumner 2010; of 36 mg or 1.1 mg/kg. The duration of methylphenidate treat- 11 Swanson 1998; Swanson 2002a; Tirosh 1993; Tirosh 1993a; ment ranged from one to 56 days with an average of 15.6 days. 12 Wilens 2008; Wilkison 1995) and 88 trials reported the presence Three trials did not report the duration (Kelly 1989; Sunohara 13 of comorbidity. Oppositional defiant disorder was the most com- 1999; Tannock 1993). 14 monly reported comorbidity ranging from 1.4% to 84% (aver- All trials used placebos as a control. 15 age 42%; 61 trials) followed by conduct disorder which ranged Three trials used concomitant co-interventions (antidepressant: 16 from 0% to 100% (average 24%; 49 trials). Participants with Carlson 1995; behavioural modification: Kolko 1999; antipsy- 17 Tourette was reported in four trials (Castellanos 1997; Gadow chotic: Zeni 2009) similarly in both intervention and control 18 2007; Gadow 2011; Kent 1999) and ranged from 12% to 100% groups. 19 (average 75%). One trial included only participants with epilepsy 20 (Gonzalez-Heydrich 2010), one trial included only patients with Outcomes - All included studies (? Really, this should 21 cerebral palsy (Symons 2007), and one trial included only partic- be a description of studies, rather than the data 22 ipants with bipolar disorder (Findling 2007). available for your MA, but if Table 1 deals with that, 23 Participants taking other medications were reported in 13 tri- OK - please just make this clearer) (OJ: have added als (Buitelaar 1995; Carlson 1995; Castellanos 1997; Cox 2006; 24 “in the included trials”) 25 Findling 2007; Gadow 2007; Gonzalez-Heydrich 2010; Kaplan 26 1990; McBride 1988a; Pearson 2013; Pelham 1989; Szobot 2008; Some psychometric ADHD instruments measure total score for 27 Zeni 2009), whereas in 42 trials it was stated that co-medication ADHD symptoms whereas others only assess the specific symptom 28 was not used (Ashare 2010; Brams 2008; Brown 1988a; Brown domains of ADHD (e.g., inattention, hyperactivity or impulsiv- 29 1991; Bukstein 1998; Forness 1992; Gadow 1995; Garfinkel ity). We categorised all scales into five subgroups: ADHD symp- 30 1983; Gorman 2006; Gruber 2007; Klorman 1990; Kollins toms; serious adverse events; non-serious adverse events; general 31 2006 (PATS); Konrad 2004; Leddy 2009; Lufi 1997; Lufi 2007; behaviour; and quality of life. Some psychometric instruments are abbreviated versions or revised versions, but all are validated. 32 McGough 2006; Moshe 2012; Muniz 2008; Oesterheld 1998; The list in the Table 1primarily refers to the original articles de- 33 Pelham 2001a; Pelham 2005; Pelham 2011a; Pliszka 1990; Quinn scribing the psychometric properties of the measurement scales 34 2004; Ramtvedt 2013; Rapport 1985a; Rapport 1987; Rubinsten used to measure ADHD symptoms in the included trials. In a few 35 2008; Schulz 2010a; Schwartz 2004; Sharp 1999; Smith 1998; cases the trial describing the use of a specific measurement scale is 36 Solanto 2009; Stein 1996; Stein 2003; Sumner 2010; Swanson referred. 37 1998; Tirosh 1993; Tirosh 1993a; Wigal 2013; Wigal 2014). It 38 was not clear whether co-medications were allowed in the remain- ing 92 trials. 39 ADHD symptoms 40 We included 25 parallel group trials and 74 cross-over trials re- 41 porting ADHD symptoms in our analyses. Interventions 42 Conners questionnaires were the most frequently used measures 43 101 trials reported use of a single type of methylphenidate (with- for ADHD symptoms with more than 30 versions all measuring 44 out specifying the type)) intervention, whereas 12 trials reported the core symptoms of ADHD. Normative data is generally well 45 use of a single immediate-release methylphenidate and 19 reported intercorrelated in revised versions (Goyette 1978). 46 use of a single extended-release methylphenidate. Both imme- The following measures for ADHD symptoms were used in in- 47 diate- and extended-release methylphenidate were used in seven cluded studies see Table 1. 48 trials (Döpfner 2004a; Fitzpatrick 1992; Pelham 1990a; Pelham 49 2001a; Schachar 2008; Swanson 2002b; Wigal 2003), two differ- For PreviewSerious and non-serious Only adverse events 50 ent types of extended-release methylphenidate were used in four 51 trials (Lopez 2003; Schulz 2010a; Silva 2005a; Swanson 2004), We included 26 parallel group trials reporting adverse events, 52 and transdermal methylphenidate patches were used in four trials of which nine trials concerned serious adverse events (Carlson 53 (Pelham 2005; Pelham 2011a; Wilens 2008; Wilens 2010). The 2007; Childress 2009; Coghill 2013; Findling 2010; Jacobi- 54 method of reporting the dose of methylphenidate varied consider- Polishook 2009; Lehmkuhl 2002; Palumbo 2008; Riggs 2011; 55 ably between trials, and three trials did not report dose (Bliznakova Wolraich 2001) and 26 trials concerned non-serious adverse 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 20 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 66 of 615
1 2 3 4 events (Arnold 2004; Biederman 2003; Carlson 2007; Childress 1976a). 5 2009; Coghill 2013; Findling 2006; Findling 2008; Findling For the purpose of measuring specific adverse events, some tri- 6 2010; Greenhill 2002; Greenhill 2006; Jacobi-Polishook 2009; als used rating scales such as Paediatric Sleep Questionnaire 7 Jensen 1999 (MTA); Kollins 2006 (PATS); Lehmkuhl 2002; Lin (PSQ) (Chervin 2000), Sleep Disturbances Scale for Children 8 Confidential:2014; Newcorn 2008; Palumbo 2008; Pliszka 2000; RiggsFor 2011; (SDSC) Review (Bruni 1996), Children’s Only Sleep Habits Questionnaire 9 Schachar 1997; Tourette’s-Syndrome-Study-Group 2002; Tucker (CSHQ) (Owens 2000), Child Depression Rating Scale (CDRS- 10 2009; Van der Meere 1999; Wigal 2004; Wilens 2006; Wolraich R) (Poznanski 1983), Young Mania Rating Scale (YMRS) (Young 11 2001). 1978), Yale Global Tic Severity Scale (YGTSS) (Leckman 1989), 12 We included 68 cross-over trials reporting adverse events of which Tic Symptom Self report Scale (TSSR) (Leckman 1988), and 13 eight trials reported serious events (Brams 2008; Brams 2012; the Massachusett’s Gernal Hospital (MGH) Abuse and Diversion 14 Buitelaar 1995; Cox 2006; Grizenko 2012; Schachar 2008; Silva Questionnaire (Wilens 2006a). 15 2008; Wigal 2013) and 67 trials reported non-serious adverse 16 events (Barkley 1989; Barkley 2000; Borcherding 1990; Brams 17 2008; Brams 2012; Brown 1984a; Brown 1988a; Brown 1991; General behaviour 18 Buitelaar 1995; Bukstein 1998; Carlson 1995; Castellanos 1997; For this outcome, we were able to include seven parallel group 19 Chacko 2005; Chronis 2003; Corkum 2008; Cox 2006; Döpfner trials and 19 cross-over trials reporting general behaviour in our 20 2004a; DuPaul 1996; Findling 2007; Fine 1993; Fitzpatrick 1992; analyses. 21 Gadow 1995; Gadow 2007; Gorman 2006; Klorman 1990; Kolko There are many different scales for general behaviour. These scales 22 1999; Manos 1999; McBride 1988a; McGough 2006; Muniz have quite different foci, such as aggression or oppositional be- 23 2008; Murray 2011; Musten 1997; Overtoom 2003; Pearson haviour, but they all describe the participants’ behaviour and the 24 2013; Pelham 1990a; Pelham 1999; Pelham 2001a; Pelham 2005; influence of methylphenidate. Higher scores on general behaviour 25 Pelham 2011a; Pelham 2014; Quinn 2004; Ramtvedt 2013; symptom scales mean better outcomes. 26 Rapport 1987; Rapport 2008; Schachar 2008; Schulz 2010a; The list in the Table 2primarily refers to the original articles de- 27 Schwartz 2004; Sharp 1999; Silva 2005a; Silva 2006; Silva 2008; scribing the psychometric properties of the measurement scales 28 Smith 1998; Solanto 2009; Stein 1996; Stein 2003; Stein 2011; used to measure General behaviour in the included trials.In a few 29 Swanson 2004; Tannock 1989; Tannock 1993; Tannock 1995; cases the trial describing the use of a specific measurement scale is 30 Taylor 1987; Tirosh 1993a; Urman 1995; Wigal 2013; Wilens referred. 31 2010; Zeiner 1999; Zeni 2009). Adverse events were measured either by rating scales, by sponta- 32 Quality of life 33 neous reports, and/or recorded by the investigators at regular in- 34 terviews or visits. Furthermore, some trials included physical ex- We could only include data from three parallel group trials and 35 aminations or paraclinical examinations, or both, such as blood zero cross-over trials reporting quality of life in our analyses. Seven scales measured quality of life both in relation to ADHD 36 tests, electrocardiogram, blood pressure, heart rate, and weight and and life in general. All of these scales (except the CGI-SI) produced 37 height control. Serious adverse events were recorded according to higher values equating to better health. 38 the ICH classification (ICH 1996). When we were in doubt, we Table quality of life see Table 3. 39 asked the authors which classification or definition they had used 40 in their trial. 41 Some trials combined all of the above modes of measurement Risk of bias in included studies while others used a single measure such as spontaneous reports or 42 rating scales. Fifty-two trials employed rating scales in which the 43 most frequently used was Barkley Side Effects Rating Scale (SERS) 44 Risk of bias in included parallel group and cross-over (Barkley 1990). 45 randomised clinical trials Other scales used were the Significant Adverse Event Reviews 46 Risk of bias was assessed using the Cochrane Risk of Bias tool questionnaire (SAERS) (Barkley 1990; Zeni 2009), Pittsburgh 47 (Higgins 2011), a summary of which is displayed in Figure 3 and Side Effect Rating Scale (PSERS) (Pelham 1993b; Pelham 2005a), 48 Figure 4.In total, zero parallel group trials and six cross-over trials and Subject’s Treatment Emergent Symptom Scale (STESS) (Guy 49 For Preview(3 %) had low riskOnly of bias in all domains. We judged 179 trials 50 (97%) to be high risk of bias trials. 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 21 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 67 of 615 BMJ
1 2 3 4 Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as 5 percentages across all included studies. 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 22 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 68 of 615
1 2 3 4 Figure 4. Risk of bias summary: review authors’ judgements about each risk of bias item for each included 5 trial. 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 23 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 69 of 615 BMJ
1 2 3 4 5 Parallel group trials 6 Wigal 2004; Wilens 2006; Wolraich 2001); method of blind- 7 None of the 38 included parallel group trials had low risk of bias ing was unclear in six trials (Biederman 2003; Childress 2009; 8 Confidential:in all bias domains. ForFindling Review 2010; Greenhill 2006; Lin Only 2014; Tucker 2009), and four 9 trials were not blinded (Brown 1985; Duric 2012; Jensen 1999 10 (MTA); Perez-Alvarez 2009). 11 The method of blinding of outcome assessors was adequately de- 12 Random sequence generation scribed in 23 trials (Arnold 2004; Carlson 2007; Coghill 2013; 13 We considered the random sequence generation to be at low Connor 2000; Firestone 1981; Heriot 2008; Horn 1991; Ialongo 14 risk of bias in 22 trials (Arnold 2004; Biederman 2003; Carlson 1994; Jacobi-Polishook 2009; Kollins 2006 (PATS); Lehmkuhl 15 2007; Childress 2009; Coghill 2013; Duric 2012; Findling 2008; 2002; Newcorn 2008; Palumbo 2008; Pliszka 2000; Riggs 2011; 16 Findling 2010; Horn 1991; Jacobi-Polishook 2009; Jensen 1999 Schachar 1997; Szobot 2004; Tourette’s-Syndrome-Study-Group 17 (MTA); Kollins 2006 (PATS); Lehmkuhl 2002; Martins 2004; 2002; Tucker 2009; Van der Meere 1999; Wigal 2004; Wilens 18 Palumbo 2008; Pliszka 2000; Riggs 2011; Schachar 1997; Szobot 2006; Wolraich 2001); method of blinding was unclear in 11 19 2004; Tourette’s-Syndrome-Study-Group 2002; Van der Meere trials (Biederman 2003; Butter 1983; Childress 2009; Findling 20 1999; Wolraich 2001), and at high risk of bias in three tri- 2006; Findling 2008; Findling 2010; Green 2011; Greenhill 2002; 21 als (Connor 2000; Green 2011; Heriot 2008). The method of Greenhill 2006; Lin 2014; Martins 2004), and four trials did not 22 random sequence generation was unclear in 13 trials (Brown have blinded outcome assessors (Brown 1985; Duric 2012; Jensen 23 1985; Butter 1983; Findling 2006; Firestone 1981; Greenhill 1999 (MTA); Perez-Alvarez 2009). 24 2002; Greenhill 2006; Ialongo 1994; Lin 2014; Newcorn 2008; 25 Perez-Alvarez 2009; Tucker 2009; Wigal 2004; Wilens 2006). 26 Incomplete outcome data 27 Incomplete data were addressed adequately in 24 trials (Arnold 28 Allocation concealment 2004; Biederman 2003; Brown 1985; Butter 1983; Carlson 29 2007; Childress 2009; Connor 2000; Duric 2012; Green 2011; We considered the allocation concealment to be at low risk of bias 30 Greenhill 2002; Greenhill 2006; Horn 1991; Jacobi-Polishook in 18 trials (Arnold 2004; Carlson 2007; Childress 2009; Coghill 31 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); Lehmkuhl 2013; Connor 2000; Findling 2008; Findling 2010; Jacobi- 32 2002; Martins 2004; Newcorn 2008; Perez-Alvarez 2009; Riggs Polishook 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); 33 2011; Szobot 2004; Tourette’s-Syndrome-Study-Group 2002; Lehmkuhl 2002; Martins 2004; Palumbo 2008; Riggs 2011; 34 Van der Meere 1999; Wolraich 2001), and inadequately in ten Schachar 1997; Szobot 2004; Tourette’s-Syndrome-Study-Group 35 trials (Findling 2006; Findling 2008;Findling 2010; Heriot 2008; 2002; Wolraich 2001), and at high risk of bias in one trial (Green 36 Ialongo 1994; Lin 2014; Pliszka 2000; Schachar 1997; Tucker 2011). The method of allocation concealment was not sufficiently 37 2009; Wilens 2006). In four trials, there was insufficient infor- reported in 19 trials (Biederman 2003; Brown 1985; Butter 1983; 38 mation to assess whether missing data were handled and whether Duric 2012; Findling 2006; Firestone 1981; Greenhill 2002; 39 missing data were likely to bias the estimate of effect (Coghill Greenhill 2006; Heriot 2008; Horn 1991; Ialongo 1994; Lin 40 2013; Firestone 1981; Palumbo 2008; Wigal 2004). 41 2014; Newcorn 2008; Perez-Alvarez 2009; Pliszka 2000; Tucker 42 2009; Van der Meere 1999; Wigal 2004; Wilens 2006). 43 44 Selective reporting 45 All predefined or otherwise expected outcomes were reported in Blinding 46 25 trials (Arnold 2004; Biederman 2003; Brown 1985; Carlson 47 The method of blinding of participants and personnel was ade- 2007; Childress 2009; Coghill 2013; Connor 2000; Duric 2012; 48 quately described in 28 trials (Arnold 2004; Butter 1983; Carlson Findling 2006; Findling 2008; Findling 2010; Green 2011; Jacobi- 49 2007; Coghill 2013; Connor 2000; Findling 2006; Findling Polishook 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); 2008; Firestone 1981For; Green 2011; Greenhill Preview 2002; Heriot 2008; Lehmkuhl 2002 ; OnlyMartins 2004; Newcorn 2008; Palumbo 2008; 50 51 Horn 1991; Ialongo 1994; Jacobi-Polishook 2009; Kollins 2006 Pliszka 2000; Riggs 2011; Tourette’s-Syndrome-Study-Group 52 (PATS); Lehmkuhl 2002; Martins 2004; Newcorn 2008; Palumbo 2002; Van der Meere 1999; Wigal 2004; Wilens 2006). All pre- 53 2008; Pliszka 2000; Riggs 2011; Schachar 1997; Szobot 2004; defined or otherwise expected outcomes were not reported in two 54 Tourette’s-Syndrome-Study-Group 2002; Van der Meere 1999; trials (Greenhill 2006; Lin 2014) and were unclear in 11 trials 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 24 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 70 of 615
1 2 3 4 (Butter 1983; Firestone 1981; Greenhill 2002; Heriot 2008; Horn Wilens 2008; Wilkison 1995; Zeni 2009), and at high risk of bias 5 1991; Ialongo 1994; Perez-Alvarez 2009; Schachar 1997; Szobot in 10 trials (Carlson 1995; Fitzpatrick 1992; Kaplan 1990; Kelly 6 2004; Tucker 2009; Wolraich 2001). 1989; Manos 1999; McBride 1988a; Szobot 2008; Tirosh 1993a; 7 Whalen 1990; Wigal 2014). The method of random sequence 8 Confidential: Forgeneration Review was unclear in 79 trials (OnlyAbikoff 2009; Ahmann 1993; 9 Ashare 2010; Barkley 2000; Ben 2002; Bliznakova 2007; Blum 10 Vested interests - industry bias 2011; Borcherding 1990; Brown 1984a; Brown 1991; Brown 11 Twenty-three trials were founded by industry (Arnold 2004; 1988a; Buitelaar 1995; Bukstein 1998; Castellanos 1997; Chacko 12 Biederman 2003; Carlson 2007; Childress 2009; Coghill 2013; 2005; Chronis 2003; Douglas 1986; Douglas 1995; Forness 1992; 13 Findling 2006; Findling 2008; Findling 2010; Greenhill 2002; Froehlich 2011; Gadow 1995; Gadow 2011; Garfinkel 1983; 14 Greenhill 2006; Kollins 2006 (PATS); Lehmkuhl 2002; Lin 2014; Gruber 2007; Hicks 1985; Hoeppner 1997; Kent 1995; Kolko 15 Newcorn 2008; Palumbo 2008; Pliszka 2000; Riggs 2011; Szobot 1999; Konrad 2004; Leddy 2009; Lijffijt 2006; Lufi 1997; Lufi 16 2004; Tucker 2009; Van der Meere 1999; Wigal 2004; Wilens 2007; McInnes 2007; Muniz 2008; Murray 2011; Overtoom 17 2006; Wolraich 2001). In five trials, information was insuffi- 2003; Pelham 1989; Pelham 1990a; Pelham 1993a, Pelham 18 cient to allow assessment of whether potential vested interest 1999; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 2011a; 19 was likely to induce bias on the estimate of effect (Horn 1991; Pelham 2014; Pliszka 1990; Pliszka 2007; Quinn 2004; Rapport 20 Ialongo 1994; Jacobi-Polishook 2009; Martins 2004; Tourette’s- 1985a; Rapport 1987; Samuels 2006; Schwartz 2004; Shiels 2009; 21 Syndrome-Study-Group 2002). In the remaining nine trials there Silva 2005a; Silva 2008; Smithee 1998; Solanto 2009; Sumner 22 were no vested interests (Brown 1985; Butter 1983; Connor 2000; 2010; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 23 Duric 2012; Firestone 1981; Green 2011; Heriot 2008; Jensen 2002a; Swanson 2002b; Swanson 2004; Symons 2007; Tannock 24 1999 (MTA); Perez-Alvarez 2009). 1992; Tannock 1993; Tannock 1995; Taylor 1993; Tervo 2002; 25 Ullmann 1985; Ullmann 1986; Urman 1995; Wigal 2013; Wilens 26 2010; Wodrich 1998; Zeiner 1999). 27 Other potential sources of bias 28 29 Allocation concealment 30 We considered the allocation concealment to be low risk of bias 31 We identified no other source of bias. in 53 trials (Barkley 1991; Brams 2008; Brown 1984a; Brown 32 1988a; Coghill 2007; Cook 1993; Corkum 2008; Douglas 1995; 33 DuPaul 1996; Fabiano 2007; Findling 2007; Fine 1993; Flapper 34 Cross-over trials 2008; Gadow 1990; Gadow 1995; Gadow 2007; Garfinkel 1983; 35 Only six of the 147 included trials had low risk of bias in all bias Gonzalez-Heydrich 2010; Gorman 2006; Grizenko 2012; Hale 36 domains (DuPaul 1996; Flapper 2008; Gorman 2006; Rapport 2011; Hoeppner 1997; Kaplan 1990; Klorman 1990; Kollins 37 2008; Stein 1996; Wilkison 1995). 2006 (PATS); McGough 2006; Moshe 2012; Musten 1997; Nikles 38 2006; Pearson 2013; Pelham 2011a; Pliszka 2007; Rapport 1985a; 39 Rapport 2008; Silva 2006; Smith 2004; Solanto 2009; Stein 1996; 40 Stein 2011; Stoner 1994; Tannock 1992; Tannock 1993; Tannock 41 Random sequence generation 1995; Taylor 1987; Tervo 2002; Tirosh 1993; Ullmann 1986; 42 We considered the random sequence generation to be low risk of Waxmonsky 2008; Wigal 2003; Wilens 2010; Wilkison 1995; 43 bias in 58 trials (Armstrong 2012; Barkley 1989; Barkley 1991; Zeni 2009), and high risk of bias in five trials (Carlson 1995; 44 Bedard 2008; Brams 2008; Brams 2012; Coghill 2007; Cook Fitzpatrick 1992; Szobot 2008; Ullmann 1985; Wigal 2014). 45 1993; Corkum 2008; Cox 2006; Döpfner 2004a; DuPaul 1996; The method of allocation concealment was not sufficiently re- 46 Fabiano 2007; Findling 2007; Fine 1993; Flapper 2008; Gadow ported in 82 trials (Abikoff 2009; Ahmann 1993; Armstrong 2012; 47 1990; Gadow 2007; Gonzalez-Heydrich 2010; Gorman 2006; Ashare 2010; Barkley 1991; Barkley 2000; Bedard 2008; Ben 48 Grizenko 2012; Hale 2011; Johnston 1988; Kent 1999; Klorman 2002; Bliznakova 2007; Blum 2011; Borcherding 1990; Brams 49 1990; Kollins 2006For (PATS); Konrad 2005 Preview; Lopez 2003; McGough 2012; Brown 1991Only, Buitelaar 1995; Bukstein 1998, Castellanos 50 2006; Moshe 2012; Musten 1997; Nikles 2006; Oesterheld 1998; 1997; Chacko 2005, Chronis 2003; Cox 2006; Douglas 1986; 51 Pearson 2013; Ramtvedt 2013; Rapport 2008; Rubinsten 2008; Döpfner 2004a, Epstein 2011; Forness 1992; Froehlich 2011; 52 Schachar 2008; Schulz 2010a; Sharp 1999; Silva 2006; Smith Gadow 2011; Gruber 2007; Hicks 1985; Johnston 1988; Kelly 53 1998; Smith 2004; Stein 1996; Stein 2003; Stein 2011; Stoner 1989; Kent 1995; Kent 1999; Kolko 1999; Konrad 2004; Konrad 54 1994; Tannock 1989; Tannock 1995a; Taylor 1987; Tirosh 1993; 2005; Leddy 2009; Lijffijt 2006; Lopez 2003; Lufi 1997; Lufi 55 Wallace 1994; Wallander 1987; Waxmonsky 2008; Wigal 2003; 2007; Manos 1999; McBride 1988a; McInnes 2007; Muniz 2008; 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 25 Copyright © 2015 The Cochrane Collaboration. 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1 2 3 4 Murray 2011; Oesterheld 1998; Overtoom 2003; Pelham 1989; 1991; Bukstein 1998; Carlson 1995; Chronis 2003; Coghill 2007; 5 Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Cook 1993; Corkum 2008; Douglas 1995; DuPaul 1996; Epstein 6 Pelham 2002; Pelham 2005; Pelham 2014; Pliszka 1990; Quinn 2011; Fabiano 2007; Findling 2007; Fine 1993; Flapper 2008; 7 2004; Ramtvedt 2013; Rapport 1987; Rubinsten 2008; Samuels Gadow 1990; Gadow 1995; Garfinkel 1983; Gonzalez-Heydrich 8 Confidential:2006; Schachar 2008; Schulz 2010a; Schwartz 2004; SharpFor 1999; 2010 Review; Gorman 2006; Grizenko 2012Only; Hale 2011; Hoeppner 9 Shiels 2009; Silva 2005a; Silva 2008; Smith 1998; Smithee 1998; 1997; Klorman 1990; Kollins 2006 (PATS); Konrad 2004; Lopez 10 Stein 2003; Tannock 1989; Tannock 1995a; Taylor 1993; Tirosh 2003; Lufi 1997; McGough 2006; McInnes 2007; Moshe 2012; 11 1993a; Urman 1995; Wallace 1994; Wallander 1987; Whalen Muniz 2008; Musten 1997; Nikles 2006; Oesterheld 1998; 12 1990; Wigal 2013; Wilens 2008; Wodrich 1998; Zeiner 1999). Pearson 2013; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 13 2011a; Pelham 2014; Pliszka 1990; Pliszka 2007; Rapport 1985a; 14 Rapport 2008; Rubinsten 2008; Schulz 2010a; Sharp 1999; Silva 15 Blinding 2005a; Silva 2006; Silva 2008; Smith 2004; Smithee 1998; Stein 16 1996; Stein 2003; Stein 2011; Stoner 1994; Sumner 2010; Szobot The method of blinding of participants and personnel was ad- 17 2008; Tannock 1995; Taylor 1987; Tervo 2002; Tirosh 1993; equately described in 110 trials (Ahmann 1993; Armstrong 18 Tirosh 1993a; Ullmann 1985; Ullmann 1986; Urman 1995; 2012; Barkley 1989; Barkley 1991; Barkley 2000; Bedard 2008; 19 Waxmonsky 2008; Wigal 2014; Wilkison 1995; Zeiner 1999; Borcherding 1990; Brams 2008; Brams 2012; Brown 1984a; 20 Zeni 2009); method of blinding was unclear in 63 trials (Abikoff Brown 1988a; Brown 1991; Buitelaar 1995; Bukstein 1998; 2009; Ahmann 1993; Ashare 2010; Barkley 2000; Ben 2002; 21 Carlson 1995; Castellanos 1997; Chacko 2005; Chronis 2003; Bliznakova 2007; Blum 2011; Borcherding 1990; Brown 1988a; 22 Cook 1993; Corkum 2008; Döpfner 2004a; Douglas 1995; Buitelaar 1995; Castellanos 1997; Chacko 2005; Döpfner 2004a; 23 DuPaul 1996; Epstein 2011; Fabiano 2007; Findling 2007; Fine Fitzpatrick 1992; Forness 1992; Froehlich 2011; Gadow 2007; 24 1993; Fitzpatrick 1992; Flapper 2008; Gadow 1990; Gadow 1995; Gadow 2011; Gruber 2007; Hicks 1985; Johnston 1988; Kaplan 25 Gadow 2007; Gadow 2011; Garfinkel 1983; Gonzalez-Heydrich 1990; Kelly 1989; Kent 1995; Kent 1999; Kolko 1999; Konrad 26 2010; Gorman 2006; Grizenko 2012; Gruber 2007; Hale 2011; 2005; Leddy 2009; Lijffijt 2006; Lufi 2007; McBride 1988a; 27 Hoeppner 1997; Johnston 1988; Kelly 1989; Kent 1995; Kent Murray 2011;Overtoom 2003; Pelham 1989; Pelham 1990a; 28 1999; Klorman 1990; Kolko 1999; Kollins 2006 (PATS); Konrad Pelham 1993a; Pelham 1999; Ramtvedt 2013; Quinn 2004; 29 2004; Konrad 2005; Lufi 1997; Lufi 2007; McBride 1988a; Rapport 1987; Samuels 2006; Schachar 2008; Schwartz 2004; 30 McGough 2006; McInnes 2007; Moshe 2012; Muniz 2008; Shiels 2009; Smith 1998; Solanto 2009; Sunohara 1999; Swanson 31 Murray 2011; Musten 1997; Nikles 2006; Oesterheld 1998; 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 32 Pelham 1989; Pelham 1990a; Pelham 1993a; Pelham 2001a; 2004; Symons 2007; Szobot 2008; Tannock 1989; Tannock 1992; 33 Pelham 2002; Pelham 2005; Pelham 2011a; Pliszka 1990; Quinn Tannock 1993; Tannock 1995a; Taylor 1993; Wallace 1994; 34 2004; Rapport 1985a; Rapport 2008; Rubinsten 2008; Samuels Wallander 1987; Wilens 2008; Wilens 2010) and six trials did not 35 2006; Schulz 2010a; Sharp 1999; Shiels 2009; Silva 2005a; Silva have blinded outcome assessors (Cox 2006; Douglas 1986; Manos 36 2006; Silva 2008; Smithee 1998; Solanto 2009; Stein 1996; 1999; Whalen 1990; Wigal 2013; Wodrich 1998). 37 Stein 2011; Stoner 1994; Sumner 2010; Swanson 1998; Swanson 38 1999; Swanson 2004; Symons 2007; Szobot 2008; Tannock 1989; 39 Tannock 1992; Tannock 1993; Tannock 1995; Tannock 1995a; 40 Taylor 1987; Taylor 1993; Tervo 2002; Tirosh 1993; Tirosh Incomplete outcome data 41 1993a; Ullmann 1986; Urman 1995; Waxmonsky 2008; Wigal Incomplete data were addressed adequately in 64 trials (Abikoff 42 2003; Wigal 2014; Wilens 2008; Wilkison 1995; Wodrich 1998; 2009; Ahmann 1993; Ashare 2010; Barkley 1991; Bedard 2008; 43 Zeiner 1999; Zeni 2009); method of blinding was unclear in 28 tri- Bliznakova 2007; Borcherding 1990; Brams 2008; Brams 2012; 44 als (Abikoff 2009; Ashare 2010; Ben 2002; Bliznakova 2007; Blum Brown 1984a; Brown 1988a; Brown 1991; Buitelaar 1995; 45 2011; Coghill 2007; Cox 2006; Douglas 1986; Forness 1992; Bukstein 1998; Chacko 2005; Cook 1993; Cox 2006; DuPaul 46 Froehlich 2011; Hicks 1985; Kaplan 1990; Leddy 2009; Lijffijt 1996; Findling 2007; Flapper 2008; Froehlich 2011; Gadow 47 2006; Overtoom 2003; Pelham 1999; Pliszka 2007; Rapport 1990; Gadow 1995; Gadow 2007; Gorman 2006; Grizenko 2012; 48 1987; Schachar 2008; Schwartz 2004; Smith 1998; Smith 2004; Gruber 2007; Hoeppner 1997; Kelly 1989; Kent 1995; Kollins 49 Sunohara 1999; SwansonFor 2002a; Swanson Preview 2002b; Wallace 1994; 2006 (PATS); LijffijtOnly 2006; Lopez 2003; Lufi 2007; McBride 50 Wallander 1987; Wilens 2010) and nine trials were not blinded 1988a; McInnes 2007; Muniz 2008; Oesterheld 1998; Overtoom 51 (Lopez 2003; Manos 1999; Pearson 2013; Pelham2014; Ramtvedt 2003; Pelham 1990a; Pelham 1993a; Pelham 2011a;; Pliszka 52 2013; Stein 2003; Ullmann 1985; Whalen 1990; Wigal 2013). 2007; Rapport 2008; Rubinsten 2008; Schulz 2010a; Silva 2006; 53 The method of blinding of outcome assessors was adequately de- Silva 2008; Smith 2004; Solanto 2009; Stein 1996; Stein 2011; 54 scribed in 78 trials (Armstrong 2012; Barkley 1989; Barkley 1991; Stoner 1994; Swanson 2004; Tannock 1995; Tannock 1995a; 55 Bedard 2008; Brams 2008; Brams 2012; Brown 1984a; Brown Taylor 1987; Ullmann 1985; Ullmann 1986; Waxmonsky 2008; 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 26 Copyright © 2015 The Cochrane Collaboration. 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1 2 3 4 Whalen 1990; Wigal 2014; Wilkison 1995; Zeni 2009). In 54 Rubinsten 2008; Samuels 2006; Schulz 2010a; Schwartz 2004; 5 trials, information was insufficient to allow assessment of whether Sharp 1999; Shiels 2009; Silva 2005a; Silva 2006; Smith 1998; 6 the method used to handle missing data was likely to induce Smith 2004; Smithee 1998; Stoner 1994; Sumner 2010; Swanson 7 bias on the estimate of effect (Armstrong 2012; Barkley 1989; 2002b; Swanson 2004; Symons 2007; Szobot 2008; Tannock 8 Confidential:Ben 2002; Carlson 1995; Chronis 2003; Corkum 2008 For; Döpfner 1989 Review; Tannock 1992; Taylor 1987 Only; Tirosh 1993; Tirosh 1993a; 9 2004a; Douglas 1986; Douglas 1995; Epstein 2011; Fine 1993; Ullmann 1985; Ullmann 1986; Urman 1995; Wallace 1994; 10 Fitzpatrick 1992; Forness 1992; Gadow 2011; Garfinkel 1983; Wallander 1987; Wigal 2003; Wilens 2008; Wodrich 1998). 11 Gonzalez-Heydrich 2010; Hicks 1985; Johnston 1988; Kaplan 12 1990; Kent 1999; Klorman 1990; Konrad 2005; Leddy 2009; 13 Lufi 1997; Manos 1999; Moshe 2012; Nikles 2006; Pelham 14 1989; Pelham 2001a; Pelham 2002; Pelham 2014; Pliszka 1990; 15 Ramtvedt 2013; Quinn 2004; Schwartz 2004; Sharp 1999; 16 Shiels 2009; Silva 2005a; Smith 1998; Smithee 1998; Stein Vested interests - Industry bias 17 2003; Sumner 2010; Sunohara 1999; Swanson 1998; Swanson Fifty-four trials were funded by industry (Abikoff 2009; 18 2002a; Symons 2007; Szobot 2008; Tannock 1989; Tannock Armstrong 2012; Blum 2011; Brams 2008; Brams 2012; Chacko 19 1993; Tirosh 1993; Tirosh 1993a; Urman 1995; Wallander 1987; 2005;Chronis 2003; Cox 2006; Döpfner 2004a; Fine 1993; 20 Wodrich 1998). Seven trials had incomplete outcome data (Kolko Froehlich 2011;Gruber 2007; Kent 1999; Kollins 2006 (PATS); 1999; Konrad 2004; Rapport 1987;Taylor 1993; Wigal 2003; 21 Leddy 2009; Lopez 2003; McInnes 2007; Manos 1999; McGough Wilens 2008; Zeiner 1999) 22 2006; Muniz 2008; Murray 2011; Pelham 1999; Pelham 2001a; 23 Pelham 2002; Pelham 2005; Pelham 2011a; Quinn 2004; 24 Ramtvedt 2013; Solanto 2009; Schachar 1997; Schachar 2008; 25 Selective reporting Shiels 2009; Schulz 2010a; Schwartz 2004; Silva 2005a; Silva 26 All predefined or otherwise expected outcomes were reported in 2006; Silva 2008; Stein 2003; Stein 2011; Sumner 2010; Sunohara 27 49 trials (Abikoff 2009; Armstrong 2012; Barkley 1989; Barkley 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 28 2000; Bliznakova 2007; Blum 2011; Brown 1984a; Brown 1988a; 2002b; Swanson 2004; Szobot 2008; Taylor 1987; Waxmonsky 29 Chronis 2003; Cook 1993; Corkum 2008; Cox 2006; DuPaul 2008; Wigal 2003; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 30 1996; Epstein 2011; Fabiano 2007; Flapper 2008; Garfinkel 1983; 2010). In 41 trials, information was insufficient to allow as- 31 Gorman 2006; Grizenko 2012; Hoeppner 1997; Kollins 2006 sessment of whether potential vested interest was likely to in- 32 (PATS); McBride 1988a; Moshe 2012; Muniz 2008; Murray duce bias on the estimate of effect (Ben 2002; Bliznakova 2007; 33 2011; Nikles 2006; Pearson 2013; Pliszka 1990; Rapport 2008; Borcherding 1990; Brown 1984a; Brown 1991; Buitelaar 1995; 34 Schachar 2008; Silva 2008; Solanto 2009; Stein 1996; Stein Carlson 1995; Coghill 2007; Gadow 1990; Gonzalez-Heydrich 35 2011; Swanson 1998; Swanson 1999; Swanson 2002a; Tannock 2010; Grizenko 2012; Findling 2007;Hoeppner 1997; Kaplan 36 1993; Tannock 1995; Tannock 1995a; Tervo 2002; Waxmonsky 1990; Kelly 1989; Kolko 1999; Lijffijt 2006; Lufi 1997; Lufi 37 2008; Whalen 1990; Wigal 2013; Wigal 2014; Wilens 2010; 2007; McBride 1988a; Nikles 2006; Pelham 1989; Pelham 1990a; 38 Wilkison 1995; Zeiner 1999; Zeni 2009). Not all outcomes Pelham 1993a; Rapport 1985a; Rapport 1987; Samuels 2006; 39 were reported in eight trials (Castellanos 1997; Chacko 2005; Sharp 1999; Smith 2004; Sumner 2010; Symons 2007; Taylor 40 Gonzalez-Heydrich 2010; McGough 2006; McInnes 2007; Stein 1993; Tervo 2002; Tirosh 1993; Tirosh 1993a; Ullmann 1985; 41 2003; Sunohara 1999; Taylor 1993) and whether all were reported Ullmann 1986; Wallace 1994; Whalen 1990; Wodrich 1998; Zeni 42 was unclear in 90 trials (Ahmann 1993; Ashare 2010; Barkley 2009). The remaining 54 trials had no vested interests (Ashare 43 1991; Bedard 2008; Ben 2002; Borcherding 1990; Brams 2008; 2010; Barkley 1989; Barkley 1991; Barkley 2000; Bedard 2008; 44 Brams 2012; Brown 1991, Buitelaar 1995; Bukstein 1998, Carlson Brown 1988a; Bukstein 1998, Castellanos 1997; Cook 1993; 45 1995; Coghill 2007; Douglas 1986; Douglas 1995; Döpfner Corkum 2008; Cox 2006; Douglas 1986; Douglas 1995; DuPaul 46 2004a, Findling 2007; Fine 1993; Fitzpatrick 1992; Forness 1992; 1996; Epstein 2011; Fabiano 2007; Fitzpatrick 1992; Flapper 47 Froehlich 2011; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2008; Forness 1992; Gadow 1995; Gadow 2007; Gadow 2011; 48 2011; Gruber 2007; Hale 2011; Hicks 1985; Johnston 1988; Garfinkel 1983; Gorman 2006; Hale 2011; Hicks 1985; Johnston 49 Kaplan 1990; KellyFor 1989; Kent 1995; KentPreview 1999; Klorman 1990; 1988; Kent 1995 Only; Klorman 1990; Konrad 2004; Konrad 2005; 50 Kolko 1999; Konrad 2004; Konrad 2005; Leddy 2009; Lijffijt Moshe 2012; Musten 1997; Oesterheld 1998; Overtoom 2003; 51 2006; Lopez 2003; Lufi 1997; Lufi 2007; Manos 1999; Musten Pearson 2013; Pelham 2014; Pliszka 1990; Pliszka 2007; Rapport 52 1997; Oesterheld 1998; Overtoom 2003; Pelham 1989; Pelham 2008; Rubinsten 2008; Smith 1998; Smithee 1998; Stein 1996; 53 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham Stoner 1994; Tannock 1989; Tannock 1992; Tannock 1993; 54 2002; Pelham 2005; Pelham 2011a; Pelham 2014; Pliszka 2007; Tannock 1995; Tannock 1995a; Urman 1995; Wallander 1987; 55 Ramtvedt 2013; Quinn 2004; Rapport 1985a; Rapport 1987; Wilkison 1995; Zeiner 1999). 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 27 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 73 of 615 BMJ
1 2 3 4 Other potential sources of bias of treatment, with a lower effect in long-term trials (SMD -0.47, 5 We identified no other sourse of bias. 95% CI -0.72 to -0.22, 1 trial, n = 253) compared to short-term 2 6 In total, zero parallel group trials and six cross-over trials (3.2%) trials (SMD -0.81, 95% CI -0.94 to -0.68, I = 25%, 18 trials, n 7 had low risk of bias in all domains. We judged the remaining 179 = 1445) (test of subgroup difference P value = 0.02 (Analysis 1.3); 8 Confidential:trials (96.8%) to be high risk of bias trials. Forand Review medication status before randomisation, Only with a better effect 9 in trials with no medication naive patients (SMD -1.06 95% CI - 10 1.33 to -0.79, 2 trials, n=286) compared to trials with medication 11 Cohort selection bias of all participants naive patient (SMD -0.79, 95% CI -1.08 to -0.50, 4 trials, n=431 12 Methylphenidate non responders, and/or placebo responders, (test for subgroup difference P value = 0.04) (Analysis 1.11), The 13 and/or patients with methylphenidate adverse events before ran- SMD effect of -0.47 for ADHD long-term trials corresponds to a 14 domisation were excluded in ten parallel group trials (Biederman mean difference of only -5.75 points (95% CI -4.2 to -9.2) on the 15 2003; Coghill 2013; Findling 2006; Findling 2008; Greenhill ADHD Rating Scale. However, dose (Analysis 1.4), trial design 16 2002; Greenhill 2006; Jacobi-Polishook 2009; Newcorn 2008; (Analysis 1.5), and risk of cohort selection bias (Analysis 1.6) did 17 Wilens 2006; Wolraich 2001), and 49 cross-over trials (Armstrong not seem to significantly influence the intervention effect. One of 18 2012; Barkley 1991; Barkley 2000; Blum 2011; Brams 2008; the studies included in the meta-analysis was change from base- 19 Brams 2012; Brown 1991; Carlson 1995; Cox 2006; Döpfner lines scores (Palumbo 2008). Removing this trial did not change 20 2004a; Fabiano 2007; Gonzalez-Heydrich 2010; Grizenko 2012; the estimate significantly. 21 Gruber 2007; Kent 1995; Konrad 2005; Manos 1999; McGough The end of cross-over trials showed a treatment effect with a SMD 22 2006; Muniz 2008; Murray 2011; Overtoom 2003; Pelham of -0.93 (95% CI -1.06 to -0.80, I2 = 77%, 59 trials, n = 5145; 23 2001a; Pelham 2014; Quinn 2004; Rapport 1985a; Rapport Analysis 1.7). The variation for measured intervention effect was 24 1987; Schachar 2008; Schulz 2010a; Schwartz 2004; Silva 2005a; not significantly influenced by risk of bias (Analysis 1.7). There 25 Silva 2006; Silva 2008; Stein 2011; Sumner 2010; Swanson 1998; was significant variation for measured intervention effect in dose 26 Swanson 2002b; Swanson 2004; Tannock 1995; Tannock 1995a; of methylphenidate (Analysis 1.8). Three of these trials included 27 Taylor 1993; Wallace 1994; Waxmonsky 2008; Whalen 1990; some participants with IQ <70. (Pearson 2013; Smith 1998; Taylor 28 Wigal 2003; Wigal 2014; Wilens 2008; Wilens 2010; Wodrich 1987). Removing these trials did not change the estimate signifi- 29 1998; Zeni 2009). Such trials have limited external validity. cantly. 30 When including all parallel group trials and end of cross-over trials, 31 Effects of interventions we observed comparable findings with a SMD of -0.91(95% CI - 2 32 1.01 to -0.80 I = 72%, 75 trials, n = 6344; Analysis 1.10). Again, See: Summary of findings for the main comparison the there was no significant variation for measured intervention 33 Methylphenidate compared with placebo or no intervention for 34 effect by risk of bias (low compared to high risk of bias) (Analysis ADHD 1.10). 35 We present the results for each of the two primary outcomes 36 (ADHD symptoms and serious adverse events) and the three sec- 37 ondary outcomes (non-serious adverse events, general behaviour, Observer-rated ADHD symptoms 38 and quality of life) below.The duration of methylphenidate treat- 39 ment ranged from one to 425 days with an average of 74.8 days. The observers could be anyone, but mostly they were clinicans. 40 Most of the results are presented using a random-effects model Methylphenidate significantly reduced observer-rated ADHD 41 of meta-analysis, thus giving more weight to smaller trials. How- symptoms compared with placebo (SMD -0.64, 95% CI -0.89 to 42 ever, the statistical significance did not change when a fixed-effect -0.39, I2 = 85%, 10 trials, n = 1907; Analysis 2.1) in parallel group 43 model was applied. trials and first period cross-over trials. The SMD effect of -0.64 for 44 ADHD symptoms corresponds to a mean difference of -8.0 points 45 (95% CI -5.8 to 12.5) on the ADHD Rating Scale. All studies 46 Teacher-rated ADHD symptoms were at high risk of bias (Analysis 2.1). Types of scales (Analysis 47 Methylphenidate significantly reduced teacher-rated ADHD 2.2), duration of treatment (Analysis 2.3), trial design (Analysis 48 symptoms compard to placebo in a meta-analysis of parallel group 2.5), or risk of cohort selection bias (Analysis 2.6) did not seem 49 trials and first periodFor cross-over trials (SMDPreview -0.77, 95% CI -0.90 to show no significant Only variation for measured intervention effect. 50 to -0.64; participants = 1698; trials= 19; Analysis 1.1) The SMD of There was no available data to test the influence of dose in this 51 -0.77 for ADHD symptoms corresponds to a mean difference of - analysis (Analysis 2.4). Two of the studies in the observer-rated 52 9.6 points (95% CI -13.7 to -6.4) on the ADHD Rating Scale. All ADHD symptoms meta-analysis reported change from baseline 53 trials were at high risk of bias (Analysis 1.1). There was significant scores (Findling 2008; Newcorn 2008). Removing these studies 54 variation for measured intervention effect; in type of scales (test did not change the estimate significantly. 55 for subgroup differences P value = 0.006; Analysis 1.2); duration The end of cross-over trials also showed a beneficial treatment 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 28 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 74 of 615
1 2 3 4 effect (SMD -1.00, 95% CI -1.16 to -0.84; participants = 2471; inattentive subtype (SMD -1.31, 95% CI -1.61 to -1.01, 1 trial, 5 trials = 19; I2 = 69%; Analysis 2.7). However, this interevention n = 204) compared to ADHD combined type (SMD 0.65, 95% 6 effect was significantly influenced by dose of methylphenidate, CI -1.30 to 2.60, I² = 99%, 2 trials, n = 559) (test for subgroup 7 with the highest estimate in the high dose group (SMD -1.13, differences: P value = 0.05, Analysis 4.4). However, this difference 8 Confidential:95% CI -1.31 to -0.95; participants = 1853; trials = 12; For I2 = 66%) rested Review upon one single trial. Only 9 Analysis 2.8). All trials were at high risk of bias (Analysis 2.7). We found no evidence of a ’carry over effect’ in the cross-over trials. 10 When including all parallel group trials and end of cross-over trials, We carried out a subgroup analysis investigating the subgroup 11 we observed comparable findings (SMD -0.83, 95% CI -0.98 to difference between first period and second period data from 4 cross 12 -0.67; participants = 4215; trials = 28; I2 = 82%) (Analysis 2.9). over trials (n=794). This analysis showed no significant subgroup 13 differences (test for subgroup differences: Chi² = 2.47, df = 1 (P = 14 0.12), I² = 59.6%. (Analysis 4.5)). 15 Parent-rated ADHD symptoms 16 Methylphenidate versus placebo significantly reduced the parent- 17 rated ADHD symptoms (SMD -0.66, 95% CI -0.82 to -0.51, Adverse events 2 18 I = 60%, 21 trials, n = 2187; Analysis 3.1) in parallel group Safety findings were reported for only 95/185(51.4%) randomised 19 trials and first period cross-over trials.The SMD effect of -0.66 clinical trials included in our meta-anaysis. 20 for ADHD symptoms corresponds to a mean difference of -8.2 21 points (95% CI -6.0 to 12.9) on the ADHD Rating Scale. All 22 the trials had high risk of bias (Analysis 3.1) There was significant Serious adverse events 23 variation for measured intervention effect by type of scales (test 24 for subgroup differences: P value = 0.01; Analysis 3.2). However, 25 duration of treatment (Analysis 3.3), dose of methylphenidate Serious adverse events reported in parallel group trials and 26 (Analysis 3.4), medication status before randomisation (Analysis the first periode of cross-over trials 3.10) and risk of cohort selection bias (Analysis 3.6) did not seem 27 A total of 1532 participants from only nine parallel and first pe- to significantly influence the intervention effect. Two of the studies 28 riod cross-over trials contributed to the analysis of serious adverse in the meta-analysis reported change from baseline scores (Carlson 29 events. There was no significant difference between participants 2007; Tucker 2009). Removing these trials did not change the 30 receiving methylphenidate and those in the control group (RR estimate significantly. 31 0.98, 95% CI 0.44 to 2.22, I2 = 0%; 9 trials, Analysis 5.1), with The end of cross-over trials showed a treatment effect with a SMD 32 no evidence of heterogeneity between trials (I² = 0%) of -0.78 (95% CI -0.90 to -0.67; participants = 3734; trials = 41; 33 The serious adverse events reported in the methylphenidate group I2 = 59%)(Analysis 3.7). This intervention effect was not signif- 34 only were, cyst rupture (n = 1), kidney infection (n = 1), and icantly influenced by dose of methylphendiate (Analysis 3.8),or 35 psychosis (methylphenidate n = 2, control n = 0). Serious adverse risk of bias (Analysis 3.7), Two of these trials included some par- 36 events reported for the control group only were loss of conscious- ticipants with IQ <70 (Pearson 2013; Taylor 1987). Removing 37 ness (n = 1), drug toxicity (n = 1), asthma (n = 1), and concussion these trials did not change the estimate significantly. 38 (n = 1). Severe adverse events reported for both groups included When including all parallel group and end of cross-over trials we 39 syncope (methylphenidate n = 3, control n = 1), and aggression observed comparable findings (SMD -0.74, 95% CI -0.83 to - 40 (methylphenidate n = 1, control n = 2) (Analysis 5.1). 0.65, I2 = 58%, 59 trials, n = 5892; Analysis 3.9). 41 42 43 Comparison of raters Serious adverse events reported at the end of cross-over trials 44 When we tested differences between raters (teachers, observers, The number of participants experiencing any serious adverse 45 and parents) we found no significant differences (Test for subgroup events were extracted from eight cross-over trials (n = 1721). 46 differences: Chi² = 2.00, df = 2 (P = 0.37), I² = 0.0%) Analysis There was no difference between the methylphenidate and con- 47 4.3). trol groups in the number of people experiencing serious adverse 48 events (RR 1.62, 95% CI 0.34 to 7.71, I2 = 0%; 8 trials, Analysis 49 6.1), although data from only two trials contributed to this meta- Additional subgroupFor analyses Preview Only 50 analysis because there were zero events in the other four trials. 51 Additional subgroup analyses on ADHD symptoms in parallel 52 group trials and first period cross-over trials showed that neither 53 age (Analysis 4.1) nor comorbidity (Analysis 4.2) influenced the Trial sequential analysis 54 intervention effect. The intervention effect was significantly influ- We conducted TSA on the ’total serious adverse events’ outcome 55 enced by ADHD subtype, with a higher intervention effect for the including 9 parallel group and end of first period cross-over trials. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 29 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 75 of 615 BMJ
1 2 3 4 Trials with zero serious adverse events were included by substitut- (RR 3.80, 95% CI 2.58 to 5.59, I2 = 36%, 16 trials, n = 2962; 5 ing zero with a constant of 0.5 (Jacobi-Polishook 2009; Wolraich Analysis 7.4) and a decrease in weight (RR 3.89, 95% CI 1.43 to 6 2001). The diversity-adjusted required information size (DARIS) 10.59, I2 = 0%, 6 trials, n = 859; Analysis 7.4). There were no 7 was calculated based on serious adverse events in the control group differences for the adverse digestive events of diarrhea, dyspepsia, 8 Confidential:of 2%; relative risk reduction or increase of 20% in the experimForen- increased Review appetite, nausea, stomach Only aches or vomiting (Analysis 9 tal group; type I error of 5%; type II error of 20% (80% power); 7.4). 10 and a diversity (D-square) of 0%. The DARIS was 43,685 partic- GM Why not wrap this up with Reporductive system events 11 ipants. The cumulative Z-curve did not cross the conventional or into one sentence at the end of this section. (OJ: Done) 12 the trial sequential monitoring boundaries for benefit, harm, or Genitourinary system events: No data. 13 futility (data not shown). As only less than 4% of the DARIS was Circulatory and respiratory system events: There were no differ- 14 accrued, risks of random error cannot be excluded. ences between groups for supraventricular extrasystoles, cough, 15 nasal congestion, pharngolaryngeal pain, upper respiratory tract 16 infection, prolonged QT-interval and tachycardia (Analysis 7.5). 17 Non-serious adverse events Reproductive system events: No data. 18 Skeletal and muscular system events: There were no differences be- 19 tween participants receiving methylphenidate and controls in the 20 Non-serious adverse events reported in parallel group trials incidence of arthralgia, asthenia, back pain, myalgia, or toothache 21 and the first phase of cross-over trials (Analysis 7.6). Immune system events: There were no differences between groups 22 Data for non-serious adverse event were extracted from 21 parallel in the incidence of gastroenteritis, influenza, nasopharyngitis, 23 group trials and first period cross-over trials with a total of 3132 pyrexia, pharyngitis, rhinitis, unspecified upper respiratory tract 24 participants. infections or viral infections, or otitis media (Analysis 7.7). 25 Overall adverse events: the following AEs were found: Participants Physical measures: There were no difference between groups as 26 receiving methylphenidate were significantly more likely to expe- regards height (Analysis 7.8), or systolic or diastolic blood pressure 27 rience overall non-serious adverse events (RR 1.29, 95% CI 1.10 (Analysis 7.11), but participants in the methylphenidate group 28 to 1.51, I2 = 74%, 21 trials, n = 3132; Analysis 7.1) although there weighed significantly less (SMD -1.12, 95% CI -1.55 to -0.70, I 29 was substantial heterogeneity between trials (Tau² = 0.08; Chi² 2 = 83%, 5 trials, n = 805; Analysis 7.9), had a lower BMI (MD - 30 = 72.18, df = 19 (P < 0.00001); I² = 74%). This heterogeneity, 0.60, 95% CI -0.84 to -0.36, I2 = 0%, 1 trial, n = 215; Analysis 31 however, did not appear to be related to dose as there was no evi- 7.10), and a higher pulse rate (MD 3.91, 95% CI 2.59 to 5.22, I 32 dence of differences between low and high dose methylphenidate 2 = 70%, 8 trials, n = 1240; Analysis 7.11). 33 trials (test for subgroup differences: P value = 0.49, Analysis 7.2). Other non-serious adverse events: There were no differences be- 34 Adverse events included those pertaining to the nervous system tween groups in the incidence of accidental injury, epistasis, over- 35 (Analysis 7.3), as well as the digestive (Analysis 7.4), urinary (no does, skin disorders, or skin laceration (Analysis 7.12), but there 36 data), circulatory and respiratory (Analysis 7.5), reproductive (no was a higher likelihood of excoriation in the methylphenidate 37 data), skeletal and muscular (Analysis 7.6), and immune systems group (RR 3.52, 95% CI 1.19 to 10.46, I2 = 0%, 1 trial, n = 303; 38 (Analysis 7.7). Other reported adverse events included physical Analysis 7.12). 39 differences in height (Analysis 7.8), weight (Analysis 7.9), body 40 mass index (BMI) (Analysis 7.10), vital signs (Analysis 7.11), and 41 other adverse events (Analysis 7.12). 42 Nervous system events: Participants receiving methylphenidate Non-serious adverse events reported at the end of cross-over 43 did not seem any more likely to have affective symptoms; aggres- trials 44 sion; apathy; confusion; depression; dizziness; drowsiness; emo- Non-serious adverse events were extracted from 21 cross-over trials 45 tional lability; fatigue; headaches; insomnia; irritability; nervous- with a total of 2072 participants. 46 ness; nightmares; pain; picking at skin or fingers; nail biting or lip Overall adverse events: There was significantly more adverse events 47 or cheek chewing; sadness, tearfulness or depression; social with- in the methylphenidate group at the end of cross-over trials (RR 48 drawal; somnolence; trouble sleeping or sleep problems; tics; or 1.33, 95% CI 1.11 to 1.58, I2 = 18%, 21 trials, n = 2072; Analysis 49 worry or anxiety (Analysis 7.3). Data for these outcomes came 8.1) There was a difference in the number of events between low For Preview Only 2 50 from one to 20 studies with total participant numbers ranging or high doses (Test for subgroup differences I = 80.8%, P = 0.02, 51 from 59 to 2724. Participants were more likely to have trouble Analysis 8.2). Categories of specific non-serious adverse events 52 sleeping or sleep problems (RR 1.60, 95% CI 1.15 to 2.23, I2 = reported at the end of cross-over trials included those pertaining 53 0%, 13 trials, n = 2416). to the nervous system (Analysis 8.3), digestive system (Analysis 54 Digestive system events: Participants in the methylphenidate 8.4), urinary system (Analysis 8.5), skeletal and muscular system 55 group were significantly more likely to have a decrease in appetite (Analysis 8.6), immune system (Analysis 8.7), and skin (Analysis 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 30 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 76 of 615
1 2 3 4 8.8). Other reported adverse events included physical differences in the likelihood of incontinence (Analysis 8.5). 5 in vital signs (Analysis 8.9), height (Analysis 8.10), and weight Skeletal and muscular system events: Somatic complaints were 6 (Analysis 8.11). These are detailed below. significantly higher in the methylphenidate group (MD 0.85, 95% 7 Nervous system events: Anger (RR 0.45, 95% CI 0.26 to 0.77, CI 0.79 to 0.91, 1 trial, n = 82 participants, Analysis 8.6). 8 Confidential:I2 = 0%, 3 studies, n = 264) and behavioural complaints For (RR Immune Review system events: There wereOnly no differences between 9 0.55, 95% CI 0.35 to 0.86, 1 trial, n = 82) were significantly methylphenidate and control groups in the incidence of upper res- 10 lower in the methylphenidate group, but compulsive acts (RR piratory tract infections, pharyngitis, allergic rhinitis, lymphadeni- 11 2.57, 95% CI 1.45 to 4.56, 1 trial, n = 90), insomnia (RR 1.57, tis, pharyngolaryngeal pain, and fever (Analysis 8.7). 12 95% CI 1.20 to 2.06, I2 = 47%, 31 trials, n = 3270), being overly Skin events: There were no differences in skin laceration or rash 13 meticulous (RR 40.77, 95% CI 2.35 to 706.72, 1 trial, n = 96), (Analysis 8.8). 14 obsessive thinking (RR 2.35, 95% CI 1.53 to 3.62, 1 trial, n = Physical measures: There were no differences in systolic or diastolic 15 90 participants), daydreaming (RR 0.66, 95% CI 0.44 to 0.98, blood pressure (Analysis 8.9), height (Analysis 8.10) or weight 16 3 trials, n=222 participants, headache.(RR 1.21 95% CI 1.01 to (Analysis 8.11), but pulse/heart rate was significantly higher in 17 1.45, 37 trials, n=3752), and tics (RR 1.33, 95% CI 1.03 to 1.72, the methylphenidate group (MD 5.06, 95% CI 2.88 to 7.24, I2 18 I2 = 10%, 19 trials, n = 1403) were significantly more likely in the = 57%, 14 trials, n = 939 participants; Analysis 8.9). 19 methylphenidate group (Analysis 8.3). However, there were no 20 differences between groups as regards aggression, agitation, buccal/ 21 lingual movements, daydreaming, dizziness, drowsiness, euphoria, Trial sequential analysis 22 headaches, irritability, nightmares, picking at skin/nail biting/lip/ We conducted TSA on the ’total non-serious adverse events’ out- 23 cheek chewing, repetitive language, being sad/tearful/depressed, come including 21 parallel group and end of first period cross- 24 socially withdrawn, sleep efficiency, staring, blinking, or worry/ over trials (Figure 5). One trial with zero non-serious adverse 25 anxiety (Analysis 8.3). events was included by substituting zero with a constant of 0.5 26 Digestive system events: Appetite was significantly decreased (RR (Jacobi-Polishook 2009). The diversity-adjusted required infor- 2 27 3.04, 95% CI 2.35 to 3.94, I = 40%, 35 trials, n=3862; Analysis mation size (DARIS) was calculated based on adverse events in 28 8.4) in the methylphenidate group; stomach ache (RR 1.61, 95% the control group of 47%; relative risk reduction of 20% in the 2 29 CI 1.27 to 2.14, I = 22%, 33 trials, n = 3777; Analysis 8.4) was also experimental group; type I error of 5%; type II error of 20% (80% 30 more common. Moreover, an increase in appetite was less likely power); and a diversity (D-square) of 79%. The DARIS was 4133 31 in the methylphenidate group (RR 0.20, 95% CI 0.08 to 0.50, participants. The cumulative Z-curve (blue line) crossed the trial 32 1 study, n = 136; Analysis 8.4). There were no differences in the sequential monitoring boundaries for harm (red inward sloping 33 incidence of nausea, dry mouth, vomiting, diarrhea, or dyspepsia line) after the 7th trial and again after the 17th trial. Accordingly, 34 (Analysis 8.4). the risk of random error in the finding can be excluded according 35 Urinary system events: There was no difference between groups to the Lan-DeMetz-O’Brien-Fleming monitoring boundary. 36 37 38 39 40 41 42 43 44 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 31 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 77 of 615 BMJ
1 2 3 4 Figure 5. TSA non-serious adverse events 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 dose of methylphenidate (Analysis 9.6). However, all trials were Adverse events in observational studies 35 at high risk of bias (Analysis 9.7). 36 We are preparing a separate review of the the reporting of adverse When including all parallel group and end of cross-over trials, we 37 events in observational studies (Storebø in press). A summary of observed comparable findings with a SMD -0.79 (95% CI -0.88 38 the results of this review are presented in the discussion of the to -0.70, I2 = 0%, 21 trials, n = 1976; Analysis 9.9). 39 present review. Given the ACROBAT issue, don’t you need to The SMD effect of -0.87 for general behaviour corresponds to a 40 be a little more circumspect in reporting the results of the MD of 5.0 points on the CGI. 41 observational studies in this review? (OJ. yes I agree. You are 42 right!) Observer-rated general behaviour 43 44 We found no parallel group trials with applicable data on ob- Teacher-rated general behaviour 45 server-rated general behaviour. However, for the cross-over tri- 46 Methylphenidate versus placebo or no intervention significantly als methylphenidate versus placebo significantly reduced the ob- 47 reduced the teacher-rated general behaviour symptoms with a server-rated general behaviour symptoms (SMD -0.60, 95% CI - 2 48 SMD -0.87 (95% CI -1.04 to -0.71, I2 = 0%, 5 trials n = 668; 0.75 to -0.46; participants = 1241; trials = 12; I = 32% (Analysis 49 Analysis 9.1). All trials were at high risk of bias (Analysis 9.1). 10.1). All trials were at high risk of bias (Analysis 10.2). Neither the type ofFor scales (Analysis 9.2 ) norPreview the dose (Analysis 9.4) Only 50 51 seemed to significantly influence the intervention effect. Parent-rated general behaviour 52 The end of cross-over trials showed a treatment effect (SMD - 2 53 0.69, 95% CI -0.78 to -0.60; participants = 2014; trials = 25; I = When compared with placebo or no 54 0%; Analysis 9.6). The intervention effect was not influenced by intervention, methylphenidate significantly reduced the parent- 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 32 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 78 of 615
1 2 3 4 rated general behaviour symptoms with a SMD of -0.53 (95% CI did not influence the intervention effect (Analysis 13.1), and we 5 -0.78 to -0.27; 6 trials; I2 = 42%; Analysis 11.1). This interven- found no sign of “carry over effect” in the cross-over trials (Analysis 6 tion effect was significantly influenced by type of scales (test for 13.2). There were no data for subgroup analyses on age, sex, or 7 subgroup differences: P = 0.04), Analysis 11.3). All the trials were subtypes of ADHD. 8 Confidential:high risk of bias (Analysis 11.2). For Review Only 9 The end of cross-over trials showed a treatment effect with a SMD 10 -0.75 (95% CI -0.93 to -0.56; participants = 550; trials = 9; I2 = Quality of life 11 7%) Analysis 11.7). All the trials were high risk of bias (Analysis 12 11.8). This intervention effect was not significantly influenced by Methylphenidate versus placebo or no intervention significantly 13 dose of methylphenidate (Analysis 11.7). improved quality of life (SMD 0.61, 95% CI 0.42 to 0.80, I2 = 14 When including all parallel group and end of cross-over trials we 0%, 3 trials, n = 514) with no difference between estimates based 15 observed comparable findings with a SMD -0.68 (95% CI -0.86 on different rating scales. Allscales were parent or clinican rated 16 to -0.50, 12 trials, n = 1054; I2 = 39%; Analysis 11.9). (Analysis 14.4). All the studies were considered high risk of bias. 17 The SMD of 0.61 for quality of life corresponds to a MD of 8.0 18 (95% CI 5.49 to 10.46) on the Child Health Questionnaire which 19 Comparison of raters ranges from 0 to 100 points. 20 When we tested differences between raters, we found significant 21 differences with a higher intervention effect for the teacher-rated trials (SMD -0.87, 95% CI -1.04 to -0.71, I2 = 0%, 5 trials, n 22 Publication bias 23 = 668) compared with the parent-rated trials (SMD -0.53, 95% 2 24 CI -0.78 to -0.27, I = 42%, 6 trials, n = 670) (test for subgroup Inspection of the funnel plot in Figure 6 from our primary analysis 25 differences: P value = 0.02, Analysis 12.1). ’Teacher-rated ADHD symptoms - all parallel group trials and 26 1st period cross-over trials’ suggested potential bias (asymmetry). 27 Therefore, we performed Eggers test for small-study effects.Egger’s Additional subgroup analyses 28 regression intercept (bias) was -0.2260 (two-tailed, P value = 0.81). 29 Additional subgroup analysis on general behaviour parallel group Thus, there was no evidence of significant publication bias in this 30 trials and first period cross-over trials showed that comorbidity meta-analysis. 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 For Preview Only 50 51 52 53 54 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 33 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 79 of 615 BMJ
1 2 3 4 Figure 6. Funnel plot of comparison: 1 ADHD symptoms, teacher rated, outcome: 1.8 All data low and high 5 risk of bias (parallel and cross). 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 (CHQ), the latter amonting to 8.0 points. The apparent effects of Summary of findings 35 methylphenidate on both the ADHD-RS and the CHQ should 36 See Summary of findings table (Summary of findings for the main be considered clinically relevant based on our predefined minimal 37 comparison). relevant differences: a difference of 6.6 points on the ADHD-Rat- 38 ing Scale, ranging from 0 to 72 points based on a trial by Zang et al. 39 (Zhang 2005), and a difference of 7.0 points on the CHQ, ranging 40 from 0 to 100 points based on a trial by Rentz et al. (Rentz 2005). 41 DISCUSSION However, our present results are based on trials which by GRADE 42 is considered ’very low quality’. Furthermore, the observed effects 43 could be biased due to lack of proper blinding as a result of preva- Summary of main results 44 lent adverse effects from methylphenidate use. If blinding is bro- 45 This systematic review examined the effects of methylphenidate ken in just 20% or 30% of patients on methylphenidate, then bias 46 for children and adolesecents with attention deficit hyperactivity alone can explain these small but significant findings. We lack ran- 47 disorder (ADHD). A total of 38 parallel group trials and 147 domised clinical trials that have assessed methylphenidate versus 48 cross-over trials, including a total of more than 12,000 patients, proper nocebo tablets (’active placebo’). The use of nocebo tablets 49 described in 449 publications, were included. can strengthen the double blinding and is therefore to be recom- The results suggestFor a small effect of methylphenidate Preview on ADHD Only 50 mended (Moncrieff 2004;Jakobsen 2013; Jakobsen 2014). Use of 51 symptoms, which corresponds to a mean difference of 9.6 points nocebo tablets is ethically questionable in all diseases, so any deci- 52 on ADHD-Rating Scale (ADHD-RS). We also observed a small sion to conduct nocebo tablet-controlled trials in children should 53 beneficial effect on general behaviour (we are not able to con- be deferred pending the results of such trials in adults. If nocebo- 54 vert this into a validated rating scale) and on quality of life 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 34 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 80 of 615
1 2 3 4 controlled trials in adults demonstrate that methylphenidate is su- 0.04) between the methylphenidate effect in the trials with medi- 5 perior to nocebo in treating ADHD symptoms then there would cation naïve participants (more than 80% of the included partici- 6 be a rationale for conducting such studies in children. If i was pant were medication naïve) and the effect in trials with most par- 7 possible to mount another rationale, then nocebo-controlled trials ticipants at methylphenidate before randomization (less than 20% 8 Confidential:in children would not be ethically questionable, but currentlyForno of Review the included participants were Only medication naïve) in teacher- 9 such case is evident. Moreover, the observed treatment benefits in rated ADHD symptoms and no statistical difference (p= 0.52) in 10 trials with duration above six months showed no clinical relevant parent-rated ADHD symptoms . One might expect that the issue 11 effects of methylphenediate. Usually, this drug is given long term of withdrawal to be of concern in the cross-over trials. As we have 12 and seldomly with medication free perods. found no significant differences between the parallel group and 13 Methylphenidate does not seem to be associated with an increased the cross-over trials in both the ADHD teacher-rated and parent- 14 occurrence of serious adverse events. However, these data were rated outcomes we do not believe that the issue of withdrawal 15 in only 9/185 trials (4.9%), and accordingly these data must be symptoms and the ’cold-turkey effect’ is a major concern related 16 considered at risk of outcome reporting bias. Methylphenidate to the use of methylphenidate. ??? 17 was related to a 29% increased risk of non-serious adverse events. We are currently working on a second systematic review, assess- 18 The most common adverse events were problems with sleeping ing harms of methylphenidate in observational studies, which is 19 (60% increased risk) and decreased appetite (280% increased risk). expected to be published later in 2015 (Storebø in press). This 20 Our GRADE assessment for the adverse event outcomes were review investigates the long-term harms of methylphenidate based 21 downgraded only to low quality. Accordingly, we believe stronger on non-randomised studies with a duration up to 36 months. The 22 in the risks than in the benefits of methylphendiate. preliminary results from this review show that the proportion of 23 There have, in fact, been a lot more non-serious adverse events serious adverse events following treatment with methylphenidate 24 in many of the included studies since many patients typically ex- is low but one case control study highlighted the risk of sudden 25 perienced more than one adverse event. For methodological rea- death in adolescents. Just over a quarter of children appear to 26 sons we only used dichotomous outcomes reflecting the number experience non-serious adverse events following methylphenidate 27 of participants affected by the event per the total number of par- treatment . 28 ticipants, and this means that the increased risk of non-serious GM I’m not sure that you should be so categorial, given the 29 adverse events are in fact higher than the 29% calculated. work is ongoing. (OJ: Ok I have edited the text, now not 30 As stated above, we are not convinced that there are any real short- including any figures) 31 term benefits of methylphenidate treatment. And even if there As in randomised clinical trials, systematic reviews of randomised 32 were such beneficial effects they have to be weighed against the clinical trials assess average effects in groups of patients. Such av- 33 facts that usually the drug is used for longer periods and here the erage effects may be composed of strong benefits in a single or a 34 potential beneficial effects diminish and the risks of harms increase. few patients and no effect or negative effects in others. It would 35 Moreover, we do not know what a few points less on a ADHD therefore be extremely helpful to reviewers to gain full access to 36 symptom scale means for the child’s quality of live and ability anonymous individual patient data (Gluud 2015b) for individ- 37 to live and learn and function with other people. Such potential ual patient data meta-analyses. Particular patient subgroups may 38 benefits on ADHD symptoms need to be weighed against harms benefit from an intervention if those with reduced rates of adverse 39 such as common adverse events like insufficient sleep pattern and effects could be identified. 40 their effect on quality of life and learning abilities. These outcomes Many claims have been made about significant increases in the 41 have now been studied sufficiently. rates of methylphenidate prescribing globally. However, a recent Methylphenidate non-responders, placebo responders, and/or pa- paper demonstrated that children in primary care did not continue 42 tients with methylphenidate adverse events before randomisation the methylphenidate treatment for more than 6 months in the UK 43 were excluded in 10 parallel group trials and in 49 cross-over (Raman 2015). Furthermore, the incidence of ADHD diagnoses 44 trials. The intervention effect of methylphenidate in these trials fell between 1998 and 2010 in the UK, (Holden 2013). In the 45 were compared to that of the remaining trials in subgroup analy- USA, however, almost 70% of children with ADHD, estimated 46 ses (Analysis 1.6; Analysis 2.6; Analysis 3.6). None of these sub- to be 6.4 million children, take medication (Visser 2014). This 47 group analyses showed any statistical differences regarding the in- might mean that there is more caution among clinicians regarding 48 tervention effect of methylphenidate. This seems surprising. How- use of methylphenidate in UK, but that US clinicians assume 49 ever, as some of ourFor included trials includedPreview participants who that the evidence Only for the use of methylphenidate to be sound. We 50 were not medication naïve before the randomisation one cannot have shown that the evidence demonstrating the benefits of this 51 exclude withdrawal symptoms in those randomised to placebo medication is not that strong. 52 (the ’cold-tyrkey effect’). This may exaggerate the benefits of 53 methylphenidate. We have investigated this by performing post- 54 hoc subgroup analyses. This showed significant differences (p= Overall completeness and applicability of evidence 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 35 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 81 of 615 BMJ
1 2 3 4 Most of the trials identified in this review were conducted in high- term duration (P value = 0.08 and 0.45 respectively). We identified 5 income countries. Participants of both genders were included. All no trials that examined the effect of more extended exposure on 6 participants were aged between 3 and 20 years with an average children’s general behaviour. . Overall, there is a lack of evidence 7 age of 9.7 years. The majority of trials were short-term trials (i.e., about the long-term effects of methylphenidate for children and 8 Confidential:under six months) and consequently, there is limited informaFortion young Review people with ADHD. Only 9 about long-term efficacy. We also tested differences in the estimate based on differences in 10 ADHD symptoms Our primary result on the ADHD symptoms dosage by subgroup analyses. These showed no differences between 11 outcome is teacher-rated ADHD symptoms (parallel group trials low dose or moderate/high dose of methylphendidate (low dose: 12 and first period cross-over trials) (SMD -0.77, 95% CI -0.90 to less than or equal to 20mg/day; moderate/high dose: above 20mg/ 13 -0.64, I2 = 38%, 19 studies, n = 1698; Analysis 1.2). The SMD day). Given the many adverse events that result from using this 14 effect of -0.77 for ADHD symptoms corresponds to a mean dif- medication, the evidence suggests that there might be no need 15 ference of -9.6 (95% CI -13.75 to -6.38) on the ADHD Rating for higher doses of medication. However, this might also be due 16 Scale (ranges 0 to 72).Clinically this would normally represent a to the fact that the dosage is decided based on the effect of the 17 modest but detectable improvement in ADHD symptoms. GM medication. 18 WHAT DOES THIS MEAN CLINICALLY? What sorts of dif- Dose GM this needs to be much clearer (OJ: better now?) 19 ference might be mean for children with different scores at The dose cut-of was an arbitrary and we erred on the side of 20 baseline in relation to their education or behaviour at school caution. For children < 25 kg the maximum recommended dose 21 (e.g. low, medicum or high)? We chose to use the teacher-rated is 30 mg/day compared to 60 mg/day for children >25 kg. After 22 outcome as the primary measure for both ADHD symptoms and careful consideration regarding these arbitrary cut-offs we renamed 23 general behaviour . The robustness of this decision was tested by the high dose group “moderate/high” dose because the doses are 24 conducting subgroup analyses, which showed no significant dif- not always “high” in the heavier children 25 ferences between these scores and those of otherraters (??GM does The NICE guidelines recommend that methylphenidate can be 26 not fit well with the next sentence). Some researchers have ar- increased to 0.7 mg/kg per dose up to three times a day or a to- 27 gued that parents’ evaluations of ADHD symptoms may not be as tal daily dose of 2.1 mg/kg/day. The European guidelines recom- 28 reliable as other raters e.g. teachers of preschool children (Murray mend that the dosage should begin at a low level of 0.2 mg per 29 2007), college students (Lavigne 2012). Caye suggested that there kilogram per dose up to three times a day, increasing according to 30 was inconsistency in ratings between parents (Caye 2013). In the the response to a ceiling of 0.7 mg/kg per dose (up to three times 31 MTA, information provided by parents was not always thought to a day) or 60 mg/day 32 be strong (Efstratopoulou 2013). In spite of this, we found only In our included parallel group studies the mean dose of extended 33 small or no differences between raters. release methylphenidate was 41.0 mg/day, and the mean dose of 34 (GM careful, they are different, they are presumably based immediate release was 23.1 mg/day. In our included cross-over 35 on different observations in different settings and at different studies the mean reported total daily dose of immediate release 36 times, and inconsistency is not the same as accuracy) was 25 mg/day and 36 mg/day for extended release. 37 Quality of life Quality of life scales were rated by parents, teach- With average doses between 23.1 mg/day to 41.0 mg/day our 38 ers or observers but not by the children themselves. These exter- cut-off of 20 mg/day seems low. However, many of the included 39 nal assessors of quality of life observed small beneficial effects of studies were short term studies with medication naïve children and 40 methylphenidate on quality of life. The children might well have therefore they received lower doses. Many of the cross-over studies 41 had different views on their own quality of life and it is a flaw in involve only the morning and midday doses to achieve a cross- the studies that they did not find a way of having the children over for study purposes, with no need for a further afternoon dose. 42 themselves rate their own quality of life. Furthermore, the obser- Extended-release medication is designed to reduce symptoms in 43 vations done by parents, teachers and independent assessors on the late afternoon too, so it would be expected that the average 44 quality of life may be subject to both to systematic and random daily dose would be higher. 45 errors. Our additional subgroup analysis on age (Analysis 4.1), comor- 46 Short v long term effects When looking at the difference be- bidity (Analysis 4.2), and subtypes of ADHD (Analysis 4.4) did 47 tween short-term (six months or less) and long-term (six months not show any statistical differences regarding the intervention ef- 48 or more) studies, we found that the treatment effect on teacher- fects of methylphenidate. However there were few trials and lack 49 rated ADHD symptomsFor decreased over Preview time (test for subgroup of power to investigates Only these throughly. 50 differences: P value = 0.01). This was not the case in the ob- We used primary the random-effects models in all meta-analyses 51 server(independent assessors) (GM do you mean independent and the fixed-effect model as a sensitivity analyses, the statistical 52 assessors? If so, please make this clear throuhout the review) significance did not change when a fixed effect model was applied 53 (OJ: Done)- and parent-rated ADHD symptoms, where there except from changes in the 95% confidence interval. 54 were no significantly differences between short-term and long- This review included trials from several countries and data cov- 55 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 36 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 82 of 615
1 2 3 4 ering a total time period from 1981 to 2014. Different countries of interest to this review. Had we included these, a greater risk of 5 have different pioneers in ADHD research and psychometric in- outcome reporting bias would have arisen. 6 struments change with the trend over time, which is reflected in We know that we excluded another 287 trials assessing the effects 7 the number of different rating scales used throughout the included of methylphenidate on various outcomes in children or adoles- 8 Confidential:studies. Scales based on DSM and ICD ADHD diagnostic For cri- cents Review with ADHD but in which noOnly mention was on the outcomes 9 teria also measure slightly different constructs. We found signifi- that were of interest to the present review. Had we included these 10 cant differences between scales measuring ADHD symptoms but trials, this would have resulted in an even bigger risk of outcome 11 not between scales measuring general behaviour. There seem to be reporting bias than detected on the sample of trials that we in- 12 fewer differences when performing sensitivity analyses in which cluded.GM I find this hard to follow. Surely, by definition, set- 13 we pooled the subgroups of scales measuring the same ADHD ting particular outcomes as an inclusion criterion means that 14 subtypes, e.g., all the scales measuring the inattentive subtype. But you designed in minimal reporting bias. you are assuming that 15 there are still some differences between the scales and precisely the excluded trials set out to measure these, and did not report 16 what they measure. This problem affects all research using such them. I don’t think you have the evidence for this. (OJ: We 17 scales for outcome assessment as they are surrogate outcome mea- do not agree on this- remenber that we state that there is a 18 sures. risk of outcome reporting bias. It is very common that trials 19 GM:What does this mean? (OJ: I have tried to make it clearer) only publish some selected outcomes. These 287 trials might 20 GM sorry, again, not sure what point you are making here? have assesses some of our outcomes, but have chosen to only 21 One of the most criticised and discussed points in the differ- reports some of their other outcomes) 22 ence between ICD and DSM criteria is the age of onset (Todd It is possible that the trials judged to be at low risk of bias may 23 2008), which could supposedly inflate ADHD prevalence. How- in fact be trials at high risk of bias. This is due to the fact that 24 ever, studies on the DSM age of onset have found that there is no methylphenidate gives rise to a number of prevalent and easily 25 difference in phenotype neuropsychological impairment, course, recognisable adverse effects which can lead to loss of blinding and 26 or treatment response, whether children are diagnosed before or hence bias the rating of symptoms, resulting in an overestimation 27 after 7 years of age (Kieling 2010). The limitation of 6 years old in of benefits and an underestimation of harms 28 the ICD-10 can be probably under identifying HKD cases, and (Kjaergard 2001; Savovi 2012b; Wood 2008). In order to en- 29 loosing functional impaired cases of DSM-IV ADHD patients sure adequate blinding, it is therefore important ensto employno- 30 (Lahey 2006). In addition, extending age of onset is not impli- cebo in the control group (’active placebo). As we found no trials 31 cated in prevalence changes (Polanczyk 2010). It is important to employing nocebo tablets in the control group, the extent of this 32 highlight that, age of onset is only considered for diagnostic scales, bias cannot be assessed. The fact that the intervention effect of 33 but not for rating scales. methylphenidate on ADHD symptoms did not differ significantly 34 It is known that DSM-IV (and the current DSM-5) criteria iden- between trials at low risk of bias compared to trials at high risk 35 tifies a broader spectrum of ADHD children than the ICD-10, of bias may in fact be taken as an indication that deblinding has 36 but the overlap of cases between the two systems criteria are signif- occurred among the former trials. 37 icant (Lee 2008; Tripp 1999) and have an equal ability to predict Also, the average duration of treatment was no more than about 38 the ADHD/HKD even in the presence of comorbidity (Schachar two months. There is therefore little that can be concluded about 39 2007). Due this, we do not believe that any change in diagnostic the benefits and harms of methylphenidate use for periods longer 40 criteria would change our efficacy results. than six months. GM Earlier you make this sound like an issue 41 GM What about DSM-V?? of duration of treatment rather than follow up - please be clear and consistent. 42 43 44 Quality of the evidence 45 The overall quality of evidence measured by the GRADE approach Agreements and disagreements with other studies or reviews 46 is considered to be ’very low’ to ’low’ due to high risk of bias, 47 inconsistency, outcome reporting bias, and loss of blinding (ex- During the last 15 years, several reviews investigating the efficacy 48 plained below), which equates to considerable uncertainity in the of methylphenidate for ADHD (with or without meta-analysis) 49 robustness of estimates.For In addition, there Preview is a high risk of outcome have been published. Only About 15 reviews have pooled results of 50 reporting bias in the adverse events outcomes, as total serious ad- ADHD rating scales on the efficacy of methylphenidate treatment 51 verse events are based on only nine out of 185 trials and total non- for children and adolescents with ADHD (Bloch 2009; Charach 52 serious adverse events are based on only 21 out of 185 trials. 2011; Charach 2013; Faraone 2002; Faraone 2006; Faraone 2009; 53 We excluded another 287 trials assessing the effects of Faraone 2010; Hanwella 2011; Kambeitz 2014; King 2006; Maia 54 methylphenidate on various outcomes in children or adolescents 2014; Punja 2013; Reichow 2013; Schachter 2001; Van der Oord 55 with ADHD in which no mention was made on our outcomes 2008a). These reviews have several shortcomings, which we have 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 37 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 83 of 615 BMJ
1 2 3 4 described in detail in the subsection on Why it is important to do drug for ADHD in children is out of step with the evidence, which 5 this review. The most important concerns are that none are based is at best uncertain. 6 on a prepublished protocol and most did not assess the risk of bias If methylphenidate is considered, clinicians might need to use it 7 of the included studies or adverse events. Moreover, none of these for short periods, with careful monitoring of both benefits and 8 Confidential:reviews considered the risk of random errors. Therefore, For one does Review Only harms and cease its use if there is no evidence of clear improvement 9 not know the true estimate of the medication and information or if harmful effects appear. 10 about adverse events from a number of randomised clinical trials is 11 missing. All of these reviews and meta-analyses report a consider- 12 able effect of methylphenidate on the core symptoms of ADHD. Implications for research 13 We have carefully assessed the risks of bias and random errors in There is an urgent need for large randomised nocebo tablet (’active 14 our review, and due to the low quality of almost all the included placebo’)-controlled trials assessing whetherthere are any benefits 15 trials, we have concluded that little is reliably known about the of methylphenidate, if unblinding can be excluded. Such trials 16 true intervention effect of methylphenidate. We also found a large should be conducted in adults with ADHD first. A problem in 17 overall risk of outcome reporting bias for both serious and non- many pharmacological trials is that the participants in the exper- 18 serious adverse events with many non-serious adverse events. This imental drug group experience adverse events which compromise 19 would clearly affect the clinical evaluation of benefit versus risk the blinding as there are fewer adverse events in the patients in the 20 for prescribing. placebo group. That is the rationale for arguing that the compar- 21 There seems to be a general tendency for many meta-analyses and ison of an experimental drug with a nocebo tablet (a placebo-like 22 reviews to over-estimate the efficacy of methylphenidiate. This is substance which gives similar adverse events as in the experimental 23 the case both regarding methylphenidate treatment in children, drug arm) is needed. Use of nocebo tablets creates ethical dilem- 24 adolescents and also adults with ADHD. In a recent Cochrane masis, so to undertake nocebo tablet-controlled trials in children 25 systematic review investigating the efficacy of methylphenidate ought to await positive results of such trials in adults. If nocebo- 26 for adults with ADHD, the evidence apparently showed a benefit controlled trials in adults demonstrate that methylphenidate is su- 27 of methylphenidate with few adverse events (Epstein 2014). All perior to nocebo in treating ADHD symptoms then there would 28 the studies in this review were considered to be of high quality. be a rationale for conducting such studies in children. If one at 29 We do not agree with this assessment. On the contrary, we judge present can mount another rationale, then nocebo-controlled trials 30 the studies in that particular review to be at high risk of bias; in children would not be ethically questionable (Moncrieff 2004; 31 the meta-analyses show high inconsistency between studies and Po gain 2014). In addition, such trials ought to be designed ac- 32 the estimates are highly imprecise (Storebø 2015b [pers comm] cording to the SPIRIT (Standard Protocol Items: Recommenda- 33 on Epstein 2014). GM I am not going to ’censor’ this, but I tions for Intervention Trials) guidelines (Chan 2013) and reported 34 think it is a major distraction from YOUR review and YOUR according to the CONSORT (Consolidated Standards of Report- 35 findings. I strongly recommend that you remove most of this ing Trials) guidelines (Moher 2010). 36 text, which relates to the use of MPH in Adults. (OJ: ok, but I believe that it is not a distraction to keep the first part of the The prevelant use of cross-over trials needs to be reconsidered 37 because they are usually only short-term interventions, which can 38 text as this also is mention shortly in the “why is it important to do this review” section) limits the assessment of benefits and harms. Hovewer, we where 39 not able to identify major differences when comparing parallel 40 group trials to cross-over trials. 41 42 Future trials ought to publish depersonalised individual partici- 43 pant data and report all outcomes, including adverse events to en- 44 AUTHORS’CONCLUSIONS sure that future systematic reviews and meta-analyses can utilise 45 Implications for practice individual participant data. Only through meta-analyses will we 46 This review suggest a potential small effect for methylphenidate be able to assess differences between intervention effects according 47 on the outcomes: ADHD symptoms, general behaviour, and qual- to sex, age, type of ADHD, presence of comorbidities, and dose. ity of life. However, this evidence is limited by serious risks 48 This reviews shows that there are many different ratings scales used 49 of systematic errors (bias). Further, the evidence suggests that For Previewfor children with ADHD.Only There is a need for consistent use of good methylphenidate causes a number of adverse events. The risk of 50 validated scales and also a large need for a country wide adverse serious adverse events seems low, but these data are from only nine 51 effects reporting system such as the FDA to increase awareness of out of 185 trials. It is also problematic that only 90/185 trials re- 52 adverse effects. 53 ported on non-serious adverse events. Although we cannot recom- 54 mend or refute methylphenidate for children and adolescents with This review highlights the need for long-term high quality trials, 55 ADHD, the general perception of methylphenidate as an effective with low risk of bias and with sufficient numbers of participants, 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 38 Copyright © 2015 The Cochrane Collaboration. 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1 2 3 4 investigating the benefits and harms of methylphenidate treatment We thank Maria Gaardahl, Kim Boesen, Farhad Shokraneh and 5 versus placebo for children as well as adolescents with ADHD. Rene Spijker for helping with the translation of articles in Japanese, 6 There is a need for prepublished protocols, which could help with Italian, Turkish, Farsi, and Dutch. 7 the problem of measurement of benefits and harms caused by We thank Nadia Pedersen, stud.scient.san.publ., Psychiatric Re- 8 Confidential:the used of so many different ratings scales and no assessment Forof Review Only search Unit, for helping with finalizing the review. 9 adverse effects. Based on the findings in this review there is clearly 10 an urgent need for large randomised trials investigating the efficacy We thank Dr. Martina Riegl, Senior Medical Assessor, MHRA, 11 of non-pharamcological trials also. Special Populations Unit (Paediatrics), London for helping with 12 data extraction and assessment of risk of bias. 13 We thank Jacob Riis, User Experience Lead, the Nordic Cochrane 14 Centre, Copenhagen, Denmark for his help on issues regarding 15 ACKNOWLEDGEMENTS Review Manager. 16 17 We thank Janus Christian Jacobsen, Ph.D., the Copenhagen Trial We thank Rasmus Moustgaard, Senior Systems Architect, the 18 Unit, for elaborating the idea for this review. Nordic Cochrane Centre, Copenhagen, Denmark for his help on 19 issues regarding Review Manager. We want to thank Trine Lacoppidan Kæstel, research librarian, 20 We are grateful to the many authors who kindly responded to our 21 Psychiatric Research Unit, Region Zealand, Denmark, for her help with the search of studies and description of the measurement requests for further information on the trials in which they were 22 involved. 23 scales. 24 We want to thank Lise Aagaard, Ph.D. (pharm), University of Thanks also to the Psychiatric Research Unit, Region Zealand 25 Southern Denmark, for the advice given during the work of this Psychiatry, Roskilde, Denmark, Region Zealand Research Foun- 26 review. dation, Denmark, and the Copenhagen Trial Unit, Centre for 27 Clinical Intervention Research, Copenhagen University Hospital, 28 We thank Jesper Pedersen, Ph.D., M.D., Department of Childrens Copenhagen, Denmark for funding and enabling the review. and Youths Psychiatry, Region Zealand, Denmark for backing up 29 Finally, we wish to warmly thank Geraldine McDonald Coordinat- this project. 30 ing Editor, Joanne Wilson Managing Editor, Gemma O’Loughlin 31 We thank Torben Bille, M.D., Pediatric Department, Holbaek Assistant Managing Editor, and Margaret Anderson, Trial Search 32 Hospital, Copenhagen, Denmark for helping to write the protocol Coordinator, from the Cochrane Developmental, Psychosocial 33 and for performing the selection of studies. and Learning Problems Group for their help and support. 34 35 36 37 REFERENCES 38 References to studies included in this review Update 2010; Vol. 12, issue 1:7–8. 39 ∗ Armstrong RB, Damaraju CV, Ascher S, Schwarzman 40 Abikoff 2009 {published data only} L, O’Neill J, Starr HL. 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ADHD ∗ Corkum P,Panton R, Ironside S, Macpherson M, Williams 29 summer camp: development and evaluation of a multimodal T. Acute impact of immediate release methylphenidate 30 intervention program [Das ADHD–summer–camp administered three times a day on sleep in children with 31 – entwicklung und evaluation eines multimodalen attention-deficit/hyperactivity disorder. Journal of Pediatric 32 programms]. Kindheit und Entwicklung 2009;18(3): Psychology 2008;33(4):368–79. 162–72. 33 Ironside S, Davidson F, Corkum P.Circadian motor activity Lehmkuhl G. Double-blind, non-inferiority trial 34 affected by stimulant medication in children with attention- investigating the duration of action of Medikinet-retard 35 deficit/hyperactivity disorder. Journal of Sleep Research 2010; vs. immediate-release methylphenidate vs. placebo across 36 19(4):546–51. the day in children with attention deficit hyperactivity 37 Cox 2006 {published data only} disorder (ADHD). Integrated final report. Phase III. 38 ∗ Cox DJ, Merkel RL, Moore M, Thorndike F, Muller C, Universitätsklinikum Essen. Project number Medikinet- 39 Kovatchev B. Relative benefits of stimulant therapy with retard (R) Trial 6520-0073-01 2005. 40 OROS methylphenidate versus mixed amphetamine salts Uebel H, Albrecht B, Kirov R, Heise A, Döpfner M, 41 extended release in improving the driving performance Freisleder FJ, et al. What can actigraphy add to the concept 42 of adolescent drivers with attention-deficit/hyperactivity of labschool design in clinical trials?. Current Pharmaceutical 43 disorder. Pediatrics 2006;118(3):e704–10. Design 2010;16(22):2434–42. 44 Cox DJ, Moore M, Burket R, Merkel RL, Mikami 45 AY, Kovatchev B. Rebound effects with long-acting Douglas 1986 {published data only} amphetamine or methylphenidate stimulant medication Douglas VI, Barr RG, O’Neill ME, Britton BG. 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1 2 3 4 DuPaul 1996 {published data only} deficit/hyperactivity disorder”: correction. Journal of 5 DuPaul GJ, Anastopoulos AD, Kwasnik D, Barkley RA, Clinical Psychiatry 2008;69(2):329. 6 McMurray MB, DuPaul GJ. Methylphenidate effects on ∗ Findling RL, Bukstein OG, Melmed RD, López FA, 7 children with attention deficit hyperactivity disorder: self- Sallee FR, Arnold LE, et al. A randomized, double-blind, 8 Confidential:report of symptoms, side-effects, and self-esteem. Journal For of Reviewplacebo-controlled, parallel-group Only study of methylphenidate 9 Attention Disorders 1996;1(1):3–15. transdermal system in pediatric patients with attention- deficit/hyperactivity disorder. Journal of Clinical Psychiatry 10 Duric 2012 {published data only} 2008;69(1):149-59. Erratum in: Journal of Clinical 11 Duric NS, Assmus J, Gundersen D, Elgen IB. Psychiatry. 2008;69(2):329. 12 Neurofeedback for the treatment of children and adolescents Swanson JM. Transdermal methylphenidate more effective 13 with ADHD: a randomized and controlled clinical trial than placebo for treating ADHD. Evidence-Based Mental 14 using parental reports. BMC Psychiatry 2012; Vol. 12:107. Health 2008;11(4):118. 15 Epstein 2011 {published data only} Findling 2010 {published data only} 16 Epstein JN, Brinkman WB, Froehlich T, Langberg Findling RL, Katic A, Rubin R, Moon E, Civil R, Li Y. A 6- 17 JM, Narad ME, Antonini TN, et al. Effects of month, open-label, extension study of the tolerability and 18 stimulant medication, incentives, and event rate on effectiveness of the methylphenidate transdermal system in 19 reaction time variability in children with ADHD. adolescents diagnosed with attention-deficit/hyperactivity 20 Neuropsychopharmacology 2011;36(5):1060–72. disorder. Journal of Child and Adolescent Psychopharmacology 21 2010;20(5):365–75. ∗ Findling RL, Turnbow J, Burnside J, Melmed R, Civil R, 22 Fabiano 2007 {published data only} ∗ Li Y. A randomized, double-blind, multicenter, parallel- 23 Fabiano GA, Pelham WE Jr, Gnagy EM, Burrows- MacLean L, Coles EK, Chacko A, et al. The single group, placebo-controlled, dose-optimization study of the 24 and combined effects of multiple intensities of behavior methylphenidate transdermal system for the treatment of 25 modification and methylphenidate for children with ADHD in adolescents. CNS Spectrums 2010;15(7):419–30. 26 attention deficit hyperactivity disorder in a classroom Keating GM. Methylphenidate transdermal system in 27 setting. School Psychology Review 2007; Vol. 36, issue 2: attention-deficit hyperactivity disorder in adolescentsy: 28 195–216. profile report. Drugs in R&D 2012;12(3):171–3. 29 Pelham WE, Burrows-Maclean L, Gnagy EM, Fabiano Fine 1993 {published data only} 30 GA, Coles EK, Wymbs BT, et al. A dose-ranging study of ∗ Fine S, Johnston C. 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Differential effects of stimulant medication on reading disorder and their classmates: behavioral normalization 14 performance of boys with hyperactivity with and without with methylphenidate. Journal of the American Academy of 15 conduct disorder. Journal of Learning Disabilities 1991;24 Child and Adolescent Psychiatry 1997;36(5):597–604. 16 (5):304–10. Nolan EE, Gadow KD. Relation between ratings and 17 ∗ Forness SR, Swanson JM, Cantwell D, Guthrie D, Sena observations of stimulant drug response in hyperactive 18 R. Response to stimulant medication across six measures children. Journal of Clinical Child Psychology 1994;23(1): of school-related performance in children with ADHD 78–90. 19 Sprafkin J, Gadow KD. Double-blind versus open 20 and disruptive behavior. Behavioral Disorders 1992;18(1): 42–53. evaluations of stimulant drug response in children with 21 Froehlich 2011 {published data only} attention-deficit hyperactivity disorder. 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1 2 3 4 hyperactivity disorder: II. ECG changes and adverse events program and regular classroom settings. Journal of 5 analysis. Journal of the American Academy of Child and Consulting and Clinical Psychology 2002;70(2):320–35. 6 Adolescent Psychiatry 2008;47(2):189–98. Pelham 2005 {published data only} ∗ 7 Palumbo DR, Sallee FR, Pelham WE, Bukstein OG, Chacko A, Pelham WE, Gnagy EM, Greiner A, Vallano G, 8 Confidential:Daviss WB, McDermott MP. Clonidine for attention- For ReviewBukstein O, et al. Stimulant medication Only effects in a summer 9 deficit/hyperactivity disorder: I. Efficacy and tolerability treatment program among young children with attention- outcomes. Journal of the American Academy of Child and 10 deficit/hyperactivity disorder. Journal of the American Adolescent Psychiatry 2008;47(2):180–8. 11 Academy of Child and Adolescent Psychiatry 2005;44(3): 12 Pearson 2013 {published data only} 249–57. Pelham WE, Burrows-MacLean L, Gnagy EM, Fabiano GA, 13 Methylphenidate dosing improved behavior in children with ASD. The Brown University Child & Adolescent Coles EK, Tresco KE, et al. Transdermal methylphenidate, 14 Psychopharmacology Update 2013; Vol. 15, issue 8:4–5. behavioral, and combined treatment for children with 15 ∗ Pearson DA, Santos CW, Aman MG, Arnold LE, ADHD. Experimental and Clinical Psychopharmacology 16 Casat CD, Mansour R, et al. Effects of extended release 2005;13(2):111–26. ∗ 17 methylphenidate treatment on ratings of attention- Pelham WE, Manos MJ, Ezzell CE, Tresco KE, Gnagy 18 deficit/hyperactivity disorder (ADHD) and associated EM, Hoffman MT, et al. A dose-ranging study of a 19 behavior in children with autism spectrum disorders methylphenidate transdermal system in children with 20 and ADHD symptoms. Journal of Child and Adolescent ADHD. Journal of the American Academy of Child and 21 Psychopharmacology 2013;23(5):337–51. Adolescent Psychiatry 2005;44(6):522–9. 22 Pelham 1989 {published data only} Pelham 2011a {published data only} 23 Pelham WE, Walker JL, Sturges J, Hoza J. Comparative Pelham WE, Waxmonsky JG, Schentag J, Ballow CH, 24 effects of methylphenidate on ADD girls and ADD boys. Panahon CJ, Gnagy EM, et al. Efficacy of a methylphenidate transdermal system versus t.i.d. methylphenidate in a 25 Journal of the American Academy of Child and Adolescent Psychiatry 1989;28(5):773–6. laboratory setting. Journal of Attention Disorders 2011;15 26 (1):28–35. Pelham 1990a {published data only} 27 Pelham 2014 {published data only} Pelham Jr WE, Greenslade KE, Vodde-Hamilton M, 28 Pelham WE, Burrows-MacLean L, Gnagy EM, Fabiano Murphy DA, Greenstein JJ, Gnagy EM, et al. Relative 29 GA, Coles EK, Wymbs BT, et al. A dose-ranging study of efficacy of long-acting stimulants on children with attention 30 behavioral and pharmacological treatment in social settings deficit-hyperactivity disorder: a comparison of standard 31 for children with ADHD. Journal of Abnormal and Child methylphenidate, sustained-release methylphenidate, Psychology 2014;42(6):1019–31. 32 sustained-release dextroamphetamine, and pemoline. 33 Pediatrics 1990;86(2):226–37. Perez-Alvarez 2009 {published data only} 34 Perez-Alvarez F, Serra-Amaya C, Timoneda-Gallart CA. Pelham 1993a {published data only} 35 Cognitive versus behavioral ADHD phenotype: what is it Pelham J, Carlson C, Sams SE, Vallano G, Dixon MJ, Hoza all about?. Neuropediatrics 2009;40(1):32–8. 36 B, et al. Separate and combined effects of methylphenidate 37 and behavior modification on boys with attention deficit- Pliszka 1990 {published data only} ∗ 38 hyperactivity disorder in the classroom. Journal of Consulting Pliszka SR. Effect of anxiety on cognition, behavior, and 39 and Clinical Psychology 1993;61(3):506–15. stimulant response in ADHD. In: Chess S, Hertzig ME 40 editor(s). Annual Progress in Child Psychiatry and Child Pelham 1999 {published data only} . Routledge, 1990:454–66. 41 Development Pelham WE, Aronoff HR, Midlam JK, Shapiro CJ, Pliszka SR. Effect of anxiety on cognition, behavior, and 42 Gnagy EM, Chronis AM, et al. A comparison of ritalin stimulant response in ADHD. Journal of the American 43 and adderall: efficacy and time-course in children with Academy of Child and Adolescent Psychiatry 1989;28(6): 44 attention-deficit/hyperactivity disorder. Pediatrics 1999;103 882–7. (4):e43. 45 Pliszka 2000 {published data only} 46 Pelham 2001a {published data only} Pliszka SR, Browne RG, Olvera RL, Wynne SK. A 47 Pelham WE, Gnagy EM, Burrows-Maclean L, Williams A, double-blind, placebo-controlled study of Adderall and 48 Fabiano GA, Morrisey SM, et al. Once-a-day Concerta methylphenidate in the treatment of attention-deficit/ 49 methylphenidate versus three-times-daily methylphenidate hyperactivity disorder. Journal of the American Academy of in laboratory andFor natural settings. Pediatrics Preview2001;107(6): Child and AdolescentOnly Psychiatry 2000;39(5):619–26. 50 51 E105. Pliszka 2007 {published data only} 52 Pelham 2002 {published data only} Pliszka SR, Liotti M, Bailey BY, Perez R, Glahn D, 53 Pelham WE, Hoza B, Pillow DR, Gnagy EM, Kipp Semrud-Clikeman M. Electrophysiological effects of 54 HL, Greiner AR, et al. Effects of methylphenidate and stimulant treatment on inhibitory control in children with expectancy on children with ADHD: behavior, academic attention-deficit/hyperactivity disorder. 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1 2 3 4 Quinn 2004 {published data only} Adolescent Psychiatry 1993;32(1):190–8. 5 Quinn D, Wigal S, Swanson J, Hirsch S, Ottolini Y, Dariani DuPaul GJ, Rapport MD, Vyse SA. ADDH and 6 M, et al. Comparative pharmacodynamics and plasma methylphenidate responders: effects on behavior controlled 7 concentrations of d-threo-methylphenidate hydrochloride by complex reinforcement schedules. International Clinical 8 Confidential:after single doses of d-threo-methylphenidate hydrochloride For ReviewPsychopharmacology 1988;3(4):349–61. Only 9 and d,l-threo-methylphenidate hydrochloride in a double- Kelly KL, Rapport MD, DuPaul GJ. 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Journal of Child 18 Rapport MD, Denney C, DuPaul GJ, Gardner MJ. and Adolescent Psychopharmacology 2014;24(3):130–9. Attention deficit disorder and methylphenidate: ∗ 19 Ramtvedt BE, Røinås E, Aabech HS, Sundet KS. normalization rates, clinical effectiveness, and response 20 Clinical gains from including both dextroamphetamine and prediction in 76 children. Journal of the American Academy 21 methylphenidate in stimulant trials. Journal of Child and of Child and Adolescent Psychiatry 1994;33(6):882–93. 22 Adolescent Psychopharmacology 2013;23(9):597–604. Rapport MD, DuPaul GJ, Kelly KL. Attention deficit 23 Ramtvedt BE, Sandvik L, Sundet K. Correspondence hyperactivity disorder and methylphenidate: the 24 between children’s and adults’ ratings of stimulant- relationship between gross body weight and drug response in 25 induced changes in ADHD behaviours in a crossover children. Psychopharmacology Bulletin 1989;25(2):285–90. trial with medication-naive children. European Journal of ∗ Rapport MD, Jones JT, DuPaul GJ, Kelly KL, Gardner 26 Developmental Psychology 2014;11(6):687–700. 27 MJ, Tucker SB, et al. Attention deficit disorder and Ramtvedt BE, Sundet K. Relationships between computer- methylphenidate: group and single-subject analyses of dose 28 based testing and behavioral ratings in the assessment of effects on attention in clinic and classroom settings. Journal 29 attention and activity in a pediatric ADHD stimulant of Clinical Child Psychology 1987;16(4):329–38. 30 crossover trial. Clinical Neuropsychologist 2014;28(7): Rapport MD, Quinn SO, DuPaul GJ, Quinn EP, Kelly 31 1146–61. KL. Attention deficit disorder with hyperactivity and 32 Rapport 1985a {published data only} methylphenidate: the effects of dose and mastery level on 33 Rapport MD, DuPaul GJ. Methylphenidate: rate- children’s learning performance. Journal of Abnormal Child 34 dependent effects on hyperactivity. Psychopharmacology Psychology 1989;17(6):669–89. 35 Bulletin 1986;22(1):223–8. Rapport MD, Randall R, Moffitt C. Attention-Deficit/ 36 Rapport MD, DuPaul GJ, Stoner G, Birmingham BK, Hyperactivity Disorder and methylphenidate: a dose- response analysis and parent-child comparison of somatic 37 Masse G. Attention deficit disorder with hyperactivity: differential effects of methylphenidate on impulsivity. complaints. Journal of Attention Disorders 2002;6(1):15–24. 38 Rapport MD, Stoner G, DuPaul GJ, Kelly KL, Tucker SB, 39 Pediatrics 1985;76(6):938–43. Rapport MD, DuPaul GJ, Stoner G, Jones TJ. Comparing Schoeler T. Attention deficit disorder and methylphenidate: 40 classroom and clinic measures of attention deficit disorder: a multilevel analysis of dose-response effects on children’s 41 differential, idiosyncratic, and dose-response effects of impulsivity across settings. Journal of the American Academy 42 methylphenidate. Journal of Consulting and Clinical of Child and Adolescent Psychiatry 1988;27(1):60–9. 43 Psychology 1986;54(3):334–41. Vyse SA, Rapport MD. The effects of methylphenidate on 44 ∗ Rapport MD, Stoner G, DuPaul GJ, Birmingham learning in children with ADDH: the stimulus equivalence 45 BK, Tucker S. Methylphenidate in hyperactive children: paradigm. Journal of Consulting and Clinical Psychology 1989;57(3):425–35. 46 differential effects of dose on academic, learning, and social 47 behavior. Journal of Abnormal Child Psychology 1985;13(2): Rapport 2008 {published data only} 48 227–43. Rapport MD, Kofler MJ, Coiro MM, Raiker JS, Sarver DE, Alderson RM. Unexpected effects of methylphenidate 49 Rapport 1987 {published data only} For Previewin attention-deficit/hyperactivity Only disorder reflect decreases Denney CB, Rapport MD. Predicting methylphenidate 50 in core/secondary symptoms and physical complaints response in children with ADHD: theoretical, empirical, 51 common to all children. Journal of Child and Adolescent and conceptual models. Journal of the American Academy of 52 Psychopharmacology 2008;18(3):237–47. 53 Child and Adolescent Psychiatry 1999;38(4):393–401. 54 DuPaul GJ, Rapport MD. Does methylphenidate normalize Riggs 2011 {published data only} the classroom performance of children with attention deficit ∗ Riggs PD, Winhusen T, Davies RD, Leimberger JD, 55 disorder?. Journal of the American Academy of Child and Mikulich-Gilbertson S, Klein C, et al. Randomized 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 54 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 100 of 615
1 2 3 4 controlled trial of osmotic-release methylphenidate with Academy of Child and Adolescent Psychiatry 1997;36(6): 5 cognitive-behavioral therapy in adolescents with attention- 754–63. 6 deficit/hyperactivity disorder and substance use disorders. Schachar 2008 {published data only} 7 Journal of the American Academy of Child and Adolescent Schachar R, Ickowicz A, Crosbie J, Donnelly GAE, Reiz 8 Confidential:Psychiatry 2011;50(9):903–14. For ReviewJL, Miceli PC, et al. Cognitive andOnly behavioral effects 9 Tamm L, Adinoff B, Nakonezny PA, Winhusen T, Riggs of multilayer-release methylphenidate in the treatment P. Attention-deficit/hyperactivity disorder subtypes in 10 of children with attention-deficit/hyperactivity disorder. adolescents with comorbid substance-use disorder. American 2008;18 11 Journal of Child and Adolescent Psychopharmacology Journal of Drug and Alcohol Abuse 2012;38(1):93–100. (1):11–24. 12 Tamm L, Trello-Rishel K, Riggs P, Nakonezny PA, Acosta Schulz 2010a {published data only} 13 M, Bailey G, et al. Predictors of treatment response in Schulz E, Fleischhaker C, Hennighausen K, Heiser P, adolescents with comorbid substance use disorder and 14 Oehler K-U, Linder M, et al. A double-blind, randomized, attention-deficit/hyperactivity disorder. Journal of Substance 15 placebo/active controlled crossover evaluation of the efficacy Abuse Treatment 2013;44(2):224–30. 16 and safety of Ritalin ® LA in children with attention- Warden D, Riggs PD, Min SJ, Mikulich-Gilbertson 17 deficit/hyperactivity disorder in a laboratory classroom SK, Tamm L, Trello-Rishel K, et al. Major depression 18 setting. Journal of Child and Adolescent Psychopharmacology and treatment response in adolescents with ADHD and 19 2010;20(5):377–85. substance use disorder. Drug and Alcohol Dependence 2012; 20 120(1-3):214–9. Schwartz 2004 {published data only} 21 Winhusen TM, Lewis DF, Riggs PD, Davies RD, Adler LA, Gruber R, Grizenko N, Schwartz G, Ben Amor L, Gauthier 22 Sonne S, et al. Subjective effects, misuse, and adverse effects J, De Guzman R, et al. Sleep and COMT polymorphism 23 of osmotic-release methylphenidate treatment in adolescent in ADHD children: preliminary actigraphic data. Journal 24 substance abusers with attention-deficit/hyperactivity of the American Academy of Child and Adolescent Psychiatry disorder. 2006;45(8):982–9. 25 Journal of Child and Adolescent Psychopharmacology ∗ 2011;21(5):455–63. Schwartz G, Amor LB, Grizenko N, Lageix P, Baron C, 26 Boivin DB, et al. Actigraphic monitoring during sleep of 27 Rubinsten 2008 {published data only} children with ADHD on methylphenidate and placebo. 28 Rubinsten O, Bedard A-C, Tannock R. Methylphenidate Journal of the American Academy of Child and Adolescent 29 has differential effects on numerical abilities in ADHD Psychiatry 2004;43(10):1276–82. 30 children with and without co-morbid mathematical Sharp 1999 {published data only} 31 difficulties. Open Psychology Journal 2008;1:11–7. Borcherding BG, Keysor CS, Cooper TB, Rapoport 32 Samuels 2006 {published data only} JL. Differential effects of methylphenidate and 33 Samuels JA, Franco K, Wan F, Sorof JM. Effect of dextroamphetamine on the motor activity level of 34 stimulants on 24-h ambulatory blood pressure in children hyperactive children. Neuropsychopharmacology 1989;2(4): 35 with ADHD: a double-blind, randomized, cross-over trial. 255–63. 36 Pediatric Nephrology 2006;21(1):92–5. Castellanos FX, Elia J, Kruesi MJ, Marsh WL, Gulotta CS, Potter WZ, et al. Cerebrospinal fluid homovanillic 37 Schachar 1997 {published data only} acid predicts behavioral response to stimulants in 38 Charach A, Figueroa M, Chen S, Ickowicz A, Schachar R. 45 boys with attention deficit/hyperactivity disorder. 39 Stimulant treatment over 5 years: effects on growth. Journal Neuropsychopharmacology 1996;14(2):125–37. 40 of the American Academy of Child and Adolescent Psychiatry Elia J, Borcherding BG, Rapoport JL, Keysor CS. 41 2006;45(4):415–21. Methylphenidate and dextroamphetamine treatments of 42 Charach A, Ickowicz A, Schachar R. Stimulant treatment hyperactivity: are there true nonresponders?. Psychiatry 43 over five years: adherence, effectiveness, and adverse effects. Research 1991;36(2):141–55. 44 Journal of the American Academy of Child and Adolescent Elia J, Welsh PA, Gullotta CS, Rapoport JL. Classroom 45 Psychiatry 2004;43(5):559–67. academic performance: improvement with both Diamond IR, Tannock R, Schachar RJ. Response to methylphenidate and dextroamphetamine in ADHD 46 methylphenidate in children with ADHD and comorbid boys. Journal of Child Psychology and Psychiatry, and Allied 47 anxiety. Journal of the American Academy of Child and Disciplines 1993;34(5):785–804. 48 Adolescent Psychiatry 1999;38(4):402–9. Schmidt ME, Kruesi MJ, Elia J, Borcherding BG, Elin 49 Law SF, SchacharFor RJ. Do typical clinical Preview doses of RJ, Hosseini JM,Only et al. Effect of dextroamphetamine and 50 methylphenidate cause tics in children treated for attention- methylphenidate on calcium and magnesium concentration 51 deficit hyperactivity disorder?. Journal of the American in hyperactive boys. Psychiatry Research 1994;54(2): 52 Academy of Child and Adolescent Psychiatry 1999;38(8): 199–210. 944–51. ∗ Sharp WS, Walter JM, Marsh WL, Ritchie GF,Hamburger 53 ∗ 54 Schachar RJ, Tannock R, Cunningham C, Corkum PV. SD, Castellanos FX. 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1 2 3 4 Shiels 2009 {published data only} Journal of the American Academy of Child and Adolescent 5 ∗ Shiels K, Hawk LW, Reynolds B, Mazzullo RJ, Rhodes Psychiatry 1998;37(3):314–21. 6 JD, Pelham WE, et al. Effects of methylphenidate on 7 discounting of delayed rewards in attention deficit/ Smith 2004 {published data only} 8 Confidential:hyperactivity disorder. Experimental and Clinical For ReviewSmith R, Larsen D, Derby KM, McLaughlinOnly TF, Weber KP, Brown K, et al. A comparison of teacher checklists used 9 Psychopharmacology 2009;17(5):291–301. Spencer SV, Hawk LW, Richards JB, Shiels K, Pelham over 15 days and a one-day antecedent analysis to conduct 10 WE, Waxmonsky JG. Stimulant treatment reduces lapses a medication trial. Psychology in the Schools 2004;41(2): 11 in attention among children with ADHD: the effects 235–40. 12 of methylphenidate on intra-individual response time Smithee 1998 {published data only} 13 distributions. Journal of Abnormal Child Psychology 2009;37 Smithee JA, Klorman R, Brumaghim JT, Borgstedt AD. 14 (6):805–16. 15 Methylphenidate does not modify the impact of response Silva 2005a {published data only} frequency or stimulus sequence on performance and 16 Silva R, Muniz R, Pestreich LK, Brams M, Childress A, event-related potentials of children with attention deficit 17 Lopez FA. Efficacy of two long-acting methylphenidate hyperactivity disorder. Journal of Abnormal Child Psychology 18 formulations in children with attention- deficit/hyperactivity 1998;26(4):233–45. 19 disorder in a laboratory classroom setting. Journal of Child 20 and Adolescent Psychopharmacology 2005;15(4):637–54. Solanto 2009 {published data only} Solanto M, Newcorn J, Vail L, Gilbert S, Ivanov I, Lara R. 21 Silva 2006 {published data only} 22 Stimulant drug response in the predominantly inattentive Silva RR, Muniz R, Pestreich L, Childress A, Brams M, and combined subtypes of attention-deficit/hyperactivity 23 Lopez FA, et al. Efficacy and duration of effect of extended- disorder. Journal of Child and Adolescent Psychopharmacology 24 release dexmethylphenidate versus placebo in schoolchildren 2009;19(6):663–71. 25 with attention-deficit/hyperactivity disorder. Journal of 26 Child and Adolescent Psychopharmacology 2006;16(3): Stein 1996 {published data only} 27 239–51. Stein MA, Blondis TA, Schnitzler ER, O’Brien T, Fishkin 28 Silva 2008 {published data only} J, Blackwell B, et al. Methylphenidate dosing: twice daily 29 ∗ Silva RR, Muniz R, Pestreich L, Brams M, Mao AR, versus three times daily. Pediatrics 1996;98(4 Pt 1):748–56. Childress A, et al. Dexmethylphenidate extended-release 30 Stein 2003 {published data only} capsules in children with attention-deficit/hyperactivity 31 Stein MA, Sarampote C, Seymour K. Insomnia and tiredness disorder. Journal of the American Academy of Child and 32 in ADHD youth: relationship with methylphenidate Adolescent Psychiatry 2008;47(2):199–208. dose, age, and weight. Pediatric Research. Annual 33 Silva RR, Muniz R, Pestreich L, Lopez FA, Childress Meeting of the Pediatric Academic Societies; 2004 May 34 A, Wang J. Once-daily dexmethylphenidate: a placebo- 4; San Francisco, CA. Baltimore: International Pediatric 35 controlled crossover study in children with attention-deficit/ Research Foundation, 2004; Vol. 55 (4):74A. [WOS: 36 hyperactivity disorder. Annals of Neurology 2005;58(Suppl 000220591100437] 37 S9):S109. ∗ Stein MA, Sarampote CS, Waldman ID, Robb AS, 38 Smith 1998 {published data only} Conlon C, Pearl PL, et al. 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Efficacy of a new pattern of delivery of 12 2010;19(Suppl 1):S82. methylphenidate for the treatment of ADHD: effects on 13 activity level in the classroom and on the playground. 14 Stoner 1994 {published data only} Journal of the American Academy of Child and Adolescent 15 Stoner G, Carey SP, Ikeda MJ, Shinn MR. The utility of Psychiatry 2002;41(11):1306–14. curriculum-based measurement for evaluating the effects 16 Swanson JM, Wigal SB, Lemer MA. Comparison of of methylphenidate on academic performance. Journal of the efficacy and safety of OROS methylphenidate HCI 17 Applied Behavior Analysis 1994;27(1):101–13. 18 with methylphenidate tid and placebo in children with ADHD. Pediatric Research 2000;47(4):34A. [WOS: 19 Sumner 2010 {published data only} Sumner CR, Haynes VS, Teicher MH, Newcorn JH. Does 000086155300200] 20 Wigal S, Lerner M, Swanson J. Once-daily methylphenidate 21 placebo response differ between objective and subjective measures in children with attention-deficit/hyperactivity formulation: impact on academic productivity and activity 22 disorder?. Postgraduate Medicine 2010;122(5):52–61. levels of children with attention-deficit/hyperactivity 23 disorder. European Neuropsychopharmacology 2002;12 24 Sunohara 1999 {published data only} Suppl 3:416. 25 Sunohara GA. Methylphenidate effects on focused and Wigal S, Swanson JM, Lerner M. Comparison of duration 26 selective attention processing in children with ADHD. of effect of OROS MPH with MPH tid in ADHD children. 27 Dissertation Abstracts International: Section B: The Annual Meeting of the American Psychiatric Association; Sciences and Engineering 1998; Vol. 59, issue 6–B:3113. 2001 May 5-10. New Orleans: American Psychiatric 28 ∗ Sunohara GA, Malone MA, Rovet J, Humphries T, Association, 2001. 29 Roberts W, Taylor MJ. Effect of methylphenidate on 30 attention in children with attention deficit hyperactivity Swanson 2002b {published data only} 31 disorder (ADHD): ERP evidence. Neuropsychopharmacology Swanson J, Gupta S, Lam A, Shoulson I, Lerner M, Modi 32 1999;21(2):218–28. N, et al. Development of a new once-a-day formulation 33 of methylphenidate for the treatment of attention-deficit/ Swanson 1998 {published data only} 34 hyperactivity disorder: proof-of-concept and proof-of- Swanson J, Wigal S, Greenhill L, Browne R, Waslick B, product studies. Archives of General Psychiatry 2003;60(2): 35 Lerner M, et al. Objective and subjective measures of the 36 204–11. pharmacodynamic effects of Adderall in the treatment of Swanson J, Sadeh A, Lerner MA, Wigal SB. Comparison 37 children with ADHD in a controlled laboratory classroom of the impact of OROS methylphenidate HCI with 38 setting. Psychopharmacology Bulletin 1998;34(1):55–60. methylphenidate tid and placebo on the sleep of children ∗ 39 Swanson JM, Wigal S, Greenhill LL, Browne R, Waslik B, with ADHD. Journal of Developmental and Behavioral 40 Lerner M, et al. Analog classroom assessment of Adderall ® Pediatrics 2000;21(5):387–8. [WOS: 000089857900028] 41 in children with ADHD. Journal of the American Academy of Swanson J, Wigal S, Lerner M. Treatment with a controlled- 1998;37(5):519–26. 42 Child and Adolescent Psychiatry release formulation of methylphenidate for attention- 43 Swanson 1999 {published data only} deficit/hyperactivity disorder: onset and duration of effect. ∗ Swanson J, Gupta S, Guinta D, Flynn D, Agler D, European Neuropsychopharmacology 2002;12 Suppl 3:414. 44 ∗ 45 Lerner M, et al. Acute tolerance to methylphenidate in Swanson JM, Gupta S, Williams L, Agler D, Lerner M, Wigal S. Efficacy of a new pattern of delivery of 46 the treatment of attention deficit hyperactivity disorder in children. Clinical Pharmacology and Therapeutics 1999;66 methylphenidate for the treatment of ADHD: effects on 47 activity level in the classroom and on the playground. 48 (3):295–305. Wigal SB, Gupta S, Guinta D, Swanson JM. Reliability and Journal of the American Academy of Child and Adolescent 49 2002;41(11):1306–14. validity of the SKAMPFor rating scale in aPreview laboratory school Psychiatry Only 50 setting. Psychopharmacology Bulletin 1998;34(1):47–53. Swanson JM, Wigal SB, Lemer MA. Comparison of the 51 efficacy and safety of OROS methylphenidate HCI with 52 Swanson 2002a {published data only} methylphenidate tid and placebo in children with ADHD. 53 Swanson J, Gupta S, Lam A, Shoulson I, Lerner M, Modi Pediatric Research 2000;47(Suppl):34A. 54 N, et al. Development of a new once-a-day formulation Wigal S, Lerner M, Swanson J. Once-daily methylphenidate of methylphenidate for the treatment of attention-deficit/ formulation: Impact on academic productivity and activity 55 hyperactivity disorder: proof-of-concept and proof-of- levels of children with attention-deficit/hyperactivity 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 57 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 103 of 615 BMJ
1 2 3 4 disorder. European Neuropsychopharmacology 2002;12 substance use disorder. Brazilian Journal of Medical and 5 Suppl 3:416. Biological Research 2008;41(3):250–7. 6 Swanson 2004 {published data only} Tannock 1989 {published data only} 7 Sonuga-Barke EJ, Coghill D, Markowitz JS, Swanson JM, Tannock R, Schachar RJ, Carr RP, Chajczyk D, Logan 8 Confidential:Vandenberghe M, Hatch SJ. Sex differences in the response For ReviewGD. Effects of methylphenidate onOnly inhibitory control in 9 of children with ADHD to once-daily formulations of hyperactive children. Journal of Abnormal Child Psychology 10 methylphenidate. Journal of the American Academy of Child 1989;17(5):473-91. Erratum in: Journal of Abnormal 11 and Adolescent Psychiatry 2007;46(6):701–10. Child Psychology. 1990;18(1):119. ∗ 12 Sonuga-Barke EJ, Van Lier P, Swanson JM, Coghill D, Tannock R, Schachar RJ, Carr RP, Logan GD. 13 Wigal S, Vandenberghe M, et al. Heterogeneity in the Dose-response effects of methylphenidate on academic performance and overt behavior in hyperactive children. 14 pharmacodynamics of two long-acting methylphenidate formulations for children with attention deficit/hyperactivity Pediatrics 1989;84(4):648–57. 15 disorder. A growth mixture modelling analysis. European Tannock 1992 {published data only} 16 Child & Adolescent Psychiatry 2008;17(4):245–54. Tannock R, Schachar R. Methylphenidate and cognitive 17 Sonuga-Barke EJS, Coghill D, Wigal T, DeBacker M, perseveration in hyperactive children. Journal of Child 18 Swanson J. Adverse reactions to methylphenidate treatment Psychology and Psychiatry, and Allied Disciplines 1992;33(7): 19 for attention-deficit/hyperactivity disorder: structure and 1217–28. associations with clinical characteristics and symptom 20 Tannock 1993 {published data only} control. Journal of Child and Adolescent Psychopharmacology 21 Tannock R, Schachar RJ, Logan GD. Does methylphenidate 2009;19(6):683–90. 22 induce overfocusing in hyperactive children?. Journal of Sonuga-Barke EJS, Swanson JM, Coghill D, DeCory HH, 23 Clinical Child Psychology 1993;22(1):28–41. Hatch SJ. Efficacy of two once-daily methylphenidate 24 formulations compared across dose levels at different times Tannock 1995 {published data only} 25 of the day: preliminary indications from a secondary Tannock R, Schachar R, Logan G. Methylphenidate and 26 analysis of the COMACS study data. BMC Psychiatry 2004; cognitive flexibility: dissociated dose effects in hyperactive 27 4:28. children. Journal of Abnormal Child Psychology 1995;23(2): 28 Sonuge-Barke EJS, Swanson J, Hatch S, Van Lier P, 235–66. 29 Vandenberghe M. Heterogeneity in ADHD children’s Tannock 1995a {published data only} 30 response to two long-acting methylphenidate formulations. Tannock R, Fine J, Heintz T, Schachar RJ. A linguistic 31 Journal of Neural Transmission. Abstracts of the 39th approach detects stimulant effects in two children with 32 International Danube Symposium for Neurological Sciences attention-deficit hyperactivity disorder. Journal of Child and and Continuing Education and 1st International Congress Adolescent Psychopharmacology 1995;5(3):177–89. 33 on ADHD, from Childhood to Adult Disease 2007;114(7): ∗ Tannock R, Ickowicz A, Schachar R. Differential effects of 34 LXXXIX. methylphenidate on working memory in ADHD children 35 ∗ Swanson JM, Wigal SB, Wigal T, Sonuga-Barke E, with and without comorbid anxiety. Journal of the American 36 Greenhill LL, Biederman J, et al. A comparison of once- Academy of Child and Adolescent Psychiatry 1995;34(7): 37 daily extended-release methylphenidate formulations in 886–96. 38 children with attention-deficit/hyperactivity disorder in the Taylor 1987 {published data only} 39 laboratory school (the Comacs Study). Pediatrics 2004;113 Taylor E, Schachar R, Thorley G, Wieselberg HM, Everitt 40 (3 Pt 1):e206–16. B, Rutter M. Which boys respond to stimulant medication? 41 Symons 2007 {published data only} A controlled trial of methylphenidate in boys with disruptive 42 Symons FJ, Tervo RC, Kim O, Hoch J. The effects of behaviour. Psychological Medicine 1987;17(1):121–43. 43 methylphenidate on the classroom behavior of elementary Taylor 1993 {published data only} 44 school-age children with cerebral palsy: a preliminary Taylor MJ, Voros JG, Logan WJ, Malone MA. Changes 45 observational analysis. Journal of Child Neurology 2007;22 in event-related potentials with stimulant medication (1):89–94. 46 in children with attention deficit hyperactivity disorder. 47 Szobot 2004 {published data only} Biological Psychology 1993;36(3):139–56. 48 Szobot CM, Ketzer C, Parente MA, Biederman J, Rohde Tervo 2002 {published data only} 49 LA. The acute effect of methylphenidate in Brazilian male Tervo RC, Azuma S, Fogas B, Fiechtner H. Children with children and adolescentsFor with ADHD: aPreview randomized clinical ADHD and motorOnly dysfunction compared with children 50 trial. Journal of Attention Disorders 2004;8(2):37–43. with ADHD only. Developmental Medicine & Child 51 Neurology 2002;44(6):383–90. 52 Szobot 2008 {published data only} 53 Szobot CM, Rohde LA, Katz B, Ruaro P, Schaefer T, Tirosh 1993 {published data only} 54 Walcher M, et al. A randomized crossover clinical study Tirosh E, Elhasid R, Kamah SC, Cohen A. Predictive value showing that methylphenidate-SODAS improves attention- of placebo methylphenidate. Pediatric Neurology 1993;9(2): 55 deficit/hyperactivity disorder symptoms in adolescents with 131–3. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 58 Copyright © 2015 The Cochrane Collaboration. 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1 2 3 4 Tirosh 1993a {published data only} methylphenidate and clonidine on response inhibition and 5 Tirosh E, Sadeh A, Munvez R, Lavie P. Effects of state regulation in children with ADHD. Journal of Child 6 methylphenidate on sleep in children with attention- Psychology and Psychiatry, and Allied Disciplines 1999;40(2): 7 deficient hyperactivity disorder. An activity monitor study. 291–8. 8 Confidential:American Journal of Diseases of Children 1993;147(12): ForWallace Review 1994 {published data only} Only 9 1313–5. Wallace AE, Kofoed LL. Statistical analysis of single 10 Tourette’s-Syndrome-Study-Group 2002 {published data only} case studies in the clinical setting: the example of 11 Deputy SR. Treatment of ADHD in children with tics: a methylphenidate trials in children with attention-deficit randomized controlled trial. Clinical Pediatrics 2002;41(9): hyperactivity disorder. Journal of Child and Adolescent 12 736. Psychopharmacology 1994;4(3):141–50. 13 Kurlan R, Goldberg J. Clonidine and methylphenidate 14 Wallander 1987 {published data only} were effective for attention deficit hyperactivity disorder in Wallander JL, Schroeder SR, Michelli JA, Gualtieri CT. 15 children with comorbid tics. Evidence-Based Medicine 2002; Classroom social interactions of attention deficit disorder 16 7(5):157. with hyperactivity children as a function of stimulant 17 Kurlan R, Tourette Syndrome Study Group. Treatment medication. Journal of Pediatric Psychology 1987;12(1): 18 of attention-deficit-hyperactivity disorder in children with 61–76. Tourette’s syndrome (TACT Trial). Annals of Neurology. 19 Waxmonsky 2008 {published data only} Abstracts from the American Neurological Association’s 125th 20 Waxmonsky J, Pelham WE, Gnagy E, Cummings MR, Annual Meeting; 2000 October 15-18; Boston, Massachusetts 21 O’Connor B, Majumdar A, et al. The efficacy and 2000;48(6):953. tolerability of methylphenidate and behavior modification 22 ∗ Tourette’s Syndrome Study Group. Treatment of ADHD in children with attention-deficit/hyperactivity disorder and 23 in children with tics: a randomized controlled trial. severe mood dysregulation. Journal of Child and Adolescent 24 Neurology 2002;58(4):527–36. Psychopharmacology 2008;18(6):573–88. 25 Tucker 2009 {published data only} Whalen 1990 {published data only} 26 ∗ Tucker JD, Suter W, Petibone DM, Thomas RA, Whalen CK, Henker B, Granger DA. Ratings of medication 27 Bailey NL, Zhou Y, et al. Cytogenetic assessment of effects in hyperactive children: viable or vulnerable?. 28 methylphenidate treatment in pediatric patients treated for Behavioral Assessment 1989;11(2):179–99. 29 attention deficit hyperactivity disorder. Mutation Research ∗ Whalen CK, Henker B, Granger DA. Social judgment 2009;677(1-2):53–8. 30 processes in hyperactive boys: effects of methylphenidate Zhou Y, Muni R, Tucke JD, Kumar V. Extended- 31 and comparisons with normal peers. Journal of Abnormal release methylphenidate exposure and the frequency of 32 Child Psychology 1990;18(3):297–316. cytogenetic abnormalities in children with attention-deficit- 33 Whalen CK, Henker B, Hinshaw SP, Granger DA. hyperactivity disorder. Journal of Child and Adolescent Externalizing behavior disorders, situational generality, and 34 Psychopharmacology. Proceedings of the 49th Annual National the type A behavior pattern. Child Development 1989;60 35 Institute of Mental Health (NIMH) New Clinical Drug (6):1453–62. 36 Evaluation Unit (NCDEU) Meeting; 2009 June 29- July 2; 37 Hollywood, Florida 2009;19(6):785. Wigal 2003 {published data only} Wigal SB, Sanchez DY, DeCory HH, D’Imperio JM, 38 Ullmann 1985 {published data only} Swanson JM. Selection of the optimal dose ratio for 39 Ullmann RK, Sleator EK. Attention deficit disorder children a controlled-delivery formulation of methylphenidate. 40 with or without hyperactivity: which behaviors are helped Journal of Applied Research 2003;3(1):46–63. 41 by stimulants?. Clinical Pediatrics 1985;24(10):547–51. 42 [DOI: 10.1177/000992288502401001] Wigal 2004 {published data only} Wigal S, Swanson JM, Feifel D, Sangal RB, Elia J, 43 Ullmann 1986 {published data only} Casat CD, et al. A double-blind, placebo-controlled 44 Ullmann RK, Sleator EK. Responders, nonresponders, and trial of dexmethylphenidate hydrochloride and d,l-threo- placebo responders among children with attention deficit 45 methylphenidate hydrochloride in children with attention- disorder: importance of a blinded placebo evaluation. 46 deficit/hyperactivity disorder. Journal of the American Clinical Pediatrics 1986;25(12):594–9. 47 Academy of Child and Adolescent Psychiatry 2004;43(11): 48 Urman 1995 {published data only} 1406–14. Urman R, Ickowicz A, Fulford P,Tannock R. An exaggerated 49 Wigal 2013 {published data only} cardiovascular responseFor to methylphenidate Preview in ADHD Only 50 Liquid version of methylphenidate shows efficacy in children with anxiety. Journal of Child and Adolescent 51 school trial. The Brown University Child & Adolescent Psychopharmacology 1995;5(1):29–37. 52 Psychopharmacology Update 2013; Vol. 15, issue 3:1–3. ∗ 53 Van der Meere 1999 {published data only} Wigal SB, Childress AC, Belden HW, Berry SA. NWP06, 54 Gunning WB. A Controlled Trial of Clonidine in Hyperkinetic an extended-release oral suspension of methylphenidate, Children. Erasmus Universiteit Rotterdam, 1992. improved attention-deficit/hyperactivity disorder symptoms 55 ∗ Van der Meere J, Gunning B, Stemerdink N. The effect of compared with placebo in a laboratory classroom study. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 59 Copyright © 2015 The Cochrane Collaboration. 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1 2 3 4 Journal of Child and Adolescent Psychopharmacology 2013;23 of the methylphenidate transdermal system in children 5 (1):3–10. with attention-deficit/hyperactivity disorder. Journal of the 6 Wigal 2014 {published data only} American Academy of Child and Adolescent Psychiatry 2008; 7 Wigal SB, Greenhill LL, Nordbrock E, Connor DF, Kollins 47(6):700–8. 8 Confidential:SH, Adjei A, et al. A randomized placebo-controlled For Review Only Wilens 2010 {published data only} 9 double-blind study evaluating the time course of response Wilens T, Hammerness P, Utzinger L, Georgiopoulos 10 to methylphenidate hydrochloride extended-release capsules A, Doyle R, Brodziak K, et al. Before-school ADHD 11 in children with attention-deficit/hyperactivity disorder. symptoms and functioning in youth treated with the 12 Journal of Child and Adolescent Psychopharmacology 2014;24 Methylphenidate Transdermal Patch (MTS). Journal of (10):562–9. 13 Child and Adolescent Psychopharmacology. Abstracts of the 14 Wilens 2006 {published data only} 49th Annual National Institute of Mental Health (NIMH) 15 Oral system methylphenidate for teen ADHD. The Brown New Clinical Drug Evaluation Unit (NCDEU) Meeting; University Child & Adolescent Psychopharmacology 2009; June 29 - July 2; Hollywood, Florida. 2009; Vol. 19, 16 Update 2006; Vol. 8, issue 3:4–5. issue 6:785–6. 17 Biederman J. P.6.053 Effectiveness and safety of the once- ∗ Wilens TE, Hammerness P, Martelon MK, Brodziak 18 daily OROS formulation of methylphenidate in adolescents K, Utzinger L, Wong P. A controlled trial of the 19 with attention-deficit/hyperactivity disorder. European methylphenidate transdermal system on before-school 20 Neuropsychopharmacology 2003;13 Suppl 4:S448. functioning in children with attention-deficit/hyperactivity 21 Greenhill LL. Safety and efficacy of OROS MPH in disorder. Journal of Clinical Psychiatry 2010;71(5):548–56. 22 adolescents with ADHD. Proceedings of the 156th Annual Wilkison 1995 {published data only} 23 Meeting of the American Psychiatric Association; 2003 May Wilkison PC, Kircher JC, McMahon WM, Sloane HN. 24 17-22; San Francisco, CA. San Francisco, 2003:16. McGough JJ, McBurnett K, Bukstein O, Wilens TE, Effects of methylphenidate on reward strength in boys 25 Greenhill L, Lerner M, et al. Once-daily OROS with attention-deficit hyperactivity disorder. Journal of the 26 methylphenidate is safe and well tolerated in adolescents American Academy of Child and Adolescent Psychiatry 1995; 27 with attention-deficit/hyperactivity disorder. Journal of 34(7):897–901. 28 Child and Adolescent Psychopharmacology 2006;16(3):351–6. Wodrich 1998 {published data only} 29 Newcorn JH, Stein MA, Cooper KM. Dose-response Wodrich DL, Kush JC. The effect of methylphenidate on characteristics in adolescents with attention-deficit/ 30 teachers’ behavioral ratings in specific school situations. hyperactivity disorder treated with OROS methylphenidate 31 Psychology in the Schools 1998;35(1):81–8. 32 in a 4-week, open-label, dose-titration study. Journal 33 of Child and Adolescent Psychopharmacology 2010;20(3): Wolraich 2001 {published data only} 187–96. Greenhill LL. Efficacy and safety of once-daily 34 ∗ Wilens TE, McBurnett K, Bukstein O, McGough J, methylpheniadate HCl, standard methylphenidate and 35 Greenhill L, Lerner M, et al. Multisite controlled study of 36 placebo in children with ADHD. Proceedings of the 153rd OROS methylphenidate in the treatment of adolescents Annual Meeting of the American Psychiatric Association; 37 with attention-deficit/hyperactivity disorder. Archives of 2000 May 13-18; Chicago, Illinois. Chicago, 2000:NR. 38 Pediatrics & Adolescent Medicine 2006;160(1):82–90. 667. 39 Wilens 2008 {published data only} Greenhill LL. Evaluation of the efficacy and safety of 40 López FA, Landgraf JM, Wilens TE. Quality of life and Concerta (Methylphenidate HCI) extended-release tablets, 41 parent satisfaction with the methylphenidate transdermal ritalin, and placebo in children with ADHD. Neurology 42 system. European Neuropsychopharmacology. Papers of 2000;54(7):A420–1. [WOS: 000086557801120] 43 the 21st ECNP Congress; 2008 August 30 - September 3; Swanson J, Greenhill L, Pelham W, Wilens T, Wolraich 44 Barcelona, Spain. 2008; Vol. Suppl 4:S562. M, Abikoff H, et al. Initiating Concerta (TM) (OROS 45 López FA, Wilens TE, Wigal SB, Turnbow JM. Effects methylphenidate HCl) qd in children with attention-deficit of variable wear times on transdermal methylphenidate hyperactivity disorder. Journal of Clinical Research 2000;3: 46 in attention-deficit/hyperactivity disorder. European 59–76. 47 Neuropsychopharmacology. Papers of the 21st ECNP Wolraich ML. [Efficacy and safety of OROS(R) 48 Congress; 2008 August 30 - September 3; Barcelona, Spain. methylphenidate HCl (MPH) extended–release tablets 49 2008; Vol. 18:S561–2.For Preview(CONCERTA Only (TM)), conventional MPH, and placebo 50 Manos M, Frazier TW, Landgraf JM, Weiss M, Hodgkins in children with ADHD]. International Journal of 51 P. HRQL and medication satisfaction in children with Neuropsychopharmacology. Proceedings of the XXIIst 52 ADHD treated with the methylphenidate transdermal CINP Congress; 2000 July 9-13; Brussels, Belgium. 2000; 53 system. Current Medical Research and Opinion 2009;25(12): Vol. 3 Suppl 1:S329. 54 3001–10. Wolraich ML. Efficacy and safety of OROS Methylphenidate ∗ Wilens TE, Boellner SW, López FA, Turnbow JM, HCI (MPH) extended-release tablets (Concerta TM), 55 Wigal SB, Childress AC, et al. Varying the wear time conventional MPH, and placebo in children with ADHD. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 60 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 106 of 615
1 2 3 4 International Journal of Neuropsychopharmacology. XXIIst Aggarwal 2000 {published data only} 5 CINP Congress 2000;3(Suppl S1):329. Aggarwal A, Lillystone D. A follow-up pilot study of 6 Wolraich ML. Evaluation of efficacy and safety of objective measures in children with attention deficit 7 OROS Methylphenidate HCI (MPH) Extended-release hyperactivity disorder. Journal of Paediatrics and Child 8 Confidential:tablets, methylphenidate tid, and placebo in children For ReviewHealth 2000;36(2):134–8. Only 9 with ADHD. Pediatric Research 2000;47(4):36A. [WOS: Ajibola 1995 {published data only} 000086155300208] Ajibola O, Clement PW. Differential effects of 10 ∗ Wolraich ML, Greenhill LL, Pelham W, Swanson J, 11 methylphenidate and self-reinforcement on attention-deficit Wilens T, Palumbo D, et al. Randomized, controlled trial hyperactivity disorder. Behavior Modification 1995;19(2): 12 of OROS methylphenidate once a day in children With 211–33. 13 attention-deficit/hyperactivity disorder. Pediatrics 2001;108 Albert 1985 {published data only} 14 (4):883–92. Albert E, Mouren MC, Dugas M. A case of hallucination 15 Zeiner 1999 {published data only} from methylphenidate in an 8-year-old hyperkinetic boy. 16 Zeiner P. Body growth and cardiovascular function after Journal de Toxicologie Clinique et Expérimentale 1985;5(3): 17 extended treatment (1.75 years) with methylphenidate in 195–9. 18 boys with attention-deficit hyperactivity disorder. Journal of Alston 1992 {published data only} 19 Child and Adolescent Psychopharmacology 1995;5(2):129–38. Alston CY, Romney DM. A comparison of medicated and 20 Zeiner P. Do the beneficial effects of extended nonmedicated attention-deficit disordered hyperactive boys. 21 methylphenidate treatment in boys with attention-deficit Acta Paedopsychiatrica 1992;55(2):65–70. 22 hyperactivity disorder dissipate rapidly during placebo Aman 1974 {published data only} treatment?. Nordic Journal of Psychiatry 1999;53(1):55–60. Aman MG, Sprague RL. The state-dependent effects of 23 ∗ Zeiner P, Bryhn G, Bjercke C, Truyen K, Strand G. 24 methylphenidate and dextroamphetamine. Journal of Response to methylphenidate in boys with attention- Nervous and Mental Disease 1974;158(4):268–79. 25 deficit hyperactivity disorder. Acta Paediatrica 1999;88(3): Aman 1975 {published data only} 26 298–303. Aman MG, Werry JS. The effects of methylphenidate 27 Zeni 2009 {published data only} and haloperidol on the heart rate and blood pressure of 28 Zeni CP, Tramontina S, Ketzer CR, Pheula GF, Rohde LA. hyperactive children with special reference to time of action. 29 Methylphenidate combined with aripiprazole in children Psychopharmacologia 1975;43(2):163–8. 30 and adolescents with bipolar disorder and attention-deficit/ Aman 1975a {published data only} 31 hyperactivity disorder: a randomized crossover trial. Journal Aman MG, Werry JS. Methylphenidate in children: effects 32 of Child and Adolescent Psychopharmacology 2009;19(5): upon cardiorespiratory function on exertion. International 33 553–61. Journal of Mental Health 1975;4(1-2):119–31. 34 References to studies excluded from this review Aman 1991 {published data only} 35 Aman MG, Marks RE, Turbott SH, Wilsher CP, Merry 36 Abikoff 1985 {published data only} SN. Clinical effects of methylphenidate and thioridazine in 37 Abikoff H, Gittelman R. The normalizing effects of intellectually subaverage children. Journal of the American 38 methylphenidate on the classroom behavior of ADDH Academy of Child and Adolescent Psychiatry 1991;30(2): 39 children. Journal of Abnormal Child Psychology 1985;13(1): 246–56. 40 33–44. Aman 1991a {published data only} Aman MG, Marks RE, Turbott SH, Wilsher CP, Merry 41 Ackerman 1983 {published data only} SN. Methylphenidate and thioridazine in the treatment Ackerman PT, Dykman RA, Holcomb PJ, McCray DS. 42 of intellectually subaverage children: effects on cognitive- Effects of high and low dosages of methylphenidate 43 motor performance. Journal of the American Academy of in children with strong and sensitive nervous systems. 44 Child and Adolescent Psychiatry 1991;30(5):816–24. Pavlovian Journal of Biological Science 1983;18(1):36–48. 45 Aman 1993 {published data only} 46 Acquarone-Greiwe 2009 {published data only} Aman MG, Kern RA, McGhee DE, Arnold LE. 47 Acquarone-Greiwe D, Koch IE, Hermanns-Clausen M, Fenfluramine and methylphenidate in children with mental 48 Binscheck T. Methylphenidate: harmless intoxication but retardation and ADHD: clinical and side effects. Journal 49 severe side effects?. Clinical Toxicology. Proceedings of the of the American Academy of Child and Adolescent Psychiatry 29th InternationalFor Congress of the European Preview Association of 1993;32(4):851–9. Only 50 Poison Centres and Clinical Toxicologists; 2009 May 12-15; Aman 1997 {published data only} 51 Stockholm, Sweden 2009;47(5):457. 52 Aman MG, Kern RA, Osborne P, Tumuluru R, Rojahn 53 Adams 1982 {published data only} J, Del Medico V. Fenfluramine and methylphenidate in 54 Adams W. Effect of methylphenidate on thought processing children with mental retardation and borderline IQ: clinical time in children. Journal of Developmental and Behavioral effects. American Journal of Mental Retardation 1997;101 55 Pediatrics 1982;3(3):133–5. (5):521–34. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 61 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 107 of 615 BMJ
1 2 3 4 Aman 2003 {published data only} Barkley 1979 {published data only} 5 Aman MG, Buican B, Arnold LE. Methylphenidate Barkley RA, Cunningham CE. The effects of 6 treatment in children with borderline IQ and mental methylphenidate on the mother-child interactions of 7 retardation: analysis of three aggregated studies. Journal of hyperactive children. Archives of General Psychiatry 1979;36 8 Confidential:Child and Adolescent Psychopharmacology 2003;13(1):29–40. For Review(2):201–8. Only 9 An 2013 {published data only} Barkley 1979a {published data only} 10 An L, Cao X-H, Cao Q-J, Sun L, Yang L, Zou Q-H, et al. Barkley RA, Cunningham CE. Stimulant drugs and 11 Methylphenidate normalizes resting-state brain dysfunction activity level in hyperactive children. American Journal of in boys with attention deficit hyperactivity disorder. Orthopsychiatry 1979;49(3):491–9. 12 Neuropsychopharmacology 2013;38(7):1287–95. 13 Barkley 1983 {published data only} Anderson 1981 14 {published data only} Barkley RA, Cunningham CE, Karlsson J. The speech of Anderson EE, Clement PW, Oettinger L. Methylphenidate hyperactive children and their mothers: comparison with 15 compared with behavioral self-control in attention deficit normal children and stimulant drug effects. Journal of 16 disorder: preliminary report. Journal of Developmental and Learning Disabilities 1983;16(2):105–10. 17 Behavioral Pediatrics 1981;2(4):137–41. Barkley 1985 {published data only} 18 Anderson 2002 {published data only} Barkley RA, Karlsson J, Pollard S, Murphy JV. 19 Anderson CM, Polcari A, Lowen SB, Renshaw PF, Teicher Developmental changes in the mother-child interactions 20 MH. Effects of methylphenidate on functional magnetic of hyperactive boys: effects of two dose levels of Ritalin. 21 resonance relaxometry of the cerebellar vermis in boys Journal of Child Psychology and Psychiatry, and Allied 22 with ADHD. American Journal of Psychiatry 2002;159(8): Disciplines 1985;26(5):705–15. 1322–8. 23 Barkley 1988 {published data only} Aylett 2009 {published data only} 24 Barkley RA. The effects of methylphenidate on the Aylett S, Fosi T, Lax-Pericall T, Scott R, Neville B. 25 interactions of preschool ADHD children with their Methylphenidate treatment of ADHD in young people mothers. Journal of the American Academy of Child and 26 with learning disability and severe epilepsy: a qualitative Adolescent Psychiatry 1988;27(3):336–41. 27 study. Epilepsia. Proceedings of the 8th European Congress 28 on Epileptology; 2008 September 21-25; Berlin, Germany. Barkley 1988a {published data only} 29 2009; Vol. 50 Suppl s4:54. Barkley RA, Fischer M, Newby RF, Breen MJ. Development of a multimethod clinical protocol for assessing stimulant 30 Babilas 2004 {published data only} drug response in children with attention deficit disorder. 31 Babilas P, Roesch A, Szeimies R-M, Landthaler M, Vogt Journal of Clinical Child Psychology 1988;17(1):14–24. 32 T. Zosteriform pigmented purpura of Schamberg: case 33 report and differential diagnosis of zosteriform skin Barkley 1997 {published data only} 34 lesions [Zosteriforme pigmentpurpura Schamberg: Ein Barkley RA, Koplowitz S, Anderson T, McMurray MB. Sense of time in children with ADHD: effects of duration, 35 fallbericht und die differentialdiagnosen zosteriformer distraction, and stimulant medication. Journal of the 36 hautveranderungen]. Journal of the German Society of Dermatology 2004;2(11):931–4. International Neuropsychological Society 1997;3(4):359–69. 37 Barkley 2003 {published data only} 38 Baird 2001 {published data only} Baird PJ. Pursuing justice in the courts: lessons from the Barkley RA, Fischer M, Smallish L, Fletcher K. Does 39 experience of one school nurse. Journal of School Nursing the treatment of attention-deficit/hyperactivity disorder 40 2001;17(4):218–21. with stimulants contribute to drug use/abuse? A 13-year 41 Baird 2003 {published data only} prospective study. Pediatrics 2003;111(1):97–109. 42 Baird R, Ickowicz A. Methylphenidate and the cytochrome Barnett 2001 {published data only} 43 P450 system. Canadian Journal of Psychiatry 2003;48(6): Barnett R, Maruff P, Vance A, Luk ES, Costin J, Wood 44 425–6. C, et al. Abnormal executive function in attention deficit 45 Balázs 2007 {published data only} hyperactivity disorder: the effect of stimulant medication 46 Balázs J, Besnyo M, Gádoros J. Methylphenidate-induced and age on spatial working memory. Psychological Medicine 47 orofacial and extremity dyskinesia. Journal of Child and 2001;31(6):1107–15. 48 Adolescent Psychopharmacology 2007;17(3):378–81. Bart 2010 {published data only} 49 Ballard 1976 {published data only} Bart O, Podoly T, Bar-Haim Y. A preliminary study on Ballard JE, BoileauFor RA, Sleator EK, MasseyPreview BH, Sprague the effect of methylphenidateOnly on motor performance in 50 51 RL. Cardiovascular responses of hyperactive children to children with comorbid DCD and ADHD. Research in methylphenidate. 1976;236(25):2870–4. Developmental Disabilities 2010;31(6):1443–7. 52 JAMA 53 Barkley 1977 {published data only} Bart 2013 {published data only} 54 Barkley RA. The effects of methylphenidate on various Bart O, Daniel L, Dan O, Bar-Haim Y. Influence of types of activity level and attention in hyperkinetic children. methylphenidate on motor performance and attention 55 Journal of Abnormal Child Psychology 1977;5(4):351–69. in children with developmental coordination disorder 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 62 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 108 of 615
1 2 3 4 and attention deficit hyperactive disorder. Research in children with attention-deficit/hyperactivity disorder. 5 Developmental Disabilities 2013;34(6):1922–7. Journal of the American Academy of Child and Adolescent 6 Barter 1978 {published data only} Psychiatry 2004;43(3):260–8. 7 Barter M, Kammer H. Methylphenidate and growth Bedard 2007 {published data only} 8 Confidential:retardation. JAMA 1978;239(17):1742–3. For ReviewBedard A-C, Jain U, Hogg Johnson Only S, Tannock R. Effects 9 Basil 2006 {published data only} of methylphenidate on working memory components: 10 Basil B, Mathews M, Budur K. Methylphenidate-induced influence of measurement. Journal of Child Psychology and 11 neuroleptic malignant syndrome: a case report. Primary Psychiatry 2007;48(9):872–80. 12 Care Companion to the Journal of Clinical Psychiatry 2006;8 Bedard 2007a {published data only} 13 (1):47. Bedard A-C. Impact of methylphenidate on working 14 Bawden 1993 {published data only} memory in children with attention-deficit hyperactivity 15 Bawden D. Predicting Ritalin response with neurometric disorder. Dissertation Abstracts International: Section B: The Sciences and Engineering. Canada: U Toronto, 2007; 16 testing: case studies. Handbook of Childhood Impulse . Springfield: Vol. 68, issue 6–B:3686. 17 Disorders and ADHD: Theory and Practice Thomas, 1993:60–77. Beery 1994 18 {published data only} Bawden 1997 Beery SH. Behavioral disinhibition, anxiety, and response 19 {published data only} Bawden HN, MacDonald GW, Shea S. Treatment of to methylphenidate and behavior management in children 20 children with Williams syndrome with methylphenidate. with attention deficit hyperactivity disorder. Dissertation 21 Journal of Child Neurology 1997;12(4):248–52. Abstracts International: Section B: The Sciences and 22 Engineering. 1994; Vol. 56, issue 2–B:1096. Baxley 1979 {published data only} 23 Baxley GB, Ullmann RK. Psychoactive drug effects in a Benamor 2014 {published data only} 24 hyperactive child: a case study analysis of behavior change Benamor L. 1H-Magnetic resonance spectroscopy study of 25 and teacher attention. Journal of School Psychology 1979;17 stimulant medication effect on brain metabolites in French 26 (4):317–24. Canadian children with attention deficit hyperactivity 27 Beauchaine 2003 {published data only} disorder. Neuropsychiatric Disease and Treatment 2014;10: 28 Beauchaine TP, Gartner J. A linear growth curve analysis 47–54. 29 of inpatient treatment response by conduct-disordered, Benedetto-Nasho 1999 {published data only} 30 ADHD, and comorbid preadolescents. Aggressive Behavior Benedetto-Nasho E, Tannock R. Math computation, error 31 2003;29(5):440–56. patterns and stimulant effects in children with Attention Deficit Hyperactivity Disorder. Journal of Attention 32 Beck 1975 {published data only} Disorders 1999;3(3):121–34. 33 Beck L, Langford WS, MacKay M, Sum G. Childhood 34 chemotherapy and later drug abuse and growth curve: a Benjamin 2005 {published data only} Benjamin E, Salek S. Stimulant-atypical antipsychotic 35 follow-up study of 30 adolescents. American Journal of Psychiatry 1975;132(4):436–8. interaction and acute dystonia. Journal of the American 36 Academy of Child and Adolescent Psychiatry 2005;44(6):510- Becker 2011a {published data only} 37 2. Erratum in: Journal of the American Academy of Child Becker A, Roessner V, Breuer D, Döpfner M, 38 and Adolescent Psychiatry. 2005;44(9):960. Rothenberger A. Relationship between quality of life and 39 psychopathological profile: data from an observational Ben-Pazi 2006 {published data only} 40 study in children with ADHD. European Child & Adolescent Ben-Pazi H, Shalev RS, Gross-Tsur V, Bergman H. Age 41 Psychiatry 2011;20(Suppl 2):S267–75. and medication effects on rhythmic responses in ADHD: possible oscillatory mechanisms?. Neuropsychologia 2006;44 42 Bedard 2002 {published data only} (3):412–6. 43 Bedard A-C, Ickowicz A, Tannock R. Methylphenidate 44 improves Stroop naming speed, but not response Bental 2008 {published data only} 45 interference, in children with attention deficit hyperactivity Bental B, Tirosh E. The effects of methylphenidate 46 disorder. Journal of Child and Adolescent Psychopharmacology on word decoding accuracy in boys with attention- 47 2002;12(4):301–9. deficit/hyperactivity disorder. Journal of Clinical 2008;28(1):89–92. 48 Bedard 2003 {published data only} Psychopharmacology 49 Bedard A-C, Ickowicz A, Logan GD, Hogg-Johnson S, Berkovitch 1995 {published data only} Schachar R, TannockFor R. Selective inhibition Preview in children Berkovitch M,Only Pope E, Phillips J, Koren G. Pemoline- 50 51 with attention-deficit hyperactivity disorder off and on associated fulminant liver failure: testing the evidence for stimulant medication. causation. Clinical Pharmacology & Therapeutics 1995;57 52 Journal of Abnormal Child Psychology 2003;31(3):315–27. (6):696–8. 53 54 Bedard 2004 {published data only} Biederman 1999 {published data only} Bedard A-C, Martinussen R, Ickowicz A, Tannock R. Biederman J, Wilens T, Mick E, Spencer T, Faraone SV. 55 Methylphenidate improves visual-spatial memory in Pharmacotherapy of attention-deficit/hyperactivity disorder 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 63 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 109 of 615 BMJ
1 2 3 4 reduces risk for substance use disorder. Pediatrics 1999;104 Autistic Spectrum Disorder (ASD). Procedia - Social and 5 (2):e20. Behavioral Sciences 2010;5:655–9. 6 Biederman 2003c {published data only} Boileau 1976 {published data only} 7 Biederman J, Faraone SV, Monuteaux MC, Plunkett Boileau RA, Ballard JE, Sprague RL, Sleator EK, Massey 8 Confidential:EA, Gifford J, Spencer T. Growth deficits and attention- For ReviewBH. Effect of methylphenidate onOnly cardiorespiratory 9 deficit/hyperactivity disorder revisited: impact of gender, responses in hyperactive children. Research Quarterly 1976; 10 development, and treatment. Pediatrics 2003;111(5 Pt 1): 47(4):590–6. 1010–6. 11 Brackenridge 2011 {published data only} Biederman 2008 {published data only} Brackenridge R, McKenzie K, Murray GC, Quigley A. 12 Biederman J, Monuteaux MC, Spencer T, Wilens TE, An examination of the effects of stimulant medication on 13 MacPherson HA, Faraone SV. Stimulant therapy and risk response inhibition: a comparison between children with 14 for subsequent substance use disorders in male adults with and without attention deficit hyperactivity disorder. Research 15 ADHD: a naturalistic controlled 10-year follow-up study. in Developmental Disabilities 2011;32(6):2797–804. 16 American Journal of Psychiatry 2008;165(5):597–603. 17 Biederman 2009 {published data only} Breggin 2000 {published data only} 18 Biederman J, Monuteaux MC, Spencer T, Wilens TE, Breggin PR. The NIMH multimodal study of treatment for 19 Faraone SV. Do stimulants protect against psychiatric attention-deficit/hyperactivity disorder: a critical analysis. 20 disorders in youth with ADHD? A 10-year follow-up study. International Journal of Risk & Safety in Medicine 2000; 21 Pediatrics 2009;124(1):71–8. Vol. 13, issue 1:15–22. 22 Biederman 2010 {published data only} Bremness 1979 {published data only} 23 Biederman J, Spencer TJ, Monuteaux MC, Faraone SV. A Bremness AB, Sverd J. Methylphenidate-induced Tourette naturalistic ten-year prospective study of height and weight 24 syndrome: case report. American Journal of Psychiatry 1979; in children with attention-deficit hyperactivity disorder 136(10):1334–5. 25 grown up: sex and treatment effects. Journal of Pediatrics Broad 1982 {published data only} 26 2010;157(4):635–40.e1. Broad JC. Assessing stimulant treatment of hyperkinesis 27 Bilgiç 2007 {published data only} 28 by Bristol Social Adjustment Guides. Journal of Psychiatic Bilgiç A, Gürkan K, Türko lu S. Excessive masturbation Treatment and Evaluation 1982;4(4):355–8. 29 and hypersexual behavior associated with methylphenidate. Brossard-Racine 2012 {published data only} 30 Journal of the American Academy of Child and Adolescent Brossard-Racine M, Shevell M, Snider L, Bélanger SA, 31 Psychiatry 2007;46(7):789–90. 32 Majnemer A. Motor skills of children newly diagnosed Bilgiç 2011 {published data only} with Attention Deficit Hyperactivity Disorder prior to and 33 Bilgiç A. The possible effect of methylphenidate on following treatment with stimulant medication. Research in 34 secondary encopresis in children with attention-deficit/ Developmental Disabilities 2012;33(6):2080–7. 35 hyperactivity disorder. Progress in Neuro-Psychopharmacology 36 & Biological Psychiatry 2011;35(2):647. Brown 1979 {published data only} Brown RT, Sleator EK. Methylphenidate in hyperkinetic 37 Blader 2013 {published data only} children: differences in dose effects on impulsive behavior. Blader JC, Pliszka SR, Kafantaris V, Foley CA, Crowell JA, 38 Pediatrics 1979;64(4):408–11. 39 Carlson GA, et al. Callous-unemotional traits, proactive 40 aggression, and treatment outcomes of aggressive children Brown 1984 {published data only} Brown RT, Wynne ME. Sustained attention in boys with 41 with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 2013; attention deficit disorder and the effect of methylphenidate. 42 52(12):1281–93. Pediatric Nursing 1984;10(1):35–9. 43 Blankenship 2011 {published data only} Brown 1986 {published data only} 44 Blankenship K, Janicak PG. Pharmacotherapy of autism 45 Brown RT, Borden KA, Wynne ME, Schleser R, Clingerman spectrum disorders. Psychopharm Review : Timely Reports SR. Methylphenidate and cognitive therapy with add 46 in Psychopharmacology and Therapeutic Neuromodulation children: a methodological reconsideration. Journal of 47 2011; Vol. 46, issue 11:81–8. Abnormal Child Psychology 1986;14(4):481–97. 48 Bloom 1988 {published data only} 49 Bloom AS, Russell LJ, Weisskopf B, Blackerby JL. Brown 1988 {published data only} Methylphenidate-inducedFor delusional disorderPreview in a child Brown RT, BordenOnly KA, Wynne ME, Spunt AL, Clingerman 50 with attention deficit disorder with hyperactivity. Journal SR. Patterns of compliance in a treatment program 51 for children with attention deficit disorder. Journal of 52 of the American Academy of Child and Adolescent Psychiatry 1988;27(1):88–9. Compliance in Health Care 1988;3(1):23–39. 53 54 Bohane 2010 {published data only} Buchhorn 2012 {published data only} Bohane L, Young M, Rowlandson P. Medication in Buchhorn R, Conzelmann A, Willaschek C, Störk 55 attention deficit hyperactivity disorder and adhd with D, Taurines R, Renner TJ. Heart rate variability and 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 64 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 110 of 615
1 2 3 4 methylphenidate in children with ADHD. Attention Deficit with ADHD. European Neuropsychopharmacology. Papers 5 and Hyperactivity Disorders 2012; Vol. 4, issue 2:85–91. of the 25th ECNP Congress; 2012 October 13-17; Vienna, 6 Buchhorn R, Müller C, Willaschek C, Norozi K. How to Austria. Cagliari, Italy: Elsevier, 2012; Vol. 22 Suppl 2: 7 predict the impact of methylphenidate on cardiovascular risk S421–2. 8 Confidential:in children with attention deficit disorder: methylphenidate ForCasat Review 1986 {published data only} Only 9 improves autonomic dysfunction in children with ADHD. Casat CD, Wilson DC 3rd. Tics with combined ISRN Pharmacology 2012;2012:170935. [DOI: 10.5402/ thioridazine-methylphenidate therapy: case report. Journal 10 2012/170935] 11 of Clinical Psychiatry 1986;47(1):44–5. Buhrmester 1992 {published data only} 12 Casat 1995 {published data only} Buhrmester D, Whalen CK, Henker B, MacDonald V, Casat CD, Pearson DA, Van Davelaar MJ, Cherek DR. 13 Hinshaw SP. Prosocial behavior in hyperactive boys: effects 14 Methylphenidate effects on a laboratory aggression measure of stimulant medication and comparison with normal boys. in children with ADHD. Psychopharmacology Bulletin 1995; 15 Journal of Abnormal Child Psychology 1992;20(1):103–21. 31(2):353–6. 16 Burroughs 1994 {published data only} 17 Cavadas 2007 {published data only} Burroughs G. The dangers of Ritalin. Chiropractic Journal Cavadas M, Pereira LD, Mattos P.Effects of methylphenidate 18 1994;8(4):38. in auditory processing evaluation of children and adolescents 19 Butter 1975 {published data only} with attention deficit hyperactivity disorder [Efeito do 20 Butter HJ, Lapierre YD. The effect of methylphenidate metilfenidato no processamento auditivo em criancas 21 on sensory perception in varying degrees of hyperkinetic e adolescentes com transtorno do deficit de atencao/ 22 behaviour. Diseases of the Nervous System 1975;36(6):286–8. hiperatividade]. Arquivos de Neuro-Psiquiatria 2007;65(1): 23 Byrne 1998 {published data only} 138–43. 24 Byrne JM, Bawden HN, DeWolfe NA, Beattie TL. Chambers 2012 {published data only} 25 Clinical assessment of psychopharmacological treatment Chambers NA, Pascoe E, Kaplanian S, Forsyth I. Ingestion 26 of preschoolers with ADHD. Journal of Clinical and of stimulant medications does not alter bispectral index 27 Experimental Neuropsychology 1998;20(5):613–27. or clinical depth of anesthesia at 1 MAC sevoflurane in 28 Campbell 1996 {published data only} children. Paediatric Anaesthesia 2012;22(4):341–4. 29 Campbell L, Malone MA, Kershner JR, Roberts W, Charles 1979 {published data only} 30 Humphries T, Logan WJ. Methylphenidate slows right Charles L, Schain RJ, Guthrie D. Long-term use and 31 hemisphere processing in children with attention-deficit/ discontinuation of methylphenidate with hyperactive hyperactivity disorder. Journal of Child and Adolescent children. Developmental Medicine & Child Neurology 1979; 32 Psychopharmacology 1996;6(4):229–39. 21(6):758–64. 33 Camporeale 2012 {published data only} Charles 1979a {published data only} 34 Camporeale A, Beasley C, Tanaka Y, D’Souza D, Upadhyaya Charles L, Schain RJ, Zelniker T, Guthrie D. Effects of 35 H. Changes in blood pressure and heart rate associated with methylphenidate on hyperactive children’s ability to sustain 36 atomoxetine treatment in attention-deficit/hyperactivity attention. Pediatrics 1979;64(4):412–8. 37 disorder. European Neuropsychopharmacology 2012;22 Charles 1981 {published data only} 38 (Suppl 2):S429–30. Charles L, Schain R, Zelniker T. Optimal dosages of 39 Carlezon 2004 {published data only} methylphenidate for improving the learning and behavior 40 Carlezon S. Study finds early Ritalin exposure may have of hyperactive children. Journal of Developmental and 41 long-term effects. Mental Health Weekly 2004;14(48):3–4. Behavioral Pediatrics 1981;2(3):78–81. 42 Carlson 1991 {published data only} Charles 1981a {published data only} 43 Carlson CL, Pelham WE Jr, Swanson JM, Wagner JL. A Charles L, Schain R. A four-year follow-up study of the 44 divided attention analysis of the effects of methylphenidate effects of methylphenidate on the behavior and academic 45 on the arithmetic performance of children with attention- achievement of hyperactive children. Journal of Abnormal 46 deficit hyperactivity disorder. Journal of Child Psychology Child Psychology 1981;9(4):495–505. 47 and Psychiatry, and Allied Disciplines 1991;32(3):463–71. Chavez 1999 {published data only} 48 Carlson 1992 {published data only} Chavez H, Ozolins D, Losek JD. Hypoglycemia and 49 Carlson CL, Pelham WE Jr, Milich R, Dixon J. Single and propranolol in pediatric behavioral disorders. Pediatrics combined effectsFor of methylphenidate andPreview behavior therapy 1999;103(6 PtOnly 1):1290–92. 50 51 on the classroom performance of children with attention- Chazan 2011 {published data only} deficit hyperactivity disorder. Journal of Abnormal Child Chazan R, Borowski C, Pianca T, Ludwig H, Rohde LA, 52 Psychology 1992;20(2):213–32. 53 Polanczyk G. Do phenotypic characteristics, parental 54 Carucci 2012 {published data only} psychopathology, family functioning, and environmental Carucci S, Anchisi L, Ambu G, Melis G L, Lecca L, Zuddas stressors have a role in the response to methylphenidate 55 A. Methylphenidate effects on social functioning in children in children with attention-deficit/hyperactivity disorder?: 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 65 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 111 of 615 BMJ
1 2 3 4 A naturalistic study from a developing count. Journal of Comly 1971 {published data only} 5 Clinical Psychopharmacology 2011;31(3):309–17. Comly HH. Cerebral stimulants for children with learning disorders?. Journal of Learning Disabilities 1971;4(9): 6 Chelonis 2010 {published data only} 484–90. 7 Chelonis J, Johnson T, Ferguson S, Kubacak B, Edwards 8 Confidential:M, Paule M. Effects of methylphenidate on motivation ForConzelmann Review 2014 {published data only}Only 9 in children with attention-deficit/hyperactivity disorder. Conzelmann A, Gerdes AB, Mucha RF, Weyers P, Lesch KP, 10 Neurotoxicology and Teratology 2010;32(4):504. Bähne CG, et al. Autonomic hypoactivity in boys with attention-deficit/hyperactivity disorder and the influence 11 Chelonis 2011 {published data only} 12 of methylphenidate. World Journal of Biological Psychiatry Chelonis JJ, Johnson TA, Ferguson SA, Berry KJ, Kubacak 2014;15(1):56–65. 13 B, Edwards MC, et al. Effect of methylphenidate on 14 motivation in children with attention-deficit/hyperactivity Cooper 2011 {published data only} 15 disorder. Experimental & Clinical Psychopharmacology 2011; Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast 19(2):145–53. PG, Cheetham TC, et al. ADHD drugs and serious 16 cardiovascular events in children and young adults. New 17 Chernoff 1962 {published data only} England Journal of Medicine 2011;365(20):1896–904. 18 Chernoff RW, Wallen MH, Müller OF. Cardiac toxicity of 19 methylphenidate - report of two cases. New England Journal Correia Filho 2005 {published data only} of Medicine 1962;266:400–1. Correia Filho AG, Bodanese R, Silva TL, Alvares JP, 20 Aman M, Rohde L. Comparison of risperidone and 21 Chilcoat 1999 {published data only} methylphenidate for reducing ADHD symptoms in 22 Chilcoat HD, Breslau N. Pathways from ADHD to early children and adolescents with moderate mental retardation. 23 drug use. Journal of the American Academy of Child and Journal of the American Academy of Child and Adolescent 24 Adolescent Psychiatry 1999;38(11):1347–54. Psychiatry 2005;44(8):748–55. 25 Christ 2013 {published data only} Cotton 1988 {published data only} 26 Christ W. ADD in epileptic children. Epilepsia. Proceeding Cotton MF, Rothberg AD. Methylphenidate v. placebo--a 27 of the 50th Meeting of the German Society Against randomised double-blind crossover study in children with 28 Epilepsy; 2010 April 28- May 1; Wiesbaden, Germany. the attention deficit disorder. South African Medical Journal 29 2010; Vol. 51 Suppl s2:16. 1988;74(6):268–71. Christ W, Mayer H, Wiemer-Kruel A. Methylphenidate 30 Cox 2004a {published data only} therapy for children with epilepsy: results of a double Cox DJ, Humphrey JW, Merkel RL, Penberthy JK, 31 blinded observational study [Methylphenidattherapie bei Kovatchev B. Controlled-release methylphenidate improves 32 epilepsiekranken kindern: ergebnisse einer doppelblinden attention during on-road driving by adolescents with 33 anwendungsbeobachtung]. Monatsschrift Kinderheilkunde attention-deficit/hyperactivity disorder. Journal of the 34 2013;161:720–6. 35 American Board of Family Practice / American Board of Family Clarke 2003 {published data only} Practice 2004;17(4):235–9. 36 Clarke AR, Barry RJ, McCarthy R, Selikowitz M, Clarke Cox 2004b {published data only} 37 DC, Croft RJ. Effects of stimulant medications on children Cox DJ, Merkel RL, Penberthy JK, Kovatchev B, Hankin 38 with attention-deficit/hyperactivity disorder and excessive CS. Impact of methylphenidate delivery profiles on 39 beta activity in their EEG. Clinical Neurophysiology 2003; driving performance of adolescents with attention-deficit/ 114(9):1729–37. 40 hyperactivity disorder: a pilot study. Journal of the American 41 Cohen 1971 {published data only} Academy of Child and Adolescent Psychiatry 2004;43(3): 42 Cohen NJ, Douglas VI, Morgenstern G. The effect of 269–75. methylphenidate on attentive behavior and autonomic 43 Cunningham 1978 {published data only} activity in hyperactive children. Psychopharmacologia 1971; 44 Cunningham CE, Barkley RA. The effects of 22(3):282–94. 45 methylphenidate on the mother-child interactions of 46 Cohen 2006 {published data only} hyperactive identical twins. Developmental Medicine & 47 Cohen AL, Jhung MA, Budnitz DS. Stimulant medications Child Neurology 1978;20(5):634–42. and attention deficit-hyperactivity disorder. New England 48 Dadfarmay 2009 {published data only} Journal of Medicine 2006;354(21):2294–5. 49 For PreviewDadfarmay S,Only Dixon J. A case of acute cardiomyopathy and 50 Coleman 1979 {published data only} pericarditis associated with methylphenidate. Cardiovascular 51 Coleman M, Steinberg G, Tippett J, Bhagavan HN, Toxicology 2009;9(1):49–52. 52 Coursin DB, Gross M, et al. A preliminary study of Ghanizadeh A. Commentary on “a case of acute 53 the effect of pyridoxine administration in a subgroup of cardiomyopathy and pericarditis associated with 54 hyperkinetic children: a double-blind crossover comparison methylphenidate”; cardiovasc toxicol, DOI 10.1007/ with methylphenidate. Biological Psychiatry 1979;14(5): s12012-009-9033-7. Cardiovascular Toxicology 2009;9(2): 55 741–51. 105. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 66 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 112 of 615
1 2 3 4 Dalby 1977 {published data only} Symposium for Neurological Sciences and Continuing 5 Dalby JT, Kinsbourne M, Swanson JM, Sobol MP. Education and 1st International Congress on ADHD, from 6 Hyperactive children’s underuse of learning time: correction Childhood to Adult Disease; 2007 June 2-5; Wurzburg, 7 by stimulant treatment. Child Development 1977;48(4): Germany. 2007; Vol. 114, issue 7:XCI. 8 Confidential:1448–53. ForDeshpande Review 2011 {published data only}Only 9 Dalby 1978 {published data only} Deshpande S, Coffey BJ. Fragile X syndrome and attention- 10 Dalby JT, Kapelus GJ, Swanson JM, Kinsbourne M, deficit/hyperactivity disorder symptoms. Journal of Child 11 Roberts W. An examination of the double-blind design in and Adolescent Psychopharmacology 2011; Vol. 21, issue drug research with hyperactive children. Progress in Neuro- 12 6:639–42. Psychopharmacology 1978;2(1):123–7. 13 De Sonneville 1991 {published data only} 14 Dalsgaard 2013 {published data only} De Sonneville LM, Njiokiktjien C, Hilhorst RC. Methylphenidate-induced changes in ADDH information 15 Dalsgaard S, Mortensen PB, Frydenberg M, Maibing CM, Nordentoft M, Thomsen PH. Association between processors. Journal of Child Psychology and Psychiatry, and 16 Attention-Deficit Hyperactivity Disorder in childhood and Allied Disciplines 1991;32(2):285–95. 17 schizophrenia later in adulthood. European Psychiatry 2013; De Sonneville 1994 {published data only} 18 29(4):259–63. De Sonneville LM, Njiokiktjien C, Bos H. Methylphenidate 19 Dalsgaard S, Mortensen PB, Frydenberg M, Thomsen PH. and information processing. Part 1: differentiation 20 ADHD, stimulant treatment in childhood and subsequent between responders and nonresponders; part 2: efficacy 21 substance abuse in adulthood - a naturalistic long-term in responders. Journal of Clinical and Experimental 22 follow-up study. Addictive Behaviors 2014;39(1):325–8. Neuropsychology 1994;16(6):877–97. 23 Damodaran 2012 {published data only} Devaramane 2011 {published data only} 24 Damodaran S, Erumbala G, Abraham D, Doddamani L. A Devaramane V, Bhandary P V, Veena N, Bharti C, Vasudev 25 rare, but serious side effect of methylphenidate. Archives S. Akathisia and dyskinesia on starting methylphenidate in 26 of Disease in Childhood. Proceedings of the 4th Congress a patient on risperidone. Journal of Clinical and Diagnostic 27 of the European Academy of Paediatric Societies; 2012 Research 2011;5(1):112–3. October 5-9; Istanbul, Turkey. 2012; Vol. 97:A245–6. 28 DeVito 2008 {published data only} 29 Davidovitch 1999 {published data only} DeVito EE, Blackwell AD, Kent L, Ersche KD, Clark L, 30 Davidovitch M, Manning-Courtney P, Hartmann L, Salmond CH, et al. The effects of methylphenidate on 31 Watson J, Lutkenhoff M, Oppenheimer S. The prevalence decision making in attention-deficit/hyperactivity disorder. of attentional problems and the effect of methylphenidate Biological Psychiatry 2008;64(7):636–9. 32 in children with myelomenigocele. Pediatric Rehabilitation DeVito 2009 {published data only} 33 1999;3(1):29–35. 34 DeVito EE, Sahakian BJ. Response to comments on Dawson 1998 {published data only} ’Methylphenidate improves response inhibition but not 35 Dawson NL. Effects of methylphenidate on reflection impulsivity in children with attention deficit 36 neuropsychological functions myelomeningocele. hyperactivity disorder (ADHD)’. Psychopharmacology 2009; 37 Dissertation Abstracts International: Section B: The 203(1):187. 38 Sciences and Engineering. US: Illinois Inst of Technology, DeVito 2009a {published data only} 39 1998, issue 12–B:6805. DeVito EE, Blackwell AD, Clark L, Kent L, Dezsery AM, 40 Dech 1999 {published data only} Turner DC, et al. Methylphenidate improves response 41 Dech B. Clonidine and methylphenidate. Journal of the inhibition but not reflection-impulsivity in children 42 American Academy of Child and Adolescent Psychiatry 1999; with attention deficit hyperactivity disorder (ADHD). 43 38(12):1469–70. Psychopharmacology 2009;202(1-3):531–9. 44 Denckla 1976 {published data only} De Zeeuw 2012 {published data only} 45 Denckla MB, Bemporad JR, MacKay MC. Tics following De Zeeuw P, Mandl RC, Hulshoff Pol HE, Van Engeland 46 methylphenidate administration. A report of 20 cases. H, Durston S. Decreased frontostriatal microstructural 47 JAMA 1976;235(13):1349–51. organization in attention deficit/hyperactivity disorder. 48 De Quirós 1994 {published data only} Human Brain Mapping 2012; Vol. 33, issue 8:1941–51. 49 De Quirós GB, Kinsbourne M, Palmer RL, Rufo DT. Dillon 1985 {published data only} Attention deficitFor disorder in children: threePreview clinical variants. Dillon DC, SalzmanOnly IJ, Schulsinger DA. The use of 50 51 Journal of Developmental and Behavioral Pediatrics 1994;15 imipramine in Tourette’s syndrome and attention deficit (5):311–9. disorder: case report. Journal of Clinical Psychiatry 1985;46 52 (8):348–9. 53 De Raeymaecker 2007 {published data only} 54 De Raeymaecker D. Methylphenidate and low birth weight Di Martino 2004 {published data only} children with developmental ADHD. Journal of Neural Di Martino A, Melis G, Cianchetti C, Zuddas A. 55 Transmission. Abstracts of the 39th International Danube Methylphenidate for pervasive developmental disorders: 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 67 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 113 of 615 BMJ
1 2 3 4 safety and efficacy of acute single dose test and ongoing Dykman 1980 {published data only} 5 therapy: an open-pilot study. Journal of Child and Adolescent Dykman RA, Ackerman PT, McCray DS. Effects of 6 Psychopharmacology 2004;14(2):207–18. methylphenidate on selective and sustained attention in 7 hyperactive, reading-disabled, and presumably attention- Disenhouse 1972 {published data only} 8 Confidential: For Reviewdisordered boys. Journal of Nervous Only and Mental Disease Disenhouse HA. An academic and social follow-up 1980;168(12):745–52. 9 of children placed on dexedrine or ritalin for severe 10 hyperactive or hyperkinetic disorders. Dissertation Abstracts Eaton 1977 {published data only} 11 International 1972; Vol. 33, issue 4–A:1549–50. Eaton M, Sells CJ, Lucas B. Psychoactive medication and 12 learning disabilities. Journal of Learning Disabilities 1977; DiTraglia 1991 {published data only} 10(7):403–10. 13 DiTraglia J. Methylphenidate protocol: feasibility in a Efron 1998 {published data only} 14 pediatric practice. Clinical Pediatrics 1991;30(12):656–60. 15 Efron D. Methylphenidate versus dextroamphetamine in ADHD. 16 Döpfner 2011, OBSEER {published data only} Journal of the American Academy of Child and Becker A, Roessner V, Breuer D, Döpfner M, Adolescent Psychiatry 1999;38(5):500. 17 Efron D, Jarman FC, Barker MJ. Child and parent 18 Rothenberger A. Relationship between quality of life and psychopathological profile: data from an observational perceptions of stimulant medication treatment in attention 19 study in children with ADHD. European Child & Adolescent deficit hyperactivity disorder. Journal of Paediatrics and 20 Psychiatry 2011;20 Suppl 2:S267–75. Child Health 1998;34(3):288–92. 21 Döpfner M, Breuer D, Walter D, Rothenberger A. Efron D, Jarman FC, Barker MJ. Medium-term outcomes 22 An observational study of once-daily modified-release are comparable with short-term outcomes in children 23 methylphenidate in ADHD: the effect of previous treatment with attention deficit hyperactivity disorder treated with 24 on ADHD symptoms, other externalising symptoms and stimulant medication. Journal of Paediatrics and Child 2000;36(5):457–61. 25 quality-of-life outcomes. European Child & Adolescent Health 26 Psychiatry 2011;20(2 Suppl):277–88. Ehara 1998 {published data only} 27 Döpfner M, Hautmann C, Rothenberger A. Response Ehara H, Maegaki Y, Takeshita K. Neuroleptic malignant heterogeneity in children with ADHD during treatment 28 syndrome and methylphenidate. Pediatric Neurology 1998; with modified-release methylphenidate: a growth mixture 19(4):299–301. 29 modeling analysis. European Child & Adolescent El-Defrawi 1984 {published data only} 30 Psychiatry. Proceedings of the 14th International Congress El-Defrawi MH, Greenhill LL. Substituting stimulants in 31 of ESCAP European Society for Child and Adolescent treating behavior disorders. American Journal of Psychiatry Psychiatry; 2011 June 11-15; Helsinki, Finland. 2011; Vol. 32 1984;141(4):610. 33 20 Suppl. 34 Görtz-Dorten A, Breuer D, Hautmann C, Rothenberger Ellis 1974 {published data only} Ellis MJ, Witt P,Reynolds R, Sprague RL. Methylphenidate 35 A, Döpfner M. What contributes to patient and parent and the activity of hyperactives in the informal setting. 36 satisfaction with medication in the treatment of children with ADHD? A report on the development of a new rating Child Development 1974;45(1):217–20. 37 scale. European Child & Adolescent Psychiatry 2011; Vol. 38 El-Zein 2006 {published data only} 20 Suppl 2:S297–307. El-Zein RA, Hay MJ, Lopez MS, Bondy ML, Morris DL, 39 Rothenberger A, Becker A, Breuer D, Döpfner M. Legator MS, et al. Response to comments on ’Cytogenetic 40 An observational study of once-daily modified-release effects in children treated with methylphenidate’ by El-Zein 41 methylphenidate in ADHD: quality of life, satisfaction with et al. Cancer Letters 2006;231(1):146–8. 42 treatment and adherence. European Child & Adolescent Preston RJ, Kollins SH, Swanson JM, Greenhill LL, Wigal 43 Psychiatry 2011;20(2 Suppl):257–65. T, Elliott GR, et al. Comments on ’Cytogenetic effects in children treated with methylphenidate’ by El-Zein et al. 44 Drtílková 1990 {published data only} Cancer Letters 2005;230(2):292–4. 45 Drtílková I, Misurec J, Náhunek K. The paradox effect of 46 psychostimulants in the treatment of the child hyperkinetic Englund 2010 {published data only} 47 syndrome. Activitas Nervosa Superior 1990;32(4):302–3. Englund JL, Kerns WP,Beuhler MC. Neuroleptic malignant 48 syndrome variant in a child on aripiprazole. Clinical Duane 2000 {published data only} 49 Toxicology. Abstracts of the 2010 International Congress of Duane M, ChandranFor L, Morelli PJ. RecurrentPreviewthe European Only Association of Poisons Centres and Clinical 50 supraventricular tachycardia as a complication of nebulized Toxicologists; 2010 May 11-14; Bordeaux, France. 2010; 51 albuterol treatment. Clinical Pediatrics 2000;39(11):673–7. Vol. 48 (3):258. 52 53 Dworkin 2005 {published data only} Ensat 2012 {published data only} 54 Dworkin N. Increased blood pressure and atomoxetine. Ensat F, Edelbauer M, Wechselberger G. Unilateral Journal of the American Academy of Child and Adolescent gynecomastia in a prepubertal boy. European Journal of 55 Psychiatry 2005;44(6):510. Pediatrics 2012; Vol. 171, issue 1:197. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 68 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 114 of 615
1 2 3 4 Epstein 2007 {published data only} Fegert 2006 {published data only} 5 Epstein JN, Rabiner D, Johnson DE, Fitzgerald DP, Fegert JM, Hebebrand J, Baving L, Gerlach M, Jungmann 6 Chrisman A, Erkanli A, et al. Improving attention-deficit/ J, Oehler K-U, et al. Statement to questionable cardiac risks 7 hyperactivity disorder treatment outcomes through use of a of application of stimulants [Stellungnahme zu fraglichen 8 Confidential:collaborative consultation treatment service by community- For Reviewkardialen risiken der stimulanziengabe]. OnlyZeitschrift fur 9 based pediatricians: a cluster randomized trial. Archives of Kinder- und Jugendpsychiatrie und Psychotherapie 2006;34 Pediatrics & Adolescent Medicine 2007;161(9):835–40. (4):295–8. 10 Power TJ, Jones HA. Collaborative consultation increases 11 Feldman 1989 {published data only} use of medication titration trials but not behaviour in Feldman H, Crumrine P, Handen BL, Alvin R, Teodori J. 12 children with ADHD. Evidence-Based Mental Health 2008; Methylphenidate in children with seizures and attention- 13 11(3):74. deficit disorder. American Journal of Diseases of Children 14 Epstein 2010 {published data only} 1989;143(9):1081–6. 15 Epstein JN, Langberg JM, Lichtenstein PK, Altaye Fenichel 1995 {published data only} 16 M, Brinkman WB, House K, et al. Attention-deficit/ Fenichel RR. Combining methylphenidate and clonidine: 17 hyperactivity disorder outcomes for children treated in the role of post-marketing surveillance. Journal of Child and 18 community-based pediatric settings. Archives of Pediatrics & Adolescent Psychopharmacology 1995;5(3):155–6. 19 Adolescent Medicine 2010;164(2):160–5. Fiedler 1983 {published data only} Fiedler NL, Ullman DG. The effects of stimulant drugs on 20 Ernst 1999 {published data only} curiosity behaviors of hyperactive boys. 21 Ernst E, Pettenburger K, Gossler R, Volkl-Kernstock S, Journal of Abnormal 1983;11(2):193–206. 22 Feucht M. The use of methylphenidate in children with Child Psychology 23 Childhood Absence Epilepsy (CAE) and Attention Deficit Firestone 1978 {published data only} 24 Hyperactivity Disorder (ADHD). Epilepsia. Proceedings of Firestone P, Davey J, Goodman JT, Peters S. The effects 25 the 23rd International Epilepsy Congress; 1999 September of caffeine and methylphenidate on hyperactive children. 26 12-17; Prague, Czech Republic. 1999; Vol. 40 (Suppl s2): Journal of the American Academy of Child and Adolescent 27 177. Psychiatry 1978;17(3):445–56. 28 Evans 1986 {published data only} Fischer 1991 {published data only} 29 Evans RW, Gualtieri CT, Amara I. Methylphenidate and Fischer M. Assessment of stimulant response in ADHD children using a refined multimethod clinical protocol: 30 memory: dissociated effects in hyperactive children. Psychopharmacology 1986;90(2):211–6. erratum. Journal of Clinical Child Psychology 1996;25(1): 31 121. Erratum for: Journal of Clinical Child Psychology 32 Evans 1991 {published data only} 1991;20(3):232-44. 33 Evans SW, Pelham WE. Psychostimulant effects on Fischer M, Newby RF. Assessment of stimulant response 34 academic and behavioral measures for ADHD junior high in ADHD children using a refined multimethod clinical 35 school students in a lecture format classroom. Journal of protocol. Journal of Clinical Child Psychology 1991;20(3): 36 Abnormal Child Psychology 1991;19(5):537–52. 232–44. Fleischhaker 2011 {published data only} 37 Fallu 2006 {published data only} Fleischhaker C, Hennighausen K, Schneider-Momm K, 38 Fallu A, Richard C, Prinzo R, Binder C. Does OROS- Schulz E. A cross-over study in prepuberal boys with 39 methylphenidate improve core symptoms and deficits ADHD to investigate efficacy and bioequivalence of two 40 in executive function? Results of an open-label trial in modified release methylphenidate formulations. European adults with attention deficit hyperactivity disorder. Current 41 Child & Adolescent Psychiatry. Proceedings of the 14th Medical Research & Opinion 2006;22(12):2557–66. 42 International Congress of ESCAP European Society for 43 Fanton 2009 {published data only} Child and Adolescent Psychiatry; 2011 June 11-15; 44 Fanton J, Waslick B, Harvey E. Effectiveness of an extended Helsinki, Finland. 2011; Vol. 20 (1 Suppl):S108. 45 release stimulant medication in treating preschool children Flintoff 1982 {published data only} 46 with attention-deficit hyperactivity disorder. Journal of Flintoff MM, Barron RW, Swanson JM, Ledlow A, 47 Child and Adolescent Psychopharmacology. Proceedings Kinsbourne M. Methylphenidate increases selectivity of 48 of the 49th Annual National Institute of Mental Health, visual scanning in children referred for hyperactivity. 49 NIMH, New Clinical Drug Evaluation Unit, NCDEU Journal of Abnormal Child Psychology 1982;10(2):145–61. Meeting; 2009 JuneFor 29 - July 2; Hollywood, Preview Florida. 2009; Only Focken 1984 {published data only} 50 Vol. 19 (6):779–90. 51 Focken A, Rossel E, Wellstein A, Appel E, Costa D, Palm 52 Faraone 2007 {published data only} D. Effects of methylphenidate in hyperactive children with 53 Faraone SV, Biederman J, Zimmerman B. An analysis of minimal cerebral dysfunction: influence on psychological, 54 patient adherence to treatment during a 1-year, open- physiological and biochemical parameters in a double-blind label study of OROS ® methylphenidate in children with study [Wirkungen von methylphenidat bei hyperkinetischen 55 ADHD. Journal of Attention Disorders 2007;11(2):157–66. Kindern mit minimaler cerebraler dysfunktion – 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 69 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 115 of 615 BMJ
1 2 3 4 beeinflussung psychologischer, physiologischer und Furman 2007 {published data only} 5 biochemischer parameter im doppelblindversuch]. Furman L. Stimulants and sudden death: what is the real 6 Zeitschrift fü Kinder- und Jugendpsychiatrie 1984;12(3): risk?. Pediatrics 2007;119(2):409. 7 235–49. Gan 1982 {published data only} 8 Confidential:Foodman 1996 {published data only} For ReviewGan J, Cantwell DP. Dosage effects Only of methylphenidate 9 Foodman A, McPhillips K. ADD and soft signs. Journal of on paired associate learning: positive/negative placebo 10 the American Academy of Child and Adolescent Psychiatry responders. Journal of the American Academy of Child 11 1996;35(7):841–2. Psychiatry 1982;21(3):237–42. 12 Fosi 2013 {published data only} García Sánchez 1989 {published data only} 13 Fosi T, Lax-Pericall MT, Scott RC, Neville BG, Aylett SE. García Sánchez M, Castillo Méndez E. Effectiveness 14 Methylphenidate treatment of attention deficit hyperactivity of methylphenidate with children suffering from minor 15 disorder in young people with learning disability and cerebral dysfunctions [Efectividad del metilfenidato en 16 difficult-to-treat epilepsy: evidence of clinical benefit. ninos con una disfuncion cerebral minima]. Revista del Hospital Psiquiatrico de La Habana 1989;30(1):85–93. 17 Epilepsia 2013;54(12):2071–81. 18 Fox 2014 {published data only} Gau 2009 {published data only} 19 Fox O, Adi-Japha E, Karni A. The effect of a skipped dose Gau SS, Chiang HL. Sleep problems and disorders among 20 (placebo) of methylphenidate on the learning and retention adolescents with persistent and subthreshold attention- deficit/hyperactivity disorders. Sleep 2009;32(5):671–9. 21 of a motor skill in adolescents with Attention Deficit Hyperactivity Disorder. European Neuropsychopharmacology 22 Gau 2009a {published data only} 2014;24(3):391–6. 23 Gau SS, Chiu CD, Shang CY, Cheng AT, Soong WT. 24 Frances 2002 {published data only} Executive function in adolescence among children with attention-deficit/hyperactivity disorder in Taiwan. Journal 25 Frances C, Hoizey G, Millart H, Trenque T. Utilization of methylphenidate (Ritalin) in France [L’utilisation du of Developmental and Behavioral Pediatrics 2009;30(6): 26 methylphenidate (Ritaline) en France]. Therapie 2002;57 525–34. 27 (2):189–93. Gay 1994 {published data only} 28 Francis 2001 {published data only} Gay CT, Ryan SG. Paroxysmal kinesigenic dystonia after 29 methylphenidate administration. Journal of Child Neurology 30 Francis S, Fine J, Tannock R. Methylphenidate selectively improves story retelling in children with attention deficit 1994;9(1):45–6. 31 hyperactivity disorder. Journal of Child and Adolescent George 2005 {published data only} 32 Psychopharmacology 2001;11(3):217–28. George AK, Kunwar AR, Awasthi A. Acute myocardial 33 infarction in a young male on methylphenidate, bupropion, Francis 2004 {published data only} 34 and erythromycin. Journal of Child and Adolescent Francis J, Hamzeh RK, Lantin-Hermoso MR. Lithium 35 Psychopharmacology 2005;15(4):693–5. toxicity-induced wide-complex tachycardia in a pediatric 36 patient. Journal of Pediatrics 2004;145(2):235–40. Ghasri 2012 {published data only} 37 Ghasri P, Gattu S, Saedi N, Ganesan AK. Chemical Frank 1993 {published data only} 38 leukoderma after the application of a transdermal Frank Y. Visual event related potentials after 39 methylphenidate patch. Journal of the American Academy methylphenidate and sodium valproate in children with 40 of Dermatology 2012; Vol. 66, issue 6:e237–8. attention deficit hyperactivity disorder. Clinical EEG 41 (Electroencephalography) 1993;24(1):19–24. Ghaziuddin 2001 {published data only} 42 Ghaziuddin N, Iqbal A, Khetarpal S. Myoclonus during 43 Friederich 1996 {published data only} prolonged treatment with sertraline in an adolescent patient. 44 Friederich RL. Benign hereditary chorea improved on Journal of Child and Adolescent Psychopharmacology 2001;11 stimulant therapy. Pediatric Neurology 1996;14(4):326–7. 45 (2):199–202. 46 Fuentes 2013 {published data only} Ghofrani 1988 {published data only} 47 Fuentes J, Danckaerts M, Cardo E, Puvanendran K, Ghofrani M. Possible phenytoin-methylphenidate 48 Berquin P, De Bruyckere K, et al. Long-term quality- interaction. Developmental Medicine & Child Neurology 49 of-life and functioning comparison of atomoxetine 1988;30(2):267–8. versus other standardFor treatment in pediatric Preview attention- Only Ghuman 2001 {published data only} 50 deficit/hyperactivity disorder. Journal of Clinical Ghuman JK, Ginsburg GS, Subramaniam G, Ghuman 51 Psychopharmacology 2013;33(6):766–74. 52 HS, Kau AS, Riddle MA. Psychostimulants in preschool 53 Funk 1993 {published data only} children with attention-deficit/hyperactivity disorder: 54 Funk JB, Chessare JB, Weaver MT, Exley AR. Attention clinical evidence from a developmental disorders institution. deficit hyperactivity disorder, creativity, and the effects of Journal of the American Academy of Child and Adolescent 55 methylphenidate. Pediatrics 1993;91(4):816–9. Psychiatry 2001;40(5):516–24. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 70 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 116 of 615
1 2 3 4 Ghuman 2009 {published data only} Goetz 2012 {published data only} 5 Ghuman JK, Aman MG, Lecavalier L, Riddle MA, Goetz M, Surman CBH, Mlynarova E, Krsek P. Status 6 Gelenberg A, Wright R, et al. Randomized, placebo- epilepticus associated with the administration of long-acting 7 controlled, crossover study of methylphenidate for methylphenidate in a 7-year-old girl. Journal of Clinical 8 Confidential:attention-deficit/hyperactivity disorder symptoms in For ReviewPsychopharmacology 2012; Vol. 32,Only issue 2:300–2. preschoolers with developmental disorders. Journal of Child 9 Goetz 2012a {published data only} and Adolescent Psychopharmacology 2009;19(4):329–39. 10 Goetz M, Yeh C-B, Ondrejka I, Akay A, Herczeg I, 11 Gilbert 2006 {published data only} Dobrescu I, et al. A 12-month prospective, observational 12 Gilbert DL, Wang Z, Sallee FR, Ridel KR, Merhar S, Zhang study of treatment regimen and quality of life associated 13 J, et al. Dopamine transporter genotype influences the with ADHD in Central and Eastern Europe and Eastern physiological response to medication in ADHD. Brain: A 14 Asia. Journal of Attention Disorders. F. Martenyi, Lilly Journal of Neurology 2006;129(Pt 8):2038–46. Research Laboratories, Lilly Corporate Center, 75–03–F5 15 Gilbert DL, Wang ZW, Ridel KR, Merhar S, Sallee 301i, DC: 30, Indianapolis, IN 46285, United States. 16 FR, Zhang J, et al. The effects of methylphenidate and E–mail: [email protected]: SAGE Publications Inc. 17 atomoxetine on cortical inhibition in youth with ADHD (2455 Teller Road, Thousand Oaks CA 91320, United 18 differ by dopamine transporter genotypes. Neurology 2006; States), 2012; Vol. 16, issue 1:44–59. 66(5):269. 19 Goez 2007 {published data only} 20 Gimpel 2005 {published data only} Goez H, Back-Bennet O, Zelnik N. Differential stimulant 21 Gimpel GA, Collett BR, Veeder MA, Gifford JA, Sneddon response on attention in children with comorbid anxiety 22 P, Bushman B, et al. Effects of stimulant medication on and oppositional defiant disorder. Journal of Child Neurology 23 cognitive performance of children with ADHD. Clinical 2007;22(5):538–42. Pediatrics 2005;44(5):405–11. 24 Golden 1974 {published data only} 25 Ginsberg 2003 {published data only} Golden GS. Gilles de la Tourette’s syndrome following 26 Ginsberg DL. Selective serotonin reuptake inhibitor use methylphenidate administration. Developmental Medicine associated with decreased growth in children. 27 Primary & Child Neurology 1974;16(1):76–8. Psychiatry 2003;10(2):23–4. 28 Goldman 2008 {published data only} Gittelman-Klein 1976 {published data only} 29 Goldman W, Seltzer R, Reuman P. Association between Gittelman-Klein R, Klein DF, Abikoff H, Katz S, Gloisten 30 treatment with central nervous system stimulants and AC, Kates W. Relative efficacy of methylphenidate and 31 Raynaud’s syndrome in children: a retrospective case- behavior modification in hyperkinetic children: an interim 32 control study of rheumatology patients. Arthritis & report. Journal of Abnormal Child Psychology 1976;4(4): Rheumatism 2008;58(2):563–6. 33 361–79. 34 Gittelman-Klein 1976a {published data only} Golubchik 2009 {published data only} 35 Gittelman-Klein R, Klein DF, Katz S, Saraf K, Pollack E. Golubchik P, Weizman A. Attention-deficit hyperactivity 36 Comparative effects of methylphenidate and thioridazine in disorder, methylphenidate, and primary encopresis. 37 hyperkinetic children. I. Clinical results. Archives of General Psychosomatics 2009;50(2):178. 38 Psychiatry 1976;33(10):1217–31. Gormez 2012 {published data only} 39 Gittelman-Klein 1976b {published data only} Gormez V, Avery B, Mann H. An additional mid-afternoon 40 Gittelman-Klein R, Klein DF. Methylphenidate effects in dose of immediate release methylphenidate (MPH-IR) with 41 learning disabilities: psychometric changes. Archives of concerta XL provides better symptom control in children 42 General Psychiatry 1976; Vol. 33, issue 6:655–64. and adolescents with attention deficit/hyperactivity disorder (ADHD). European Psychiatry. Abstracts of the 20th 43 Glenngård 2011 {published data only} European Congress of Psychiatry, EPA; 2012 March 3-6; 44 Glenngård AH, Hjelmgren J, Thomsen PH, Tvedten T, Prague, Czech Republic. 2012; Vol. 27 Suppl 1. 45 Prutz C. Eliciting patient preferences for ADHD treatment 46 using Discrete Choice Experiment in Sweden, Norway and Goyer 1979 {published data only} 47 Denmark. Journal of Mental Health Policy and Economics. Goyer PF, Davis GC, Rapoport JL. Abuse of prescribed 48 Proceedings of the 10th Workshop on Costs and Assessment stimulant medication by a 13-year-old hyperactive boy. 49 in Psychiatry; 2011 March 25-27; Venice, Italy. 2011; Vol. Journal of the American Academy of Child Psychiatry 1979;18 14 Suppl 1:S8–9.For Preview(1):170–5. Only 50 51 Glenngård 2012 {published data only} Granger 1996 {published data only} 52 Glenngård AH, Hjelmgren J, Thomsen PH, Tvedten T. Granger DA, Whalen CK, Henker B, Cantwell C. 53 Patient preferences and willingness-to-pay for ADHD ADHD boys’ behavior during structured classroom social 54 treatment with stimulants using discrete choice experiment activities: effects of social demands, teacher proximity, and (DCE) in Sweden, Denmark and Norway. Nordic Journal of methylphenidate. 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1 2 3 4 Green 2012 {published data only} Gualtieri 1985 {published data only} 5 Green T, Avda S, Dotan I, Zarchi O, Basel-Vanagaite L, Gualtieri CT, Hicks RE. Neuropharmacology of 6 Zalsman G, et al. Phenotypic psychiatric characterization of methylphenidate and a neural substrate for childhood 7 children with Williams syndrome and response of those with hyperactivity. Psychiatric Clinics of North America 1985;8 8 Confidential:ADHD to methylphenidate treatment. American Journal For Review(4):875–92. Only 9 of Medical Genetics. Part B, Neuropsychiatric Genetics: The Gualtieri 1986 {published data only} Official Publication of the International Society of Psychiatric 10 Gualtieri CT, Patterson DR. Neuroleptic-induced tics in Genetics 2012;159B(1):13–20. 11 two hyperactive children. American Journal of Psychiatry Greenberg 1975 {published data only} 12 1986;143(9):1176–7. Greenberg LM, Yellin AM, Spring C, Metcalf M. Clinical Gualtieri 1986a {published data only} 13 effects of imipramine and methylphenidate in hyperactive 14 Gualtieri T, Hicks RE, Levitt J, Conley R, Schroeder children. International Journal of Mental Health 1975;4(1- SR. Methylphenidate and exercise: additive effects on 15 2):144–56. motor performance, variable effects on the neuroendocrine 16 Greenberg 1975a {published data only} response. Neuropsychobiology 1986;15(2):84–8. 17 Greenberg LM, Yellin AM. Blood pressure and pulse Gualtieri 2008 {published data only} 18 changes in hyperactive children treated with imipramine Gualtieri CT, Johnson LG. Medications do not necessarily and methylphenidate. American Journal of Psychiatry 1975; 19 normalize cognition in ADHD patients. Journal of Attention 132(12):1325–6. 20 Disorders 2008;11(4):459–69. 21 Greenhill 1980 {published data only} Guegant 2000 {published data only} Greenhill LL, Puig-Antich J, Halpern F, Sachar EJ, 22 Guegant G, Crochette A. Methylphenidate, tics and Rubinstein B, Chambers W, et al. Letter to ther editor: 23 compulsions [Methylphenidate, tics et compulsions growth disturbances in hyperkinetic children. Pediatrics 24 Methylphenidate, tics et compulsions]. L’Encéphale 2000; 1980;66(1):152–4. 25 26(2):45–7. Greenhill 2006a {published data only} 26 Guimarães 2009 {published data only} Greenhill L, Riddle M, Birmaher B, Volkmar F, McCracken 27 Guimarães AP, Zeni C, Polanczyk G, Genro JP, Roman T, J, McDougle C, et al. Medication may be effective in Rohde LA, et al. MAOA is associated with methylphenidate 28 treating hyperactivity in autism. The Brown University Child improvement of oppositional symptoms in boys with 29 & Adolescent Psychopharmacology Update 2006;8(1):1–7. 30 attention deficit hyperactivity disorder. International Journal Greiner 2009 {published data only} of Neuropsychopharmacology 2009;12(5):709–14. 31 Greiner C, Enss E, Haen E. Drug-induced psychosis Günther 2010 {published data only} 32 after intake of a modified--release formulation of Günther T, Herpertz-Dahlmann B, Konrad K. Sex 33 methylphenidate [Arzneimittelinduzierte Psychose nach differences in attentional performance and their modulation 34 Einnahme von langsam freisetzendem Methylphenidat]. by methylphenidate in children with attention-deficit/ 35 Psychiatrische Praxis 2009;36(2):89–91. hyperactivity disorder. Journal of Child and Adolescent 36 Grizenko 2010 {published data only} Psychopharmacology 2010;20(3):179–86. 37 Grizenko N, Paci M, Joober R. Is the inattentive subtype of 38 ADHD different from the combined/hyperactive subtype?. Gurkan 2011 {published data only} 39 Journal of Attention Disorders 2010;13(6):649–57. Gurkan CK, Yurumez E, Akca OF, Bilgic A, Turkoglu S, Kilic BG, et al. The effect of treatment on multiple 40 Grob 1986 {published data only} symptom domains and quality of life in children and 41 Grob CS, Coyle JT. Suspected adverse methylphenidate- adolescents with ADHD: a 3-year follow-up study. 42 imipramine interactions in children. Journal of European Child & Adolescent Psychiatry. Proceedings of the 43 Developmental & Behavioral Pediatrics 1986;7(4):265–7. 14th International Congress of ESCAP European Society for 44 Gross 1976 {published data only} Child and Adolescent Psychiatry; 2011 June 11-15; Helsinki, 45 Gross MD. Growth of hyperkinetic children taking Finland 2011;20(1 Suppl):S170. 46 methylphenidate, dextroamphetamine, or imipramine/ Hagerman 1988 {published data only} 47 desipramine. Pediatrics 1976;58(3):423–31. Hagerman RJ, Murphy MA, Wittenberger MD. A 48 Gross-Tsur 2002 {published data only} controlled trial of stimulant medication in children with the 49 Gross-Tsur V, Shalev RS, Badihi N, Manor O. Efficacy fragile X syndrome. American Journal of Medical Genetics of methylphenidateFor in patients with cerebralPreview palsy and 1988;30(1-2):377–92. Only 50 51 attention-deficit hyperactivity disorder (ADHD). Journal of Hale 1998 {published data only} Child Neurology 2002;17(12):863–6. 52 Hale JB, Hoeppner J-A, DeWitt MB, Coury DL, 53 Gualtieri 1984 {published data only} Ritacco DG, Trommer B. Evaluating medication response 54 Gualtieri CT, Evans RW. Carbamazepine-induced tics. in ADHD: cognitive, behavioral, and single-subject Developmental Medicine & Child Neurology 1984;26(4): methodology. Journal of Learning Disabilities 1998;31(6): 55 546–8. 595–607. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 72 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 118 of 615
1 2 3 4 Halliday 1976 {published data only} Handen 1992 {published data only} 5 Halliday R, Rosenthal JH, Naylor H, Callaway E. Averaged Handen BL, Breaux AM, Janosky J, McAuliffe S, Feldman 6 evoked potential predictors of clinical improvement in H, Gosling A. Effects and noneffects of methylphenidate in 7 hyperactive children treated with methylphenidate: an children with mental retardation and ADHD. Journal of the 8 Confidential:initial study and replication. Psychophysiology 1976;13 (5):For ReviewAmerican Academy of Child and AdolescentOnly Psychiatry 1992; 9 429–40. 31(3):455–61. 10 Halliday 1980 {published data only} Handen 1994 {published data only} 11 Halliday RA. The effects of methylphenidate dosage on Handen BL, Janosky J, McAuliffe S, Breaux AM, Feldman the visual evoked potential, heart rate and reaction time in H. Prediction of response to methylphenidate among 12 children with ADHD and mental retardation. Journal of the 13 hyperactive children. Dissertation Abstracts International, Section B 1980; Vol. 40, issue 12–B, Pt 1:5859. American Academy of Child and Adolescent Psychiatry 1994; 14 33(8):1185–93. Halliday 1980a {published data only} 15 Handen 1995 {published data only} Halliday R, Gnauck K, Rosenthal JR, McKibben JL, 16 Handen BL, McAuliffe S, Janosky J, Feldman H, Breaux Callaway E. The effects of methylphenidate dosage on 17 AM. Methylphenidate in children with mental retardation school and home behavior of the hyperactive child. In: 18 and ADHD: effects on independent play and academic Knights RM, Bakker DJ editor(s). Treatment of Hyperactive functioning. Journal of Developmental and Physical 19 and Learning Disordered Children. Baltimore: University Disabilities 1995;7(2):91–103. 20 Park Press, 1980:237–47. 21 Handen 1996 {published data only} Halliday 1983 {published data only} 22 Handen BL, McAuliffe S, Caro-Martinez, L. Stimulant Halliday R, Callaway E, Naylor H. Visual evoked potential 23 medication effects on learning in children with mental changes induced by methylphenidate in hyperactive retardation and ADHD. 24 Journal of Developmental and children: dose/response effects. Electroencephalography and Physical Disabilities 1996;8(4):335–46. 25 Clinical Neurophysiology 1983;55(3):258–67. 26 Handen 1997 {published data only} Halperin 1986 {published data only} Handen BL, Janosky J, McAuliffe S. Long-term follow-up 27 Halperin JM, Gittelman R, Katz S, Struve FA. Relationship of children with mental retardation/borderline intellectual 28 between stimulant effect, electroencephalogram, and clinical functioning and ADHD. Journal of Abnormal Child 29 neurological findings in hyperactive children. Journal of the Psychology 1997;25(4):287–95. 30 American Academy of Child and Adolescent Psychiatry 1986; Handen 1999 {published data only} 31 25(6):820–5. Handen BL, Feldman HM, Lurier A, Murray PJ. Efficacy 32 Hammerness 2008 {published data only} of methylphenidate among preschool children with 33 Cardiovascular monitoring during ADHD treatment with developmental disabilities and ADHD. Journal of the 34 simulants. The Brown University Child & Adolescent American Academy of Child and Adolescent Psychiatry 1999; 35 Psychopharmacology Update 2008; Vol. 10, issue 4:8–8. 38(7):805–12. 36 Hammerness PG, Wilens TE, Berul CI, Elkort MS. Handen 2000 {published data only} 37 Supraventricular tachycardia in an adolescent with Handen BL, Johnson CR, Lubetsky M. Efficacy of 38 attention-deficit/hyperactivity disorder (ADHD). Journal methylphenidate among children with autism and 39 of the American Academy of Child and Adolescent Psychiatry symptoms of attention-deficit hyperactivity disorder. Journal of Autism and Developmental Disorders 2000;30(3): 40 2008;47(2):219–20. 245–55. 41 Hammerness 2009 {published data only} Hanisch 2004 {published data only} Hammerness P, Traum AZ, Becker J, Deshpande 42 Hanisch C, Konrad K, Günther T, Herpertz-Dahlmann A. Cardiovascular risk in ADHD pharmacotherapy. 43 B. Age-dependent neuropsychological deficits and effects Contemporary Pediatrics 2009;26(11):34. 44 of methylphenidate in children with attention-deficit/ 45 Hammerness 2009a {published data only} hyperactivity disorder: a comparison of pre- and grade- 46 Hammerness P, Georgiopoulos A, Doyle RL, Utzinger L, school children. Journal of Neural Transmission 2004;111 47 Schillinger M, Martelon M, et al. An open study of adjunct (7):865–81. 48 OROS-methylphenidate in children who are atomoxetine Haskell 1984 {published data only} 49 partial responders: II. Tolerability and pharmacokinetics. Haskell EL, Joffe R. Clonidine in a case of atypical tic Journal of ChildFor and Adolescent Psychopharmacology Preview2009;19 disorder. Canadian Only Journal of Psychiatry 1984;29(8):704–6. 50 (5):493–9. 51 Hautmann 2013 {published data only} 52 Handen 1990 {published data only} Hautmann C, Rothenberger A, Döpfner M. An 53 Handen BL, Breaux AM, Gosling A, Ploof DL, Feldman observational study of response heterogeneity in children 54 H. Efficacy of methylphenidate among mentally retarded with attention deficit hyperactivity disorder following children with attention deficit hyperactivity disorder. treatment switch to modified-release methylphenidate. 55 Pediatrics 1990;86(6):922–30. BMC Psychiatry 2013;13:219. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 73 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 119 of 615 BMJ
1 2 3 4 Havemann-Reinecke 2003 {published data only} design. Journal of the Multihandicapped Person 1989;2(2): 5 Havemann-Reinecke U, Lojewski I, Poser W, Wismann B, 139–54. 6 Höger C, Rothenberger A. Does treatment of attention Henker 1979 {published data only} 7 deficit hyperactivity disorder (ADHD) with alpha- Henker B, Whalen CK, Collins BE. Double-blind and 8 Confidential:methylphenidate in the childhood induce addiction diseases. For Reviewtriple-blind assessments of medication Only and placebo 9 Naunyn-Schmiedeberg’s Archives of Pharmacology 2003;367 responses in hyperactive children. Journal of Abnormal Child (1 Suppl):R119. Psychology 1979;7(1):1–13. 10 Havemann-Reinecke U, Lojewski I, Wismann B, Höger Hergüner 2011 {published data only} 11 C, Rothenberger A. Effects of therapy of attention deficit 12 hyperactivity disorder (ADHD) in the childhood with Hergüner S, Tan d r C. Methylphenidate for treating 13 alpha-methylphenidate (MPH) on addiction diseases and kleptomania and ADHD. The Brown University Child & 14 psychiatric comorbidity. Pharmacopsychiatry. Proceedings Adolescent Psychopharmacology Update 2011;13(10):8. 15 of the 23rd Symposium of the AGNP; 2003 October 8-10; Hidas 2011 {published data only} 16 Munich. Stuttgart, Germany: Thieme Medical Publishers, Hidas A, Noy AF, Birman N, Shapira J, Matot I, Steinberg 17 2003; Vol. 36 (5):232. D, et al. Oral health status, salivary flow rate and salivary 18 Hawcutt 2012 {published data only} quality in children, adolescents and young adults with ADHD. Archives of Oral Biology 2011;56(10):1137–41. 19 Hawcutt DB, Mainie P,Riordan A, Smyth RL, Pirmohamed 20 M. Reported paediatric adverse drug reactions in the UK Hinshaw 1984 {published data only} 2000-2009. British Journal of Clinical Pharmacology 2012; Hinshaw SP, Henker B, Whalen CK. Cognitive-behavioral 21 Vol. 73, issue 3:437–46. and pharmacologic interventions for hyperactive boys: 22 Hawk 2003 {published data only} comparative and combined effects. Journal of Consulting 23 Hawk LW, Yartz AR, Pelham WE, Lock TM. The effects and Clinical Psychology 1984;52(5):739–49. 24 of methylphenidate on prepulse inhibition during attended Hinshaw SP, Henker B, Whalen CK. Self-control in 25 and ignored prestimuli among boys with attention-deficit hyperactive boys in anger-inducing situations: effects of 26 hyperactivity disorder. Psychopharmacology 2003;165(2): cognitive-behavioral training and of methylphenidate. 27 118–27. Journal of Abnormal Child Psychology 1984;12(1):55–77. 28 Hazel-Fernandez 2006 {published data only} Hinshaw 1989 {published data only} 29 Hazel-Fernandez LA, Klorman R, Wallace JM, Cook S. Hinshaw SP, Buhrmester D, Heller T. Anger control 30 Methylphenidate improves aspects of executive function in response to verbal provocation: effects of stimulant 31 in African American children with ADHD. Journal of medication for boys with ADHD. Journal of Abnormal 32 Attention Disorders 2006;9(4):582–9. Child Psychology 1989;17(4):393–407. 33 Hazell 2009 {published data only} Hinshaw 1989a {published data only} 34 Hazell PL. 8-year follow-up of the MTA sample. Journal Hinshaw SP, Henker B, Whalen CK, Erhardt D, Dunnington RE. Aggressive, prosocial, and 35 of the American Academy of Child and Adolescent Psychiatry 2009;48(5):461–2. nonsocial behavior in hyperactive boys: dose effects 36 of methylphenidate in naturalistic settings. Journal of 37 Heinzerling 2011 {published data only} Heinzerling LM, Pichler W, Anliker MD. Acute generalized Consulting and Clinical Psychology 1989;57(5):636–43. 38 exanthematous pustulosis induced by methylphenidate: a Hinshaw 1993 {published data only} 39 new adverse effect. Archives of Dermatology 2011;147(7): Hinshaw SP,Heller T, McHale JP.Covert antisocial behavior 40 872–3. in boys with attention-deficit hyperactivity disorder: 41 Heiser 2004 {published data only} external validation and effects of methylphenidate. Journal 42 Heiser P, Frey J, Smidt J, Sommerlad C, Wehmeier PM, of Consulting and Clinical Psychology 1992;60(2):274–81. 43 Hebebrand J, et al. Objective measurement of hyperactivity, Hood 2005 {published data only} 44 impulsivity, and inattention in children with hyperkinetic Hood J, Baird G, Rankin PM, Isaacs E. Immediate effects 45 disorders before and after treatment with methylphenidate. of methylphenidate on cognitive attention skills of children 46 European Child & Adolescent Psychiatry 2004;13(2):100–4. with attention-deficit-hyperactivity disorder. Developmental 47 Hellwig-Brida 2011 {published data only} Medicine & Child Neurology 2005;47(6):408–14. 48 Hellwig-Brida S, Daseking M, Keller F, Petermann F, Hoopes 1999 {published data only} 49 Goldbeck L. Effects of methylphenidate on intelligence Hoopes SP. Donepezil for Tourette’s disorder and ADHD. and attention componentsFor in boys with Preview attention-deficit/ Journal of ClinicalOnly Psychopharmacology 1999;19(4):381–82. 50 51 hyperactivity disorder. Journal of Child and Adolescent Horiuchi 2009 {published data only} Psychopharmacology 2011;21(3):245–53. 52 Horiuchi I, Matsuda H, Morimoto K, Fukuda M. Guideline 53 Helsel 1989 {published data only} for treatment of attention deficit and hyperactivity disorder 54 Helsel WJ, Hersen M, Lubetsky MJ, Fultz SA, Sisson (ADHD) with epilepsy. Annals of Neurology. Proceedings L, Harlovic CH. Stimulant drug treatment of four of the 38th Child Neurology Society, CNS Annual Meeting 55 multihandicapped children using a randomized single-case Louisville, KY United States. 2009; Vol. 66 Suppl 1:S130. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 74 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 120 of 615
1 2 3 4 Hoza 1992 {published data only} Isaacs 2002 {published data only} 5 Hoza B, Pelham WE Jr, Sams SE, Carlson C. An Isaacs JS, Watkins A, Hodgens JB, Zachor DA. Nutrition 6 examination of the ’dosage’ effects of both behavior therapy and ADHD: implications for school lunch. Topics in 7 and methylphenidate on the classroom performance of Clinical Nutrition 2002;17(2):27–39. 8 Confidential:two ADHD children. Behavior Modification 1992;16 (2):For ReviewZachor DA, Roberts AW, Hodgens Only JB, Isaacs JS, Merrick 9 164–92. J. Effects of long-term psychostimulant medication on growth of children with ADHD. Research in Developmental 10 Huang 2007 {published data only} Huang YS, Guilleminault C, Li HY, Yang CM, Wu YY, Disabilities 2006;27(2):162–74. 11 Chen NH. Attention-deficit/hyperactivity disorder with Jahromi 2009 {published data only} 12 obstructive sleep apnea: a treatment outcome study. Sleep Jahromi LB, Kasari CL, McCracken JT, Lee L, Aman MG, 13 Medicine 2007;8(1):18–30. McDougle CJ, et al. Positive effects of methylphenidate 14 Huestis 1975 {published data only} on social communication and self-regulation in children 15 Huestis RD, Arnold LE, Smeltzer DJ. Caffeine versus with pervasive developmental disorders and hyperactivity. 16 methylphenidate and d-amphetamine in minimal brain Journal of Autism and Developmental Disorders 2009;39(3): 17 dysfunction: a double-blind comparison. American Journal 395–404. 18 of Psychiatry 1975;132(8):868–70. Jenson 1996 {published data only} 19 Humphries 1979 {published data only} Jenson C. Causal attributions made by parents of 20 Humphries T, Swanson J, Kinsbourne M, Yiu L. Stimulant children taking methylphenidate for attention-deficit 21 effects on persistence of motor performance of hyperactive hyperactivity disorder. Dissertation Abstracts International Section A: Humanities and Social Sciences. US: Virginia 22 children. Journal of Pediatric Psychology 1979;4(1):55–66. Commonwealth U, 1996; Vol. 57, issue 4–A:1847. 23 Hunt 1986 {published data only} Hunt RD, Minderaa RB, Cohen DJ. The therapeutic effect Jonkman 1997 {published data only} 24 Jonkman LM, Kemner C, Verbaten MN, Koelega 25 of clonidine in attention deficit disorder with hyperactivity: a comparison with placebo and methylphenidate. HS, Camfferman G, Gaag RJ V.D, et al. Effects 26 Psychopharmacology Bulletin 1986;22(1):229–36. of methylphenidate on event-related potentials and 27 performance of attention-deficit hyperactivity disorder Husain 1980 {published data only} children in auditory and visual selective attention tasks. 28 Husain A, Chapel J, Malek-Ahmadi P. Methylphenidate, Biological Psychiatry 1997;41(6):690–702. 29 neuroleptics and dyskinesia-dystonia. Canadian Journal of 30 Psychiatry 1980;25(3):254–8. Jonkman 1999 {published data only} Jonkman LM, Kemner C, Verbaten MN, Van Engeland 31 Hutson 2006 {published data only} 32 Hutson M. Bugging out: the pesty side effects of Ritalin. H, Kenemans JL, Camfferman G, et al. Perceptual and response interference in children with attention-deficit 33 Psychology Today 2006;39(5):33. hyperactivity disorder, and the effects of methylphenidate. 34 Hwang 2012 {published data only} Psychophysiology 1999;36(4):419–29. 35 Hwang J, Kim B, Kim Y, Yoo H. Methylphenidate-osmotic 36 release oral delivery system reduces parenting stress in Jonkman 2000 {published data only} 37 parents of children and adolescents with ADHD in Korea. Jonkman LM, Kemner C, Verbaten MN, Van Engeland H, Camfferman G, Buitelaar JK, et al. Attentional capacity, 38 European Neuropsychopharmacology. Proceedings of the 25th European College of Neuropsychopharmacology, a probe ERP study: differences between children with 39 attention-deficit hyperactivity disorder and normal control 40 ECNP Congress; 2012 October 13-17; Vienna, Austria. Chuncheon, South Korea: Elsevier, 2012; Vol. 22 Suppl 2: children and effects of methylphenidate. Psychophysiology 41 S415. 2000;37(3):334–46. 42 Hwang 2013 {published data only} Kalachnik 1982 {published data only} 43 Hwang J-W, Kim B, Kim Y, Kim T-H, Seo W-S, Shin Kalachnik JE, Sprague RL, Sleator EK, Cohen MN, 44 D-W, et al. Methylphenidate-osmotic-controlled release Ullmann RK. Effect of methylphenidate hydrochloride on 45 oral delivery system treatment reduces parenting stress in stature of hyperactive children. Developmental Medicine & 46 parents of children and adolescents with attention-deficit/ Child Neurology 1982;24(6):586–95. 47 hyperactivity disorder. Human Psychopharmacology 2013;28 Kauffman 1981 {published data only} 48 (6):600–7. Kauffman RE, Smith-Wright D, Reese CA, Simpson R, 49 Ibay 2003 {published data only} Jones F. Medication compliance in hyperactive children. Ibay AD, BascelliFor LM, Graves RS. Clinical Preview inquiries: does Pediatric Pharmacology Only1981;1(3):231–7. 50 51 increasing methylphenidate dose aid symptom control in Kayser 1997 {published data only} ADHD?. 2003;52(5):396–409. 52 Journal of Family Practice Kayser KH, Wacker DP, Derby KM, Andelman MS, 53 Ickowicz 2002 {published data only} Golonka Z, Stoner E. A rapid method for evaluating 54 Ickowicz A. Bupropion-methylphenidate combination and the necessity for both a behavioral intervention and grand mal seizures. Canadian Journal of Psychiatry 2002;47 methylphenidate. Journal of Applied Behavior Analysis 1997; 55 (8):790–1. 30(1):177–80. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 75 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 121 of 615 BMJ
1 2 3 4 Keating 2011 {published data only} King 2009a {published data only} 5 Keating GM. Methylphenidate transdermal system: in King S, Waschbusch DA, Pelham WE Jr, Frankland 6 attention-deficit hyperactivity disorder in adolescents. CNS BW, Andrade BF, Jacques S, et al. Social information 7 Drugs 2011;25(4):333–42. processing in elementary-school aged children with ADHD: medication effects and comparisons with typical children. 8 Confidential:Kelly 1986 {published data only} For Review Only Journal of Abnormal Child Psychology 2009;37(4):579–89. 9 Kelly LM, Sonis W, Fialkov J, Kazdin A, Matson J. 10 Behavioral assessment of methylphenidate in a child Klein 1988 {published data only} 11 with frontal lobe damage. Journal of Psychopathology and Klein RG, Landa B, Mattes JA, Klein DF. Methylphenidate 12 Behavioral Assessment 1986;8(1):47–54. and growth in hyperactive children. A controlled withdrawal study. Archives of General Psychiatry 1988;45(12):1127–30. 13 Kelly 2012 {published data only} 14 Kelly BD, Lundon DJ, McGuinness D, Brady CM. Klein 1988a {published data only} 15 Methylphenidate-induced erections in a prepubertal child. Klein RG, Mannuzza S. Hyperactive boys almost grown up. Journal of Pediatric Urology 2012;9(1):e1–2. III. Methylphenidate effects on ultimate height. Archives of 16 General Psychiatry 1988;45(12):1131–4. 17 Kerdar 2007 {published data only} Klein 1991 18 Kerdar MS, Scheuerpflug P, Srdinko P, Wewetzer {published data only} Klein RG. Effects of high methylphenidate doses on the 19 C, Warnke A, Romanos M. Quantitative effect of treatment with methylphenidate on EEG--a pilot study cognitive performance of hyperactive children. Bratislavské 20 [EEG–veranderungen unter methylphenidat – eine Lekárske Listy 1991;92(11):534–9. 21 pilotstudie]. Zeitschrift für Kinder- und Jugendpsychiatrie Klein 1997 {published data only} 22 und Psychotherapie 2007;35(4):247–55. Klein RG, Abikoff H, Klass E, Ganeles D, Seese LM, Pollack 23 Kereszturi 2008 {published data only} S. Clinical efficacy of methylphenidate in conduct disorder 24 Kereszturi E, Tarnok Z, Bognar E, Lakatos K, Farkas L, with and without attention deficit hyperactivity disorder. 25 Gadoros J, et al. Catechol-O-methyltransferase Val158Met Archives of General Psychiatry 1997;54(12):1073–80. 26 polymorphism is associated with methylphenidate response Klein 1997a {published data only} 27 in ADHD children. American Journal of Medical Genetics. Klein RG, Abikoff H. Behavior therapy and methylphenidate 28 Part B, Neuropsychiatric Genetics: The Official Publication of in the treatment of children with ADHD. Journal of 29 the International Society of Psychiatric Genetics 2008;147b Attention Disorders 1997;2(2):89–114. 30 (8):1431–5. Klein 2002 {published data only} 31 Kesic 2012 {published data only} Klein C, Fischer B Jr, Fischer B, Hartnegg K. Effects of 32 Kesic A, Lakic A, Dronjak D, Stupar D. Effects of OROS methylphenidate on saccadic responses in patients with 33 methylphenidate (OROS MPH) treatment in children and ADHD. Experimental Brain Research 2002;145(1):121–5. 34 adolescents with ADHD, mental retardation and epilepsy. Klein 2009 {published data only} 35 European Neuropsychopharmacology. Papers of the 25th Klein HR, Schneider TC, Schrier L, De Kam ML, Van European College of Neuropsychopharmacology, ECNP Gerven N, Sukhai RN, et al. A randomized, placebo- 36 Congress; 2012 October 13-17; Vienna, Austria. Belgrade, 37 controlled trial with methylphenidate to investigate acute Serbia: Elsevier, 2012; Vol. 22 Suppl 2:S420–1. drug effects on a set of neurocognitive tasks. Basic and 38 Kim 2009 {published data only} Clinical Pharmacology and Toxicology. Abstracts of the 39 Kim W, Lim Y. Subclinical epileptiform discharges and 9th Congress of the European Association for Clinical 40 seizure occurrences in children with attention deficit Pharmacology and Therapeutics; 2009 July 12-15; 41 hyperactivity disorder. Epilepsia. Abstracts from the 8th Edinburgh, UK. 2009; Vol. 105 Suppl s1:128–9. 42 European Congress on Epileptology; 2008 September 21- Klorman 1987 {published data only} 43 25; Berlin, Germany. 2009; Vol. 50 Suppl s4:130. Klorman R, Coons HW, Borgstedt AD. Effects of 44 King 2007 {published data only} methylphenidate on adolescents with a childhood history of 45 King S. Social information processing and subtypes of attention deficit disorder: I. Clinical findings. Journal of the 46 aggressive behaviour in elementary-age children with American Academy of Child and Adolescent Psychiatry 1987; 47 and without Attention Deficit Hyperactivity Disorder. 26(3):363–7. 48 Dissertation Abstracts International, Section B, The Klorman 1988 {published data only} 49 Sciences and Engineering. Canada: Dalhousie U., 2007; Klorman R, Brumaghim JT, Salzman LF,Strauss J, Borgstedt Vol. 68, issue 5B:3400.For PreviewAD, McBride Only MC, et al. Effects of methylphenidate on 50 51 King 2009 {published data only} attention-deficit hyperactivity disorder with and without King S, Waschbusch DA, Pelham WE, Frankland BW, aggressive/noncompliant features. Journal of Abnormal 52 Psychology 1988;97(4):413–22. 53 Corkum PV, Jacques S. Subtypes of aggression in children 54 with attention deficit hyperactivity disorder: medication Klorman 1988a {published data only} effects and comparison with typical children. Journal of Klorman R, Coons HW, Brumaghim JT, Borgstedt AD, 55 Clinical Child and Adolescent Psychology 2009;38(5):619–29. Fitzpatrick P. Stimulant treatment for adolescents with 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 76 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 122 of 615
1 2 3 4 attention deficit disorder. Psychopharmacology Bulletin of the American Academy of Child and Adolescent Psychiatry 5 1988;24(1):88–92. [PUBMED: 2898797] 2006;45(1):115–8. 6 Klorman 1988b {published data only} Kugel 1975 {published data only} 7 Klorman R, Salzman LF, Borgstedt AD. Brain event- Kugel RB, Scherz RG, Seidel HM, McMahon JL, Rinker 8 Confidential:related potentials in evaluation of cognitive deficits in For ReviewA, Garell DC, et al. Medication forOnly hyperkinetic children. 9 attention deficit disorder and outcome of stimulant Pediatrics 1975;55(4):560–2. therapy. In: Bloomingdale LM editor(s). Attention Deficit 10 Kühle 2007 {published data only} Disorder, Vol. 3: New Research in Attention, Treatment, and 11 Kühle HJ, Kinkelbur J, Andes K, Heidorn FM, Zeyer S, Psychopharmacology. New York: Pergamon Press, 1988: 12 Rautzenberg P, et al. Self-regulation of visual attention and 49–80. 13 facial expression of emotions in ADHD children. Journal of 14 Klorman 1990a {published data only} Attention Disorders 2007;10(4):350-8. Erratum in: Journal Klorman R, Brumaghim JT, Salzman LF,Strauss J, Borgstedt of Attention Disorders. 2007;11(2):184-5. 15 AD, McBride MC, et al. Effects of methylphenidate on 16 processing negativities in patients with attention-deficit Kuipers 1972 {published data only} 17 hyperactivity disorder. Psychophysiology 1990;27(3):328–37. Kuipers F. Hallucination as side effect of methylphenidate 18 [Hallucinaties als bijwerking van methylfemidaat]. Klorman 1994 {published data only} Nederlands Tijdschrift voor Geneeskunde 1972;116(8):320. 19 Klorman R, Brumaghim JT, Fitzpatrick PA, Borgstedt 20 AD. Clinical and cognitive effects of methylphenidate on Kunac 2012 {published data only} 21 children with attention deficit disorder as a function of Kunac D, Tatley MV, Grimwood K, Reith DM. Active 22 aggression/oppositionality and age. Journal of Abnormal surveillance of serious adverse drug reactions in New 23 Psychology 1994;103(2):206–21. Zealand children. Archives of Disease in Childhood 2012; Vol. 97, issue 8:761–2. 24 Koehler-Troy 1986 {published data only} 25 Koehler-Troy C, Strober M, Malenbaum R. Kunin-Batson 2002 {published data only} 26 Methylphenidate-induced mania in a prepubertal child. Kunin-Batson AS. The effects of methylphenidate on 27 Journal of Clinical Psychiatry 1986;47(11):566–7. neuropsychological functioning in children with attention 28 Koizumi 1985 {published data only} deficit hyperactivity disorder. Dissertation Abstracts 29 Koizumi HM. Obsessive-compulsive symptoms following International: Section B: The Sciences and Engineering. 30 stimulants. Biological Psychiatry 1985;20(12):1332–3. US: The Herman M. Finch U Health Sciences – The Chicago Medical School, 2002, issue 11–B:5380. 31 Konkol 1990 {published data only} 32 Konkol RJ, Fischer M, Newby RF. Double-blind, Placebo- Kuperman 2003 {published data only} 33 controlled stimulant trial in children with Tourette’s Kuperman AA, Yaniv I, Stahl B, Tamary H. Methylphenidate 34 syndrome and attention-deficit hyperactivity disorder. as a possible cause of thrombocytopenia. Annals of 35 Annals of Neurology 1990;28(3):424. Pharmacotherapy 2003;37(7-8):1146. 36 Kotsopoulos 2001 {published data only} Kurt 2013 {published data only} 37 Kotsopoulos S, Spivak M. Obsessive-compulsive symptoms Kurt R, Gunes H, Yilmaz MB, Karapinar H. 38 secondary to methylphenidate treatment. Canadian Journal Methylphenidate induced myocarditis. Journal of the 39 of Psychiatry 2001;46(1):89. American College of Cardiology. Abstracts of the Turkish Society of Cardiology, TSC 29th Turkish Cardiology 40 Kouris 1998 {published data only} Congress with International Participation; 2013 October Kouris S. Methylphenidate-induced obsessive- 41 26-2; Antalya,Turkey. 2013; Vol. 62 (18 Suppl 2):29. 42 compulsiveness. Journal of the American Academy of Child 43 and Adolescent Psychiatry 1998;37(2):135. Lage 2004 {published data only} 44 Kramer 2001 {published data only} Lage M, Hwang P. Effect of methylphenidate formulation for attention deficit hyperactivity disorder on patterns and 45 Kramer AF, Cepeda NJ, Cepeda ML. Methylphenidate effects on task-switching performance in attention-deficit/ outcomes of treatment. Journal of Child and Adolescent 46 Psychopharmacology 2004;14(4):575–81. 47 hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 2001;40(11):1277–84. 48 Lahm 2002 {published data only} 49 Kratochvil 2005 {published data only} Lahm C. Methylphenidate does not increase the risk of Kratochvil CJ, LakeFor M, Pliszka SR, WalkupPreview JT. Parkinson’s diseaseOnly [Kein Parkinson durch Methylphenidat]. 50 Pharmacological management of treatment-induced Pharmazeutische Zeitung 2002;147(16):39. 51 insomnia in ADHD. Journal of the American Academy of Lajoie 2005 {published data only} 52 Child and Adolescent Psychiatry 2005;44(5):499–501. 53 Lajoie G, Anderson V, Anderson P, Tucker AR, Robertson 54 Kratochvil 2006 {published data only} IH, Manly T. Effects of methylphenidate on attention skills Kratochvil CJ, Egger H, Greenhill LL, McGough JJ. in children with attention deficit/hyperactivity disorder. 55 Pharmacological management of preschool ADHD. Journal Brain Impairment 2005;6(1):21–32. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 77 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 123 of 615 BMJ
1 2 3 4 Laki 2012 {published data only} for attention-deficit hyperactivity disorder: evidence for 5 Laki A. Depressive symptoms as a side effect of the widespread and circumscribed cognitive deficits. Journal of 6 sustained release form of methylphenidate in a 7-year- Child Neurology 2007;22(3):264–76. 7 old boy with attention-deficit hyperactivity disorder Lerer 1976 {published data only} 8 Confidential:[Depresivni simptomi kao nezeljeni efekat dejstva For ReviewLerer RJ, Lerer MP. The effects ofOnly methylphenidate on the 9 sporooslobad{stroke}ajuce forme metilfenidata kod soft neurological signs of hyperactive children. Pediatrics 10 7–godisnjeg decaka a hiperkinetickim poremecajem i 1976;57(4):521–5. poremecajem paznje]. Military-Medical and Pharmaceutical 11 Lerer 1977 {published data only} Review. A. Lakic, Faculty of Medicine, University 12 Lerer RJ, Lerer MP,Artner J. The effects of methylphenidate of Belgrade, Clinic for Neurology and Psychiatry for on the handwriting of children with minimal brain 13 Children and Adolescents, Belgrade, Serbia. E–mail: dysfunction. Journal of Pediatrics 1977;91(1):127–32. 14 [email protected]: Vojnomedicinske akademija 15 (Crnotravska 17, Belgrade 11040, Serbia), 2012; Vol. 69, Lerer 1979 {published data only} 16 issue 2:201–4. Lerer RJ, Artner J, Lerer MP. Handwriting deficits in 17 Lambert 2002 {published data only} children with minimal brain dysfunction: effects of 18 Lambert NM. Stimulant treatment as a risk factor for methylphenidate (Ritalin) and placebo. Journal of Learning 19 nicotine use and substance abuse. In: Jensen PS, Cooper JR Disabilities 1979;12(7):450–5. 20 editor(s). Attention Deficit Hyperactivity Disorder: State of Lewis 1975 {published data only} 21 the Science : Best Practices. Kingston (NJ): Civic Research Lewis JA, Young R. Deanol and methylphenidate in Institute, 2002:18:1–24. minimal brain dysfunction. Clinical Pharmacology and 22 Therapeutics 1975;17(5):534–40. 23 Lange 2007 {published data only} Lange KW, Tucha LT, Walitza S, Sontag TA, Stasik D, 24 Lewis 2001 {published data only} Linder M, et al. Effects of methylphenidate on multiple 25 Lewis BR, Aoun SL, Bernstein GA, Crow SJ. components of attention in children with attention deficit Pharmacokinetic interactions between cyclosporine and 26 hyperactivity disorder. Journal of Neural Transmission. bupropion or methylphenidate. Journal of Child and 27 Abstracts of the 39th International Danube Symposium Adolescent Psychopharmacology 2001;11(2):193–8. 28 for Neurological Sciences and Continuing Education and Licamele 1988 {published data only} 29 1st International Congress on ADHD, from Childhood to Licamele WL. Methylphenidate side effects. Journal of the Adult Disease; 2007 June 2-5; Wurzburg, Germany. 2007; 30 American Academy of Child and Adolescent Psychiatry 1988; Vol. 114 (7):LXXV. 31 27(4):515–6. 32 Lawrence 2005 {published data only} Lawrence CA, Barry RJ, Clarke AR, Johnstone SJ, Licamele 1989 {published data only} 33 Licamele WL, Goldberg RL. The concurrent use of lithium 34 McCarthy R, Selikowitz M, et al. Methylphenidate effects in attention deficit/hyperactivity disorder: electrodermal and methylphenidate in a child. Journal of the American 35 and ERP measures during a continuous performance task. Academy of Child and Adolescent Psychiatry 1989;28(5): 36 Psychopharmacology 2005;183(1):81–91. 785–7. 37 Lisska 2003 {published data only} Leary 1979 {published data only} Lisska MC, Rivkees SA. Daily methylphenidate use slows 38 Leary PM, Arens L, Marshall S, Schadle S. Clinical the growth of children: a community based study. Journal of 39 experience with methylphenidate. South African Medical Pediatric Endocrinology and Metabolism 2003;16(5):711–8. 40 Journal 1979;55(10):374–6. 41 Lee 2012 {published data only} Liu 2007 {published data only} 42 Lee S, Seo H, Lim H, Jeong J, Hong S, Han J, et al. Liu J, Zhou Y, Kang C, Xuan X, Wang Y. A randomized 43 Treatment adherence and parents’ characteristics in children comparative study on impact of methylphenidate with/ 44 with attention deficit hyperactivity disorder. European without parent training in children with comorbid attention 45 Neuropsychopharmacology. Papers of the 25th European deficit hyperactivity disorder and oppositional defiant disorder. Journal of Neural Transmission. Abstracts of the 46 College of Neuropsychopharmacology, ECNP Congress; 39th International Danube Symposium for Neurological 47 2012 October 13-17; Vienna, Austria. Suwon, South Korea: Elsevier, 2012; Vol. 22 Suppl 2:S426–7. Sciences and Continuing Education and 1st International 48 Congress on ADHD, from Childhood to Adult Disease; 49 Leitner 2007 {published data only} Leitner Y, BarakFor R, Giladi N, Peretz C,Preview Eshel R, 2007 June 2-5;Only Wu rzburg, Germany. 2007; Vol. 114 (7): 50 51 Gruendlinger L, et al. Gait in attention deficit hyperactivity XCVII. disorder : effects of methylphenidate and dual tasking. Livingston 1992 {published data only} 52 Journal of Neurology 2007;254(10):1330–8. 53 Livingston RL, Dykman RA, Ackerman PT. Psychiatric 54 Leitner 2007a {published data only} comorbidity and response to two doses of methylphenidate Leitner Y, Doniger GM, Barak R, Simon ES, Hausdorff JM. in children with attention deficit disorder. Journal of Child 55 A novel multidomain computerized cognitive assessment and Adolescent Psychopharmacology 1992;2(2):115–22. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 78 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 124 of 615
1 2 3 4 Loney 1981 {published data only} children with attention deficit disorder. Journal of Abnormal 5 Loney J, Whaley-Klahn MA, Ponto LB, Adney K. Predictors Child Psychology 1988;16(4):379–95. 6 of adolescent height and weight in hyperkinetic boys treated Malone 1993 {published data only} 7 with methylphenidate [proceedings]. Psychopharmacology Malone MA, Swanson JM. Effects of methylphenidate on 8 Confidential:Bulletin 1981;17(1):132–4. For Reviewimpulsive responding in children Only with attention-deficit 9 Loney 2004 {published data only} hyperactivity disorder. Journal of Child Neurology 1993;8 10 Loney J, Kramer JR, Roberts MA, McIntosh M, Rickels (2):157–63. H, Richards C. Midlife outcomes of 100 ADHD boys: 11 Malone 1994 {published data only} prediction by aspects of treatment with methylphenidate. 12 Malone MA, Couitis J, Kershner JR, Logan WJ. Right Journal of Child and Adolescent Psychopharmacology. hemisphere dysfunction and methylphenidate effects in 13 Abstracts of the Child and Adolescent Program of the 44th 14 children with attention-deficit/hyperactivity disorder. Annual National Institute of Mental Health (NIMH) New Journal of Child and Adolescent Psychopharmacology 1994;4 15 Clinical Drug Evaluation Unit (NCDEU) Meeting; 2004 (4):245–53. 16 June 1-4; Phoenix, Arizona. 2004; Vol. 14 (4):509. Mannuzza 2003 {published data only} Loo 1999 {published data only} 17 Mannuzza S, Klein RG, Moulton JL 3rd. Does stimulant Loo SK, Teale PD, Reite ML. EEG correlates of 18 treatment place children at risk for adult substance abuse? methylphenidate response among children with ADHD: 19 A controlled, prospective follow-up study. Journal of Child a preliminary report. Biological Psychiatry 1999;45(12): 20 and Adolescent Psychopharmacology 2003;13(3):273–82. 1657–60. 21 Marotta 1998 {published data only} Loo 2003 {published data only} 22 Marotta PJ, Roberts EA. Pemoline hepatotoxicity in Loo SK, Specter E, Smolen A, Hopfer C, Teale PD, Reite children. 1998;132(5):894–7. 23 ML. Functional effects of the DAT1 polymorphism on Journal of Pediatrics 24 EEG measures in ADHD. Journal of the American Academy Marta 2010 {published data only} 25 of Child and Adolescent Psychiatry 2003;42(8):986–93. Marta R, Guerra PM, Rocha L, Duarte A, Lourenco L, 26 Lowe 1982 {published data only} Ventosa L, et al. Sleep disorders in children with ADHD: a 27 Lowe TL, Cohen DJ, Detlor J, Kremenitzer MW, Shaywitz case-control study. Acta Paediatrica. Abstracts from the 2nd 28 BA. Stimulant medications precipitate Tourette’s syndrome. Excellence in Paediatrics Conference; 2010 December 2-4; 29 JAMA 1982;247(12):1729–31. 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Measurement of the subjective effects of 48 Pediatric Neurosurgery 1998;29(3):121–6. methylphenidate in 11- to 15-year-old children with 49 Mahon 2008 {published data only} attention-deficit/hyperactivity disorder. Journal of Child and Mahon AD, StephensFor BR, Cole AS. ExercisePreview responses in Adolescent PsychopharmacologyOnly2007;17(1):63–73. 50 51 boys with attention deficit/hyperactivity disorder: effects of Marx 1999 {published data only} 52 stimulant medication. Journal of Attention Disorders 2008; Marx J. How stimulant drugs may calm hyperactivity. 12(2):170–6. Science 1999;283(5400):306. 53 54 Malone 1988 {published data only} Matier 1992 {published data only} Malone MA, Kershner JR, Siegel L. 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1 2 3 4 ADHD children: distinctions on laboratory measures of children’s vigilance performance and evoked potentials. 5 symptoms. Journal of the American Academy of Child and Psychophysiology 1981;18(6):665–77. 6 Adolescent Psychiatry 1992;31(2):219–25. Milich 1989 {published data only} 7 Mattes 1983 {published data only} Milich R, Licht BG, Murphy DA, Pelham WE. Attention- 8 Confidential:Mattes JA, Gittelman R. Growth of hyperactive children For Reviewdeficit hyperactivity disordered boys’Only evaluations of and 9 on maintenance regimen of methylphenidate. Archives of attributions for task performance on medication versus 10 General Psychiatry 1983;40(3):317–21. placebo. Journal of Abnormal Psychology 1989;98(3):280–4. 11 Mayes 1993 {published data only} Milich 1991 {published data only} 12 Mayes SD, Bixler EO. Reliability of global impressions for Milich R, Carlson CL, Pelham WE, Licht BG. Effects 13 assessing methylphenidate effects in children with attention- of methylphenidate on the persistence of ADHD boys 14 deficit hyperactivity disorder. Perceptual and Motor Skills following failure experiences. Journal of Abnormal Child 1991;19(5):519–36. 15 1993;77(3 Pt 2):1215–8. Psychology 16 McBride 1986 {published data only} Miller 1994 {published data only} 17 McBride MC. Methylphenidate in therapeutic doses does Miller LG, Kraft IA. Application of actigraphy in the clinical setting: use in children with attention-deficit hyperactivity 18 not lower seizure threshold. Annals of Neurology 1986;20 (3):428. disorder. Pharmacotherapy 1994;14(2):219–23. 19 20 McBride 1988 {published data only} Miller 1996 {published data only} McBride MC. An individual double-blind crossover trial Miller DC, Kavcic V, Leslie JE. ERP changes induced by 21 for assessing methylphenidate response in children with methylphenidate in boys with attention-deficit hyperactivity 22 attention deficit disorder. Journal of Pediatrics 1988;113(1 disorder. Journal of Attention Disorders 1996; Vol. 1, issue 23 Pt 1):137–45. 2:95–113. 24 McCracken 2012 {published data only} Millichap 1968 {published data only} 25 McCracken JT. Pharmacogenetics of ADHD: ready for the Millichap JG, Aymat F, Sturgis LH, Larsen KW, Egan 26 clinic?. Biological Psychiatry 2012; Vol. 71, issue 8 Suppl: RA. Hyperkinetic behavior and learning disorders: III. 27 235S. Battery of neuropsychological tests in controlled trial of 28 McDougle 2004 {published data only} methylphenidate. American Journal of Diseases of Children 29 McDougle CJ. Methylphenidate an effective treatment for 1968;116(3):235–44. 30 ADHD?. Journal of Autism and Developmental Disorders Millichap 1972 {published data only} 31 2004;34(5):593–4. Millichap JG. Drugs in the management of minimal brain dysfunction. International Journal of Child 32 McNutt 1977 {published data only} Psychotherapy 1972; Vol. 1, issue 3:65–81. [PsycINFO: 33 McNutt BA, Boileau RA, Cohen MN. The effects of 1974–23672–001] 34 long-term stimulant medication on the growth and body Millichap 1978 {published data only} 35 composition of hyperactive children. Psychopharmacology Bulletin 1977;13(2):36–8. Millichap JG. Letter to the editor: Dr. Gross’s findings 36 supported. Pediatrics 1978;61(1):146–7. 37 Mehta 2004 {published data only} Millichap 1978a {published data only} 38 Mehta MA, Goodyer IM, Sahakian BJ. Methylphenidate improves working memory and set-shifting in AD/HD: Millichap JG. Growth of hyperactive children treated with 39 relationships to baseline memory capacity. Journal of Child methylphenidate. Journal of Learning Disabilities 1978;11 40 Psychology and Psychiatry, and Alllied Disciplines 2004;45(2): (9):567–70. 41 293–305. Millichap 1997 {published data only} 42 Meisel 2013 {published data only} Millichap JG. Temporal lobe arachnoid cyst-attention 43 Meisel V, Servera M, Garcia-Banda G, Cardo E, Moreno I. deficit disorder syndrome: role of the electroencephalogram 44 Neurofeedback and standard pharmacological intervention in diagnosis. Neurology 1997;48(5):1435–9. 45 in ADHD: a randomized controlled trial with six-month Miranda 2006 {published data only} 46 follow-up. Biological Psychology 2013;94(1):12–21. Miranda A, Jarque S, Rosel J. Treatment of children with 47 Mendhekar 2006 {published data only} ADHD: psychopedagogical program at school versus 48 Ginsberg DL. Methylphenidate-induced rabbit syndrome. psychostimulant medication. Psicothema 2006;18(3): 49 Primary Psychiatry 2006;13(12):28–9. [EMBASE: 335–41. 2006624978] For PreviewMitchell 1980 {publishedOnly data only} 50 51 Mendhekar DN, Duggal HS. Methylphenidate-induced Mitchell E, Matthews KL. 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1 2 3 4 of practice patterns across countries. European Niederhofer 2012 {published data only} 5 Neuropsychopharmacology. Papers of the 23rd European Niederhofer H. Agomelatine treatment with adolescents 6 College of Neuropsychopharmacology Congress; 2010 with ADHD. Journal of Attention Disorders 2012;16(6): 7 August 28 - September 1; Amstersdam,The Netherlands. 530–2. 8 Confidential:2010; Vol. 20 Suppl 3:S625–6. ForNigg Review 1977 {published data only} Only 9 Monden 2012 {published data only} Nigg JT, Swanson JM, Hinshaw SP. Covert visual spatial 10 Monden Y, Dan H, Nagashima M, Dan I, Kyutoku Y, attention in boys with attention deficit hyperactivity 11 Okamoto M, et al. Clinically-oriented monitoring of acute disorder: lateral effects, methylphenidate response and results for parents. Neuropsychologia 1997;35(2):165–76. 12 effects of methylphenidate on cerebral hemodynamics in 13 ADHD children using fNIRS. Clinical Neurophysiology Nikles 2005 {published data only} 2012; Vol. 123, issue 6:1147–57. 14 Nikles CJ, Clavarino AM, Del Mar CB. Using n-of-1 trials as a clinical tool to improve prescribing. British Journal of 15 Monden 2012a {published data only} General Practice 2005;55(512):175–80. 16 Monden Y, Dan H, Nagashima M, Dan I, Tsuzuki D, Kyutoku Y, et al. Right prefrontal activation as a neuro- 17 NIMH NCDEU 2006 {published data only} functional biomarker for monitoring acute effects of NIMH NCDEU. Posters most relevant to child and 18 methylphenidate in ADHD children: an fNIRS study. adolescent psychopharmacology. Journal of Child and 19 NeuroImage. Clinical 2012;1(1):131–40. Adolescent Psychopharmacology. Proceedings of the 46th 20 Annual National Institute of Mental Health (NIMH) New Mulhern 2004 {published data only} 21 Clinical Drug Evaluation Unit (NCDEU) Meeting; 2006 Mulhern RK, Khan RB, Kaplan S, Helton S, Christensen R, June 12-15; Boca Raton, Florida. 2006; Vol. 16 (6): 22 Bonner M, et al. Short-term efficacy of methylphenidate: a 649–64. 23 randomized, double-blind, placebo-controlled trial among 24 survivors of childhood cancer. Journal of Clinical Oncology Nolan 1999 {published data only} 25 2004;22(23):4795-803. Erratum in: Journal of Clinical Nolan EE, Gadow KD, Sprafkin J. Stimulant medication 26 Oncology 2005;23(1):248. withdrawal during long-term therapy in children with 27 comorbid attention-deficit hyperactivity disorder and Murphy 1992 {published data only} chronic multiple tic disorder. 1999;103(4): 28 Pediatrics Murphy DA, Pelham WE, Lang AR. Aggression in boys with 730–7. 29 attention deficit-hyperactivity disorder: methylphenidate No named author 2001 {published data only} 30 effects on naturalistically observed aggression, response to No named author. Update on investigation of Ritalin provocation, and social information processing. Journal of 31 conspiracy. Journal of Psychosocial Nursing and Mental Abnormal Child Psychology 1992;20(5):451–66. 32 Health Services 2001;39(1):10. 33 Na 2013 {published data only} Novak 1995 {published data only} 34 Osmotic-release oral system MPH tested in teens with Novak GP, Solanto M, Abikoff H. Spatial orienting and 35 ADHD. The Brown University Child & Adolescent focused attention in attention deficit hyperactivity disorder. Psychopharmacology Update 2013; Vol. 15, issue 6:8–8. 36 Psychophysiology 1995;32(6):546–59. 37 Nagel-Hiemke 1984 {published data only} O’Brien 2003 {published data only} 38 Nagel-Hiemke M, Berg B, Reinhardt D, Karch D, O’Brien LM, Ivanenko A, Crabtree VM, Holbrook CR, 39 Pothmann R. The influence of methylphenidate on the Bruner JL, Klaus CJ, et al. The effect of stimulants on 40 sympathoadrenal reactivity in children diagnosed as sleep characteristics in children with attention deficit/ 41 hyperactive. Klinische Pädiatrie 1984;196(2):78–82. hyperactivity disorder. Sleep Medicine 2003;4(4):309–16. 42 Nazir 2008 {published data only} O’Toole 1995 {published data only} 43 Nazir R, Sedky K, Lippmann S. An absence seizure: O’Toole KM. The effects of methylphenidate dose on 44 methylphenidate, clonidine and photic stimulation. Eastern attention and nonverbal learning in children with attention- 45 Journal of Medicine 2008;13(1-2):43–4. deficit hyperactivity disorder. Dissertation Abstracts 46 Neef 2005 {published data only} International Section A: Humanities and Social Sciences. 47 Neef NA, Bicard DF, Endo S, Coury DL, Aman MG. US: Georgia State U, 1995; Vol. 55, issue 10–A:3141. 48 Evaluation of pharmacological treatment of impulsivity O’Toole 1997 {published data only} 49 in children with attention deficit hyperactivity disorder. O’Toole K, Abramowitz A, Morris R, Dulcan M. Effects Journal of AppliedFor Behavior Analysis 2005; Preview38(2):135–46. of methylphenidate Only on attention and nonverbal learning 50 in children with attention-deficit hyperactivity disorder. 51 Negrao 2011 {published data only} Negrao BL, Bipath P, Van der Westhuizen D, Viljoen M. Journal of the American Academy of Child and Adolescent 52 Psychiatry 1997;36(4):531–8. 53 Autonomic correlates at rest and during evoked attention in 54 children with attention-deficit/hyperactivity disorder and Ohashi 2010 {published data only} effects of methylphenidate. Neuropsychobiology 2011;63(2): Ohashi K, Vitaliano G, Polcari A, Teicher MH. Unraveling 55 82–91. the nature of hyperactivity in children with attention- 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 81 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 127 of 615 BMJ
1 2 3 4 deficit/hyperactivity disorder. Archives of General Psychiatry Daehak–No, Chongno–Gu, Seoul, South Korea. E–mail: 5 2010;67(4):388–96. [email protected]: Elsevier Ireland Ltd (P.O. Box 85, 6 Olfson 2006 {published and unpublished data} Limerick, Ireland), 2012; Vol. 514, issue 2:159–63. 7 Olfson M. Longer acting MPH increases compliance Pearson 1996 {published data only} 8 Confidential:in medicaid population. The Brown University For ReviewPearson DA, Santos CW, Roache Only JD, Loveland KA, Casat 9 Psychopharmacology Update 2006;17(2):3. CD, Farwell EC, et al. Effects of methylphenidate on 10 Oliveiro-Van 2004 {published data only} behavioral adjustment in children with mental retardation 11 Oliveiro-Van Norel D, Monster-Simons MH, Van and ADHD: preliminary findings from a study in progress. 12 Grootheest AC. Raynaud’s phenomenon as side-effect of Journal of Developmental and Physical Disabilities 1996;8(4): 13 methylphenidate [Het Raynaud–fenomeen als bijwerking 313–33. 14 van methylfenidaat]. Pharmaceutisch Weekblad 2004;139 Pearson 2003 {published data only} 15 (17):576–79. Pearson DA, Santos CW, Roache JD, Casat CD, Loveland 16 Orgill 1996 {published data only} KA, Lachar D, et al. Treatment effects of methylphenidate Orgill A, Serfontein S. Behavioural & cognitive effects of on behavioral adjustment in children with mental 17 retardation and ADHD. Journal of the American Academy of 18 stimulant & non stimulant drugs in childhood attention deficit disorder. European Neuropsychopharmacology 1996;6 Child and Adolescent Psychiatry 2003;42(2):209–16. 19 (Suppl 3):56. 20 Pearson 2004 {published data only} Pearson D, Lane DM, Santos CW, Casat CD, Jerger SW, 21 Overcash 2005 {published data only} Overcash SJ. The effect of ROSHI protocol and cranial Loveland KA, et al. Effects of methylphenidate treatment in 22 electrotherapy stimulation on a nine-year-old anxious, children with mental retardation and ADHD: individual 23 dyslexic male with attention deficit disorder: a case study. variation in medication response. Journal of the American 24 Journal of Neurotherapy 2005;9(2):63–77. Academy of Child and Adolescent Psychiatry 2004;43(6): 25 686–98. Ozdag 2004 {published data only} 26 Ozdag MF, Yorbik O, Ulas UH, Hamamcioglu K, Pearson 2004a {published data only} 27 Vural O. Effect of methylphenidate on auditory Pearson D, Santos CW, Casat CD, Lane DM, Jerger SW, 28 event related potential in boys with attention deficit Roache JD, et al. Treatment effects of methylphenidate on 29 hyperactivity disorder. International Journal of Pediatric cognitive functioning in children with mental retardation 30 Otorhinolaryngology 2004;68(10):1267–72. and ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 2004;43(6):677–85. 31 Padolsky 2008 {published data only} 32 Padolsky I. A comparison of cognitive and psychosocial Peeke 1984 {published data only} 33 function for males within the ADHD continuum. Clinical Peeke S, Halliday R, Callaway E, Prael R, Reus V. Effects 34 Case Studies 2008;7(6):521–37. of two doses of methylphenidate on verbal information 35 Palomino 2012 {published data only} processing in hyperactive children. Journal of Clinical 36 Palomino MD, Martin-Calero MJ, Marques G. Involvement Psychopharmacology 1984;4(2):82–8. 37 of community pharmacists on attention-defi cit/ Pelham 1977 {published data only} 38 hyperactivity disorder patients. A pilot study [Implicacion Pelham WE. Withdrawal of a stimulant drug and concurrent 39 del farmaceutico comunitario en la dispensacion a pacientes behavioral intervention in the treatment of a hyperactive 40 con trastorno por deficit de atencion e hiperactividad. Un child. Behavior Therapy 1977; Vol. 8, issue 3:473–9. estudio piloto]. Pharmaceutical Care Espana 2012;14(5): 41 183–92. Pelham 1985 {published data only} 42 Pelham WE, Bender ME, Caddell J, Booth S, Moorer Park 2010 {published data only} SH. Methylphenidate and children with attention deficit 43 Park YM, Jung YK. Manic switch and serotonin disorder. Dose effects on classroom academic and social 44 syndrome induced by augmentation of paroxetine with behavior. Archives of General Psychiatry 1985;42(10): 45 methylphenidate in a patient with major depression. 948–52. 46 Progress in Neuro-Psychopharmacology & Biological Psychiatry 47 2010;34(4):719–20. Pelham 1986 {published data only} Pelham WE, Milich R, Walker JL. Effects of continuous 48 Park 2012 {published data only} and partial reinforcement and methylphenidate on learning 49 Park M-H, Kim J-W, Yang Y-H, Hong S-B, Park S, Kang For Previewin children withOnly Attention Deficit Disorder. Journal of 50 H, et al. Regional brain perfusion before and after treatment Abnormal Psychology 1986;95(4):319–25. 51 with methylphenidate may be associated with the G1287A 52 polymorphism of the norepinephrine transporter gene Pelham 1990 {published data only} 53 in children with attention-deficit/hyperactivity disorder. Pelham WE, McBurnett K, Harper GW, Milich R, Murphy 54 Neuroscience Letters. S.–C. Cho, Division of Child DA, Clinton J, et al. Methylphenidate and baseball playing and Adolescent Psychiatry, Department of Psychiatry, in ADHD children: who’s on first?. Journal of Consulting 55 Seoul National University College of Medicine, 101 and Clinical Psychology 1990;58(1):130–3. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 82 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 128 of 615
1 2 3 4 Pelham 1992 {published data only} Pierce 2008 {published data only} 5 Pelham WE, Murphy DA, Vannatta K, Milich R, Licht Pierce D, Dixon CM, Wigal SB, McGough JJ. 6 BG, Gnagy EM, et al. Methylphenidate and attributions in Pharmacokinetics of methylphenidate transdermal system 7 boys with attention-deficit hyperactivity disorder. Journal (MTS): results from a laboratory classroom study. Journal 8 Confidential:of Consulting and Clinical Psychology 1992;60(2):282–92. For Reviewof Child and Adolescent Psychopharmacology Only2008;18(4): 9 [PsycINFO: 1994–34504–001] 355–64. 10 Pelham 1993 {published data only} Pleak 1995 {published data only} 11 Pelham WE, Murphy DA, Vannatta K, Milich R. Pleak RR. Adverse effects of chewing methylphenidate. 1995;152(5):811. 12 Methylphenidate and attributions in boys with attention- American Journal of Psychiatry deficit hyperactivity disorder. Annual Progress in Child Pollack 1977 {published data only} 13 Psychiatry & Child Development. American Psychological Pollack MA, Cohen NL, Friedhoff AJ. Gilles de la Tourette’s 14 Association, 1993:242–65. 15 syndrome. Familial occurrence and precipitation by Pelham 1997 {published data only} methylphenidate therapy. Archives of Neurology 1977;34 16 Pelham WE, Hoza B, Kipp HL, Gnagy EM, Trane ST. (10):630–2. 17 Effects of methylphenidate and expectancy on ADHD Porges 1975 {published data only} 18 children’s performance, self-evaluations, persistence, and Porges SW, Walter GF, Korb RJ, Sprague RL. The influences 19 attributions on a cognitive task. Experimental and Clinical of methylphenidate on heart rate and behavioral measures Psychopharmacology 1997;5(1):3–13. 20 of attention in hyperactive children. Child Development 21 Pelham 2001 {published data only} 1975;46(3):725–33. 22 Pelham WE Jr, Waschbusch DA, Hoza B, Pillow DR, Porges 1981 {published data only} Gnagy EM. Effects of methylphenidate and expectancy on 23 Porges SW, Bohrer RE, Keren G, Cheung MN, Franks performance, self-evaluations, persistence, and attributions 24 GJ, Drasgow F. The influence of methylphenidate on on a social task in boys with ADHD. Experimental and 25 spontaneous autonomic activity and behavior in children Clinical Psychopharmacology 2001;9(4):425–37. 26 diagnosed as hyperactive. Psychophysiology 1981;18(1): 27 Pelham 2011 {published data only} 42–8. Pelham WE Jr, Waschbusch DA, Hoza B, Gnagy EM, 28 Posey 2004 {published data only} Greiner AR, Sams SE, et al. Music and video as distractors Posey DJ, McDougle CJ, Aman MG, Arnold LE, Scahill L, 29 for boys with ADHD in the classroom: comparison with McCracken JT, et al. A randomized, double-blind, placebo- 30 controls, individual differences, and medication effects. controlled, crossover trial of methylphenidate in children 31 Journal of Abnormal Child Psychology. D.A. Waschbusch, with hyperactivity associated with pervasive developmental 32 Department of Psychology, Center for Children and disorders. Neuropsychopharmacology 2004;29(Suppl 1): 33 Families, Florida International University, 11200 SW S142–3. 34 8th Street, Miami, FL 33199, United States. E–mail: 35 dwaschbu@fiu.edu: Springer New York (233 Springer Posey 2007 {published data only} Posey DJ, Aman MG, McCracken JT, Scahill L, Tierney E, 36 Street, New York NY 10013–1578, United States), 2011; Vol. 39, issue 8:1085–98. Arnold LE, et al. Positive effects of methylphenidate on 37 inattention and hyperactivity in pervasive developmental Perera 2012 {published data only} 38 disorders: an analysis of secondary measures. Biological Perera H, Jeewandara KC, Seneviratne S, Guruge C. 39 Psychiatry 2007;61(4):538–44. Combined ω3 and ω6 supplementation in children with 40 attention-deficit hyperactivity disorder (ADHD) refractory Poulton 2013 {published data only} 41 to methylphenidate treatment: a double-blind, placebo- Poulton AS, Melzer E, Tait PR, Garnett SP, Cowell CT, 42 controlled study. Journal of Child Neurology 2012; Vol. Baur L, et al. Growth and pubertal development of 43 27, issue 6:747–53. adolescent boys on stimulant medication for attention 44 Perruchoud 2008 {published data only} deficit hyperactivity disorder. Medical Journal of Australia 45 Perruchoud C, Chollet-Rivier M. Cardiac arrest during 2013;198(1):29–32. 46 induction of anaesthesia in a child on long-term Powell 2011 {published data only} 47 amphetamine therapy. British Journal of Anaesthesia 2008; Powell SG, Thomsen PH, Frydenberg M, Rasmussen H. 48 100(3):421–2. Long-term treatment of ADHD with stimulants: a large 49 Petty 1980 {published data only} observational study of real-life patients. Journal of Attention Petty LK, Spar CJ.For Haloperidol-induced Preview tardive dyskinesia Disorders 2011;Only Vol. 15, issue 6:439–51. 50 51 in a 10-year-old girl. American Journal of Psychiatry 1980; Prehn-Kristensen 2011 {published data only} 52 137(6):745–6. Prehn-Kristensen A, Krauel K, Hinrichs H, Fischer J, 53 Peyre 2012 {published data only} Malecki U, Schuetze H, et al. Methylphenidate does not 54 Peyre H, Delorme R. A case of severe hyperthermia after improve interference control during a working memory administration of methylphenidate. Journal of Clinical task in young patients with attention-deficit hyperactivity 55 Psychopharmacology 2012; Vol. 32, issue 2:299–300. disorder. Brain Research 2011;1388:56–68. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 83 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 129 of 615 BMJ
1 2 3 4 Preskorn 2006 {published data only} responding. Pharmacology, Biochemistry, and Behavior 1985; 5 Preskorn SH. Patient with bipolar disorder and familial QT 23(1):77–83. 6 prolongation: what to do?. Journal of Psychiatric Practice Rapport 1989b {published data only} 7 2006;12(2):109–12. Rapport MD, Quinn SO, DuPaul GJ, Quinn EP, Kelly 8 Confidential:Prichep 1975 {published data only} For ReviewKL. Attention deficit disorder withOnly hyperactivity and 9 Prichep LS. Attention and the auditory evoked potential in methylphenidate: the effects of dose and mastery level on 10 hyperkinetic children treated by methylphenidate and in children’s learning performance. Journal of Abnormal Child 11 normal children. Dissertation Abstracts International. City Psychology 1989;17(6):669–89. U New York, 1975; Vol. 35, issue 12–B, Pt 1:6141. 12 Rapport 1993 {published data only} 13 Prichep 1976 {published data only} Rapport MD, Carlson GA, Kelly KL, Pataki C. Prichep LS, Sutton S, Hakerem G. Evoked potentials Methylphenidate and desipramine in hospitalized children: 14 in hyperkinetic and normal children under certainty 15 I. Separate and combined effects on cognitive function. and uncertainty: a placebo and methylphenidate study. Journal of the American Academy of Child and Adolescent 16 Psychophysiology 1976;13(5):419–28. Psychiatry 1993;32(2):333–42. 17 Prinz 1986 {published data only} 18 Rapport 1995 {published data only} Prinz RJ, Loney J. The hyperactive child grows up: teachers’ Rapport MD, Loo S, Denney C. The paired associate 19 descriptions and their predictors. Advances in Learning & learning task: is it an externally valid instrument for 20 Behavioral Disabilities 1986;5:247–93. assessing methylphenidate response in children with 21 Quinn 1975 {published data only} attention deficit disorder?. Journal of Psychopathology and 22 Quinn PO, Rapoport JL. One-year follow-up of hyperactive Behavioral Assessment 1995;17(2):125–44. 23 boys treated with imipramine or methylphenidate. American Reid 1984 {published data only} 24 Journal of Psychiatry 1975;132(3):241–5. Reid MK, Borkowski JG. Effects of methylphenidate 25 Quintana 1995 {published data only} (Ritalin) on information processing in hyperactive children. 26 Quintana H, Birmaher B, Stedge D, Lennon S, Freed J, Journal of Abnormal Child Psychology 1984;12(1):169–85. Bridge J, et al. Use of methylphenidate in the treatment 27 Reinhardt 2007 {published data only} 28 of children with autistic disorder. Journal of Autism and Reinhardt MC, Benetti L, Victor MM, Grevet EH, 29 Developmental Disorders 1995;25(3):283–94. Belmonte-de-Abreu P, Faraone SV, et al. Is age-at-onset 30 Quintana 2007 {published data only} criterion relevant for the response to methylphenidate in 31 Quintana H, Cherlin EA, Duesenberg DA, Bangs attention-deficit/hyperactivity disorder?. Journal of Clinical 32 ME, Ramsey JL, Feldman PD, et al. Transition from Psychiatry 2007;68(7):1109–16. methylphenidate or amphetamine to atomoxetine in 33 Ren 2008 {published data only} children and adolescents with attention-deficit/hyperactivity Ren YL, Dong X, Wang SH, Sheng W, Wang JB, Liu DB. 34 disorder--a preliminary tolerability and efficacy study. Effects of methylphenidate in children with ADHD: an 35 Clinical Therapeutics 2007;29(6):1168–77. 36 event-related potentials comparison study. Chinese Mental Rajesh 2006 {published data only} Health Journal 2008;22(1):11–5. 37 Rajesh AS, Bates G, Wright JGC. Atomoxetine-induced Rhodes 2004 {published data only} 38 electrocardiogram changes. Archives of Disease in Childhood Rhodes SM, Coghill DR, Matthews K. Methylphenidate 39 2006;91(12):1023–24. restores visual memory, but not working memory function in 40 Rao 1998 {published data only} attention deficit-hyperkinetic disorder. Psychopharmacology 41 Rao JK, Julius JR, Breen TJ, Blethen SL. Response to 2004;175(3):319–30. 42 growth hormone in attention deficit hyperactivity disorder: Rhodes 2006 {published data only} effects of methylphenidate and pemoline therapy. Pediatrics 43 Rhodes SM, Coghill DR, Matthews K. Acute 1998;102(Suppl 3):497–500. 44 neuropsychological effects of methylphenidate in stimulant 45 Rapaport 1976 {published data only} drug-naïve boys with ADHD II - broader executive and 46 Rapaport HG, Flint SH. Is there a relationship between non-executive domains. Journal of Child Psychology and 47 allergy and learning disabilities?. Journal of School Health Psychiatry 2006;47(11):1184–94. 1976;46(3):139–41. 48 Richardson 1988 {published data only} 49 Rapoport 1974 {published data only} Kupietz SS, Winsberg BG, Sverd J. Learning ability and Rapoport JL, QuinnFor PO, Bradbard G,Preview Riddle KD. Only 50 methylphenidate (Ritalin(®)) plasma concentration in 51 Imipramine and methylphenidate treatments of hyperactive hyperkinetic children: a preliminary investigation. Journal boys: a double-blind comparison. Archives of General of the American Academy of Child and Adolescent Psychiatry 52 Psychiatry 1974;30(6):789–93. 53 1982;21(1):27–30. 54 Rapport 1985 {published data only} Richardson E, Kupietz SS, Winsberg BG, Maitinsky Rapport MD, DuPaul GJ, Smith NF. Rate-dependency S, Mendell N. Effects of methylphenidate dosage in 55 and hyperactivity: methylphenidate effects on operant hyperactive reading-disabled children: II. Reading 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 84 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 130 of 615
1 2 3 4 achievement. Journal of the American Academy of Child and Ross 2006 {published data only} 5 Adolescent Psychiatry 1988;27(1):78–87. Ross RG. Psychotic and manic-like symptoms during 6 Rie 1976 {published data only} stimulant treatment of attention deficit hyperactivity 7 Rie HE, Rie ED, Stewart S, Ambuel JP. Effects of disorder. American Journal of Psychiatry 2006;163(7): 8 Confidential:methylphenidate on underachieving children. Journal ofFor Review1149–52. Only 9 Consulting and Clinical Psychology 1976;44(2):250–60. Rosse 1984 {published data only} 10 Rietjens 2012 {published data only} Rosse RB, Licamele WL. Slow-release methylphenidate: 11 Rietjens S, Hondebrink L, Meulenbelt J, Vries ID. problems when children chew tablets. Journal of Clinical 12 Methylphenidate exposure: what is the risk?. Toxicology Psychiatry 1984;45(12):525. 13 Letters. Abstracts of the 48th Congress of the European Societies of Toxicology, EUROTOX; 2012 June 17-20; Rossel 1987 {published data only} 14 Stockholm, Sweden. Elsevier Ireland Ltd, 2012; Vol. 211: Rossel E. Sustained attention in hyperactive children: 15 S15–6. [EMBASE: 70760508] signal detection analysis of the effect of methylphenidate [Daueraufmerksamkeit bei hyperkinetischen Kindern: eine 16 Robbins 1979 {published data only} signal–detection–analyse der wirkung von methylphenidat]. 17 Robbins TW, Sahakian BJ. “Paradoxical” effects of Zeitschrift für Kinder- und Jugendpsychiatrie 1987;15(1): 18 psychomotor stimulant drugs in hyperactive children 6–17. 19 from the standpoint of behavioural pharmacology. 20 Neuropharmacology 1979;18(12):931–50. Rothermel 2010 {published data only} 21 Rodrigues 2008 {published data only} Rothermel B, Poustka L, Banaschewski T, Becker K. Bipolar 22 Rodrigues J, Botelho C, Cadinha S, Castel-Branco MG. disorders as co-morbidity in childhood and adolescence-- 23 Desensitization to methylphenidate--the relevance of underdiagnosed or overinterpreted? Therapy of a 14-year- 24 continued drug intake for a successful outcome. Allergologia old boy with hyperkinetic conduct disorder and hypomania et Immunopathologia 2008;36(5):303–5. [Bipolare Störungen als Komorbidität im Kindes– und 25 Jugendalter—-unterdiagnostiziert oder uberinterpretiert? Rogeness 1983 {published data only} 26 Therapie eines 14–Jahrigen mit Hyperkinetischer Störung Rogeness GA, Macedo CA. Therapeutic response of a 27 des Sozialverhaltens und Hypomanie]. Zeitschrift fur schizophrenic boy to a methylphenidate-chlorpromazine 28 Kinder-und Jugendpsychiatrie und Psychotherapie 2010;38(2): combination. American Journal of Psychiatry 1983;140(7): 29 123–9. 932–3. 30 Roman 2002 {published data only} Rubia 2003 {published data only} 31 Roman T, Szobot C, Martins S, Biederman J, Rohde LA, Rubia K, Noorloos J, Smith A, Gunning B, Sergeant J. 32 Hutz MH. Dopamine transporter gene and response to Motor timing deficits in community and clinical boys with 33 methylphenidate in attention-deficit/hyperactivity disorder. hyperactive behavior: the effect of methylphenidate on 34 Pharmacogenetics 2002;12(6):497–9. motor timing. Journal of Abnormal Child Psychology 2003; 35 Romanos 2008 {published data only} 31(3):301–13. 36 Romanos M, Renner TJ, Schecklmann M, Hummel B, Rubia 2009 {published data only} 37 Roos M, Von Mering C, et al. Improved odor sensitivity in Rubia K, Halari R, Cubillo A I, Taylor ET. Methylphenidate 38 attention-deficit/hyperactivity disorder. Biological Psychiatry modulates inferior and orbitofrontal brain activation in 39 2008;64(11):938–40. ADHD during sustained attention and reward. European 40 Rooney 2011 {published data only} Neuropsychopharmacology. Papers of the 22nd ECNP 41 Rooney M, Alfano CA, Walsh KS, Parr AF. Differential Congress; 2009 September 12-16; Istanbul, Turkey. K. 42 diagnosis and treatment of obsessive-compulsive, Rubia, Institute of Psychiatry, Department of Child inattentive, and sleep symptoms in a 7-year-old with PDD- Psychiatry, SGDP, London, United Kingdom: Elsevier, 43 NOS. Clinical Case Studies 2011;10(2):133–46. 2009; Vol. 19 Suppl 3:S304–5. 44 Rosén 1985 {published data only} Rubia 2009a {published data only} 45 Rosén LA, O’Leary SG, Conway G. The withdrawal Rubia K, Halari R, Cubillo A, Mohammad A-M, Brammer 46 of stimulant medication for hyperactivity: overcoming M, Taylor E. Methylphenidate normalises activation 47 detrimental attributions. Behavior Therapy 1985;16(5): and functional connectivity deficits in attention and 48 538–44. motivation networks in medication-naïve children with Rosenfeld 1979 {published data only} 49 ADHD during a rewarded continuous performance task. Rosenfeld AA. DepressionFor and psychotic Preview regression Only 50 Neuropharmacology 2009;57(7-8):640–52. 51 following prolonged methylphenidate use and withdrawal: 52 case report. American Journal of Psychiatry 1979;136(2): Rubinstein 1994 {published data only} 53 226–8. Rubinstein S, Silver LB, Licamele WL. Clonidine for 54 Rosenthal 1995 {published data only} stimulant-related sleep problems. Journal of the American Rosenthal NE. Syndrome triad in children and adolescents. Academy of Child and Adolescent Psychiatry 1994;33(2): 55 American Journal of Psychiatry 1995;152(9):1402. 281–2. 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 85 Copyright © 2015 The Cochrane Collaboration. 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Randomized, controlled, crossover trial of predicts teacher-rated medication response in boys with methylphenidate in pervasive developmental disorders with 14 attention deficit hyperactivity disorder. International hyperactivity. Archives of General Psychiatry 2005;62(11): Journal of Disability, Development and Education 2006;53 15 1266–74. (1):93–109. 16 Safer 1972 {published data only} Schleifer 1975 {published data only} 17 Safer D, Allen R, Barr E. Depression of growth in Schleifer M, Weiss G, Cohen N, Elman M, Cvejic H, 18 hyperactive children on stimulant drugs. New England Kruger E. Hyperactivity in preschoolers and the effect of 19 Journal of Medicine 1972;287(5):217–20. methylphenidate. American Journal of Orthopsychiatry 1975; 20 Safer 1973 {published data only} 45(1):38–50. 21 Safer DJ, Allen RP. Factors influencing the suppressant Schmiedeler 2009 {published data only} 22 effects of two stimulant drugs on the growth of hyperactive Schmiedeler S, Schwenck C, Schneider W. The mental 23 children. Pediatrics 1973;51(4):660–7. process of negating values in children with ADHD and effects of medical treatment [Die verarbeitung von 24 Safer 1989 {published data only} negationen bei kindern mit ADHS und der einfluss 25 Safer DJ, Allen RP. Absence of tolerance to the behavioral medikamentoser behandlung]. 26 effects of methylphenidate in hyperactive and inattentive Kindheit und Entwicklung 2009;18(3):137–43. 27 children. Journal of Pediatrics 1989;115(6):1003–8. Schnackenberg 1971 {published data only} 28 Sangal 2006 {published data only} Schnackenberg RC, Bender EP. The effect of 29 Sangal RB, Sangal JM. Attention-deficit/hyperactivity methylphenidate hydrochloride on children with minimal 30 disorder: use of cognitive evoked potential (P300) to predict brain dysfunction syndrome and subsequent hyperkinetic treatment response. Clinical Neurophysiology 2006;117(9): 31 syndrome. Psychiatric Forum 1971;2(2):32–6. 32 1996–2006. 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J.H. 42 Sattout 2009 {published data only} Newcorn, Department of Psychiatry, Mount Sinai School of 43 Sattout AH, Nicol MF. Cardiac arrest following cannabis Medicine, One Gustave L Levy Pl, New York, NY 10029, use: a case report. Cases Journal 2009;2(11):208. United States: American Medical Association (515 North 44 State Street, Chicago IL 60654, United States), 2012; Vol. Schain 1975 {published data only} 45 69, issue 9:952–61. Schain RJ, Reynard CL. Observations on effects of a 46 Schulz KP, Fan J, Bédard AV. Medications for ADHD show central stimulant drug (methylphenidate) in children with 47 similarities and differences in action. The Brown University hyperactive behavior. Pediatrics 1975;55(5):709–16. 48 Child & Adolescent Psychopharmacology Update 2012;14 49 Schain 1975a {published data only} (11):4–4. Schain RJ, ReynardsFor CL. Effect of methylphenidate Preview on Only 50 Schürmann 2012 {published data only} 51 children with hyperactive behavior. Pediatric Research 1975; Schürmann S, Breuer D, Wolff Metternich-Kaizman 9(4):766. [EMBASE: 0976067478] 52 T, Döpfner M. Intellectual abilities in adolescents with 53 Schecklmann 2011 {published data only} former ADHD diagnoses - relationships to current ADHD 54 Schecklmann M, Schaldecker M, Aucktor S, Brast symptoms, comorbid symptoms, and medication history: J, Kirchgässner K, Mühlberger A, et al. Effects of results of an 8.5-year follow-up of the Cologne Adaptive 55 methylphenidate on olfaction and frontal and temporal Multimodal Treatment Study (CAMT) [Intellektuelle 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 86 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 132 of 615
1 2 3 4 fahigkeiten bei jugendlichen mit fruherer ADHS–diagnose Shea 2006 {published data only} 5 – zusammenhange zu aktuellen ADHS–symptomen, Shea SE. Methylphenidate hydrochloride reduces 6 komorbidität und früherer medikation: ergebnisse der hyperactivity in children with pervasive development 7 8.5–jahre–katamnese der Kölner Adaptiven Multimodalen disorders. Evidence-Based Mental Health 2006;9(2):45. 8 Confidential:Therapiestudie (KAMT)]. Zeitschrift fur Kinder-und ForSheppard Review 1999 {published data only} Only 9 Jugendpsychiatrie und Psychotherapie 2012;40(1):51–60. Sheppard DM, Bradshaw JL, Mattingly JB, Lee P. Effects of stimulant medication on the lateralisation of line bisection 10 Sells 1977 {published data only} judgements of children with attention deficit hyperactivity 11 Sells CJ, Eaton M, Lucas B. Central nervous system disorder. Journal of Neurology, Neurosurgery & Psychiatry 12 stimulants--their use in the “non-classical” hyperkinetic 1999;66(1):57-63. Erratum in: Journal of Neurology, syndrome: a case-controlled study. Clinical Pediatrics 1977; 13 Neurosurgery & Psychiatry, 2000;68(2):256. 14 16(3):279–83. Silk 2012 15 {published data only} Semrud-Clikeman 2008 {published data only} Silk T. Resting-state functional connectivity anomalies in 16 Semrud-Clikeman M, Pliszka S, Liotti M. Executive ADHD and responses to methylphenidate medication. 17 functioning in children with attention-deficit/hyperactivity Brain Connectivity 2012; Vol. 2, issue 4:A128. 18 disorder: combined type with and without a stimulant medication history. Neuropsychology 2008;22(3):329–40. Silva 2011 {published data only} 19 Silva F, Nobre S, Campos AP, Vasconcelos M, Gonçalves 20 Sengupta 2008 {published data only} I. Behavioural and psychiatric disorders in paediatric 21 Sengupta S, Grizenko N, Schmitz N, Schwartz G, Wilson’s disease. BMJ Case Reports 2011. [DOI: 10.1136/ 22 Bellingham J, Polotskaia A, et al. 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Psychopharmacology Bulletin 1974;10 42 Shaywitz 1982 {published data only} (4):29–33. 43 Shaywitz SE, Hunt RD, Jatlow P, Cohen DJ, Young JG, Sleator 1974b {published data only} 44 Pierce RN, et al. Psychopharmacology of attention deficit Sleator EK, Von Neumann A, Sprague RL. Hyperactive 45 disorder: pharmacokinetic, neuroendocrine, and behavioral children. A continuous long-term placebo-controlled 46 measures following acute and chronic treatment with follow-up. JAMA 1974;229(3):316–7. 47 methylphenidate. Pediatrics 1982;69(6):688–94. Smith 2013 {published data only} 48 Shaywitz 1982a {published data only} Smith A, Cubillo A, Barrett N, Giampietro V, Simmons 49 Sebrechts MM, Shaywitz SE, Shaywitz BA, Jatlow P, A, Brammer M, et al. Neurofunctional effects of For Previewmethylphenidate Only and atomoxetine in boys with attention- 50 Anderson GM, Cohen DJ. Components of attention, 51 methylphenidate dosage, and blood levels in children with deficit/hyperactivity disorder during time discrimination. Biological Psychiatry 2013;74(8):615–22. 52 attention deficit disorder. Pediatrics 1986;77(2):222–8. 53 Shaywitz SE, Sebrects MM, Jatlow P. Plasma Snyder 2008 {published data only} 54 methylphenidate levels predict attention and activity: results Snyder AM, Maruff P, Pietrzak RH, Cromer JR, Snyder PJ. in a double-blind placebo study. Pediatric Research 1982;16 Effect of treatment with stimulant medication on nonverbal 55 (4II):88. [EMBASE: 1982211722] executive function and visuomotor speed in children with 56 57 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents (Review) 87 Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 59 60 https://mc.manuscriptcentral.com/bmj Page 133 of 615 BMJ
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1 2 3 4 NCT02039908 {unpublished data only} Achenbach 2001 5 NCT02039908. Examining tolerance to CNS stimulants Achenbach TM, Rescorla LA. Manual for the ASEBA School- 6 in ADHD. https://clinicaltrials.gov/. Age Forms and Profiles. Burlington, VT: ASEBA, 2001. 7 Nurmi 2013 {published data only} Aman 1996 8 Confidential:Nurmi EL, Mallya A, Mallya KS, Hellemann GS, For ReviewAman MG, Tassé MJ, Rojahn J, HammerOnly D. The Nisonger 9 McGough J, Loo SK, et al. Pharmacogenetics CBRF: a child behavior rating form for children with 10 of growth effects complicating ADHD treatment. developmental disabilities. Research in Developmental 11 Neuropsychopharmacology. Proceedings of the Disabilities 1996;17(1):41–57. 52nd Annual Meeting of the American College of 12 American Academy of Pediatrics 2011 Neuropsychopharmacology; 2013 December 8-12; 13 Subcommittee on Attention-Deficit/Hyperactivity Activity Hollywood, USA. 2013 (S2); Vol. 38:S492–3. 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