Metilfenidato para niños y adolescentes con trastorno de déficit de atención e hiperactividad (TDAH)
Information
- DOI:
- https://doi.org/10.1002/14651858.CD009885.pub3Copy DOI
- Database:
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- Cochrane Database of Systematic Reviews
- Version published:
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- 27 March 2023see what's new
- Type:
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- Intervention
- Stage:
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- Review
- Cochrane Editorial Group:
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Cochrane Developmental, Psychosocial and Learning Problems Group
- Copyright:
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- Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Authors
Contributions of authors
OJS has overall responsibility for the review and is a guarantor for the review.
OJS developed the design of the review and was responsible for the co‐ordination of the review.
CG, ES and MZ updated the background sections of the review.
OJS, HEC, JPS, JPR, MROS, PDR, and CMLH selected the studies.
MROS, CMLH, JPR, JPS, MS, and OJS extracted data and evaluated risk of bias.
OJS and HEC assessed the certainty of the body of evidence.
OJS, CGl and HEC interpreted the data.
OJS and CGl developed the analytical strategy.
MS, HEC, JPR, JPS, MROS, and OJS entered data into Review Manager 5.
OJS, MS, RK, HEC, JPR, and MROS conducted the statistical analysis.
All review authors participated in discussion and writing of the final review.
Sources of support
Internal sources
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Psychiatric Research Unit, Region Zealand Psychiatry, Roskilde, Denmark
Ole Jakob Storebø, Johanne Pereira Ribeiro, Julie Schaug, Maja Rosenberg Overby Storm, and Erik Simonsen worked on this review during office hours
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Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Denmark
Christian Gluud worked on this review during office hours
External sources
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None, Other
N/A
Declarations of interest
Ole Jakob Storebø: works at Psychiatric Research Unit, Region Zealand Psychiatry, Denmark. He is an Editor for Cochrane Developmental, Psychosocial and Learning Problems (CDPLP) but was not involved in the editorial process for this review. He is also an Editor‐in‐Chief for the Scandinavian Journal of Child and Adolescent Psychiatry and Psychology. He has declared that he has no conflicts of interest.
Maja Rosenberg Overby Storm: has declared that she has no conflicts of interest.
Johanne Perieira Ribeiro: has declared that she has no conflicts of interest.
Christel‐Mie‐Lykke Huus: has declared that she has no conflicts of interest.
Pernille Darling Rasmussen: has declared that she has no conflicts of interest.
Julie Perrine Schaug: has declared that she has no conflicts of interest.
Henriette Edeman Callesen: has declared that she has no conflicts of interest.
Maria Skoog: has declared that she has no conflicts of interest.
Camilla Groth works at the Children's Department at Hillerød Hospital, Denmark, where she conducts paediatric clinical research. She has declared that she has no conflicts of interest.
Morris Zwi (MZ) is a Child and Adolescent Psychiatrist working part time in private practice; previously, he worked exclusively for the NHS for 32 years, before retiring. He is a former Editor for CDPLP and occasionally is consulted by the group for his expertise; however, he was not involved in the editorial process for this review and it has been over one year since he did any editorial work. MZ declares a payment from the Paediatric Medicines Expert Advisory Board of the Medicines and Healthcare Products Regulatory Agency for his attendance at their monthly/bimonthly (i.e. every two months) meetings.
Richard Kirubakaran: has declared that he has no conflicts of interest.
Erik Simonsen: has declared that he has no conflicts of interest.
Christian Gluud: is the Co‐ordinating Editor of the Cochrane Hepato‐Biliary Group. He has declared that he has no conflicts of interest.
Acknowledgements
We thank Trine Lacoppidan Kæstel, Research Librarian, at the Psychiatric Research Unit, Region Zealand, Denmark, for helping with searches and descriptions of measurement scales.
We thank Anne Fink for helping with the review.
We are grateful to the many authors who kindly responded to our requests for further information on the trials in which they were involved.
Thanks also to the Psychiatric Research Unit, Region Zealand Psychiatry, Roskilde, Denmark; Region Zealand Research Foundation, Denmark; and the Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital — Rigshospitalet, Copenhagen, Denmark, for funding and enabling the review.
We also wish to warmly thank Geraldine McDonald (Co‐ordinating Editor), Joanne Duffield (Managing Editor), Sarah Davies (Assistant Managing Editor), and Margaret Anderson (Information Specialist) of Cochrane Developmental, Psychosocial and Learning Problems for providing help and support.
Cochrane Developmental, Psychosocial and Learning Problems supported the authors in the development of this update.
The following people conducted the editorial process for this article.
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Sign‐off Editor (final editorial decision): Geraldine Macdonald, University of Bristol;
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Managing Editor (provided editorial guidance to authors, edited the article): Joanne Duffield, Queen's University Belfast;
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Deputy Managing Editor (conducted editorial policy checks and supported editorial team): Sarah Davies, University of Bristol;
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Information Specialist (search review): Margaret Anderson, Queen's Univeristy Belfast; and
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Copy Editor (copy editing and production): Denise Mitchell, Cochrane Evidence, Production and Methods Directorate.
Version history
| Published | Title | Stage | Authors | Version |
| 2023 Mar 27 | Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD) | Review | Ole Jakob Storebø, Maja Rosenberg Overby Storm, Johanne Pereira Ribeiro, Maria Skoog, Camilla Groth, Henriette E Callesen, Julie Perrine Schaug, Pernille Darling Rasmussen, Christel-Mie L Huus, Morris Zwi, Richard Kirubakaran, Erik Simonsen, Christian Gluud | |
| 2015 Nov 25 | Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD) | Review | Ole Jakob Storebø, Erica Ramstad, Helle B. Krogh, Trine Danvad Nilausen, Maria Skoog, Mathilde Holmskov, Susanne Rosendal, Camilla Groth, Frederik L Magnusson, Carlos R Moreira‐Maia, Donna Gillies, Kirsten Buch Rasmussen, Dorothy Gauci, Morris Zwi, Richard Kirubakaran, Bente Forsbøl, Erik Simonsen, Christian Gluud | |
| 2012 May 16 | Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents | Protocol | Ole Jakob Storebø, Susanne Rosendal, Maria Skoog, Camilla Groth, Torben Bille, Kirsten Buch Rasmussen, Erik Simonsen, Christian Gluud | |
Differences between protocol and review
Methods
Criteria for considering studies for this review
Types of studies
We split the review into two systematic reviews to make the review more manageable. The Storebø 2015a review deals with benefits and harms of methylphenidate as reported by RCTs. Storebø 2018b assessed the risk of harms based on the findings of non‐randomised studies.
Types of participants
We decided to include trials in which at least 75% of participants were 18 years of age or younger, and the mean age of the trial population was 18 years of age or younger. We included two trials with such participants. These two trials included a few participants at 19 and 20 years of age and we thought it was better to include these trials than to exclude them. The effects of methylphenidate intervention on any outcome did not change when these two trials were removed from the analysis.
We decided to include trials in which at least 75% of participants had a normal intellectual quotient (IQ > 70). We included four trials with such participants. These four trials included a few participants with IQ below 70 and we thought it was better to include these trials than to exclude them. The effects of methylphenidate intervention on any outcome did not change when these four trials were removed from the analysis.
Types of outcome measures. Duration of studies
We changed the subdivision of duration from short term (≤ 6 months), medium term (6 to 12 months) and long term (> 12 months) to short term (≤ 6 months) and long term (> 6 months) because no trials had a duration of between 6 and 12 months. Only one trial (Jensen 1999 (MTA)), provided data on a duration longer than six months (14 months). We included the change in duration classification in analyses of ADHD symptoms and general behaviour.
Search methods for identification of studies Electronic searches
We did not search OpenGrey as this database closed down in 2020. We did not contact the medical authorities in the European Union for information about beneficial and adverse events. We did not ask for access to security updates and risk management plans of pharmaceutical companies due to lack of time and resources.
Data collection and analysis
Selection of studies and data extraction and management
More review authors than stated in the protocol screened titles and abstracts, extracted data, entered data into Review Manager 5 and conducted statistical analyses in Review Manager 5 (Review Manager 2020). More authors were added to the review as it became a bigger review than we expected at the protocol stage.
Measures of treatment effect. Continuous data
For the primary outcome of teacher‐rated attention deficit hyperactivity disorder (ADHD) symptoms, we recalculated the standardised mean difference (SMD) as mean difference (MD) on the ADHD‐Rating Scale (DuPaul 1991a), to check whether our result exceeded the minimum clinically important difference (MCID; Zhang 2005), for this specific rating scale. This was not stated in the protocol (Storebø 2012).
For the secondary outcome of quality of life, we recalculated the SMD as MD on the Child Health Questionnaire (Landgraf 1998), to check whether our results exceeded the MCID (Rentz 2005) for this specific rating scale. This was not stated in the protocol (Storebø 2012).
Dealing with missing data
We tried to obtain missing data by contacting the authors of the trials that we included in this review. When we were not able to obtain missing data, we conducted the analyses using the available (incomplete) data. We had intended to assess the impact of missing data by applying intention‐to‐treat as well as 'best‐case scenario' and 'worst‐case scenario' analyses. We could not use 'best‐case scenario' and 'worst‐case scenario' analyses in our assessment of benefits as there were no dichotomous outcomes. We decided not to use 'best‐case scenario' and 'worst‐case scenario' analyses in our assessment of adverse events, because we evaluated these analyses to be imprecise due to the high number of trials not reporting adverse events, and due to the high number of dropouts in the trials reporting adverse events. Moreover, we were unable to conduct intention‐to‐treat analyses for continuous outcomes due to lack of data for imputing means.
Data synthesis. Heterogeneity‐adjusted required information size and Trial Sequential Analysis
We performed a Trial Sequential Analysis on the total number of serious adverse events and on the total number of non‐serious adverse events only, as they were the only outcomes with dichotomous data with a substantial number of outcomes. Trial Sequential Analysis can be conducted on individual types of adverse events, but for this, the accrued information would represent a minute fraction of the required information size (RIS). We were not able to conduct a Trial Sequential Analysis for teacher‐, independent assessor‐ or parent‐rated outcomes, as the programme can be used only for MDs, not for SMDs.
Subgroup analysis and investigation of heterogeneity
We planned few subgroup analyses in our protocol. Due to large methodological and clinical heterogeneity in the included trials, we decided to conduct several post‐hoc subgroup analyses.
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Types of scales (e.g. Conners' Teacher Rating Scale (CTRS; Conners 1998a) compared to Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) Scale (Swanson 2006). We did this subgroup analysis to test the potential differences in effect estimates between the numerous scales measuring comparable content.
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Dose of methylphenidate (low dose (≤ 20 mg/d or ≤ 0.6 mg/kg/day) compared to moderate/high dose (> 20 mg/day or > 0.6 mg/kg/day)). We did this subgroup analysis to test the potential differences in effect estimates between doses, as this is very relevant for clinicians and patients.
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Duration of treatment (short‐term trials (≤ 6 months) compared to long‐term trials (> 6 months)). We did this subgroup analysis to test the potential differences in effect estimates between short‐ compared to long‐term trials.
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Trial design (parallel‐group trials compared to cross‐over trials (first period data and endpoint data)). We conducted this subgroup analysis as we pooled first‐period data with parallel‐group data and we used end‐of‐period data from cross‐over trials without adjusting for unit of analysis error.
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Medication status before randomisation (medication‐naive (> 80% of included participants were medication‐naive) compared to not medication‐naive (< 20% of included participants were medication‐naive)). We did this subgroup analysis to test the potential differences in effect estimates between medication‐naïve and not medication‐naïve participants, as this is very relevant for clinicians and patients.
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Risk of bias (trials at low risk of bias compared to trials at high risk of bias). We did this subgroup analysis to test the potential differences in effect estimates between trials at low risk of bias compared to those at high risk of bias.
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Cohort selection bias (trials with enrichment design compared to trials without enrichment design). We did this subgroup analysis to test the potential differences in effect estimates between the trials that had used the enrichment design to those that did not use this design.
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Vested interest (trials at high or unclear compared to trials at low risk of vested interests). There is empirical evidence showing that trials funded by industry might overestimate the benefits compared to trials not funded by industry and therefore we wanted to do this subgroup analysis.
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Type of control group (trials with placebo control group compared to trials with no‐intervention control group). We wanted to test the impact of choice of control group on estimated intervention effects.
Differences between this update and the original review
Methods
Search methods for identification of studies. Electronic searches
We updated the search strategy to include additional brand names for methylphenidate. Instead of conducting two separate searches for efficacy and adverse effects, we combined these into a single search. We also added a new source of systematic reviews (Epistemonikos) for reference list checking.
Data collection and analysis. Assessment of risk of bias in included studies. Vested interests
We did not evaluate vested interest as a risk of bias domain in this update as this is not recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Results
Description of studies
During this update, we found that one of the included trials was actually a subpublication of another trial (Bhat 2020). Therefore, the number of trials from the 2015 version is only 184 trials. Furthermore, we excluded one of the studies awaiting classification due to ineligible study design. Two studies that were included in the 2015 review based on reports of preliminary data had their study ID changed to match the primary reference included in the present version (Bhat 2020; Hawk 2018). One additional trial had its primary reference and study ID changed for naming consistency (Wigal 2011).
Included studies
In the 2015 version of this review (Storebø 2015b), we did not describe the trials that did not contribute to the analyses because they had no usable data. We have now added this information to the Included studies section and also made reference to these trials in the 'Main results' section of the abstract and additional Table 2.
Risk of bias in included studies
We did not assess all trials included in the 2015 review for enrichment (evaluated under the 'Notes' heading in all inclusion tables) and 'Selection bias' (evaluated under incomplete outcome data bias in all bias assessment tables). However, in this update, we reassessed all trials to include both of these assessments consistently throughout the review.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
Medical Subject Headings Check Words
Adolescent; Child; Female; Humans; Male;
PICOs
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial
Funnel plot of comparison 1. Teacher‐rated ADHD symptoms, outcome: 1.8 All data at low and high risk of bias (parallel‐group and cross‐over trials)
Trial Sequential Analysis: proportion of participants with one or more serious adverse events
Trial Sequential Analysis: proportion of participants with one or more non‐serious adverse events
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 1: All parallel‐group trials and first‐period cross‐over trials
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 2: Subgroup analysis: types of scales
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 3: Subgroup analysis: duration of treatment
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 4: Subgroup analysis: dose
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 5: Subgroup analysis: medication status ‐ medication naive versus not medication naive
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 6: Subgroup analysis: trials with enrichment design compared with trials without enrichment design
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 7: Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 8: Subgroup analysis: vested interest
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 9: Subgroup analysis: type of control group
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 10: Cross‐over trial (endpoint data)
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 11: Subgroup analysis: cross‐over trials (endpoint data): dose
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 12: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data)
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 13: All parallel‐group trials and cross‐over trials: risk of bias
Comparison 1: Teacher‐rated ADHD symptoms, Outcome 14: All parallel‐group trials and cross‐over trials: vested interest
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 1: All parallel‐group trials and first‐period cross‐over trials
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 2: Subgroup analysis: types of scales
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 3: Subgroup analysis: duration of treatment
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 4: Subgroup analysis: dose
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 5: Subgroup analysis: trials with enrichment design compared with trials without enrichment design
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 6: Subgroup analysis: type of control group
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 7: Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 8: Cross‐over trials (endpoint data)
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 9: Subgroup analysis: cross‐over trials (endpoint data): dose
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 10: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data)
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 11: All parallel‐group trials and cross‐over trials: risk of bias
Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 12: All parallel‐group trials and cross‐over trials: vested interest
Comparison 3: Parent‐rated ADHD symptoms, Outcome 1: All parallel‐group trials and first‐period cross‐over trials
Comparison 3: Parent‐rated ADHD symptoms, Outcome 2: Subgroup analysis: types of scales
Comparison 3: Parent‐rated ADHD symptoms, Outcome 3: Subgroup analysis: duration of treatment
Comparison 3: Parent‐rated ADHD symptoms, Outcome 4: Subgroup analysis: dose
Comparison 3: Parent‐rated ADHD symptoms, Outcome 5: Subgroup analysis: medication status ‐ medication naive versus not medication naive
Comparison 3: Parent‐rated ADHD symptoms, Outcome 6: Subgroup analysis: trials with enrichment design compared with trials without enrichment design
Comparison 3: Parent‐rated ADHD symptoms, Outcome 7: Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials
Comparison 3: Parent‐rated ADHD symptoms, Outcome 8: Subgroup analysis: type of control group
Comparison 3: Parent‐rated ADHD symptoms, Outcome 9: Cross‐over trials (endpoint data)
Comparison 3: Parent‐rated ADHD symptoms, Outcome 10: Subgroup analysis: cross‐over trials (endpoint data): dose
Comparison 3: Parent‐rated ADHD symptoms, Outcome 11: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data)
Comparison 3: Parent‐rated ADHD symptoms, Outcome 12: All parallel‐group trials and cross‐over trials: risk of bias
Comparison 3: Parent‐rated ADHD symptoms, Outcome 13: All parallel‐group trials and cross‐over trials: vested interest
Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 1: Parallel‐group trials and first‐period cross‐over trials: comparison of raters
Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 2: Parallel‐group trials and first‐period cross‐over trials: age
Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 3: Parallel‐group trials and first‐period cross‐over trials: comorbidity versus no comorbidity
Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 4: Parallel‐group trials and first‐period cross‐over trials: subtypes ADHD: ADHD Rating Scale (parent‐, teacher‐ or independent assessor‐rated)
Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 5: Cross‐over trials: first‐period data versus endpoint data (parent‐, independent assessor‐ and teacher‐rated)
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 1: Proportions of participants with serious adverse events (SAE)
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 2: Nervous system (including psychiatry)
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 3: Digestive system
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 4: Cardiovascular systems
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 5: Respiratory systems
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 6: Urinary system
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 7: Skeletal and muscular system (including pain)
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 8: Immune system (including infections)
Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 9: Other
Comparison 6: Serious adverse events: cross‐over trials (endpoint data), Outcome 1: Proportion of participants with serious adverse events (SAE)
Comparison 6: Serious adverse events: cross‐over trials (endpoint data), Outcome 2: Nervous system (including psychiatry)
Comparison 6: Serious adverse events: cross‐over trials (endpoint data), Outcome 3: Urinary system
Comparison 6: Serious adverse events: cross‐over trials (endpoint data), Outcome 4: Immune system
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 1: Proportion of participants with non‐serious adverse events
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 2: Subgroup analysis: proportion of participants with non‐serious adverse events according to dose
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 3: Nervous system (including psychiatry)
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 4: Digestive system
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 5: Cardiovascular system
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 6: Respiratory system
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 7: Urinary system
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 8: Skeletal and muscular systems (including pain)
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 9: Immune system (including infections)
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 10: Integumentary system
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 11: Sleep variability
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 12: Sleep variability continuous outcomes
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 13: Vital signs
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 14: Physical parameters
Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 15: Other (including drug toxicity)
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 1: Proportion of participants with non‐serious events
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 2: Subgroup analysis: total number of non‐serious adverse events according to dose
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 3: Nervous system (including psychiatry)
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 4: Nervous system (including psychiatry) continuous outcomes
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 5: Digestive system
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 6: Cardiovascular system
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 7: Respiratory system
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 8: Urinary system
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 9: Skeletal and muscular system
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 10: Skeletal and muscular system continuous outcomes
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 11: Immune system (including infections)
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 12: Integumentary system
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 13: Sleep variability continuous outcomes
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 14: Sleep variability
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 15: Vital signs
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 16: Physical parameters
Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 17: Other (including drug toxicity)
Comparison 9: Teacher‐rated general behaviour, Outcome 1: All parallel‐group trials and first‐period cross‐over trials
Comparison 9: Teacher‐rated general behaviour, Outcome 2: Subgroup analysis: types of scales
Comparison 9: Teacher‐rated general behaviour, Outcome 3: Subgroup analysis: dose
Comparison 9: Teacher‐rated general behaviour, Outcome 4: Subgroup analysis: duration of treatment
Comparison 9: Teacher‐rated general behaviour, Outcome 5: Subgroup analysis: parallel‐group trials versus first‐period cross‐over trials
Comparison 9: Teacher‐rated general behaviour, Outcome 6: Cross‐over trials (endpoint data)
Comparison 9: Teacher‐rated general behaviour, Outcome 7: Subgroup analysis: cross‐over trials (endpoint data): dose
Comparison 9: Teacher‐rated general behaviour, Outcome 8: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (teacher‐rated) versus cross‐over trials (endpoint data)
Comparison 9: Teacher‐rated general behaviour, Outcome 9: Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest
Comparison 10: Independent assessor‐rated general behaviour, Outcome 1: All parallel‐group trials and first‐period cross‐over trials
Comparison 10: Independent assessor‐rated general behaviour, Outcome 2: Cross‐over trials (endpoint data)
Comparison 10: Independent assessor‐rated general behaviour, Outcome 3: Subgroup analysis: general behaviour, cross‐over trials (endpoint data): dose
Comparison 10: Independent assessor‐rated general behaviour, Outcome 4: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (independent assessor‐rated) compared with cross‐over trials (endpoint data)
Comparison 10: Independent assessor‐rated general behaviour, Outcome 5: Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest
Comparison 11: Parent‐rated general behaviour, Outcome 1: All parallel‐group trials and first‐period cross‐over trials
Comparison 11: Parent‐rated general behaviour, Outcome 2: Subgroup analysis: types of scales
Comparison 11: Parent‐rated general behaviour, Outcome 3: Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials
Comparison 11: Parent‐rated general behaviour, Outcome 4: Subgroup analysis: duration of treatment
Comparison 11: Parent‐rated general behaviour, Outcome 5: Subgroup analysis: dose
Comparison 11: Parent‐rated general behaviour, Outcome 6: Cross‐over trials (endpoint data)
Comparison 11: Parent‐rated general behaviour, Outcome 7: Subgroup analysis: cross‐over trials (endpoint data): dose
Comparison 11: Parent‐rated general behaviour, Outcome 8: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (parent‐rated) compared with cross‐over trials (endpoint data)
Comparison 11: Parent‐rated general behaviour, Outcome 9: All parallel‐group trials and cross‐over trials: risk of bias
Comparison 11: Parent‐rated general behaviour, Outcome 10: Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest
Comparison 12: Additional subgroup analyses of general behaviour, Outcome 1: Parallel‐group trials and first‐period cross‐over trials: comparisons of raters
Comparison 12: Additional subgroup analyses of general behaviour, Outcome 2: Parallel‐group trials and first‐period cross‐over trials: comorbidity versus no comorbidity
Comparison 12: Additional subgroup analyses of general behaviour, Outcome 3: Cross‐over trials: first‐period data versus endpoint data in the same trials (teacher‐, parent‐, and independent assessor‐rated)
Comparison 13: Quality of life: parallel‐group trials and first‐period cross‐over trials, Outcome 1: Subgroup analysis: types of scales
| Methylphenidate compared with placebo or no intervention for ADHD | ||||||
| Patient or population: children and adolescents (up to and including 18 years of age) with ADHD | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo or no intervention | Methylphenidate | |||||
| ADHD symptoms: all parallel‐group trials and first‐period cross‐over trials Average trial duration: 68.7 days | Mean ADHD symptom score in the intervention groups corresponds to a mean difference of −10.58 (95% CI −12.58 to −8.72) on ADHD Rating Scale | SMD −0.74 (−0.88 to −0.61) | 1728 (21 trials) | ⊕⊝⊝⊝ | The analysis was conducted on a standardised scale with data from studies that used different teacher‐rated scales of symptoms (Conners' Teacher Rating Scale (CTRS), Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) Scale, The Swanson, Nolan and Pelham (SNAP) Scale ‐ Teacher, Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS)). We translated the effect size on to the ADHD Rating Scale from the SMD. | |
| Proportion of participants with one or more serious adverse events | Trial population | RR 0.80 (0.39 to 1.67) | 3673 (26 trials) | ⊕⊝⊝⊝ | TSA RIS = 9349 TSA showed a RR of 0.91 (TSA‐adjusted Cl 0.31 to 2.68) | |
| 8 per 1000 | 6 per 1000 | |||||
| Proportion of participants with one or more adverse events considered non‐serious | Trial population | RR 1.23 (1.11 to 1.37) | 5342 (35 trials) | ⊕⊝⊝⊝ | TSA RIS = 9139 | |
| 437 per 1000 | 538 per 1000 | |||||
| General behaviour: all parallel‐group trials and first‐period cross‐over trials | Mean general behaviour score in the intervention groups was 0.62 standard mean deviations lower (95% CI 0.91 lower to 0.33 lower) | SMD −0.62 (−0.91 to −0.33) | 792 | ⊕⊝⊝⊝ | ||
| Quality of life (parent‐rated) | Mean quality‐of‐life score in the intervention groups corresponds to a mean difference of 4.94 (95% CI −0.37 to 10.25) on the Child Health Questionnaire | SMD 0.40 (−0.03 to 0.83) | 608 | ⊕⊝⊝⊝ | ||
| *The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ADHD: attention deficit hyperactivity disorder; CI: confidence interval; RIS: required information size; RR: risk ratio; SMD: standardised mean difference; TSA: Trial Sequential Analysis | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. | ||||||
| aDowngraded two levels due to high risk of bias (systematic errors causing overestimation of benefits and underestimation of harms) in several risk of bias domains, including lack of sufficient blinding and selective outcome reporting (many of the included trials did not report on this outcome). | ||||||
| Study | Vested interest | Support for judgement |
|---|---|---|
| High | Funding: investigator‐initiated trial funded by a grant from Ortho‐McNeil Janssen Scientific Affairs to Dr Abikoffx Conflicts of interest: Drs Abikoff and Gallagher have a contract with Multi‐Health Systems to further develop the Children’s Organizational Skills Scale (COSS) used in this trial. Dr Abikoff has served on the ADHD Advisory Board of Shire Pharmaceuticals and of Novartis Pharmaceuticals. Dr Boorady has served on the ADHD Advisory Board and Speakers’ Bureau of Shire Pharmaceuticals. Other trial authors report no conflicts of interest | |
| Low | Funding: trial was funded by Marshfield Clinic grants Conflict of interest: not declared | |
| High | Funding: trial was supported by the Celgene Corporation Conflicts of interest: Drs Arnold, Wigal and Bohan received research Funding from Celgene for the trial reported. Dr Wigal and Dr West are on the Advisory Panel and Speakers' Bureau for Novartis. Dr Arnold and Dr Bohan are on the Speakers' Bureau for Novartis. Dr Zeldis is Chief Medical Officer and Vice President of Medical Affairs at the Celgene Corporation. | |
| Low | Funding: trial was internally funded by the medical school Conflict of interest: not declared | |
| Low | Funding: research was supported by the National Institute of Mental Health (NIMH) Conflicts of interest: not declared | |
| Low | Funding: University of Massachusetts Medical School Conflict of interest: not declared | |
| High | Funding: trial was funded by Vifor Pharma Conflict of interest: trial authors affiliated with the medical industry | |
| Low | Funding: funding and operating grant from the Canadian Institute of Health Research and Funding from the Canada Research Chairs Programme Conflicts of interest: none | |
| High | Funding: this work was supported in part by a grant from the Fond de Recherche du Québec and the Canadian Institutes of Health Research. Weam Fageera is a recipient of a PhD scholarship from the Ministry of Education of Saudi Arabia. Conflicts of interest: authors affiliated with medical industry | |
| High | Funding: received from Novartis Conflict of interest: not declared | |
| Unclear | Funding: not declared Conflict of interest: not declared | |
| High | Funding: trial was supported by an investigator‐initiated grant from Ortho McNeil Janssen Scientific Affairs, the manufacturer of OROS methylphenidate (Concerta) Conflict of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: sponsored by Novartis Pharmaceuticals Corporation Conflicts of interest: first trial author has been a speaker, consultant and advisory board member for Novartis and Shire | |
| High | Funding: Novartis Pharmaceuticals Corporation, with the following involvement reported: design and conduct of the trial; collection, management, analysis and interpretation of data; and preparation, review and approval of the manuscript. All trial authors are employees or consultants or have received research grants from pharmaceutical companies. Conflicts of interest: all trial authors are employees or consultants or have received research grants from pharmaceutical companies. | |
| Unclear | Funding: funded by National institute of Mental Health and National institutes of Health. Placebo and methylphenidate were supplied by CIBA‐GEIGY Corporation, Summit, New Jersey Conflicts of interest: not declared | |
| Unclear | Funding: research supported by US Public Health Services Grant from the National Institute of Mental Health (NIMH), and by the Biomedical Research Award from the National Institutes of Health (NIH). Methylphenidate provided by CIBA‐GEIGY Corporation, Summit, New Jersey Conflicts of interest: not declared | |
| Low | Funding: Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health and Emory University Research Conflicts of interest: not declared | |
| Unclear | Funding: Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health, and by the Emory University Research Fund Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: no affiliations with pharmaceutical companies were declared | |
| Unclear | Funding: no Funding declared Conflicts of interest: not declared | |
| Low | Funding: the Scientific Development Group, Organon International BV, Oss, the Netherlands Conflicts of interest: none | |
| Unclear | Funding: not declared Conflict of interest: not declared | |
| High | Funding: research was funded by Eli Lilly and Company, Indianapolis, Indiana Conflicts of interest: Dr Carlson has received research support or has consulted with the following companies: Abbott Laboratories, Cephalon, Eli Lilly and Company, Janssen, McNeil, Otsuka and Shire Pharmaceuticals. Dr Dunn has received research support or has served on Speakers' Bureaus of the following companies: AstraZeneca, Eli Lilly and Company, National Institues of Health, Otsuka and Pfizer Pharmaceuticals. Drs Kelsey, Ruff, Ball and Allen and Ms Ahrbecker are employees and/or shareholders of Eli Lilly and Company. | |
| Unclear | Funding: unclear Conflicts of interest: not declared | |
| High | Funding: during the conduct of this research, Dr Pelham was supported by grants from the National Institute of Mental Health (NIMH) (MH48157, MH47390, MH45576, MH50467, MH53554, MH62946), NIAAA (AA06267, AA11873), National Institute on Drug Abuse (NIDA) (DA05605, DA12414), National Institute of Neurological Disorders and Stroke (NINDS) (NS39087), National Institute for Environmental Studies (NIES) (ES05015) and National Institute of Child Health and Human Development (NICHHD) (HD42080) Conflicts of interest: several trial authors have affiliations with medical companies | |
| High | Funding: Novartis Pharmaceuticals Corporation. Novartis Pharma has been helping with development of the manuscript. Conflicts of interest: several trial authors have received research support from, are speakers for, are consultants of, are on the Advisory Board, have served on the Speakers' Bureaus of or are employees of several pharmaceutical companies | |
| High | Funding: this trial was supported by funds from Neos Therapeutics, Inc, PI. Conflicts of interest: Carolyn R Sikes is affiliated with Neos Therapeutics, Inc. | |
| High | Funding: trial was funded by Purdue Pharma Conflict of interest: trial authors affiliated with medical industry | |
| High | Funding: trial funded by Ironshore Pharmaceuticals Conflict of interest: trial authors affiliated with the medical industry | |
| High | Funding: trial funded by Rhodes Pharmaceuticals LP. Conflict of interest: authors affiliated with medical industry | |
| High | Funding: supported by a grant from Shire‐Richwood Pharmaceuticals, Incorporated ‐ manufacturer of Adderall ‐ and from the National Institute of Mental Health (NIMH) Conflict of interest: not declared | |
| High | Funding: this work was supported by a local trust through a Tenovus Scotland initiative. Conflicts of interest: some trial authors have affiliations with different pharmaceutical companies | |
| High | Funding: Shire Development LLC Conflicts of interest: C Anderson, R Civil, N Higgins, A Lyne and L Squires are employees of Shire and own stock/stock options. Some trial authors have received compensation for serving as consultants or speakers, or they or the institutions they work for have received research support or royalties from different companies or organisations. | |
| Low | Funding: supported by a UMMS (University of Massachusetts Medical School) Small Grants Project Award Conflicts of interest: not declared | |
| Low | Funding: supported by the Medical Center Rehabilitation Hospital Foundation and the School of Medicine, University North Dakota; the Veterans Hospital; the Dakota Clinic; and The Neuropsychiatric Institute, Fargo, North Dakota Conflicts of interest: not declared | |
| Low | Funding: research was supported by a grant from the Izaak Walton Killam IWK Health Centre in Halifax, Nova Scotia Conflicts of interest: "none declared" | |
| Low | Funding: the Canadian Institutes of Health Research Conflicts of interest: there were no conflicts of interest of any trial investigator with the pharmaceutical or equipment manufacturers. | |
| High | Funding: trial was supported by Funding from McNeil Pediatrics, a division of McNeil‐PPC Incorporated Conflicts of interest: none declared | |
| High | Funding: trial by Novartis Conflicts of interest: no information on investigators | |
| High | Funding: trial was conducted and sponsored by MEDICE Arzneimittel Pütter GmbH & Co. KG as part of the drug approval process for Medikinet‐Retard Conflicts of interest: some trial authors have affiliations with medical companies | |
| Low | Funding: research was supported by Grant Number MA 6913, from the Medical Research Council of Canada Conflicts of interest: not declared | |
| Low | Funding: grants from the Medical Research Council of Canada and by William T Grant Foundation Faculty Scholar Program Conflicts of interest: none | |
| Unclear | Funding: unclear Conflict of interest: no conflicts of interest declared | |
| Low | Funding: the Child and Adolescent Psychiatry Department of Helse Fonna Hospital Haugesund, Helse Fonna Trust Haugesund, Norway Conflicts of interest: trial authors declare no potential conflicts of interests with regard to authorship or publication of this article. | |
| Low | Funding: National Institutes of Health (NIH) and National Institute of Mental Health (NIMH) Conflicts of interest: no evidence of conflicts of interest | |
| Low | Funding: National Institute of Mental Health (NIMH) grant MH62946 Conflicts of interest: supported only by National Institutes | |
| High | Funding: provided by Celltech Americas Incorporated, currently part of UCB (Union Chimique Belge) Conflicts of interest: Drs Hatch and DeCory and Miss Cameron were employees of Celltech at the time of this trial. Dr Findling received research support, acted as a consultant and/or served on a Speakers' Bureau for Abbott, AstraZeneca, Bristol‐Myers Squibb, Celltech‐Medeva, Forest, GlaxoSmithKline, Johnson & Johnson, Lilly, New River, Novartis, Otsuka, Pfizer, Sanofi‐Synthelabo, Shire, Solvay and Wyeth. Dr Quinn claims no competitive interests. Dr McDowell has consulted for Janssen‐Cilag and Lilly. | |
| High | Funding: the Stanley Medical Research Institute Conflicts of interest: some trial authors have affiliations with pharmaceutical companies | |
| High | Funding: Shire Development Incorporated, Wayne, Pennsylvania Conflicts of interest: some trial authors received research support, acted as consultants and/or served on a Speakers' Bureau for several pharmaceutical companies. | |
| High | Funding: Shire Development Incorporated, which was involved in trial design, conduct and data analysis. The open‐label trial was industry‐sponsored. Conflicts of interest: Dr Findling has acted as consultant to, has served on Speakers' Bureaus of and/or has received research support from Abbott, Addrenex, AstraZeneca, Biovail, Bristol‐Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, KemPharm, Johnson & Johnson, Lundbeck, Neuropharm, Novartis, Noven, Organon, Otsuka, Pfizer, Sanofi‐Aventis, Sepracor, Shire, Solvay, Supernus, Validus and Wyeth. Dr. Turnbow receives or has received research support, acted as a consultant and/or served on Speakers' Bureaus for Eli Lilly, Novartis US, Sanofi‐Aventis, Shire and UCB (Union Chimique Belge). Dr Burnside has acted as consultant to, has served on Speakers’ Bureaus of and/or has received research support from Eli Lilly, Johnson & Johnson, Shire and Wyeth. Dr Melmed has acted as consultant to, has served on Speakers' Bureaus of and/or has received research support from Bristol‐Myers, Eli Lilly, McNeil, Novartis and Shire. Drs Civil and Li are full‐time employees of Shire Development Incorporated. | |
| High | Funding: CIBA‐GEIGY Canada Conflicts of interest: not declared | |
| Low | Funding: Ministry of Health Conflicts of interest: not stated | |
| Low | Funding: National Institute of Mental Health (NIMH) grant MH38118 Conflicts of interest: not declared | |
| Low | Funding: none (no funding was available). This double‐blind placebo‐controlled (DBPC) trial of methylphenidate was performed as a clinical treatment program as best clinical practice to determine the effects of methylphenidate and optimal dose compared with placebo. Conflicts of interest: no affiliations with pharmaceutical companies or similar declared. | |
| Low | Funding: Florida International University Conflicts of interest: nothing declared for trial investigators | |
| Low | Funding: National Institute of Mental Health (NIMH) grant MH38686 Conflicts of interest: no affiliations described | |
| High | Funding: National Institute of Mental Health (NIMH) and Cincinnati Children’s Hospital Center for Education and Research Therapeutics Award Conflicts of interest: Dr Epstein receives Funding from Eli Lilly and Co. Dr Stein has received research support from Eli Lilly and Co., McNeil Pharmaceuticals, Novartis and Shire. He has served on a Speakers' Bureau for Novartis and has served as consultant to Novartis, Shire and Shinogi Pharmaceuticals. | |
| High | Funding: data collection for the project was supported by the National Institute of Mental Health (Bethesda, MD) by R01MH074770 [Epstein] and K23MH083881 [Froehlich], while investigators’ time on the project was funded by National Institute of Mental Health K24MH064478 [Epstein], K23MH083027 [Brinkman], and R01MH070564 [Stein]). Conflicts of interest: trial authors are affiliated with the medical industry | |
| Unclear | Funding: Ciba Pharmaceutical Company supplied methylphenidate placebo Conflicts of interest: not declared | |
| Low | Funding: research grants from the Tourette Syndrome Association and the National Institute of Mental Health (NIMH) Conflicts of interest: not declared | |
| Low | Funding: this trial was supported in part by a research grant from the Tourette Syndrome Association Incorporated, and by Public Health Service (PHS) grant number MH45358 from the National Institute of Mental Health (NIMH). Conflicts of interest: trial authors have no financial relationships to disclose. | |
| Unclear | Funding: National Institute of Mental Health (NIMH) and the Tourette Syndrome Association Incorporated. CIBA Pharmaceutical Company supplied methylphenidate placebos. Novartis supplied immediate‐release methylphenidate. Conflicts of interest: "Kenneth D. Gadow is a shareholder in Checkmate Plus, publisher of the Child Symptom Inventory‐4" | |
| Low | Funding: Ontario Mental Health Foundation Conflicts of interest: none | |
| High | Funding: supported by National Institute of Mental Health (NIMH) Grant, Number K23 MH066835 Conflicts of interest: 4 trial authors are involved in the pharmaceutical sector. | |
| Low | Funding: National Institute of Mental Health (NIMH) Conflicts of interest: trial authors have no financial relationships to declare | |
| Low | Funding: the Basil O’Connor Starter Scholar Research Award of the March of Dimes, NARSAD (National Alliance for Research in Schizophrenia and Affective Disorders) Young Investigator Award, the Marguerite Stolz Award from the Sackler Faculty of Medicine and the National Institute on Drug Abuse (NIDA) Conflicts of interest: trial authors have had no institutional or corporate/commercial relationships for the past 36 months that might pose a conflict of interest. | |
| High | Funding: Celltech Pharmaceuticals Incorporated Conflicts of interest: Dr Greenhill is a consultant for Celltech‐Medeva and a member of its medical advisory board. Drs Findling and Swanson are consultants for Celltech‐Medeva. | |
| High | Funding: Novartis Conflicts of interest: 2 trial authors are employed by Novartis. Only Roberta R Ball has no conflicts of interest. | |
| Low | Funding: this was not an industry‐supported trial. Conflicts of interest: trial authors have indicated no financial conflicts of interest. | |
| Low | Funding: research part funded by the Neuropsychiatric Research Institute, Fargo, North Dakota, USA Conflicts of interest: trial authors disclose no conflicts of interest | |
| Low | Funding: supported by grants from the National Institute of Mental Health (NIMH) and from the National Institute on Drug Abuse (NIDA) Conflicts of interest: no conflicts declared | |
| Low | Funding: no funding to conduct the trial was received from any party. Conflicts of interest: none of the trial authors are affiliated with pharmaceutical companies. | |
| Low | Funding: National Institutes of Health (NIH) Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: this work is supported by Orient Pharma Co, Ltd. Conflicts of interest: authors affiliated with medical industry | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: this trial was supported by several grants from the National Institute of Mental Health, Bethesda, Maryland. Conflicts of interest: several trial authors have affiliations with medical companies. | |
| Unclear | Funding: not declared. During the writing of this report, C Johnston was supported by a Doctoral Fellowship from the Social Sciences and Humanities Research Council of Canada. Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Unclear | Funding: CIBA Geigy Pharmaceuticals provided placebos Conflicts of interest: not declared | |
| Low | Funding: this work was supported by the John and Maxine Bendheim Fellowship and by the Leon Lowenstein Foundation. Conflicts of interest: not declared | |
| High | Funding: Ms Kent was a summer medical student supported in part by the IWK Grace Research Foundation, Halifax, NovaScotia, and by the Pharmaceutical Manufacturers Association of Canada Studentship, Ottawa, Ontario Conflicts of interest: trial authors sponsored by Pharmaceutical Manufacturers’ Association of Canada Studentship | |
| Low | Funding: National Institute of Mental Health (NIMH) grant MH38118 Conflicts of interest: no corporate affiliations declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding:
Conflicts of interest:
| |
| High | Funding: clinical research was funded by KemPharm, Inc. Funding for editorial and writing assistance in the form of proofreading, copyediting, and fact‐checking was provided by Corium, Inc. Conflicts of interest: authors affiliated with medical industry | |
| Low | Funding: the German Society for the Advancement of Scientific Research (DFG grant KFO112) Conflicts of interest: none declared | |
| Low | Funding: provided through a grant from the German Research Foundation (DFG grant: KFO112–TP5) Conflicts of interest: none declared | |
| High | Funding: unclear, but Shire was a collaborator Conflicts of interest: the second trial author has some affiliation to the medical industry. | |
| Low | Funding: Shalvata Mental Health Center Conflicts of interest: “The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.” | |
| High | Funding: not declared Conflicts of interest: Dr Waxmonsky has served on the Speakers' Board for Novartis, received an honorarium from Shire and received research support from Shire and Eli Lilly. Dr Erbe has received educational and research support from Genzyme Corporation. Dr Pelham was paid an honorarium by Shire Pharmaceuticals. | |
| High | Funding: Medice Arzneimittel Pütter GmbH & Co. KG, Kuhloweg 37, D‐58638 Iserlohn Conflicts of interest: Dr Doepfner is a consultant for Lilly, Medice, Novartis and Union Chimique Belge; serves on the Advisory Boards of Lilly, Medice, Shire, Novartis and Union Chimique Belge; participates as a member of the Speakers' Bureaus of Lilly, Medice, Janssen‐Cilag and Union Chimique Belge; and has research contracts with Lilly, Medice, Novartis, Union Chimique Belge, the German Research Foundation and the Federal Ministry of Health. Dr Lehmkuhl is on the Advisory Boards of Lilly and Medice. Dr Sinzig has no financial relationships to disclose. | |
| Unclear | Funding: not declared Conflicts of interest: none declared | |
| High | Funding: Ely Lilly Conflicts of interest: 5 authors work for Lilly. | |
| High | Funding: Novartis Conflicts of interest: Dr Silva is a consultant and a member of the Speakers' Bureau for Novartis. Dr Lopez is a consultant for Eli Lilly, Novartis and Shire. He is also a member of the Speakers' Bureaus for Novartis and Shire. | |
| Unclear | Funding: not declared Conflits of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: in part by from Shire Pharmaceutical Development Incorporated to Dr Faraone Conflicts of interest: trial authors acknowledge partial support to the second author from the National Institute on Drug Abuse (NIDA) (grants R01‐DA07957 and MCJ‐390592) and from the Maternal and Child Health Program, Health Resources and Service Administration, Department of Health and Human Services (grant 390715), and to the third author from the Stanley Foundation. | |
| Unclear | Funding: methylphenidate and placebo pills were supplied by Novartis Pharmaceuticals (São Paulo, Brazil) at no cost and without restrictions. No additional funding was requested or received from Novartis or any other commercial entity. Conflicts of interest: trial authors have reported no conflicts of interest | |
| Low | Funding: The Netherlands Organization for Health Research and development (ZonMw, grant 836011014) Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: National Institute of Mental Health (NIMH) Research Center grant P50MH077248, “Translational Research to Enhance Cognitive Control” Conflicts of interest: trial authors affiliated with the medical industry | |
| High | Funding: Shire US Inc Conflicts of interest: 2 medical writers acknowledged (Amy M Horton & Michelle Roberts) but were unclear about where they came from or what their role was in the publication. | |
| High | Funding: the Psychiatric Endowment Fund Conflicts of interest: trial authors had received Funding from Eli Lilly, Shire Pharmaceuticals, Janssen‐Ortho and McNeil Pharmaceuticals | |
| Unclear | Funding: not stated Conflicts of interest: trial authors declare that they have no conflict of interest | |
| Low | Funding: none Conflicts of interest: none declared | |
| High | Funding: "This study was funded by Novartis Pharmaceuticals Corporation and reports the following involvement: design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, and approval of the manuscript" Conflicts of interest: Dr Muniz is an employee of Novartis Pharmaceuticals Corporation. He has no other relationships to disclose. Dr Brams reports the following relationships: serves as speaker, consultant and Advisory Board member for Novartis and Shire; receives grant research support from Novartis, Shire and Eli Lilly. Dr Mao reports the following relationships: speaker for Novartis, Eli Lilly, Bristol‐Myers Squibb, AstraZeneca and Shire; consultant for Eli Lilly, Novartis and Shire; receives grant research support from Novartis. Mr McCague is an employee of Novartis Pharmaceuticals Corporation. He has no other relationships to disclose. Ms Pestreich is an employee of Novartis Pharmaceuticals Corporation. She has no other relationships to disclose. Dr Silva reports the following relationships: none since 15 December 2006; before that, she was a speaker for Novartis, AstraZeneca and Janssen; received grant/research support from Novartis and Celgene. | |
| High | Funding: Ortho‐McNeil Janssen Scientific Affairs, LLC Conflicts of interest: several trial authors had affiliations with pharmaceutical companies producing methylphenidate | |
| Low | Funding: Health Canada grant Conflicts of interest: none declared | |
| High | Funding: Novartis Conflicts of interest: no information on investigators | |
| Unclear | Funding: Children's Hospital Medical Center, Cincinnati Conflicts of interest: not stated | |
| High | Funding: Massachusetts General Hospital Conflicts of interest: trial investigators affiliated with the medical industry | |
| High | Funding: Eli Lilly and Company Conflicts of interest: Dr Newcorn receives grant support from Eli Lilly and McNeil; is a consultant and/or advisor for Eli Lilly, McNeil, Shire, Novartis and Sanofi‐Aventis; and is a member of Speakers' Bureaus for Eli Lilly and Novartis. Dr Kratochvil receives grant support from Abbott, Cephalon, Eli Lilly, McNeil, Pfizer, Shire and Somerset; receives from Eli Lilly trial medication for an NIMH (National Institute of Mental Health)‐funded trial; is a consultant for Abbott, AstraZeneca, Eli Lilly and Pfizer; and is a member of the Eli Lilly Speakers' Bureau. Dr Casat receives research Funding from Eli Lilly, Novartis and Abbott, and serves on an advisory board for Eli Lilly. Dr Allen and Dr Ruff are employees and shareholders of Eli Lilly. Dr Michelson and Dr Moore are former employees of Eli Lilly. | |
| High | Funding: Shire Conflicts of interest: trial authors affiliated with pharmaceutical companies | |
| High | Funding: Shire Conflicts of interest: trial authors heavily affiliated with pharmaceutical companies | |
| Low | Funding: the General Practice Evaluation Program, the Department of Health and Aged Care, Queensland Medical Laboratory, and the Royal Australian College of General Practitioners Conflicts of interest: trial authors have indicated that they have no financial relationships relevant to this article to disclose | |
| Low | Funding: University of South Dakota/USF‐Mini Grant Conflicts of interest: none declared | |
| Low | Funding: Netherlands Organisation for Scientific Research (NWO) Grant 575‐63‐082 Conflicts of interest: not declared | |
| High | Funding: NIH (National Institutes of Health) and NINDS (National Institute of Neurological Disorders and Stroke) Conflicts of interest: some trial authors are on the ADHD Advisory Board and the Speakers' Bureau of; are scientific consultants or principal or site investigators for; and/or have received educational or funding support from several pharmaceutical companies. | |
| Low | Funding: grant number MH072263 from National Institute of Mental Health (NIMH) Conflicts of interest: none declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: grants from the Shire Richwood Pharmaceutical Company and National Institute of Mental Health (Grants MH53554, MH45576 and MH50467) Conflicts of interest: not declared | |
| High | Funding: ALZA Corporation, the manufacturers of Concerta Conflicts of interest: Dr Pelham is a member of the ALZA advisory committee on Concerta and its development. Drs Hoffman and Lock are members of the ALZA paediatric advisory board. | |
| High | Funding: NIMH (Grant MH48157) Conflicts of interest: Pelham served as an advisor for ALZA Corporation (see Pelham 2001a) | |
| High | Funding: Noven Pharmaceuticals. Furthermore, Dr Pelham was supported by grants from NIAAA, NIDA, NIMH and NINDS. Conflicts of interest: several trial authors have received consulting fees and research funding and have been consultants and/or served on the Speakers' Bureaus of several pharmaceutical companies in the past year. | |
| High | Funding: grant from Noven Pharmaceuticals Conflicts of interest: Dr Pelham has served as a consultant for Shire, McNeil, Noven, Celltech/Medeva, Novartis and Abbott Laboratories; has received honoraria from Shire and Janssen and research support from Shire, Alza, Eli Lilly, Noven and Cephalon; and holds common stock in Abbott Laboratories. Dr Waxmonsky has served on the Speakers' Bureau for Novartis and has received research support from Eli Lilly and Shire Incorporated. Dr Hoffman has served on the advisory board and Speakers’ Bureau for Shire Pharmaceuticals and on the Speakers' Bureau for McNeil. Dr Ballow has received research support from GlaxoSmithKline, Panacos, Boehringer Ingelheim, Pharmasset, Jacobus and Pharmena. Dr Schentag has served as a consultant for or received support from Noven, Wyeth, Daiichi, Targanta Therapeutics and Astellas. Dr Gonzalez is a full‐time employee of P’Kinetics International Incorporated. No other conflicts of interest are known. | |
| Low | Funding: grant from the National Institute of Mental Health (MH62946). Dr Pelham was funded by grants from the National Institutes of Health (MH62946, MH69614, MH53554, MH69434, MH65899, MH78051, MH062946, NS39087, AA11873, DA12414, HD42080) and the Institute of Education Sciences (L03000665A). Dr Fabiano was supported in part by a Ruth S Kirschstein National Research Service Award Predoctoral Fellowship (1F31MH064243‐01A1) and by the Department of Education, Institute of Education Sciences (R324J06024, R324B06045). Conflicts of interest: not declared | |
| Low | Funding: none. Research was part of the work day, participants were voluntary and no funding was needed to implement the trial Conflicts of interest: none. Investigators are staff members at institutions (affiliations) reported in the paper. | |
| Low | Funding: National Institute of Mental Health (NIMH) Conflicts of interest: not declared | |
| High | Funding: Shire Richwood Incorporated Conflicts of interest: Dr Browne is currently with Watson Pharmaceuticals, Corona, California | |
| High | Funding: National Institute of Mental Health Grant R01 MH63986 Conflicts of interest: Pliszka received honoraria and research support from Shire and MacNeil and research support from Ely Lilly and Cephalon | |
| High | Funding: Ironshore Pharmaceuticals Conflicts of interest: trial authors affiliated with the medical industry | |
| High | Funding: Celgene Conflicts of interest: all trial authors disclosed that they have past and present affiliations with the pharmaceutical industry. | |
| High | Funding: the first phase was conducted as part of ordinary clinical practice at Neuropsychiatric Unit, Østfold Hospital Trust. The second and third phases, data analysis and preparation of manuscript were sponsored by South‐Eastern Norway Regional Health Authority, and also by Østfold Hospital Trust and National Resource Centre for ADHD, both under the umbrella of South‐Eastern Norway Regional Health Authority. Conflicts of interest: Henning Aabech is a member of the Strattera Advisory Board, Eli Lilly, Norway. | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Low | Funding: none, neither external nor internal. This project was supported in part by a Biomedical Research Support Grant (no. S07 RR05712), which was awarded to the first trial author by the Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health. Conflicts of interest: not declared | |
| Low | Funding: none Conflicts of interest: no financial, corporate or commercial relationships to disclose | |
| Unclear | Funding: not declared Conflict of interest: none | |
| High | Funding: OROS methylphenidate and matching placebo were supplied to the Clinical Trials Network contract pharmacy (EMINENT Services Corporation) by McNeil Consumer and Specialty Pharmaceuticals (distributor for Concerta), at no cost. Principal investigators are not employed by the organisation sponsoring the trial. No agreement between principal investigators and trial sponsor (or its agents) restricts the principal investigator's rights to discuss or publish trial results after the trial is complete Conflicts of interest: some trial authors have received research support from, served on Speakers' Bureaus of or acted as consultants for pharmaceutical companies. | |
| Low | Funding: the research was completed while Dr Rubinsten was a post‐doctoral fellow at the Hospital for Sick Children (HSC), in Toronto, Canada, and was supported by the Rothschild Fellowship from Israel. It was undertaken, in part, through funding received from the Canadian Institutes of Health (CIHR: grant #MOP 64312), a CIHR post‐doctoral fellowship, and the Canada Research Chairs Program (RT). Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: Medical Research Council of Canada, National Health Research Development Program of Canada and the Department of Psychiatry, The Hospital for Sick Children, Toronto. Placebo pills were provided by Ciba Geigy, Canada, Ltd Conflicts of interest: 2 trial authors have reported working as consultants for pharmaceutical companies, and 1 has furthermore received industry‐sponsored research grants. | |
| High | Funding: Purdue Pharma (Canada) Conflicts of interest: some trial authors are working for Purdue Pharma | |
| Low | Funding: this trial was funded by faculty resources of the Academic Medical Center, University of Amsterdam, and by grant 11.32050.26 from the European Research Area Network Priority Medicines for Children (Sixth Framework Programme). Dr Rombouts was supported by Vici (Netherlands Organisation for Scientific Research), and Dr Andersen was supported by grant DA‐015403 from the National Institute on Drug Abuse Conflicts of interest: Dr Niessen reported being cofounder, shareholder, and part‐time scientific officer of Quantib BV. No other disclosures were reported. Through personal correspondence it was clarified that Dr Niessen did not facilitate any part of the trial, but was involved in the data‐analysis of MRI imaging sequence technique used (arterial spin labelling). | |
| High | Funding: Novartis Pharma GmbH, Germany. Trial aimed at showing efficacy of Ritalin LA with purpose of obtaining marketing authorisation Conflicts of interest: almost all trial authors have received grants, research support or other kinds of financial support from the medical industry. | |
| High | Funding: grants from Le Fonds de la Recherche en Santé du Québec and the Canadian Institutes of Health Research Conflicts of interest: yes. Dr Joober is a principal investigator on a clinical trial not related to this trial that is sponsored by AstraZeneca Canada Incorporated, and receives no direct compensation for this trial. Dr Boivin has the following industry financial ties: The Litebook Company Ltd., Medicine Hat, Alberta, Canada; and Pulsar Informatics Inc., Vancouver, British Columbia, Canada. | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: National Institute of Mental Health Conflicts of interest: "In the past 3 years, James G. Waxmonsky has served on the Speakers Bureau for Novartis, received honoraria from Scepter, and received research support from Eli Lilly" | |
| High | Funding: Novartis Pharmaceuticals Corporation Conflicts of interest: all trial authors have been consultants, have received honoraria or have worked for Novartis. | |
| High | Funding: Novartis Conflicts of interest: some trial authors have affiliations with medical companies | |
| High | Funding: Novartis Conflicts of interest: some trial authors have affiliations with medical companies | |
| Low | Funding: grants from the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Child Health and Human Development Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Low | Funding: National Institute of Mental Health (NIMH) Grant MH 38228; Rafael Klorman Conflicts of interest: not declared | |
| High | Funding: the National Institute of Mental Health Conflicts of interest: 3 trial authors have served or received grants from pharmaceutical companies in the past. | |
| Low | Funding: Guilan University of Medical Sciences Conflicts of interest: none declared | |
| Low | Funding: the work was supported by the Smart Family Foundation. Conflicts of interest: no affiliations with pharmaceutical companies stated | |
| High | Funding: the National Institute of Mental Health, the General Clinical Research Center Program of the National Center for Research Resources and the National Institutes of Health, Department of Health and Human Services Conflicts of interest: Drs Stein, Robb, Conlon and Newcorn participate in the Speakers' Bureau for McNeil Consumer and Specialty Pharmaceuticals, and Drs Stein and Newcorn are members of the Concerta National Advisory Committee. | |
| High | Funding: investigator‐initiated trial sponsored by Novartis Pharmaceuticals, with additional support provided by the University of Illinois at Chicago (UIC) Center for Clinical and Translational Science (CCTS) Conflicts of interest: some trial authors are affiliated with pharmaceutical companies | |
| Low | Funding: National Association of School Psychologists Conflicts of interest: not declared | |
| Unclear | Funding: it was not clear who sponsored the trial, but someone did (see authors' affiliations). Conflicts of interest: Calvin R Sumner is an employee of and an equity holder for the trial sponsor. Virginia S Haynes, PhD, is an employee of 3i Global (Basking Ridge, NJ) and a paid consultant for the trial sponsor. Martin H Teicher, MD, PhD, served as paid consultant and clinical investigator for the sponsor. Jeffrey H Newcorn, MD, serves as advisor and consultant for Lilly, Ortho‐McNeil Janssen, Schering‐Plough and Shire. He receives research support from Lilly, Ortho‐McNeil Janssen and Shire. | |
| High | Funding: RESTRACOM graduate studentship for The Hospital for Sick Children Research Institute and Novartis Pharmaceuticals Conflicts of interest: not declared | |
| High | Funding: grant from Richwood Pharmaceutical Company Conflicts of interest: not declared | |
| High | Funding: ALZA Corporation, Palo Alto, California Conflicts of interest: not declared | |
| High | Funding: ALZA Corporation Conflicts of interest: not declared | |
| High | Funding: ALZA Corporation Conflicts of interest: not declared | |
| High | Funding: Celltech Pharmaceuticals Incorporated Conflicts of interest: some trial authors are consultants for pharmaceutical companies | |
| Unclear | Funding: A McKnight Land‐Grant Professorship to the first author Conflicts of interest: this work was supported, in part, by a McKnight Land‐Grant Professorship to Frank Symons. | |
| High | Funding: research funds from Hospital de Clínicas de Porto Alegre, FAPERGS and NOVARTIS Conflicts of interest: not declared | |
| High | Funding: "The ADHD outpatient program receives research support from Bristol‐Myers Squibb, Eli‐Lilly, Janssen‐Cilag and Novartis" Conflicts of interest: trial authors are consultants and speakers for various companies | |
| Low | Funding: jointly funded by Ontario Mental Health Foundation (Grant No. 963‐86/88) and Health and Welfare Canada (Grant No. 6606‐3166‐42) Conflict of interest: not declared | |
| Low | Funding: grant from the Canadian Psychiatric Research Foundation and a post‐doctoral fellowship by the Ontario Mental Health Foundation Conflicts of interest: not declared | |
| Low | Funding: the Canadian Psychiatric Research Foundation and the Medical Research Council of Canada Conflicts of interest: not declared | |
| Low | Funding: Medical Research Council of Canada and Health and Welfare Canada Conflicts of interest: nothing to declare | |
| Low | Funding: in part, by the Ontario Mental Health Foundation and the National Health Research and Development Program, Health Canada Conflicts of interest: not declared | |
| Unclear | Funding: an operating grant from the Canadian Institutes of Health Research (Grant # MT 13366), and by the donation of placebo medication from Novartis Pharmaceuticals Conflict of interest: none declared | |
| High | Funding: partially funded by grant from CIBA Ltd., which provided medicine and placebo Conflicts of interest: Dr Schachar was supported during this period by a fellowship from the Medical Research Council of Canada. | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: no conflicts of interest have been disclosed | |
| Unclear | Funding: none Conflicts of interest: not declared | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| Unclear | Funding: National Institute of Neurological Disorders and Stroke, the General Clinical Research Center, the National Center for Research Resources, the Tourette Syndrome Association Boeringer Ingelheim Inc. (particularly Dr Virgil Dias), for supplying clonidine and matching placebo; Bausch and Lomb, Inc., for supplying small gifts for our trial participants Conflicts of interest: none declared | |
| High | Funding: Novartis Pharmaceuticals Corporation Conflicts of interest: some trial authors were employed by Novartis (5 of 8 had a Novartis email address) | |
| Unclear | Funding: National Institutes of Mental Health (NIMH). Ciba‐Geigy provided medication and placebo Conflicts of interest: not declared | |
| Unclear | Funding: in part by a National Institute of Mental Health (NIMH) grant. Ciba‐Geigy provided medication and placebo Conflicts of interest: not declared | |
| Low | Funding: in part by funds from the Medical Research Council of Canada and the Research Institute of the Hospital for Sick Children Conflicts of interest: not declared | |
| High | Funding: grants from the Sophia Foundation for Medical Research and Boehringer Ingelheim BV, the Netherlands Conflicts of interest: not declared | |
| Low | Funding: The Veterans Administration Medical Center, Vermont Conflicts of interest: not declared | |
| Low | Funding: in part by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grants and the University of Southern California Faculty Research and Innovation Fund Conflicts of interest: not declared | |
| High | Funding: National Institute of Mental Health (NIMH) Grant MH62946 and a Klingenstein Third Generation Foundation Fellowship in Child and Adolescent Depression Research Conflicts of interest: several authors have affiliations with pharmaceutical companies | |
| High | Funding: Rhodes Pharmaceuticals, LP Conflict of interest: the trial authors are affiliated with the medical industry. | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: Celltech Americas Incorporated Conflicts of interest: some trial authors are working for Celltech Americas Incorporated | |
| High | Funding: Celgene Corporation Conflicts of interest: Dr Wigal reports extensive disclosure. | |
| High | Funding: Ortho‐McNeil‐Janssen Scientific Affairs, LLC. Phase IV trial Conflicts of interest: several trial authors had affiliations with pharmaceutical companies producing methylphenidate | |
| High | Funding: trial received funds from NextWave Pharmaceutics (Belden and Berry are with NextWave) Conflicts of interest: all trial authors are affiliated with NextWave Pharmaceuticals. | |
| High | Funding: Rhodes Pharmaceuticals LP Conflicts of interest: several trial authors work for, or have received grant and research support or both from pharmaceutical companies | |
| High | Funding: Rhodes Pharmaceuticals […]. Medical writing assistance was provided by Linda Wagner, PharmD, from Excel Scientific Solutions and funded by Rhodes Pharmaceuticals LP Conflicts of interest: not declared | |
| High | Funding: the research was sponsored by NextWave Pharmaceuticals, a wholly owned subsidiary of Pfizer, Inc. Conflicts of interest: trial authors are affiliated with the medical industry | |
| High | Funding: McNeil Consumer and Specialty Pharmaceuticals Conflicts of interest: several trial authors have had commitments (e.g. speakers, consultants, advisors) with various pharmaceutical companies | |
| High | Funding: Shire Development Incorporated Conflicts of interest: several trial authors have affiliations with medical companies | |
| High | Funding: trial and medication/placebo were funded by a grant through Shire Pharmaceuticals. Shire had no role in design, collection, analysis, interpretation, writing or decision to submit Conflicts of interest: some trial authors have received research support from medical companies | |
| Low | Funding: a University of Utah Biomedical Sciences research grant and a grant from the University Research Committee Conflicts of interest: no corporate affiliations described | |
| Unclear | Funding: not declared Conflicts of interest: not declared | |
| High | Funding: ALZA Corporation Conflicts of interest: trial authors are part of the Concerta Study Group | |
| Low | Funding: the Norwegian Medical Research Council, the Norwegian Public Health Association and the Legacy of Haldis and Josef Andresen Conflicts of interest: not declared | |
| High | Funding: research grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil) (Grant 471761=03‐6) and Hospital de Clinicas de Porto Alegre (GPPG 03‐325). Aripiprazole was provided by Bristol‐Myers Squibb without restriction. Conflicts of interest: stated, "this is an independent investigator trial"; however some study authors have affiliations with medical companies. | |
| ADHD: Attention deficit hyperactivity disorder; BV: besloten vennootschap (corresponding to a private limited liability company (LLC) in the USA); DFG: Deutsche Forschungsgemeinschaft; NIH: National Institutes of Health; Inc.: Incorporated; IWK: Izaak Walton Killam; LA: Long acting; Ldt.: Limited liability; LLC: Limited liability company; LP: Limited partnership; MRI: Magnetic resonance imaging; NIAAA: National Institute on Alcohol Abuse and Alcoholism; NIDA: National Institute on Drug Abuse; NIMH: National Institute of Mental Health; NINDS: National institute of Neurological Disorders and Stroke; OROS: osmotic‐release oral system; PI: Primary Investigator; ZonMw: Organisation for Health Research and Development in the Netherlands | ||
| Name of scale | Abbreviation | Reference |
|---|---|---|
| Abbreviated Conners’ Rating Scales, Parent (ACPRS) and Teacher (ACTRS), including Abbreviated Parent Rating Scale (APRS) and Teacher Rating Scale, Hyperkinesis Index and ADHD and Emotional Lability subscales | ACRS | |
| Abbreviated Symptom Questionnaire, including ASQ Teacher and ASQ Parent | ASQ | |
| Academic Performance Rating Scale | APRS | |
| The ADD/H Comprehensive Teacher Rating Scale | ACTeRS | |
| ADHD/ODD Rating Scale, Parent‐ and Teacher‐Rated | ADHD‐RS | |
| ADHD Rating Scale, including ADHD Rating Scale Parent and Teacher Ratings | ADHD‐RS | |
| ADHD Rating Scale‐IV, including ADHD Rating Scale‐IV Parent and Teacher Versions | ADHD‐RS‐IV | |
| Brief Psychiatric Rating Scale for Children | BPRS | |
| Child Attention Problems Rating Scale | CAP | |
| Child Attention Profile | CAP | |
| Child Behavior Rating Form | NCBHF | |
| Child Symptom Inventory | CSI | |
| Children’s Psychiatric Rating Scale | CPRS | |
| Conners’ Abbreviated Hyperactivity Questionnaire | C‐HI | |
| Conners’ Abbreviated Questionnaire | ASQ | |
| Conners’ Abbreviated Parent Teacher Questionnaire | APTQ | |
| Conners’ Abbreviated Rating Scale | ABRS | |
| Conners’ Abbreviated Symptom Questionnaire | ASQ | |
| Conners Abbreviated Symptom Questionnaire for Parents | ASQ‐Parent | |
| Conners’ Abbreviated Symptom Questionnaire for Teachers | ASQ‐Teacher | |
| Conners’ Abbreviated Teacher Rating Scale | ABTRS | |
| Conners’ ADHD/DSM‐IV Scales Adolescent | CADS‐A | |
| Conners’ ADHD/DSM‐IV Scales Parent | CADS–P, CADS‐P DSM‐IV | |
| Conners’ ADHD/DSM‐IV Scale Teacher, including Inattentive and Hyperactive‐Impulsive subscales | CADS‐T, CADS‐T DSM‐IV | |
| Conners’ Rating Scale ‐ Revised, Parent and Teacher: Hyperactivity and Conduct Factors score | CPRS‐R and CTRS‐R | |
| Conners’ Hyperactivity Index, Parent and Teacher, including abbreviated versions | CPRS/CTRS‐Hyperactivity index | |
| Conners’ Hyperkinesis Index | ‐ | |
| Conners, Loney and Milich Scale | CLAM | |
| Conners’ Parent and Teacher Rating Scale ‐ Revised, Short Form | CRS‐R:S | |
| Conners’ Parent Rating Scale, including abbreviated versions | CPRS | |
| Conners’ Parent Rating Scale ‐ Revised | CPRS‐R | |
| Conners’ Parent Rating Scale ‐ Revised, Short Form | CPRS‐R:S | |
| Conners’ Parent Rating Scale ‐ Revised, Long Version | CPRS‐R:L | |
| Conners’ Rating Scale ‐ Revised | CRS‐R | |
| Conners’ Short Form Rating Scale, Parent and Teacher | ‐ | |
| Conners’ Teacher Rating Scale | CTRS | |
| Conners’ Teacher Rating Scale ‐ Revised, Long Version | CTRS‐R:L | |
| Diagnostic and Statistical Manual of Mental Disorders Total | DSM‐IV | |
| Diagnostiksystem für Psychische Störungen im Kindes ‐ und Jugendalter nach ICD‐10 und DSM‐IV Parental Questionnaire of ADHD symptoms | DISYPS | |
| Fremdbeurteilungsbogen für Hyperkinetische Störungen | FBB‐HKS | |
| German Teacher’s report on ADHD symptoms | FBB‐HKS of the DISYPS | |
| Hyperactivity Index of the Revised Conners Parent and Teacher Rating Scales | ‐ | |
| IOWA Conners Parent Rating Scale, including abbreviated versions | IOWA CPRS | |
| IOWA Conners Teacher Rating Scale, including abbreviated versions | IOWA CTRS | |
| IOWA Conners Teacher Rating Scale, Inattention/Overactivity (I/O) and Oppositional/Defiant (O/D) subscales | IOWA‐I/O and O/D subscales | |
| IOWA Inattention/Overactivity and Aggression/Noncompliance scales ‐ Parent and Teacher rating | IOWA | |
| Lehrer‐Fragenbogen von Steinhausen | LF | |
| Loney’s Time on Task Scale, Hyperactivity, Attention and Aggression subscales | TOTS | |
| Modified Conner Scale Parent and Teacher | ACR | |
| Mothers’ Objective Method for Subgrouping | MOMS | |
| Parent Symptom Checklist | PSC ADHD | |
| Parental Account of Children’s Symptoms | PACS | |
| Restricted Academic Situation Scale | RASS | |
| Schedule for Affective Disorders and Schizophrenia | K‐SADS/ K‐SADS‐E for diagnosis | |
| Swanson, Nolan, and Pelham ‐ IV SNAP‐ADHD Rating scale | SNAP‐ADHD | |
| Swanson, Nolan, and Pelham ‐ IV SNAP‐IV (Brazilian Version) | SNAP‐IV | Clark 1993; Clark 1996 |
| Swanson, Kotkin, Atkins, M‐Flynn, Pelham Scale (SKAMP combined, SKAMP attention, and SKAMP deportment) | SKAMP (SKAMP combined, SKAMP attention, and SKAMP deportment) | |
| Teacher Self‐control Rating Scale | SCRS | |
| Turgay ‐ DSM‐IV Scale, Parent | T‐DSM‐IV Scale, Parent | |
| Turgay ‐ DSM‐IV Scale, Teacher | T‐DSM‐IV Scale, Teacher | |
| Teacher Hyperactivity Index | THI | |
| Teacher Symptom Checklist | TSC | |
| Vanderbilt ADHD Rating Scale | VADP(T)RS | |
| Wender Utah Rating Scale | WURS | |
| Wide Range Achievement Test | WRAT‐4 | |
| Wide Range Achievement Test Revised | WRAT‐R | |
| ADD/H: Attention deficit disorder/with hyperactivity; ADHD: Attention deficit hyperactivity disorder; DSM‐IV:Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ICD‐10:International Classification of Diseases, Tenth Edition; ODD: ODD | ||
| Name of scale | Abbreviation | Reference |
|---|---|---|
| Achenbach Child Behaviour Checklist | CBCL | |
| Achenbach’s Teacher Report | ATRF | |
| ADHD Rating Scale | ADHD‐RS | |
| ADHD School Observation Code | ADHD‐SOC | |
| Barkley Scales, Disruptive Behavior Disorders Rating Scale | ‐ | |
| Before School Functioning Questionnaire | BSFQ | |
| Behavior Rating Inventory of Executive Function | BRIEF | |
| Child Attention Problems Scale | CAP | |
| Child Attention Profile | CAP | |
| Child Behavior Checklist | CBCL | |
| Child Health Questionnaire | CHQ | |
| Child and Adolescent Psychiatric Assessment, selected items | CAPA | |
| Children’s Psychiatric Rating Scale | CPRS | |
| Classroom Observation Code (Abikoff Classroom Observational System) | COC | |
| Code for Observing Social Activity | COSA | |
| Conners' Child Behavior Scale | UC‐CCBS | |
| Conners Early Childhood Behavior—Parent Short Response scale | ‐ | |
| Conners' Global Index Scale | CGI‐S | |
| Conners’ Global Index ‐ Parent | CGI‐P | |
| Conners' Global Index ‐ Teacher | CGI‐T | |
| Conners', Loney and Milich Scale | CLAM | |
| Conners’ Parent Questionnaire | CPQ | |
| Conners’ Parent Rating Scale | CPRS | |
| Conners’ Teacher Rating Scale | CTRS | |
| Conners’ Teacher Rating Conduct Problems | ‐ | |
| Disruptive Behavior Disorders Rating Scale, Parent‐ and Teacher‐Rated | DBS | |
| Disruptive Behavior Disorders Rating Scale | DBD | |
| Groninger Behaviour Observation Scale | GOO and GBO | |
| Groninger Behaviour Checklists, Parent and Teacher Versions of the abbreviated Groninger | GGGS and GGBS | |
| Hillside Behavior Rating Scale | HBRS | |
| Home Situations Questionnaire | HSQ | |
| Home Situations Questionnaire ‐ Revised | HSQ‐R | |
| Humphrey’s Teacher Self‐Control Rating Scale | TSCRS | |
| Hyperactivity Index from the Conners Revised Teacher Rating Scale | CTRS‐R‐Hyperactivity Index | |
| Impairment Rating Scale | IRS | |
| Inpatient Global Rating Scale, Revised | IGRS | |
| Inpatient Global Rating Scale, Somatic factor | IGRS‐S | |
| IOWA Conners' Rating Scale, Oppositional/Defiant (O/D) subscales | IOWA‐O/D subscales | |
| Nisonger Child Behavior Rating Form | NCBRF | |
| Paired Associates Learning | PAL | |
| Parent Global Assessment for Improvement | PGA | |
| Parent Rating of Evening and Morning Behavior‐Revised, Morning | PREMP‐R AM | |
| Parent Rating of Evening and Morning Behavior‐Revised, Evening | PREMP‐R PM | |
| Peer Conflict Scale | PCS | |
| Personality Inventory for Children | PIC | |
| School Situations Questionnaire | SSQ | |
| School Situations Questionnaire ‐ Revised | SSQ‐R | |
| Retrospective Modified Overt Aggression Scale | R‐MOAS | |
| Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Scale, Parent and Teacher | SWAN | |
| Subjective Treatment Emergent Symptom Scale | STESS‐R | |
| Swanson, Nolan and Pelham, Fourth Edition | SNAP‐IV | |
| Teachers Report Form | TRF | |
| Telephone Interview Probe (Parent and Teacher) | TIP | |
| Vanderbilt ADHD rating scales: Vanderbilt ADHD Diagnostic Parent Rating Scale and Vanderbilt ADHD Diagnostic Teacher Rating Scale | VADPRS and VADTRS | |
| Wahler, House and Stambaugh’s Ecobehavioral Assessment System | ECO | |
| The Weekly Parent Ratings of Evening and Morning Behaviour | WREMB‐R | |
| Werry‐Weiss‐Peters Activity Rating Scale | WWP | |
| Woodcock‐Johnson Achievement Battery | WJ‐III Ach | |
| ADHD: attention deficit hyperactivity disorder | ||
| Name of scale | Abbreviation | Reference |
|---|---|---|
| ADHD Impact Module‐Child | AIM‐C | |
| Child Impact Scale and Home Impact Scale | CIS/HIS | |
| Child Health and Illness Profile, Child Edition: Parent Report Form | CHIP‐CE:PRF | |
| Child Health Questionnaire | CHQ‐P | |
| Children's Global Assessment Scale | CGAS | |
| Comprehensive Psychopathological Rating Scale | CPRS | |
| Health Utilities Index ‐ 2 | HUI‐2 | |
| The parent‐ and child‐rated Revised questionnaire for Children and adolescents to record health‐related quality of life | KINDL‐R | |
| ADHD: attention deficit hyperactivity disorder | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 All parallel‐group trials and first‐period cross‐over trials Show forest plot | 21 | 1728 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐0.88, ‐0.61] |
| 1.1.1 Low risk of bias | 3 | 206 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐1.11, ‐0.22] |
| 1.1.2 High risk of bias | 18 | 1522 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.90, ‐0.61] |
| 1.2 Subgroup analysis: types of scales Show forest plot | 20 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.2.1 Conners' Teacher Rating Scale (CTRS) | 9 | 470 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.82, ‐0.45] |
| 1.2.2 Abbreviated Conners' Rating Scale (ACRS) ‐ Teacher | 2 | 105 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐1.79, 0.29] |
| 1.2.3 Conners' Abbreviated Symptom Questionnaire for Teachers (ASQ‐Teacher) | 1 | 59 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.28 [‐0.79, 0.23] |
| 1.2.4 IOWA Conners' Teacher Rating Scale (IOWA CTRS) ‐ hyperactivity | 2 | 193 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.08 [‐1.39, ‐0.77] |
| 1.2.5 The Swanson, Nolan, and Pelham (SNAP) Scale ‐ Teacher | 2 | 328 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.61 [‐0.96, ‐0.25] |
| 1.2.6 Teacher ratings of attention | 1 | 20 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.55 [‐1.45, 0.35] |
| 1.2.7 Teacher ratings of impulsivity | 1 | 20 | Std. Mean Difference (IV, Random, 95% CI) | 0.04 [‐0.83, 0.92] |
| 1.2.8 IOWA Conners' Teacher Rating Scale ‐ Inattention/Overactivity (IOWA‐I/O) | 2 | 197 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.03 [‐1.36, ‐0.69] |
| 1.2.9 Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS) | 1 | 85 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.06 [‐1.52, ‐0.61] |
| 1.2.10 Conners’ ADHD/DSM‐IV Scales ‐ Teacher (CADS‐T) | 2 | 254 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.05 [‐1.31, ‐0.78] |
| 1.2.11 Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) Scale | 1 | 64 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.33 [‐0.82, 0.17] |
| 1.3 Subgroup analysis: duration of treatment Show forest plot | 21 | 1728 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐0.88, ‐0.61] |
| 1.3.1 Short term (up to 6 months) | 20 | 1475 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.77 [‐0.91, ‐0.64] |
| 1.3.2 Long term (over 6 months) | 1 | 253 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.47 [‐0.72, ‐0.22] |
| 1.4 Subgroup analysis: dose Show forest plot | 21 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.4.1 Low dose | 7 | 361 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.60 [‐0.82, ‐0.39] |
| 1.4.2 High dose | 8 | 766 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐1.00, ‐0.50] |
| 1.4.3 Unknown dose | 8 | 753 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.85 [‐1.02, ‐0.68] |
| 1.5 Subgroup analysis: medication status ‐ medication naive versus not medication naive Show forest plot | 11 | 882 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.76 [‐0.94, ‐0.59] |
| 1.5.1 Medication naive | 7 | 480 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.70 [‐0.88, ‐0.51] |
| 1.5.2 Not medication naive | 4 | 402 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.85 [‐1.20, ‐0.50] |
| 1.6 Subgroup analysis: trials with enrichment design compared with trials without enrichment design Show forest plot | 20 | 1679 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.89, ‐0.62] |
| 1.6.1 Trials with enrichment design of all participants | 8 | 1072 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐0.96, ‐0.53] |
| 1.6.2 Trials without enrichment design of all participants | 12 | 607 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.78 [‐0.96, ‐0.60] |
| 1.7 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials Show forest plot | 21 | 1728 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐0.88, ‐0.61] |
| 1.7.1 Parallel‐group trials | 19 | 1633 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.76 [‐0.90, ‐0.61] |
| 1.7.2 First‐period cross‐over trials | 2 | 95 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.57 [‐0.98, ‐0.15] |
| 1.8 Subgroup analysis: vested interest Show forest plot | 18 | 1460 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐0.90, ‐0.58] |
| 1.8.1 Low risk of vested interest | 4 | 186 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.49 [‐0.79, ‐0.20] |
| 1.8.2 High risk of vested interest | 14 | 1274 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.78 [‐0.96, ‐0.60] |
| 1.9 Subgroup analysis: type of control group Show forest plot | 21 | 1728 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐0.88, ‐0.61] |
| 1.9.1 Placebo control group | 17 | 1358 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.77 [‐0.92, ‐0.63] |
| 1.9.2 No‐intervention control group | 4 | 370 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.99, ‐0.24] |
| 1.10 Cross‐over trial (endpoint data) Show forest plot | 64 | 6341 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.88 [‐1.01, ‐0.75] |
| 1.10.1 Low risk of bias | 7 | 733 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.84, ‐0.40] |
| 1.10.2 High risk of bias | 57 | 5608 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.06, ‐0.77] |
| 1.11 Subgroup analysis: cross‐over trials (endpoint data): dose Show forest plot | 58 | 7403 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.82 [‐0.93, ‐0.71] |
| 1.11.1 Low dose | 43 | 4530 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.72 [‐0.86, ‐0.59] |
| 1.11.2 High dose | 31 | 2873 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.96 [‐1.15, ‐0.77] |
| 1.12 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data) Show forest plot | 81 | 7564 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.82 [‐0.87, ‐0.77] |
| 1.12.1 All parallel‐group trials and first‐period cross‐over trials | 21 | 1728 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.74 [‐0.84, ‐0.64] |
| 1.12.2 Cross‐over trials (endpoint data) | 60 | 5836 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.85 [‐0.90, ‐0.79] |
| 1.13 All parallel‐group trials and cross‐over trials: risk of bias Show forest plot | 81 | 7564 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.85 [‐0.96, ‐0.74] |
| 1.13.1 Low risk of bias | 8 | 518 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.68 [‐0.91, ‐0.45] |
| 1.13.2 High risk of bias | 73 | 7046 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.87 [‐0.99, ‐0.75] |
| 1.14 All parallel‐group trials and cross‐over trials: vested interest Show forest plot | 77 | 7212 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.85 [‐0.96, ‐0.73] |
| 1.14.1 Low risk of vested interest | 23 | 1446 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.83 [‐1.08, ‐0.58] |
| 1.14.2 High risk of vested interest | 54 | 5766 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.85 [‐0.98, ‐0.72] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 All parallel‐group trials and first‐period cross‐over trials Show forest plot | 22 | 3724 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐1.44, ‐0.77] |
| 2.1.1 Low risk of bias | 4 | 942 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐0.78, ‐0.03] |
| 2.1.2 High risk of bias | 18 | 2782 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.30 [‐1.70, ‐0.89] |
| 2.2 Subgroup analysis: types of scales Show forest plot | 22 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.2.1 Swanson, Kotkin, Agler, M‐Glynn and Pelham (SKAMP) Scale | 6 | 778 | Std. Mean Difference (IV, Random, 95% CI) | ‐2.79 [‐4.10, ‐1.47] |
| 2.2.2 ADHD Rating Scale (ADHD‐RS ) | 14 | 2802 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.60 [‐0.81, ‐0.38] |
| 2.2.3 Swanson, Nolan and Pelham (SNAP) Scale | 1 | 221 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.35 [‐0.61, ‐0.08] |
| 2.2.4 Unknown | 1 | 78 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.94 [‐1.41, ‐0.47] |
| 2.3 Subgroup analysis: duration of treatment Show forest plot | 22 | 3724 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐1.44, ‐0.77] |
| 2.3.1 Short term (up to 6 months) | 21 | 3503 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.15 [‐1.50, ‐0.80] |
| 2.3.2 Long term (over 6 months) | 1 | 221 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.35 [‐0.61, ‐0.08] |
| 2.4 Subgroup analysis: dose Show forest plot | 22 | 3724 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐1.44, ‐0.77] |
| 2.4.1 Low dose | 1 | 138 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.19 [‐0.52, 0.15] |
| 2.4.2 High dose | 17 | 3005 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.84 [‐1.13, ‐0.55] |
| 2.4.3 Unknown dose | 4 | 581 | Std. Mean Difference (IV, Random, 95% CI) | ‐2.57 [‐4.40, ‐0.74] |
| 2.5 Subgroup analysis: trials with enrichment design compared with trials without enrichment design Show forest plot | 22 | 3724 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐1.44, ‐0.77] |
| 2.5.1 Trials with enrichment design of all participants | 19 | 3245 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.24 [‐1.61, ‐0.87] |
| 2.5.2 Trials without enrichment design of all participants | 3 | 479 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.62, 0.17] |
| 2.6 Subgroup analysis: type of control group Show forest plot | 22 | 3724 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐1.44, ‐0.77] |
| 2.6.1 Placebo control group | 20 | 3200 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.58, ‐0.85] |
| 2.6.2 No‐intervention control group | 2 | 524 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.52, 0.23] |
| 2.7 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials Show forest plot | 22 | 3724 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐1.44, ‐0.77] |
| 2.7.1 Parallel‐group trials | 19 | 3550 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.17 [‐1.54, ‐0.80] |
| 2.7.2 First‐period cross‐over trials | 3 | 174 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.72 [‐1.03, ‐0.41] |
| 2.8 Cross‐over trials (endpoint data) Show forest plot | 22 | 3854 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.97 [‐1.11, ‐0.83] |
| 2.8.1 High risk of bias | 22 | 3854 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.97 [‐1.11, ‐0.83] |
| 2.9 Subgroup analysis: cross‐over trials (endpoint data): dose Show forest plot | 22 | 5257 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.88 [‐1.00, ‐0.76] |
| 2.9.1 Low dose | 17 | 3067 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.72 [‐0.86, ‐0.58] |
| 2.9.2 High dose | 13 | 2051 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.07 [‐1.27, ‐0.86] |
| 2.9.3 Unknown dose | 1 | 139 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.03 [‐1.39, ‐0.68] |
| 2.10 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data) Show forest plot | 42 | 7277 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.99 [‐1.18, ‐0.80] |
| 2.10.1 All parallel‐group trials and first‐period cross‐over trials | 21 | 3586 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.15 [‐1.50, ‐0.81] |
| 2.10.2 Cross‐over trials (endpoint data) | 21 | 3691 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.93 [‐1.07, ‐0.78] |
| 2.11 All parallel‐group trials and cross‐over trials: risk of bias Show forest plot | 42 | 7277 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.99 [‐1.18, ‐0.80] |
| 2.11.1 Low risk of bias | 4 | 942 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐0.78, ‐0.03] |
| 2.11.2 High risk of bias | 38 | 6335 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.06 [‐1.25, ‐0.86] |
| 2.12 All parallel‐group trials and cross‐over trials: vested interest Show forest plot | 43 | 7414 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.98 [‐1.17, ‐0.80] |
| 2.12.1 Low risk of vested interest | 6 | 600 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.96 [‐1.43, ‐0.48] |
| 2.12.2 High risk or unclear risk of vested interest | 37 | 6814 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.99 [‐1.19, ‐0.79] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 All parallel‐group trials and first‐period cross‐over trials Show forest plot | 27 | 2927 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.76, ‐0.50] |
| 3.1.1 Low risk of bias | 6 | 702 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.49 [‐0.71, ‐0.26] |
| 3.1.2 High risk of bias | 21 | 2225 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.66 [‐0.81, ‐0.51] |
| 3.2 Subgroup analysis: types of scales Show forest plot | 27 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 3.2.1 Conners' Parent Rating Scale (CPRS) | 8 | 800 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.53 [‐0.80, ‐0.26] |
| 3.2.2 ADHD Rating Scale ‐ Fourth Edition (ADHD‐RS‐IV) | 5 | 753 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.37 [‐0.53, ‐0.21] |
| 3.2.3 Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS) | 1 | 85 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.36, ‐0.46] |
| 3.2.4 Conners’ ADHD/DSM‐IV Scales ‐ Parent (CADS‐P) | 2 | 195 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.12 [‐1.44, ‐0.81] |
| 3.2.5 CADS‐P Inattentive subscale | 1 | 109 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.78 [‐1.17, ‐0.39] |
| 3.2.6 CADS‐P Hyperactivity subscale | 1 | 109 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.93 [‐1.32, ‐0.53] |
| 3.2.7 Clinican's Manual for the Assesment of Disruptive Behavior Disorders Rating Scale for Parents (Barkley) | 1 | 41 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.82, 0.41] |
| 3.2.8 Abbreviated Conners' Rating Scale (ACRS) ‐ Parent | 2 | 121 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.99, ‐0.25] |
| 3.2.9 Swanson, Nolan, and Pelham, Fourth Edition ‐ Parent (SNAP‐IV‐Parent) Scale | 4 | 390 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.59 [‐0.80, ‐0.39] |
| 3.2.10 Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) Scale | 1 | 86 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.43 [‐0.86, 0.00] |
| 3.2.11 IOWA Conners' Rating Scale ‐ Inattention/Overactivity (IOWA‐I/O) | 3 | 352 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.78 [‐1.35, ‐0.21] |
| 3.2.12 Parent Vanderbilt ADHD Rating Scale | 1 | 97 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐1.23, ‐0.11] |
| 3.3 Subgroup analysis: duration of treatment Show forest plot | 27 | 2927 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.76, ‐0.50] |
| 3.3.1 Short term (up to 6 months) | 25 | 2605 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.78, ‐0.49] |
| 3.3.2 Long term (over 6 months) | 2 | 322 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.56 [‐0.79, ‐0.34] |
| 3.4 Subgroup analysis: dose Show forest plot | 27 | 3075 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.61 [‐0.74, ‐0.48] |
| 3.4.1 Low dose | 4 | 254 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.51 [‐1.14, 0.13] |
| 3.4.2 High dose | 12 | 1650 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.58 [‐0.80, ‐0.37] |
| 3.4.3 Unknown dose | 13 | 1171 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐0.83, ‐0.51] |
| 3.5 Subgroup analysis: medication status ‐ medication naive versus not medication naive Show forest plot | 11 | 992 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.65 [‐0.87, ‐0.43] |
| 3.5.1 Medication naive | 7 | 544 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.58 [‐0.84, ‐0.32] |
| 3.5.2 Not medication naive | 4 | 448 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐1.16, ‐0.35] |
| 3.6 Subgroup analysis: trials with enrichment design compared with trials without enrichment design Show forest plot | 25 | 2803 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.77, ‐0.49] |
| 3.6.1 Trials with enrichment design of all participants | 13 | 2155 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.78, ‐0.48] |
| 3.6.2 Trials without enrichment design of all participants | 12 | 648 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.61 [‐0.88, ‐0.34] |
| 3.7 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials Show forest plot | 27 | 2927 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.76, ‐0.50] |
| 3.7.1 Parallel‐group trials | 25 | 2874 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.76, ‐0.49] |
| 3.7.2 First‐period cross‐over trials | 2 | 53 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.68 [‐1.25, ‐0.11] |
| 3.8 Subgroup analysis: type of control group Show forest plot | 27 | 2927 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.76, ‐0.50] |
| 3.8.1 Placebo control group | 19 | 2263 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.64 [‐0.80, ‐0.48] |
| 3.8.2 No‐intervention control group | 8 | 664 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.59 [‐0.84, ‐0.34] |
| 3.9 Cross‐over trials (endpoint data) Show forest plot | 45 | 4971 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.70 [‐0.86, ‐0.55] |
| 3.9.1 Low risk of bias | 8 | 853 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.56 [‐0.72, ‐0.40] |
| 3.9.2 High risk of bias | 37 | 4118 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.94, ‐0.57] |
| 3.10 Subgroup analysis: cross‐over trials (endpoint data): dose Show forest plot | 45 | 6155 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.76, ‐0.50] |
| 3.10.1 Low dose | 26 | 3242 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.58 [‐0.71, ‐0.45] |
| 3.10.2 High dose | 29 | 2508 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.90, ‐0.60] |
| 3.10.3 Unknown dose | 3 | 405 | Std. Mean Difference (IV, Random, 95% CI) | 0.19 [‐1.55, 1.93] |
| 3.11 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data) Show forest plot | 69 | 7838 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐0.78, ‐0.56] |
| 3.11.1 All parallel‐group trials and first‐period cross‐over trials | 27 | 2955 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.76, ‐0.50] |
| 3.11.2 Cross‐over trials (endpoint data) | 43 | 4883 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.71 [‐0.86, ‐0.55] |
| 3.12 All parallel‐group trials and cross‐over trials: risk of bias Show forest plot | 69 | 7503 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.68 [‐0.79, ‐0.57] |
| 3.12.1 Low risk of bias | 12 | 1234 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.53 [‐0.68, ‐0.39] |
| 3.12.2 High risk of bias | 57 | 6269 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.71 [‐0.84, ‐0.58] |
| 3.13 All parallel‐group trials and cross‐over trials: vested interest Show forest plot | 69 | 7503 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.68 [‐0.79, ‐0.57] |
| 3.13.1 Low risk of vested interest | 19 | 1187 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.69 [‐0.84, ‐0.54] |
| 3.13.2 High risk or unclear risk of vested interest | 50 | 6316 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.68 [‐0.82, ‐0.54] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Parallel‐group trials and first‐period cross‐over trials: comparison of raters Show forest plot | 46 | 7965 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.73 [‐0.85, ‐0.60] |
| 4.1.1 Teacher‐rated | 21 | 1759 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.90, ‐0.60] |
| 4.1.2 Independent assessor‐rated | 20 | 3601 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.88 [‐1.18, ‐0.58] |
| 4.1.3 Parent‐rated | 26 | 2605 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.64 [‐0.77, ‐0.51] |
| 4.2 Parallel‐group trials and first‐period cross‐over trials: age Show forest plot | 13 | 2374 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.93 [‐1.35, ‐0.50] |
| 4.2.1 2 to 6 years | 2 | 153 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.50 [‐0.82, ‐0.18] |
| 4.2.2 7 to 11 years | 5 | 623 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.77 [‐3.24, ‐0.29] |
| 4.2.3 12 to 18 years | 6 | 1598 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.48 [‐0.77, ‐0.19] |
| 4.3 Parallel‐group trials and first‐period cross‐over trials: comorbidity versus no comorbidity Show forest plot | 29 | 3433 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.69 [‐0.84, ‐0.54] |
| 4.3.1 ADHD with comorbidity | 20 | 2128 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐0.88, ‐0.47] |
| 4.3.2 ADHD without comorbidity | 9 | 1305 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.73 [‐0.91, ‐0.54] |
| 4.4 Parallel‐group trials and first‐period cross‐over trials: subtypes ADHD: ADHD Rating Scale (parent‐, teacher‐ or independent assessor‐rated) Show forest plot | 2 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.4.1 Combined ADHD | 2 | 559 | Std. Mean Difference (IV, Random, 95% CI) | 0.65 [‐1.30, 2.60] |
| 4.4.2 Inattentive ADHD | 1 | 204 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.31 [‐1.61, ‐1.01] |
| 4.5 Cross‐over trials: first‐period data versus endpoint data (parent‐, independent assessor‐ and teacher‐rated) Show forest plot | 4 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.5.1 First‐period data | 4 | 191 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.64 [‐0.93, ‐0.34] |
| 4.5.2 Endpoint data | 4 | 372 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.18, ‐0.65] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Proportions of participants with serious adverse events (SAE) Show forest plot | 26 | 3673 | Risk Ratio (IV, Random, 95% CI) | 0.80 [0.39, 1.67] |
| 5.2 Nervous system (including psychiatry) Show forest plot | 12 | 4199 | Risk Ratio (IV, Random, 95% CI) | 0.70 [0.29, 1.71] |
| 5.2.1 Aggression | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 0.50 [0.05, 5.49] |
| 5.2.2 Concussion | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 0.34 [0.01, 8.17] |
| 5.2.3 Loss of consciousness | 1 | 221 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.01, 8.02] |
| 5.2.4 Psychosis | 4 | 919 | Risk Ratio (IV, Random, 95% CI) | 0.81 [0.13, 5.12] |
| 5.2.5 Syncope | 3 | 741 | Risk Ratio (IV, Random, 95% CI) | 1.39 [0.23, 8.47] |
| 5.2.6 Suicidal ideation | 6 | 1032 | Risk Ratio (IV, Random, 95% CI) | 1.63 [0.07, 38.55] |
| 5.2.7 Suicidal behaviour | 2 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 5.2.8 Oppositional behaviour/negativism | 1 | 217 | Risk Ratio (IV, Random, 95% CI) | 0.17 [0.01, 4.04] |
| 5.2.9 Adjustment disorder | 1 | 230 | Risk Ratio (IV, Random, 95% CI) | 0.78 [0.03, 18.91] |
| 5.3 Digestive system Show forest plot | 2 | 414 | Risk Ratio (IV, Random, 95% CI) | 2.11 [0.22, 20.04] |
| 5.3.1 Appendicitis | 2 | 414 | Risk Ratio (IV, Random, 95% CI) | 2.11 [0.22, 20.04] |
| 5.4 Cardiovascular systems Show forest plot | 2 | 280 | Risk Ratio (IV, Random, 95% CI) | 1.02 [0.11, 9.65] |
| 5.4.1 Haematoma | 1 | 221 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.01, 8.02] |
| 5.4.2 Tachycardia | 1 | 59 | Risk Ratio (IV, Random, 95% CI) | 3.10 [0.13, 73.14] |
| 5.5 Respiratory systems Show forest plot | 1 | 606 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.11, 9.62] |
| 5.5.1 Bronchitis | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 0.34 [0.01, 8.17] |
| 5.5.2 Asthma | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 3.02 [0.12, 73.54] |
| 5.6 Urinary system Show forest plot | 2 | 578 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.14 [0.23, 19.81] |
| 5.6.1 Renal cyst | 1 | 275 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.06, 36.27] |
| 5.6.2 Kidney infection | 1 | 303 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.02 [0.12, 73.54] |
| 5.7 Skeletal and muscular system (including pain) Show forest plot | 1 | 221 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 8.02] |
| 5.7.1 Clavical fracture | 1 | 221 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 8.02] |
| 5.8 Immune system (including infections) Show forest plot | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 3.02 [0.12, 73.54] |
| 5.8.1 Cyst rupture | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 3.02 [0.12, 73.54] |
| 5.9 Other Show forest plot | 2 | 524 | Risk Ratio (IV, Random, 95% CI) | 1.00 [0.10, 9.55] |
| 5.9.1 Drug toxicity | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 0.34 [0.01, 8.17] |
| 5.9.2 Overdose | 1 | 221 | Risk Ratio (IV, Random, 95% CI) | 2.97 [0.12, 72.20] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Proportion of participants with serious adverse events (SAE) Show forest plot | 16 | 3323 | Risk Ratio (IV, Random, 95% CI) | 2.46 [0.50, 12.03] |
| 6.2 Nervous system (including psychiatry) Show forest plot | 2 | 304 | Risk Ratio (IV, Random, 95% CI) | 2.05 [0.22, 19.14] |
| 6.2.1 Hallucinations | 1 | 37 | Risk Ratio (IV, Random, 95% CI) | 1.33 [0.06, 30.42] |
| 6.2.2 Psychiatric disorder | 1 | 267 | Risk Ratio (IV, Random, 95% CI) | 3.21 [0.13, 78.04] |
| 6.3 Urinary system Show forest plot | 1 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.12, 72.37] |
| 6.3.1 Proteinuria | 1 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.12, 72.37] |
| 6.4 Immune system Show forest plot | 1 | 644 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.93 [0.31, 27.99] |
| 6.4.1 Peritonsillar abscess | 1 | 322 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.93 [0.12, 71.32] |
| 6.4.2 Oral bullae | 1 | 322 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.93 [0.12, 71.32] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Proportion of participants with non‐serious adverse events Show forest plot | 35 | 5342 | Risk Ratio (IV, Random, 95% CI) | 1.23 [1.11, 1.37] |
| 7.2 Subgroup analysis: proportion of participants with non‐serious adverse events according to dose Show forest plot | 32 | 4718 | Risk Ratio (IV, Random, 95% CI) | 1.24 [1.12, 1.37] |
| 7.2.1 Low dose | 3 | 289 | Risk Ratio (IV, Random, 95% CI) | 1.02 [0.97, 1.07] |
| 7.2.2 High dose | 22 | 3365 | Risk Ratio (IV, Random, 95% CI) | 1.23 [1.14, 1.32] |
| 7.2.3 Unknown dose | 8 | 1064 | Risk Ratio (IV, Random, 95% CI) | 1.37 [0.93, 2.02] |
| 7.3 Nervous system (including psychiatry) Show forest plot | 37 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 7.3.1 Affective | 4 | 456 | Risk Ratio (IV, Random, 95% CI) | 2.39 [0.48, 11.96] |
| 7.3.2 Aggression | 3 | 503 | Risk Ratio (IV, Random, 95% CI) | 1.23 [0.30, 5.08] |
| 7.3.3 Apathy | 1 | 59 | Risk Ratio (IV, Random, 95% CI) | 0.80 [0.19, 3.33] |
| 7.3.4 Confusion or confusional state | 3 | 823 | Risk Ratio (IV, Random, 95% CI) | 0.75 [0.17, 3.24] |
| 7.3.5 Depression | 1 | 59 | Risk Ratio (IV, Random, 95% CI) | 0.83 [0.22, 3.10] |
| 7.3.6 Dizziness | 11 | 2149 | Risk Ratio (IV, Random, 95% CI) | 1.77 [0.95, 3.30] |
| 7.3.7 Drowsiness | 4 | 811 | Risk Ratio (IV, Random, 95% CI) | 1.27 [0.82, 1.98] |
| 7.3.8 Emotional lability | 5 | 624 | Risk Ratio (IV, Random, 95% CI) | 1.24 [0.54, 2.85] |
| 7.3.9 Fatigue | 14 | 2228 | Risk Ratio (IV, Random, 95% CI) | 0.67 [0.44, 1.02] |
| 7.3.10 Headache | 32 | 5041 | Risk Ratio (IV, Random, 95% CI) | 1.33 [1.04, 1.70] |
| 7.3.11 Irritability | 20 | 3290 | Risk Ratio (IV, Random, 95% CI) | 1.05 [0.82, 1.34] |
| 7.3.12 Nervousness | 2 | 362 | Risk Ratio (IV, Random, 95% CI) | 2.52 [0.82, 7.76] |
| 7.3.13 Pain | 1 | 132 | Risk Ratio (IV, Random, 95% CI) | 1.91 [0.21, 17.60] |
| 7.3.14 Picking at skin or fingers, nail biting, lip or cheek chewing | 5 | 686 | Risk Ratio (IV, Random, 95% CI) | 0.97 [0.60, 1.57] |
| 7.3.15 Sad, tearful or depressed | 7 | 1015 | Risk Ratio (IV, Random, 95% CI) | 1.47 [0.95, 2.28] |
| 7.3.16 Thirst | 2 | 179 | Risk Ratio (IV, Random, 95% CI) | 3.00 [0.13, 71.82] |
| 7.3.17 Dull, tired, listless | 1 | 110 | Risk Ratio (IV, Random, 95% CI) | 1.70 [0.51, 5.68] |
| 7.3.18 Tics or nervous movements | 12 | 1556 | Risk Ratio (IV, Random, 95% CI) | 0.77 [0.27, 2.22] |
| 7.3.19 Worried or anxious | 3 | 596 | Risk Ratio (IV, Random, 95% CI) | 1.37 [0.84, 2.25] |
| 7.3.20 Feeling jittery | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.52 [0.05, 5.56] |
| 7.3.21 Malaise | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.3.22 Dysgeusia | 2 | 171 | Risk Ratio (IV, Random, 95% CI) | 0.79 [0.19, 3.30] |
| 7.3.23 Lethargy | 2 | 224 | Risk Ratio (IV, Random, 95% CI) | 0.69 [0.40, 1.17] |
| 7.3.24 Aphonia | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.3.25 Psychomotor hyperactivity | 3 | 522 | Risk Ratio (IV, Random, 95% CI) | 3.67 [0.61, 22.01] |
| 7.3.26 Syncope | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.3.27 Tremor | 3 | 231 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.3.28 Social withdrawal | 1 | 110 | Risk Ratio (IV, Random, 95% CI) | 2.56 [0.24, 26.71] |
| 7.3.29 Sedation | 1 | 138 | Risk Ratio (IV, Random, 95% CI) | 1.30 [0.66, 2.53] |
| 7.3.30 Mood swings | 2 | 247 | Risk Ratio (IV, Random, 95% CI) | 2.53 [0.94, 6.82] |
| 7.3.31 Anger | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.3.32 Anxiety | 2 | 180 | Risk Ratio (IV, Random, 95% CI) | 0.64 [0.08, 5.08] |
| 7.3.33 Change in sustained attention | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.3.34 Emotional poverty | 2 | 175 | Risk Ratio (IV, Random, 95% CI) | 3.47 [0.37, 32.68] |
| 7.3.35 Trichotillomania | 1 | 85 | Risk Ratio (IV, Random, 95% CI) | 2.80 [0.12, 66.85] |
| 7.3.36 Stuttering | 1 | 94 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.01, 7.98] |
| 7.3.37 Emotional disorder | 2 | 174 | Risk Ratio (IV, Random, 95% CI) | 0.42 [0.02, 10.16] |
| 7.3.38 Negativism | 2 | 174 | Risk Ratio (IV, Random, 95% CI) | 3.83 [0.16, 91.41] |
| 7.3.39 Migraine | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.3.40 Tension | 1 | 60 | Risk Ratio (IV, Random, 95% CI) | 23.00 [1.42, 373.44] |
| 7.4 Digestive system Show forest plot | 34 | 22299 | Risk Ratio (IV, Random, 95% CI) | 1.81 [1.54, 2.14] |
| 7.4.1 Change in appetite | 1 | 94 | Risk Ratio (IV, Random, 95% CI) | 0.78 [0.32, 1.92] |
| 7.4.2 Decreased appetite | 30 | 5127 | Risk Ratio (IV, Random, 95% CI) | 3.35 [2.49, 4.50] |
| 7.4.3 Increased appetite | 2 | 265 | Risk Ratio (IV, Random, 95% CI) | 0.15 [0.02, 1.34] |
| 7.4.4 Change in weight | 1 | 94 | Risk Ratio (IV, Random, 95% CI) | 0.40 [0.08, 1.96] |
| 7.4.5 Increased weight | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.4.6 Decreased weight | 11 | 2001 | Risk Ratio (IV, Random, 95% CI) | 5.44 [2.47, 11.98] |
| 7.4.7 Dyspepsia | 5 | 390 | Risk Ratio (IV, Random, 95% CI) | 0.71 [0.16, 3.19] |
| 7.4.8 Upper abdominal pain | 10 | 1745 | Risk Ratio (IV, Random, 95% CI) | 1.25 [0.79, 1.96] |
| 7.4.9 Stomachache (abdominal pain) | 18 | 3069 | Risk Ratio (IV, Random, 95% CI) | 1.19 [0.94, 1.50] |
| 7.4.10 Vomiting | 20 | 3105 | Risk Ratio (IV, Random, 95% CI) | 1.26 [0.85, 1.86] |
| 7.4.11 Constipation | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.4.12 Oral pain | 2 | 171 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.4.13 Retching | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.4.14 Diarrhoea | 8 | 1088 | Risk Ratio (IV, Random, 95% CI) | 0.83 [0.35, 1.94] |
| 7.4.15 Dry mouth | 4 | 1057 | Risk Ratio (IV, Random, 95% CI) | 3.79 [1.26, 11.39] |
| 7.4.16 Nausea | 19 | 3484 | Risk Ratio (IV, Random, 95% CI) | 1.40 [1.00, 1.95] |
| 7.4.17 Flatulence | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.4.18 Gastritis | 1 | 89 | Risk Ratio (IV, Random, 95% CI) | 3.83 [0.16, 91.40] |
| 7.4.19 Gastrointestinal concerns (unspecified) | 1 | 94 | Risk Ratio (IV, Random, 95% CI) | 1.00 [0.06, 15.52] |
| 7.4.20 Polydipsia | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.5 Cardiovascular system Show forest plot | 12 | 3047 | Risk Ratio (IV, Random, 95% CI) | 1.41 [0.81, 2.46] |
| 7.5.1 ECG: prolonged QT‐interval | 2 | 466 | Risk Ratio (IV, Random, 95% CI) | 0.81 [0.13, 5.00] |
| 7.5.2 ECG: tachycardia | 5 | 686 | Risk Ratio (IV, Random, 95% CI) | 0.66 [0.20, 2.22] |
| 7.5.3 Increased diastolic blood pressure | 1 | 119 | Risk Ratio (IV, Random, 95% CI) | 1.07 [0.43, 2.68] |
| 7.5.4 Increased systolic blood pressure | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.5.5 Increased heart rate | 2 | 422 | Risk Ratio (IV, Random, 95% CI) | 4.99 [0.86, 28.85] |
| 7.5.6 Supraventricular extrasystoles | 1 | 17 | Risk Ratio (IV, Random, 95% CI) | 3.00 [0.11, 84.55] |
| 7.5.7 Ventricular arrhythmia | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.5.8 Epistaxis | 3 | 303 | Risk Ratio (IV, Random, 95% CI) | 1.71 [0.29, 10.07] |
| 7.5.9 Increased blood pressure | 2 | 414 | Risk Ratio (IV, Random, 95% CI) | 2.72 [0.00, 7037727483218459000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000.00] |
| 7.5.10 Orthostatic hypotension | 1 | 329 | Risk Ratio (IV, Random, 95% CI) | 2.72 [0.00, 7037727483218459000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000.00] |
| 7.5.11 Palpitations | 1 | 60 | Risk Ratio (IV, Random, 95% CI) | 11.00 [0.64, 190.54] |
| 7.5.12 Pallor | 1 | 60 | Risk Ratio (IV, Random, 95% CI) | 23.00 [1.42, 373.44] |
| 7.6 Respiratory system Show forest plot | 13 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 7.6.1 Pharyngolaryngeal pain | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 1.12 [0.59, 2.13] |
| 7.6.2 Upper respiratory tract infection | 3 | 421 | Risk Ratio (IV, Random, 95% CI) | 1.14 [0.56, 2.34] |
| 7.6.3 Bronchitis | 1 | 85 | Risk Ratio (IV, Random, 95% CI) | 0.31 [0.01, 7.43] |
| 7.6.4 Oropharyngeal pain | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 7.33 [0.39, 137.67] |
| 7.6.5 Rhinorrhoea | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 5.23 [0.26, 105.88] |
| 7.6.6 Allergic bronchitis | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.6.7 Sneezing | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.6.8 Nasal congestion | 3 | 565 | Risk Ratio (IV, Random, 95% CI) | 1.24 [0.62, 2.48] |
| 7.6.9 Cough | 9 | 1656 | Risk Ratio (IV, Random, 95% CI) | 1.31 [0.62, 2.78] |
| 7.6.10 Shortness of breath | 2 | 179 | Risk Ratio (IV, Random, 95% CI) | 3.00 [0.13, 71.82] |
| 7.7 Urinary system Show forest plot | 1 | 178 | Risk Ratio (M‐H, Random, 95% CI) | 3.83 [0.41, 36.08] |
| 7.7.1 Pollakiuria | 1 | 89 | Risk Ratio (M‐H, Random, 95% CI) | 3.83 [0.16, 91.40] |
| 7.7.2 Urinary incontinence | 1 | 89 | Risk Ratio (M‐H, Random, 95% CI) | 3.83 [0.16, 91.40] |
| 7.8 Skeletal and muscular systems (including pain) Show forest plot | 7 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 7.8.1 Arthralgia | 2 | 388 | Risk Ratio (IV, Random, 95% CI) | 0.67 [0.24, 1.84] |
| 7.8.2 Asthenia | 1 | 177 | Risk Ratio (IV, Random, 95% CI) | 0.21 [0.01, 4.25] |
| 7.8.3 Back pain | 3 | 474 | Risk Ratio (IV, Random, 95% CI) | 0.77 [0.38, 1.57] |
| 7.8.4 Myalgia | 3 | 474 | Risk Ratio (IV, Random, 95% CI) | 0.55 [0.22, 1.35] |
| 7.8.5 Toothache | 1 | 303 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.43, 2.35] |
| 7.8.6 Ligament strain | 1 | 85 | Risk Ratio (IV, Random, 95% CI) | 0.31 [0.01, 7.43] |
| 7.8.7 Muscle strain | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.8.8 Fractures | 1 | 94 | Risk Ratio (IV, Random, 95% CI) | 3.00 [0.13, 71.82] |
| 7.8.9 Muscle cramps | 1 | 94 | Risk Ratio (IV, Random, 95% CI) | 3.00 [0.13, 71.82] |
| 7.8.10 Pain in extremity | 1 | 89 | Risk Ratio (IV, Random, 95% CI) | 0.26 [0.01, 5.16] |
| 7.8.11 Pain | 1 | 132 | Risk Ratio (IV, Random, 95% CI) | 1.87 [0.22, 16.19] |
| 7.9 Immune system (including infections) Show forest plot | 17 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 7.9.1 Gastroenteritis | 5 | 606 | Risk Ratio (IV, Random, 95% CI) | 2.41 [0.66, 8.78] |
| 7.9.2 Influenza | 4 | 709 | Risk Ratio (IV, Random, 95% CI) | 0.55 [0.23, 1.30] |
| 7.9.3 Nasopharyngitis | 10 | 1623 | Risk Ratio (IV, Random, 95% CI) | 1.14 [0.76, 1.70] |
| 7.9.4 Otitis media | 3 | 271 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.15, 6.61] |
| 7.9.5 Pharyngitis | 5 | 614 | Risk Ratio (IV, Random, 95% CI) | 2.02 [0.55, 7.35] |
| 7.9.6 Pyrexia | 5 | 678 | Risk Ratio (IV, Random, 95% CI) | 0.68 [0.12, 3.81] |
| 7.9.7 Rhinitis | 1 | 132 | Risk Ratio (IV, Random, 95% CI) | 1.28 [0.43, 3.79] |
| 7.9.8 Upper respiratory tract infection ‐ not otherwise specified (NOS) | 12 | 1929 | Risk Ratio (IV, Random, 95% CI) | 0.95 [0.65, 1.39] |
| 7.9.9 Viral infection NOS | 5 | 1029 | Risk Ratio (IV, Random, 95% CI) | 0.97 [0.44, 2.14] |
| 7.9.10 Seasonal allergy | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.9.11 Streptococcal impetigo | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.9.12 Sinusitis | 1 | 89 | Risk Ratio (IV, Random, 95% CI) | 0.42 [0.02, 10.16] |
| 7.9.13 Cellulitis | 1 | 89 | Risk Ratio (IV, Random, 95% CI) | 0.42 [0.02, 10.16] |
| 7.9.14 Pleurisy | 1 | 275 | Risk Ratio (IV, Random, 95% CI) | 1.49 [0.06, 36.27] |
| 7.10 Integumentary system Show forest plot | 7 | 1455 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.37, 1.58] |
| 7.10.1 Purple spots | 1 | 94 | Risk Ratio (M‐H, Random, 95% CI) | 3.00 [0.13, 71.82] |
| 7.10.2 Skin disorder (rash) | 5 | 460 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.12, 4.96] |
| 7.10.3 Skin laceration | 3 | 474 | Risk Ratio (M‐H, Random, 95% CI) | 0.47 [0.18, 1.22] |
| 7.10.4 Burns second degree | 1 | 85 | Risk Ratio (M‐H, Random, 95% CI) | 2.80 [0.12, 66.85] |
| 7.10.5 Burns first degree | 1 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.10.6 Subcutaneous haematoma | 1 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.10.7 Periorbital haematoma | 1 | 0 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 7.10.8 Rash maculo‐papular | 1 | 0 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 7.11 Sleep variability Show forest plot | 29 | 7308 | Risk Ratio (IV, Random, 95% CI) | 1.57 [1.23, 2.02] |
| 7.11.1 Somnolence | 6 | 757 | Risk Ratio (IV, Random, 95% CI) | 0.87 [0.52, 1.46] |
| 7.11.2 Trouble sleeping or sleep problems | 15 | 2620 | Risk Ratio (IV, Random, 95% CI) | 1.62 [1.18, 2.21] |
| 7.11.3 Insomnia | 15 | 2315 | Risk Ratio (IV, Random, 95% CI) | 1.90 [1.12, 3.22] |
| 7.11.4 Initial insomnia | 5 | 917 | Risk Ratio (IV, Random, 95% CI) | 2.25 [0.89, 5.71] |
| 7.11.5 Middle insomnia | 2 | 171 | Risk Ratio (IV, Random, 95% CI) | 1.05 [0.07, 16.22] |
| 7.11.6 Sleep disorder | 2 | 528 | Risk Ratio (IV, Random, 95% CI) | 0.67 [0.22, 2.10] |
| 7.12 Sleep variability continuous outcomes Show forest plot | 2 | 943 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.01, 0.06] |
| 7.12.1 Sleep efficiency after treatment discontinuation (percentage) | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | 5.42 [0.21, 10.63] |
| 7.12.2 Sleep onset latency (min) | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐20.16 [‐45.74, 5.42] |
| 7.12.3 Total sleep time (min) | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | 30.82 [‐7.73, 69.37] |
| 7.12.4 Total in‐bed time (min) | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐2.07 [‐33.82, 29.68] |
| 7.12.5 Wake after sleep onset (min) | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐7.89 [‐22.87, 7.09] |
| 7.12.6 Number of wake bouts | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐0.66 [‐8.38, 7.06] |
| 7.12.7 Mean wake bout time (min) | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐0.17 [‐0.47, 0.13] |
| 7.12.8 Interdaily stability | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.06, 0.12] |
| 7.12.9 Interdaily variability | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.01, 0.07] |
| 7.12.10 Amount of activity during the 5 hours with the lowest activity | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐0.46 [‐1.62, 0.70] |
| 7.12.11 Amount of activity during the 10 hours with the highest activity | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐0.59 [‐3.57, 2.39] |
| 7.12.12 Amplitude of sleep‐wake rhythm | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐0.12 [‐2.87, 2.63] |
| 7.12.13 Pittsburgh Sleep Quality Index (PSQI) | 1 | 367 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.83, 1.03] |
| 7.13 Vital signs Show forest plot | 14 | 6407 | Mean Difference (IV, Random, 95% CI) | 2.12 [1.26, 2.98] |
| 7.13.1 Diastolic blood pressure (mmHg) | 13 | 2032 | Mean Difference (IV, Random, 95% CI) | 1.90 [0.68, 3.11] |
| 7.13.2 Systolic blood pressure (mmHg) | 13 | 2032 | Mean Difference (IV, Random, 95% CI) | 0.85 [‐0.20, 1.89] |
| 7.13.3 Pulse or heart rate (bpm) | 13 | 2205 | Mean Difference (IV, Random, 95% CI) | 3.86 [2.09, 5.63] |
| 7.13.4 ECG: changes in QTcB | 1 | 138 | Mean Difference (IV, Random, 95% CI) | ‐1.70 [‐7.94, 4.54] |
| 7.14 Physical parameters Show forest plot | 7 | 2425 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.97 [‐1.24, ‐0.70] |
| 7.14.1 Height | 1 | 215 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.06 [‐0.35, 0.22] |
| 7.14.2 Weight | 7 | 1400 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.13 [‐1.40, ‐0.85] |
| 7.14.3 BMI | 3 | 810 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.00 [‐1.26, ‐0.73] |
| 7.15 Other (including drug toxicity) Show forest plot | 9 | 4145 | Risk Ratio (IV, Random, 95% CI) | 1.13 [0.74, 1.72] |
| 7.15.1 Accidental injury | 3 | 656 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.48, 2.07] |
| 7.15.2 Excoriation | 2 | 389 | Risk Ratio (IV, Random, 95% CI) | 3.22 [1.20, 8.64] |
| 7.15.3 Overdose | 1 | 221 | Risk Ratio (IV, Random, 95% CI) | 2.97 [0.12, 72.20] |
| 7.15.4 Arthropod‐bite | 2 | 171 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.15.5 Contusion | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.12 [0.01, 2.10] |
| 7.15.6 Wound | 2 | 171 | Risk Ratio (IV, Random, 95% CI) | 0.73 [0.06, 9.22] |
| 7.15.7 Tinnitus | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 5.23 [0.26, 105.89] |
| 7.15.8 Dry eye | 2 | 171 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.15.9 Excessive eye blinking | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.15.10 Occular hyperaemia | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.15.11 Visual impairment | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.15.12 Red eyes | 1 | 94 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.01, 7.98] |
| 7.15.13 Conjunctival abrasion | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.15.14 Radius fracture | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.15.15 Snake bite | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 3.14 [0.13, 74.98] |
| 7.15.16 Enuresis | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.15.17 Night sweats | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.15.18 Abnormal liver function test | 1 | 85 | Risk Ratio (IV, Random, 95% CI) | 0.31 [0.01, 7.43] |
| 7.15.19 Alopecia | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.15.20 Nail injury | 1 | 86 | Risk Ratio (IV, Random, 95% CI) | 0.35 [0.01, 8.33] |
| 7.15.21 Itching | 2 | 179 | Risk Ratio (IV, Random, 95% CI) | 5.00 [0.25, 101.43] |
| 7.15.22 Ear pain | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.15.23 Corneal injury | 1 | 89 | Risk Ratio (IV, Random, 95% CI) | 0.42 [0.02, 10.16] |
| 7.15.24 Wrist fracture | 1 | 329 | Risk Ratio (IV, Random, 95% CI) | 1.51 [0.06, 36.85] |
| 7.15.25 Dysmennorhea | 1 | 329 | Risk Ratio (IV, Random, 95% CI) | 1.51 [0.06, 36.85] |
| 7.15.26 Myopia | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 7.15.27 Other AEs unspecified | 1 | 60 | Risk Ratio (IV, Random, 95% CI) | 0.40 [0.08, 1.90] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 8.1 Proportion of participants with non‐serious events Show forest plot | 24 | 2696 | Risk Ratio (IV, Random, 95% CI) | 1.39 [1.13, 1.70] |
| 8.2 Subgroup analysis: total number of non‐serious adverse events according to dose Show forest plot | 24 | 3483 | Risk Ratio (IV, Random, 95% CI) | 1.31 [1.12, 1.53] |
| 8.2.1 Low dose | 16 | 1539 | Risk Ratio (IV, Random, 95% CI) | 1.11 [0.94, 1.31] |
| 8.2.2 High dose | 12 | 1080 | Risk Ratio (IV, Random, 95% CI) | 1.57 [1.22, 2.01] |
| 8.2.3 Unknown dose | 5 | 864 | Risk Ratio (IV, Random, 95% CI) | 1.50 [0.88, 2.56] |
| 8.3 Nervous system (including psychiatry) Show forest plot | 52 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 8.3.1 Aggression | 3 | 743 | Risk Ratio (IV, Random, 95% CI) | 0.52 [0.17, 1.60] |
| 8.3.2 Agitation | 2 | 273 | Risk Ratio (IV, Random, 95% CI) | 1.93 [0.37, 10.16] |
| 8.3.3 Anger | 3 | 264 | Risk Ratio (IV, Random, 95% CI) | 0.45 [0.26, 0.77] |
| 8.3.4 Behavioural complaints | 1 | 82 | Risk Ratio (IV, Random, 95% CI) | 0.55 [0.35, 0.86] |
| 8.3.5 Buccal or lingual movements | 5 | 569 | Risk Ratio (IV, Random, 95% CI) | 1.12 [0.81, 1.55] |
| 8.3.6 Compulsive acts | 1 | 90 | Risk Ratio (IV, Random, 95% CI) | 2.57 [1.45, 4.56] |
| 8.3.7 Daydreaming | 3 | 222 | Risk Ratio (IV, Random, 95% CI) | 0.66 [0.44, 0.98] |
| 8.3.8 Dizziness | 12 | 2163 | Risk Ratio (IV, Random, 95% CI) | 1.06 [0.91, 1.23] |
| 8.3.9 Drowsiness: dull, tired, listless or sleepy | 24 | 3011 | Risk Ratio (IV, Random, 95% CI) | 0.98 [0.80, 1.20] |
| 8.3.10 Euphoria | 7 | 1457 | Risk Ratio (IV, Random, 95% CI) | 0.97 [0.72, 1.31] |
| 8.3.11 Headache | 43 | 5981 | Risk Ratio (IV, Random, 95% CI) | 1.25 [1.06, 1.48] |
| 8.3.12 Thirst | 1 | 211 | Risk Ratio (IV, Random, 95% CI) | 2.78 [0.11, 69.04] |
| 8.3.13 Irritability | 27 | 4110 | Risk Ratio (IV, Random, 95% CI) | 0.97 [0.74, 1.27] |
| 8.3.14 Nightmares | 11 | 1738 | Risk Ratio (IV, Random, 95% CI) | 1.00 [0.73, 1.35] |
| 8.3.15 Overly meticulous | 1 | 96 | Risk Ratio (IV, Random, 95% CI) | 40.77 [2.35, 706.72] |
| 8.3.16 Obsessive thinking | 1 | 90 | Risk Ratio (IV, Random, 95% CI) | 2.35 [1.53, 3.62] |
| 8.3.17 Picking at skin or fingers, nail biting, lip or cheek chewing | 18 | 2549 | Risk Ratio (IV, Random, 95% CI) | 1.04 [0.86, 1.25] |
| 8.3.18 Repetitive language | 1 | 48 | Risk Ratio (IV, Random, 95% CI) | 1.00 [0.32, 3.10] |
| 8.3.19 Sad, tearful or depressed | 26 | 3510 | Risk Ratio (IV, Random, 95% CI) | 1.15 [0.96, 1.37] |
| 8.3.20 Socially withdrawn ‐ decreased interaction with others | 15 | 2432 | Risk Ratio (IV, Random, 95% CI) | 1.36 [0.95, 1.95] |
| 8.3.21 Stares a lot | 11 | 2110 | Risk Ratio (IV, Random, 95% CI) | 1.04 [0.83, 1.31] |
| 8.3.22 Tics or nervous movements | 24 | 3429 | Risk Ratio (IV, Random, 95% CI) | 1.23 [1.02, 1.50] |
| 8.3.23 Unusual blinking | 1 | 48 | Risk Ratio (IV, Random, 95% CI) | 3.13 [0.12, 80.68] |
| 8.3.24 Worried or anxious | 23 | 3366 | Risk Ratio (IV, Random, 95% CI) | 0.85 [0.66, 1.11] |
| 8.3.25 Fatique | 1 | 211 | Risk Ratio (IV, Random, 95% CI) | 4.59 [0.22, 94.57] |
| 8.3.26 Emotional lability | 1 | 154 | Risk Ratio (IV, Random, 95% CI) | 9.25 [2.24, 38.22] |
| 8.3.27 Dysphoria | 1 | 154 | Risk Ratio (IV, Random, 95% CI) | 4.63 [0.23, 94.88] |
| 8.3.28 Moody | 1 | 211 | Risk Ratio (IV, Random, 95% CI) | 4.59 [0.22, 94.57] |
| 8.3.29 Uninterested | 1 | 1052 | Risk Ratio (IV, Random, 95% CI) | 1.20 [0.82, 1.75] |
| 8.3.30 Prone to crying | 1 | 1052 | Risk Ratio (IV, Random, 95% CI) | 1.72 [1.04, 2.86] |
| 8.4 Nervous system (including psychiatry) continuous outcomes Show forest plot | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | ‐0.80 [‐3.56, 1.96] |
| 8.4.1 Anxiety | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | ‐0.80 [‐3.56, 1.96] |
| 8.5 Digestive system Show forest plot | 48 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 8.5.1 Decreased appetite or loss of appetite | 41 | 6091 | Risk Ratio (IV, Random, 95% CI) | 3.89 [2.76, 5.48] |
| 8.5.2 Diarrhoea | 5 | 767 | Risk Ratio (IV, Random, 95% CI) | 0.95 [0.38, 2.34] |
| 8.5.3 Dry mouth | 6 | 496 | Risk Ratio (IV, Random, 95% CI) | 1.32 [0.59, 2.97] |
| 8.5.4 Dyspepsia | 1 | 62 | Risk Ratio (IV, Random, 95% CI) | 0.22 [0.02, 2.14] |
| 8.5.5 Nausea | 11 | 1182 | Risk Ratio (IV, Random, 95% CI) | 1.67 [1.13, 2.46] |
| 8.5.6 Increased appetite | 1 | 136 | Risk Ratio (IV, Random, 95% CI) | 0.20 [0.08, 0.50] |
| 8.5.7 Stomach ache (abdominal pain) | 38 | 5803 | Risk Ratio (IV, Random, 95% CI) | 1.70 [1.35, 2.15] |
| 8.5.8 Vomiting | 7 | 1278 | Risk Ratio (IV, Random, 95% CI) | 2.47 [0.82, 7.47] |
| 8.5.9 Upper abdominal pain | 1 | 107 | Risk Ratio (IV, Random, 95% CI) | 442413.39 [0.00, 294025957312946900000000000000000000000000000000000000000000000000000000000000000000000000000.00] |
| 8.5.10 Decreased weight | 2 | 365 | Risk Ratio (IV, Random, 95% CI) | 5.04 [0.59, 43.15] |
| 8.5.11 Gastrointestinal distress | 1 | 77 | Risk Ratio (IV, Random, 95% CI) | 8103.08 [0.00, 1011052702371868400000000000000000000000000000000000000000000000000000000.00] |
| 8.5.12 Constipation | 1 | 154 | Risk Ratio (IV, Random, 95% CI) | 4.63 [0.23, 94.88] |
| 8.5.13 Oropharyngeal pain | 1 | 211 | Risk Ratio (IV, Random, 95% CI) | 2.72 [0.00, 11653710777400273000000000000000000000000000000000000000000000000000000000000000000000000000000.00] |
| 8.5.14 Anorexia | 1 | 203 | Risk Ratio (IV, Random, 95% CI) | 2.97 [0.61, 14.37] |
| 8.6 Cardiovascular system Show forest plot | 2 | 730 | Risk Ratio (M‐H, Random, 95% CI) | 4.97 [1.09, 22.76] |
| 8.6.1 Epistaxis | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [0.11, 67.14] |
| 8.6.2 Heart palpitations | 2 | 365 | Risk Ratio (M‐H, Random, 95% CI) | 5.65 [0.67, 47.90] |
| 8.6.3 Chest pain | 1 | 211 | Risk Ratio (M‐H, Random, 95% CI) | 6.43 [0.34, 123.02] |
| 8.7 Respiratory system Show forest plot | 2 | 673 | Risk Ratio (M‐H, Random, 95% CI) | 1.29 [0.36, 4.68] |
| 8.7.1 Nasal congestion | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.06, 14.52] |
| 8.7.2 Strep throat/sore throat | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [0.30, 26.09] |
| 8.7.3 Cough | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.04, 5.00] |
| 8.7.4 Dyspnea | 1 | 211 | Risk Ratio (M‐H, Random, 95% CI) | 2.76 [0.11, 66.91] |
| 8.8 Urinary system Show forest plot | 1 | 136 | Risk Ratio (IV, Random, 95% CI) | 0.50 [0.05, 5.39] |
| 8.8.1 Urinary incontinence | 1 | 136 | Risk Ratio (IV, Random, 95% CI) | 0.50 [0.05, 5.39] |
| 8.9 Skeletal and muscular system Show forest plot | 2 | 673 | Risk Ratio (M‐H, Random, 95% CI) | 4.86 [0.83, 28.54] |
| 8.9.1 Ankle pain/strain | 1 | 0 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 8.9.2 Muscle strain/pain | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 12.04 [0.69, 210.03] |
| 8.9.3 Toe fracture | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [0.11, 67.14] |
| 8.9.4 Asthenia | 1 | 211 | Risk Ratio (M‐H, Random, 95% CI) | 2.76 [0.11, 66.91] |
| 8.10 Skeletal and muscular system continuous outcomes Show forest plot | 1 | 82 | Mean Difference (IV, Random, 95% CI) | 0.85 [0.79, 0.91] |
| 8.10.1 Somatic complaints | 1 | 82 | Mean Difference (IV, Random, 95% CI) | 0.85 [0.79, 0.91] |
| 8.11 Immune system (including infections) Show forest plot | 9 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 8.11.1 Allergic rhinitis | 4 | 475 | Risk Ratio (IV, Random, 95% CI) | 1.38 [0.35, 5.51] |
| 8.11.2 Fever | 2 | 91 | Risk Ratio (IV, Random, 95% CI) | 1.39 [0.09, 20.56] |
| 8.11.3 Lymphadenitis | 2 | 296 | Risk Ratio (IV, Random, 95% CI) | 3.93 [0.44, 35.11] |
| 8.11.4 Pharyngolaryngeal pain | 1 | 160 | Risk Ratio (IV, Random, 95% CI) | 2.00 [0.19, 21.62] |
| 8.11.5 Pharyngitis | 4 | 754 | Risk Ratio (IV, Random, 95% CI) | 0.71 [0.19, 2.62] |
| 8.11.6 Upper respiratory tract infection | 7 | 1245 | Risk Ratio (IV, Random, 95% CI) | 1.21 [0.51, 2.86] |
| 8.11.7 Nasopharyngitis | 1 | 203 | Risk Ratio (IV, Random, 95% CI) | 0.79 [0.22, 2.87] |
| 8.11.8 Influenza | 1 | 154 | Risk Ratio (IV, Random, 95% CI) | 4.63 [0.23, 94.87] |
| 8.11.9 Mouth ulcers/bad breath | 1 | 154 | Risk Ratio (IV, Random, 95% CI) | 4.63 [0.23, 94.87] |
| 8.11.10 Urinary tract infection | 1 | 154 | Risk Ratio (IV, Random, 95% CI) | 2.78 [0.11, 67.14] |
| 8.11.11 Otitis media (ear pain) | 1 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 8.12 Integumentary system Show forest plot | 4 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 8.12.1 Rash | 3 | 362 | Risk Ratio (IV, Random, 95% CI) | 1.49 [0.35, 6.37] |
| 8.12.2 Skin laceration | 1 | 167 | Risk Ratio (IV, Random, 95% CI) | 2.96 [0.12, 71.75] |
| 8.12.3 Cellulitis | 1 | 154 | Risk Ratio (IV, Random, 95% CI) | 2.78 [0.11, 67.14] |
| 8.13 Sleep variability continuous outcomes Show forest plot | 1 | 512 | Mean Difference (IV, Fixed, 95% CI) | ‐2.21 [‐5.23, 0.81] |
| 8.13.1 Actigraphic total sleep time | 1 | 52 | Mean Difference (IV, Fixed, 95% CI) | ‐29.80 [‐60.86, 1.26] |
| 8.13.2 Actigraphic sleep onset latency | 1 | 52 | Mean Difference (IV, Fixed, 95% CI) | 21.10 [1.33, 40.87] |
| 8.13.3 Actigraphic sleep efficiency | 1 | 52 | Mean Difference (IV, Fixed, 95% CI) | ‐3.30 [‐8.16, 1.56] |
| 8.13.4 Polysonmnographic total sleep time | 1 | 252 | Mean Difference (IV, Fixed, 95% CI) | ‐24.60 [‐52.20, 3.00] |
| 8.13.5 Polysomnographic sleep onset latency | 1 | 52 | Mean Difference (IV, Fixed, 95% CI) | 8.40 [‐7.11, 23.91] |
| 8.13.6 Polysomnographic sleep efficiency | 1 | 52 | Mean Difference (IV, Fixed, 95% CI) | ‐2.20 [‐6.34, 1.94] |
| 8.14 Sleep variability Show forest plot | 39 | 5810 | Risk Ratio (IV, Random, 95% CI) | 1.81 [1.34, 2.44] |
| 8.14.1 Insomnia or sleep problems | 37 | 5499 | Risk Ratio (IV, Random, 95% CI) | 1.88 [1.39, 2.56] |
| 8.14.2 Sleep efficiency (SEF) | 2 | 108 | Risk Ratio (IV, Random, 95% CI) | 0.48 [0.02, 14.28] |
| 8.14.3 Initial insomnia | 1 | 203 | Risk Ratio (IV, Random, 95% CI) | 0.59 [0.15, 2.42] |
| 8.15 Vital signs Show forest plot | 14 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 8.15.1 Diastolic blood pressure (mmHg) | 11 | 755 | Std. Mean Difference (IV, Random, 95% CI) | 0.15 [‐0.04, 0.34] |
| 8.15.2 Systolic blood pressure (mmHg) | 11 | 755 | Std. Mean Difference (IV, Random, 95% CI) | 0.05 [‐0.15, 0.26] |
| 8.15.3 Pulse or heart rate (bpm) | 14 | 939 | Std. Mean Difference (IV, Random, 95% CI) | 0.43 [0.23, 0.64] |
| 8.16 Physical parameters Show forest plot | 6 | 576 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.04 [‐0.20, 0.13] |
| 8.16.1 Height (cm) | 1 | 46 | Std. Mean Difference (IV, Random, 95% CI) | 0.20 [‐0.38, 0.78] |
| 8.16.2 Weight | 6 | 530 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.06 [‐0.23, 0.11] |
| 8.17 Other (including drug toxicity) Show forest plot | 2 | 1443 | Risk Ratio (M‐H, Random, 95% CI) | 3.25 [0.99, 10.62] |
| 8.17.1 Growth hormone deficiency | 1 | 0 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 8.17.2 Eye pain | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [0.11, 67.14] |
| 8.17.3 Carious teeth | 1 | 0 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 8.17.4 Foreign body swallowed | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [0.11, 67.14] |
| 8.17.5 Bug bites/bee stings | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 4.63 [0.23, 94.87] |
| 8.17.6 Sunburn | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [0.11, 67.14] |
| 8.17.7 Finger laceration | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [0.11, 67.14] |
| 8.17.8 Flat affect (lack of emotional expression) | 1 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 4.63 [0.23, 94.87] |
| 8.17.9 Peripheral oedema | 1 | 211 | Risk Ratio (M‐H, Random, 95% CI) | 2.76 [0.11, 66.91] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 9.1 All parallel‐group trials and first‐period cross‐over trials Show forest plot | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 9.1.1 High risk of bias | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 9.2 Subgroup analysis: types of scales Show forest plot | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 9.2.1 Conners' Global Index ‐ Teacher (CGI‐T) | 1 | 314 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.14, ‐0.68] |
| 9.2.2 Groninger Behaviour Observation Scale (GBOS) | 1 | 43 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.84 [‐1.46, ‐0.21] |
| 9.2.3 Conners' Teacher Rating Scale (CTRS‐RS) | 1 | 75 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐0.54, 0.37] |
| 9.2.4 Conners' Teacher Rating Scale ‐ Oppositional behaviour (CRS‐R) | 1 | 49 | Std. Mean Difference (IV, Random, 95% CI) | 0.06 [‐0.50, 0.62] |
| 9.2.5 Conners' Teacher Rating Scale ‐ Conduct problems | 1 | 25 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐1.48, 0.14] |
| 9.2.6 IOWA Conners' Rating Scale ‐ Oppositional/Defiant (IOWA‐O/D) | 2 | 286 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.86 [‐1.12, ‐0.59] |
| 9.3 Subgroup analysis: dose Show forest plot | 7 | 820 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.61 [‐0.88, ‐0.34] |
| 9.3.1 Low dose | 2 | 71 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐1.16, ‐0.19] |
| 9.3.2 High dose | 4 | 541 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.66 [‐1.05, ‐0.27] |
| 9.3.3 Unknown dose | 2 | 208 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.41 [‐1.29, 0.46] |
| 9.4 Subgroup analysis: duration of treatment Show forest plot | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 9.4.1 Short term (up to 6 months) | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 9.5 Subgroup analysis: parallel‐group trials versus first‐period cross‐over trials Show forest plot | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 9.5.1 Parallel‐group trials | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 9.6 Cross‐over trials (endpoint data) Show forest plot | 16 | 1302 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.87, ‐0.63] |
| 9.6.1 High risk of bias | 16 | 1302 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.87, ‐0.63] |
| 9.7 Subgroup analysis: cross‐over trials (endpoint data): dose Show forest plot | 16 | 2008 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.69 [‐0.78, ‐0.60] |
| 9.7.1 Low dose | 13 | 1104 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.60 [‐0.72, ‐0.48] |
| 9.7.2 High dose | 12 | 904 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.82 [‐0.95, ‐0.68] |
| 9.8 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (teacher‐rated) versus cross‐over trials (endpoint data) Show forest plot | 23 | 2094 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.72 [‐0.84, ‐0.60] |
| 9.8.1 All parallel‐group trials and first‐period cross‐over trials | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 9.8.2 Cross‐over trials (endpoint data) | 16 | 1302 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.87, ‐0.63] |
| 9.9 Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest Show forest plot | 23 | 2094 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.72 [‐0.84, ‐0.60] |
| 9.9.1 Low risk of vested interest | 6 | 509 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐0.90, ‐0.43] |
| 9.9.2 High risk of vested interest | 17 | 1585 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐0.89, ‐0.60] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 10.1 All parallel‐group trials and first‐period cross‐over trials Show forest plot | 1 | 94 | Mean Difference (IV, Fixed, 95% CI) | 1.10 [‐1.01, 3.21] |
| 10.1.1 High risk of bias | 1 | 94 | Mean Difference (IV, Fixed, 95% CI) | 1.10 [‐1.01, 3.21] |
| 10.2 Cross‐over trials (endpoint data) Show forest plot | 9 | 987 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.98 [‐1.39, ‐0.57] |
| 10.2.1 High risk of bias | 9 | 987 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.98 [‐1.39, ‐0.57] |
| 10.3 Subgroup analysis: general behaviour, cross‐over trials (endpoint data): dose Show forest plot | 9 | 1319 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.02 [‐1.39, ‐0.64] |
| 10.3.1 Low dose | 9 | 987 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.82 [‐1.23, ‐0.41] |
| 10.3.2 High dose | 5 | 332 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.49 [‐2.37, ‐0.61] |
| 10.4 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (independent assessor‐rated) compared with cross‐over trials (endpoint data) Show forest plot | 10 | 1081 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.86 [‐1.27, ‐0.46] |
| 10.4.1 Parallel‐group trials and first‐period cross‐over trials | 1 | 94 | Std. Mean Difference (IV, Random, 95% CI) | 0.21 [‐0.20, 0.61] |
| 10.4.2 Cross‐over trials (endpoint data) | 9 | 987 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.98 [‐1.39, ‐0.57] |
| 10.5 Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest Show forest plot | 9 | 1031 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.24, ‐0.39] |
| 10.5.1 Low risk of vested interest | 2 | 190 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.32 [‐1.36, 0.72] |
| 10.5.2 High risk of vested interest | 6 | 799 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.59 [‐0.77, ‐0.41] |
| 10.5.3 Unclear risk of vested interest | 1 | 42 | Std. Mean Difference (IV, Random, 95% CI) | ‐5.99 [‐7.46, ‐4.51] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 11.1 All parallel‐group trials and first‐period cross‐over trials Show forest plot | 10 | 1376 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.62, ‐0.23] |
| 11.1.1 Low risk of bias | 3 | 386 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.64, 0.41] |
| 11.1.2 High risk of bias | 7 | 990 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.51 [‐0.69, ‐0.33] |
| 11.2 Subgroup analysis: types of scales Show forest plot | 10 | 1376 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.62, ‐0.23] |
| 11.2.1 The Weekly Parent Ratings of Evening and Morning Behaviour (WPREMB) ‐ Revised | 2 | 167 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.18 [‐1.32, 0.96] |
| 11.2.2 Conners' Global Index (CGI) ‐ Parent | 2 | 352 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.41 [‐0.63, ‐0.20] |
| 11.2.3 Swanson, Nolan and Pelham, Fourth Edition ‐ Oppositional (SNAP‐IV‐Oppositional) | 1 | 15 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.86 [‐1.95, 0.23] |
| 11.2.4 IOWA Conners' Rating Scale ‐ Oppositional/Defiant (IOWA‐I/O) | 2 | 286 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐1.01, ‐0.49] |
| 11.2.5 Conners' Early Childhood Behavior ‐ Parent Short Response Scale | 1 | 117 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.44 [‐0.81, ‐0.07] |
| 11.2.6 Strengths and Dificulties Questionnaire (SDQ) | 1 | 85 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.04 [‐0.46, 0.39] |
| 11.2.7 Behaviour Rating Inventory of Executive Function (BRIEF) | 1 | 354 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.38, 0.14] |
| 11.3 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials Show forest plot | 10 | 1376 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.62, ‐0.23] |
| 11.3.1 Parallel‐group trials | 9 | 1361 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.41 [‐0.61, ‐0.21] |
| 11.3.2 First‐period cross‐over trials | 1 | 15 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.86 [‐1.95, 0.23] |
| 11.4 Subgroup analysis: duration of treatment Show forest plot | 10 | 1376 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.62, ‐0.23] |
| 11.4.1 Short term (up to 6 months) | 10 | 1376 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.62, ‐0.23] |
| 11.5 Subgroup analysis: dose Show forest plot | 10 | 1376 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.62, ‐0.23] |
| 11.5.1 High dose | 7 | 1052 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.32 [‐0.54, ‐0.10] |
| 11.5.2 Unknown dose | 3 | 324 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.71 [‐0.95, ‐0.47] |
| 11.6 Cross‐over trials (endpoint data) Show forest plot | 6 | 384 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.84 [‐1.05, ‐0.63] |
| 11.6.1 High risk of bias | 6 | 384 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.84 [‐1.05, ‐0.63] |
| 11.7 Subgroup analysis: cross‐over trials (endpoint data): dose Show forest plot | 6 | 550 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐0.93, ‐0.56] |
| 11.7.1 Low dose | 5 | 248 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.65 [‐0.93, ‐0.38] |
| 11.7.2 High dose | 4 | 302 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.83 [‐1.07, ‐0.60] |
| 11.8 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (parent‐rated) compared with cross‐over trials (endpoint data) Show forest plot | 16 | 1760 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.56 [‐0.74, ‐0.39] |
| 11.8.1 All parallel‐group trials and first‐period cross‐over trials | 10 | 1376 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.62, ‐0.23] |
| 11.8.2 Cross‐over trials (endpoint data) | 6 | 384 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.84 [‐1.05, ‐0.63] |
| 11.9 All parallel‐group trials and cross‐over trials: risk of bias Show forest plot | 16 | 1760 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.56 [‐0.74, ‐0.39] |
| 11.9.1 Low risk of bias | 3 | 386 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.64, 0.41] |
| 11.9.2 High risk of bias | 13 | 1374 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.78, ‐0.47] |
| 11.10 Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest Show forest plot | 16 | 1760 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.56 [‐0.74, ‐0.39] |
| 11.10.1 Low risk of vested interest | 4 | 223 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐1.14, ‐0.10] |
| 11.10.2 High risk of vested interest | 12 | 1537 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.56 [‐0.75, ‐0.38] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 12.1 Parallel‐group trials and first‐period cross‐over trials: comparisons of raters Show forest plot | 13 | 2262 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.46 [‐0.64, ‐0.27] |
| 12.1.1 Teacher‐rated | 7 | 792 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐0.91, ‐0.33] |
| 12.1.2 Independent assessor‐rated | 1 | 94 | Std. Mean Difference (IV, Random, 95% CI) | 0.21 [‐0.20, 0.61] |
| 12.1.3 Parent‐rated | 10 | 1376 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.62, ‐0.23] |
| 12.2 Parallel‐group trials and first‐period cross‐over trials: comorbidity versus no comorbidity Show forest plot | 8 | 696 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.65 [‐0.90, ‐0.40] |
| 12.2.1 ADHD with comorbidity | 6 | 265 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.59 [‐0.95, ‐0.23] |
| 12.2.2 ADHD without comorbidity | 2 | 431 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.70 [‐1.16, ‐0.24] |
| 12.3 Cross‐over trials: first‐period data versus endpoint data in the same trials (teacher‐, parent‐, and independent assessor‐rated) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 12.3.1 First‐period data | 1 | 16 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.75, 0.13] |
| 12.3.2 Endpoint data | 1 | 14 | Mean Difference (IV, Random, 95% CI) | 0.14 [‐0.71, 1.00] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 13.1 Subgroup analysis: types of scales Show forest plot | 4 | 608 | Std. Mean Difference (IV, Random, 95% CI) | 0.40 [‐0.03, 0.83] |
| 13.1.1 Child Health Questionnaire (CHQ) | 1 | 257 | Std. Mean Difference (IV, Random, 95% CI) | 0.54 [0.25, 0.83] |
| 13.1.2 Children´s Global Assessment Scale (CGAS) | 1 | 36 | Std. Mean Difference (IV, Random, 95% CI) | 0.79 [0.10, 1.47] |
| 13.1.3 Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP‐CE:PRF) | 1 | 221 | Std. Mean Difference (IV, Random, 95% CI) | 0.64 [0.37, 0.91] |
| 13.1.4 Parent & child reported Revised questionnaire for Children and adolescents to record health‐related quality of life (KINDL‐R) | 1 | 94 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.30 [‐0.71, 0.11] |
