Metilfenidat s produljenim otpuštanjem za poremećaj s nedostatkom pažnje i hiperaktivnošću (ADHD) u odraslih
Información
- DOI:
- https://doi.org/10.1002/14651858.CD012857.pub2Copiar DOI
- Base de datos:
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- Cochrane Database of Systematic Reviews
- Versión publicada:
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- 24 febrero 2022see what's new
- Tipo:
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- Intervention
- Etapa:
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- Review
- Grupo Editorial Cochrane:
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Grupo Cochrane de Problemas de desarrollo, psicosociales y de aprendizaje
- Copyright:
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- Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cifras del artículo
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Autores
Contributions of authors
KB: Data extraction, data analysis, writing first draft of final review, revision of draft. Guarantor of review.
ASP: Data extraction, data analysis, revision of draft.
PCG: Data analysis, revision of draft, supervision of project.
KJ: Data analysis, revision of draft, supervision of project.
All authors approved submission and publication of the manuscript.
Data sharing statement
The full dataset is available in Excel format at osf.io/39wzk/?view_only=a1d2c58b069c4e99b8c836107e99fcad.
Sources of support
Internal sources
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Nordic Cochrane Centre, Denmark
Supported the review authors in the form of salary: KB, ASP and KJ.
External sources
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None, Other
Declarations of interest
Kim Boesen: none known.
Asger Sand Paludan‐Müller: none known.
Peter C Gøtzsche: none known.
Karsten Juhl Jørgensen: none known.
Acknowledgements
We thank Geraldine McDonald (Coordinating editor) and Joanne Duffield (Managing Editor) from the Cochrane Developmental, Psychosocial and Learning Problems Review Group.
Version history
| Published | Title | Stage | Authors | Version |
| 2022 Feb 24 | Extended‐release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults | Review | Kim Boesen, Asger Sand Paludan-Müller, Peter C Gøtzsche, Karsten Juhl Jørgensen | |
| 2017 Nov 15 | Extended‐release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults | Protocol | Kim Boesen, Pia Brandt Danborg, Peter C Gøtzsche, Karsten Juhl Jørgensen | |
Differences between protocol and review
Searching regulatory databases
We did not update our searches of regulatory databases (last searched May 2020), since ‐ to our knowledge ‐ new methylphenidate formulations have not been approved for adult ADHD after that time.
Eligibility criteria ‐ minimum trial duration
In our protocol (Boesen 2017b) we did not define a minimum trial duration as an inclusion criterion. However, we did not include single‐dose studies. Many single‐dose experiments have been conducted in laboratory settings where the participants are tested with, for instance, cognitive tests or in driving simulators.
Eligibility criteria ‐ trials with more than one phase
Some included trials consisted of several ‘phases’ (e.g. Biederman 2003; Medori 2005; Huss 2010), where the participants were re‐randomised to participate in additional 'phases' depending on their clinical response during the placebo‐controlled trial. We included only the first randomised phase of such trials to avoid participant‐level unit‐of‐analysis errors. There are also several methodological problems related to such study designs that limit their generalisability: the blinding would be difficult to maintain; there would be a risk of exposing those participants re‐randomised to placebo to withdrawal effects; and the trial design would favour those who tolerate the drug, which is responder selection ('enriched design').
Naming the included trials
We named the included studies after the year the study started rather than the year of the first trial publication, which is often common practice. We did not specify this in the protocol. We did this to increase transparency, as there might be many years of difference between when the study was conducted and the trial publication, e.g. the Goodman 2009 trial was conducted between 2009 and 2010, but the trial results were published in a medical journal in 2016.
Counting records
For trial registries, regulatory databases, and pharmaceutical companies, we counted trial entries and separately available documents with data as separate records in our flowchart. We did this to make the counting of references in the review and in the flowchart easier.
Risk of bias ‐ assessing attrition bias
In our protocol (Boesen 2017b), we stated that we would assess whether 'missing data were adequately addressed' and whether dropout rates were 'balanced' between the groups. To avoid making subjective judgements, we instead extracted information on total dropout rates, dropouts due to adverse events and the statistical method to account for missing data, and based our bias assessments on this information.
Risk of bias ‐ assessing selective reporting
In our protocol (Boesen 2017b), we stated that we would use the ORBIT tool (Kirkham 2018), to assess selective outcome reporting. Due to our review's complexity and different data sources (published reports, clinical trial registries, and drug regulatory documents), we tailored our outcome reporting assessment as described in our Assessment of risk of bias in included studies. However, it should be noted that our methodology overlaps with that proposed by Kirkham 2018.
Adverse events – specifying outcomes
In our protocol (Boesen 2017b), we did not specify which specific harms‐related outcomes to assess; neither the individual events nor the high‐level outcomes such as ‘proportion experiencing any event’. We consider the high‐level outcomes to be standard measures of harms and their selection was not ‘data‐driven’, i.e. chosen because of specific results. However, in future reviews and updates, it will be preferable to prespecify the specific harms‐related outcomes at the protocol stage.
Adverse events ‐ data extraction
In our protocol (Boesen 2017b), we did not specify how we would extract individual adverse events. In some trial reports, two or more events were reported that were related to the same type of event. For insomnia, if two or more types of insomnia events (e.g. initial and middle insomnia) were reported, we preferred ‘initial insomnia’. For sexual dysfunction, we chose those events that seemed to describe more general problems related to sexual function.
Adverse events ‐ analyses
We pooled adverse events and serious adverse events from the short‐term and medium‐term periods, as only one trial reported medium‐term data. We wanted to avoid splitting up the analyses, and since we used risk ratios, we considered it a feasible method.
Trial Sequential Analysis
In our protocol (Boesen 2017b), we specified we would run such analyses. However, we judged that this would be uninformative, since 20 of 21 trials were at high risk of bias and had limited generalisability.
Subgroup analyses of symptom rating scales
Mean differences on a rating scale may be more clinically relevant than a unitless standardised mean difference. Therefore, we also reported the mean differences based on the rating scales used in the trials. We grouped scales assessing the same items and using the same range.
Subgroup analyses
We did not conduct two of the six prespecified subgroup analyses (Boesen 2017b):
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'Treatment status'; i.e. trials of CNS stimulant‐naïve participants versus trials of previously CNS stimulant treated participants. This analysis was practically the same analysis as our 'withdrawal effects' analysis (called 'washout' in our protocol) and was deemed redundant.
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'Publication status'; we did not consider this analysis as feasible. We included data from many different sources including regulatory documents, trial registries, and data sent directly from the investigators, which blurred the distinction between published and non‐published data.
Sensitivity analyses
We did not perform the planned sensitivity analysis based on our risk of bias assessment. There were no trials rated as having an overall low risk of bias.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
Medical Subject Headings Check Words
Adult; Humans;
PICO
Flow diagram.
BfArM= Bundesinstitut für Arzneimittel und Medizinprodukte, FDA= US Food and Drug Administration, MEB= Medicines Evaluation Board, MHRA= Medicines and Healthcare products Regulatory Agency, TGA= Therapeutic Goods Administration, YODA= Yale University Open Data Access.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Funnel plot. Extended‐release methylphenidate versus placebo: ADHD symptoms (self‐rated).
Funnel plot of comparison: 1 Extended‐release methylphenidate versus placebo ‐ primary outcomes (short and medium term), outcome: 1.8 Serious adverse events.
Funnel plot of comparison: 2 Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short‐ and medium‐term), outcome: 2.4 ADHD symptoms (investigator‐rated) (short‐term).
Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 1: Days missed at work/school/training (week 13)
Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 2: Days missed at work/school/training (weeks 13‐26)
Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 3: Days missed at work/school/training (weeks 26‐52)
Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 4: ADHD symptoms (self‐rated) (short‐term)
![Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 5: ADHD symptoms (self‐rated) [subgroup MD] (short‐term)](/es/cdsr/doi/10.1002/14651858.CD012857.pub2/media/CDSR/CD012857/image_n/nCD012857-CMP-001.05.svg)
Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 5: ADHD symptoms (self‐rated) [subgroup MD] (short‐term)
Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 6: ADHD symptoms (self‐rated) (medium‐term)
![Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 7: ADHD symptoms (self‐rated) [LMCF data] (medium‐term)](/es/cdsr/doi/10.1002/14651858.CD012857.pub2/media/CDSR/CD012857/image_n/nCD012857-CMP-001.07.svg)
Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 7: ADHD symptoms (self‐rated) [LMCF data] (medium‐term)
Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 8: Serious adverse events
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 1: Quality of life (self‐rated) (short‐term)
![Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 2: Quality of life (self‐rated) [subgroup MD] (short‐term)](/es/cdsr/doi/10.1002/14651858.CD012857.pub2/media/CDSR/CD012857/image_n/nCD012857-CMP-002.02.svg)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 2: Quality of life (self‐rated) [subgroup MD] (short‐term)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 3: Quality of life (self‐rated) (medium‐term)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 4: ADHD symptoms (investigator rated) (short‐term)
![Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 5: ADHD symptoms (investigator‐rated) [subgroup MD] (short‐term)](/es/cdsr/doi/10.1002/14651858.CD012857.pub2/media/CDSR/CD012857/image_n/nCD012857-CMP-002.05.svg)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 5: ADHD symptoms (investigator‐rated) [subgroup MD] (short‐term)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 6: ADHD symptoms (investigator‐rated) (medium‐term)
![Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 7: ADHD symptoms (investigator‐rated) [LMCF data] (medium‐term)](/es/cdsr/doi/10.1002/14651858.CD012857.pub2/media/CDSR/CD012857/image_n/nCD012857-CMP-002.07.svg)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 7: ADHD symptoms (investigator‐rated) [LMCF data] (medium‐term)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 8: ADHD symptoms (peer‐rated) (short‐term)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 9: Cardiovascular: pulse (beats per minute)
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 10: Cardiovascular: systolic blood pressure
Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 11: Cardiovascular: diastolic blood pressure
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 1: Dropout (overall)
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 2: Dropout (due to adverse events)
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 3: Adverse events (proportion experiencing any adverse event)
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 4: Psychiatric adverse events (proportion of participants)
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 5: Weight (change in kilograms)
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 6: Adverse event: decreased appetite
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 7: Adverse event: dry mouth
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 8: Adverse event: headache
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 9: Adverse event: palpitations
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 10: Adverse event: insomnia
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 11: Adverse event: sexual dysfunction
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 12: Adverse event: anxiety
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 13: Adverse event: depression
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 14: Adverse event: irritability
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 15: Adverse event: feeling jittery
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 16: Adverse event: agitation
Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 17: Adverse event: aggression
Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 1: Overall dropout rate: psychiatric comorbidity (subgroup analysis)
Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 2: Overall dropout rate: 'enriched design' (subgroup analysis)
Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 3: Overall dropout rate: withdrawal effects (subgroup analysis)
Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 4: Overall dropout rate: funding (subgroup analysis)
Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 5: Proportion experiencing any adverse event: psychiatric comorbidity (subgroup analysis)
Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 6: Proportion experiencing any adverse event: withdrawal effects (subgroup analysis)
Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 7: Proportion experiencing any adverse event: funding (subgroup analysis)
Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 8: Proportion experiencing any adverse event: dropout rates (sensitivity analysis)
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 1: ADHD symptoms (self‐rated)
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 2: Serious adverse events
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 3: Adverse event: initial insomnia
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 4: Weight
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 5: ADHD symptoms (investigator‐rated)
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 6: Overall dropout
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 7: Adverse events (AE): proportion experiencing any AE
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 8: Adverse events (leading to dropout)
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 9: Adverse event: headache
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 10: Adverse event: decreased appetite
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 11: Adverse event: irritability
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 12: Adverse event: dry mouth
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 13: Adverse event: decreased libido
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 14: Adverse event: feeling jittery
Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 15: Adverse events: palpitations
Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 1: ADHD symptoms (self‐rated)
Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 2: Overall dropout
Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 3: Dropouts due to adverse events
| Extended‐release methylphenidate compared to placebo for ADHD | ||||||
| Patient or population: adults diagnosed with ADHD | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with extended‐release methylphenidate | |||||
| Functional outcome:days missed at work/ school/ training
Time of assessment: 13 weeks | The mean number of days missed at work, school or training in the control group was 2.4 | The mean number of days missed at work, school or training was 0.15 days fewer | ‐ | 409 | ⊕⊝⊝⊝ | ‐ |
| ADHD symptoms (self‐rated)
Time of assessment: median 8 weeks (range 2 ‐ 26) | ‐ | The mean ADHD score in the intervention groups was 0.37 SDlower | ‐ | 3799 | ⊕⊝⊝⊝ | An SMD of 0.37 may be considered a small‐to‐moderate effect size |
| Serious adverse events
Time of assessment: median 8 weeks (range 4 ‐ 52) | Study population | RR1.43 | 4078 | ⊕⊝⊝⊝ | ‐ | |
| 12 per 1000 | 17 per 1000 | |||||
| Quality of life (self‐rated)
Time of assessment: median 6 weeks (range 4 ‐ 52) | ‐ | The mean quality of life score in the intervention groups was 0.15 SD lower (0.25 lower to 0.05 lower) | ‐ | 1888 | ⊕⊝⊝⊝ | An SMD of 0.15 may be considered a small effect size |
| ADHD symptoms (investigator‐rated)
Time of assessment: median 8 weeks (range 2 ‐ 26) | ‐ | The mean investigator‐rated ADHD score in the intervention groups was 0.42 SD lower | ‐ | 4183 | ⊕⊝⊝⊝ | An SMD of 0.42 may be considered a small‐to‐moderate effect size |
| ADHD symptoms (peer‐rated)
Time of assessment: median 7.5 weeks (range 6 ‐ 9) | ‐ | The mean peer‐rated ADHD score in the intervention groups was 0.31 SD lower | ‐ | 1005 | ⊕⊝⊝⊝ | An SMD of 0.31 may be considered a small‐to‐moderate effect size |
| Adverse events (proportion experiencing any adverse event)
Time of assessment: median 8 weeks (range 4 ‐ 52) | Study population | RR1.27 | 4214 | ⊕⊝⊝⊝ | ‐ | |
| 641 per 1000 | 814 per 1000 | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aWe downgraded two levels due to risk bias; primarily due to blinding issues caused by methylphenidate's effects, high attrition (dropout) rates, and selective reporting of the included trials. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Days missed at work/school/training (week 13) Show forest plot | 2 | 409 | Mean Difference (IV, Random, 95% CI) | ‐0.15 [‐2.11, 1.81] |
| 1.2 Days missed at work/school/training (weeks 13‐26) Show forest plot | 2 | 327 | Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐2.48, 1.64] |
| 1.3 Days missed at work/school/training (weeks 26‐52) Show forest plot | 2 | 292 | Mean Difference (IV, Random, 95% CI) | 0.71 [‐1.61, 3.03] |
| 1.4 ADHD symptoms (self‐rated) (short‐term) Show forest plot | 17 | 3799 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.37 [‐0.43, ‐0.30] |
| 1.5 ADHD symptoms (self‐rated) [subgroup MD] (short‐term) Show forest plot | 17 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.5.1 DSM‐IV Total ADHD (18 items, 0‐54 points) | 7 | 1189 | Mean Difference (IV, Random, 95% CI) | ‐3.05 [‐4.34, ‐1.76] |
| 1.5.2 ASRS (18 items, 0‐72 points) | 2 | 953 | Mean Difference (IV, Random, 95% CI) | ‐6.25 [‐8.25, ‐4.25] |
| 1.5.3 CAARS: short version (26 items, 0‐78 points) | 5 | 1451 | Mean Difference (IV, Random, 95% CI) | ‐5.21 [‐7.14, ‐3.29] |
| 1.5.4 CAARS: long version (66 items, 0‐90 points) | 1 | 162 | Mean Difference (IV, Random, 95% CI) | ‐28.40 [‐48.28, ‐8.52] |
| 1.5.5 CAARS: unspecified subscale | 2 | 44 | Mean Difference (IV, Random, 95% CI) | ‐8.23 [‐17.79, 1.32] |
| 1.6 ADHD symptoms (self‐rated) (medium‐term) Show forest plot | 2 | 234 | Mean Difference (IV, Random, 95% CI) | ‐1.59 [‐4.26, 1.09] |
| 1.7 ADHD symptoms (self‐rated) [LMCF data] (medium‐term) Show forest plot | 2 | 419 | Mean Difference (IV, Random, 95% CI) | ‐2.23 [‐3.50, ‐0.95] |
| 1.8 Serious adverse events Show forest plot | 14 | 4078 | Risk Ratio (IV, Random, 95% CI) | 1.43 [0.85, 2.43] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Quality of life (self‐rated) (short‐term) Show forest plot | 7 | 1888 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.15 [‐0.25, ‐0.05] |
| 2.2 Quality of life (self‐rated) [subgroup MD] (short‐term) Show forest plot | 7 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.2.1 Q‐LES‐QSF (14‐70 points) | 5 | 1234 | Mean Difference (IV, Random, 95% CI) | ‐0.93 [‐2.17, 0.31] |
| 2.2.2 AIM‐A total score | 1 | 279 | Mean Difference (IV, Random, 95% CI) | ‐0.50 [‐0.99, ‐0.00] |
| 2.2.3 AAQOL | 1 | 375 | Mean Difference (IV, Random, 95% CI) | ‐6.10 [‐10.67, ‐1.53] |
| 2.3 Quality of life (self‐rated) (medium‐term) Show forest plot | 2 | 419 | Mean Difference (IV, Random, 95% CI) | ‐0.66 [‐2.97, 1.64] |
| 2.4 ADHD symptoms (investigator rated) (short‐term) Show forest plot | 19 | 4183 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.49, ‐0.36] |
| 2.5 ADHD symptoms (investigator‐rated) [subgroup MD] (short‐term) Show forest plot | 19 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.5.1 DSM‐IV Total ADHD (18 items, 0‐54 points) | 12 | 3121 | Mean Difference (IV, Random, 95% CI) | ‐4.74 [‐5.65, ‐3.84] |
| 2.5.2 DSM‐5 Total ADHD (18 items, 0‐54 points) | 1 | 375 | Mean Difference (IV, Random, 95% CI) | ‐4.38 [‐7.37, ‐1.39] |
| 2.5.3 WRAADDS (28 items, 0‐56 points) | 2 | 521 | Mean Difference (IV, Random, 95% CI) | ‐6.06 [‐8.48, ‐3.63] |
| 2.5.4 CGI (range 0‐7) | 2 | 36 | Mean Difference (IV, Random, 95% CI) | 0.09 [‐0.67, 0.86] |
| 2.5.5 TAADS (7 items, 0‐28 points) | 1 | 106 | Mean Difference (IV, Random, 95% CI) | ‐3.50 [‐7.85, 0.85] |
| 2.5.6 CAARS: unspecified scale | 1 | 24 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐10.21, 10.41] |
| 2.6 ADHD symptoms (investigator‐rated) (medium‐term) Show forest plot | 2 | 243 | Mean Difference (IV, Random, 95% CI) | ‐1.29 [‐3.38, 0.80] |
| 2.7 ADHD symptoms (investigator‐rated) [LMCF data] (medium‐term) Show forest plot | 2 | 419 | Mean Difference (IV, Random, 95% CI) | ‐2.18 [‐3.55, ‐0.80] |
| 2.8 ADHD symptoms (peer‐rated) (short‐term) Show forest plot | 3 | 1005 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.31 [‐0.48, ‐0.14] |
| 2.9 Cardiovascular: pulse (beats per minute) Show forest plot | 11 | 2558 | Mean Difference (IV, Random, 95% CI) | 4.64 [3.13, 6.15] |
| 2.10 Cardiovascular: systolic blood pressure Show forest plot | 10 | 2276 | Mean Difference (IV, Random, 95% CI) | 1.11 [‐0.06, 2.27] |
| 2.11 Cardiovascular: diastolic blood pressure Show forest plot | 10 | 2276 | Mean Difference (IV, Random, 95% CI) | 1.24 [0.04, 2.44] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Dropout (overall) Show forest plot | 22 | 4769 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.84, 1.21] |
| 3.2 Dropout (due to adverse events) Show forest plot | 15 | 3963 | Risk Ratio (IV, Random, 95% CI) | 2.36 [1.62, 3.43] |
| 3.3 Adverse events (proportion experiencing any adverse event) Show forest plot | 14 | 4214 | Risk Ratio (IV, Random, 95% CI) | 1.27 [1.19, 1.37] |
| 3.4 Psychiatric adverse events (proportion of participants) Show forest plot | 7 | 2737 | Risk Ratio (IV, Random, 95% CI) | 1.83 [1.43, 2.34] |
| 3.5 Weight (change in kilograms) Show forest plot | 10 | 2302 | Mean Difference (IV, Random, 95% CI) | ‐1.78 [‐2.36, ‐1.20] |
| 3.6 Adverse event: decreased appetite Show forest plot | 16 | 4491 | Risk Ratio (IV, Random, 95% CI) | 4.08 [3.34, 4.98] |
| 3.7 Adverse event: dry mouth Show forest plot | 16 | 4491 | Risk Ratio (IV, Random, 95% CI) | 3.36 [2.61, 4.34] |
| 3.8 Adverse event: headache Show forest plot | 16 | 4238 | Risk Ratio (IV, Random, 95% CI) | 1.35 [1.18, 1.54] |
| 3.9 Adverse event: palpitations Show forest plot | 15 | 4265 | Risk Ratio (IV, Random, 95% CI) | 3.67 [2.42, 5.57] |
| 3.10 Adverse event: insomnia Show forest plot | 16 | 4435 | Risk Ratio (IV, Random, 95% CI) | 1.97 [1.51, 2.57] |
| 3.11 Adverse event: sexual dysfunction Show forest plot | 7 | 3057 | Risk Ratio (IV, Random, 95% CI) | 2.66 [1.31, 5.39] |
| 3.12 Adverse event: anxiety Show forest plot | 13 | 3829 | Risk Ratio (IV, Random, 95% CI) | 2.23 [1.40, 3.57] |
| 3.13 Adverse event: depression Show forest plot | 7 | 2791 | Risk Ratio (IV, Random, 95% CI) | 1.47 [0.87, 2.49] |
| 3.14 Adverse event: irritability Show forest plot | 11 | 3377 | Risk Ratio (IV, Random, 95% CI) | 1.39 [1.00, 1.93] |
| 3.15 Adverse event: feeling jittery Show forest plot | 7 | 2254 | Risk Ratio (IV, Random, 95% CI) | 5.52 [2.77, 10.99] |
| 3.16 Adverse event: agitation Show forest plot | 8 | 3166 | Risk Ratio (IV, Random, 95% CI) | 2.16 [1.25, 3.71] |
| 3.17 Adverse event: aggression Show forest plot | 2 | 1319 | Risk Ratio (IV, Random, 95% CI) | 2.10 [1.32, 3.33] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Overall dropout rate: psychiatric comorbidity (subgroup analysis) Show forest plot | 22 | 4769 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.84, 1.21] |
| 4.1.1 Low risk | 1 | 54 | Risk Ratio (IV, Random, 95% CI) | 0.74 [0.53, 1.03] |
| 4.1.2 Unclear risk | 1 | 30 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 4.1.3 High risk | 20 | 4685 | Risk Ratio (IV, Random, 95% CI) | 1.04 [0.86, 1.25] |
| 4.2 Overall dropout rate: 'enriched design' (subgroup analysis) Show forest plot | 22 | 4769 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.84, 1.21] |
| 4.2.1 Unclear risk | 2 | 247 | Risk Ratio (IV, Random, 95% CI) | 1.02 [0.26, 3.98] |
| 4.2.2 High risk | 20 | 4522 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.83, 1.19] |
| 4.3 Overall dropout rate: withdrawal effects (subgroup analysis) Show forest plot | 22 | 4769 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.84, 1.21] |
| 4.3.1 Low risk | 1 | 357 | Risk Ratio (IV, Random, 95% CI) | 0.91 [0.61, 1.34] |
| 4.3.2 Unclear risk | 5 | 822 | Risk Ratio (IV, Random, 95% CI) | 0.90 [0.62, 1.30] |
| 4.3.3 High risk | 16 | 3590 | Risk Ratio (IV, Random, 95% CI) | 1.07 [0.85, 1.34] |
| 4.4 Overall dropout rate: funding (subgroup analysis) Show forest plot | 22 | 4769 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.84, 1.21] |
| 4.4.1 Industry funded | 13 | 3782 | Risk Ratio (IV, Random, 95% CI) | 1.14 [0.88, 1.47] |
| 4.4.2 Publicly funded with industry involvement | 3 | 688 | Risk Ratio (IV, Random, 95% CI) | 0.73 [0.59, 0.91] |
| 4.4.3 Publicly funded | 5 | 279 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.70, 1.40] |
| 4.4.4 Unclear funding | 1 | 20 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.04, 2.69] |
| 4.5 Proportion experiencing any adverse event: psychiatric comorbidity (subgroup analysis) Show forest plot | 14 | 4214 | Risk Ratio (IV, Random, 95% CI) | 1.27 [1.19, 1.37] |
| 4.5.1 High | 13 | 4184 | Risk Ratio (IV, Random, 95% CI) | 1.26 [1.18, 1.36] |
| 4.5.2 Unclear | 1 | 30 | Risk Ratio (IV, Random, 95% CI) | 2.40 [1.12, 5.13] |
| 4.6 Proportion experiencing any adverse event: withdrawal effects (subgroup analysis) Show forest plot | 14 | 4214 | Risk Ratio (IV, Random, 95% CI) | 1.27 [1.19, 1.37] |
| 4.6.1 High | 11 | 3310 | Risk Ratio (IV, Random, 95% CI) | 1.28 [1.18, 1.38] |
| 4.6.2 Unclear | 2 | 555 | Risk Ratio (IV, Random, 95% CI) | 1.21 [0.95, 1.53] |
| 4.6.3 Low | 1 | 349 | Risk Ratio (IV, Random, 95% CI) | 1.46 [1.22, 1.74] |
| 4.7 Proportion experiencing any adverse event: funding (subgroup analysis) Show forest plot | 14 | 4214 | Risk Ratio (IV, Random, 95% CI) | 1.27 [1.19, 1.37] |
| 4.7.1 Industry funded | 12 | 3545 | Risk Ratio (IV, Random, 95% CI) | 1.32 [1.23, 1.41] |
| 4.7.2 Publicly funded with industry involvement | 2 | 669 | Risk Ratio (IV, Random, 95% CI) | 1.09 [1.05, 1.14] |
| 4.8 Proportion experiencing any adverse event: dropout rates (sensitivity analysis) Show forest plot | 14 | 4214 | Risk Ratio (IV, Random, 95% CI) | 1.27 [1.19, 1.37] |
| 4.8.1 High | 10 | 3363 | Risk Ratio (IV, Random, 95% CI) | 1.21 [1.14, 1.29] |
| 4.8.2 Unclear | 1 | 375 | Risk Ratio (IV, Random, 95% CI) | 1.46 [1.12, 1.89] |
| 4.8.3 Low | 3 | 476 | Risk Ratio (IV, Random, 95% CI) | 1.56 [1.35, 1.81] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 ADHD symptoms (self‐rated) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5.2 Serious adverse events Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.3 Adverse event: initial insomnia Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.4 Weight Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5.5 ADHD symptoms (investigator‐rated) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5.6 Overall dropout Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.7 Adverse events (AE): proportion experiencing any AE Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.8 Adverse events (leading to dropout) Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.9 Adverse event: headache Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.10 Adverse event: decreased appetite Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.11 Adverse event: irritability Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.12 Adverse event: dry mouth Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.13 Adverse event: decreased libido Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.14 Adverse event: feeling jittery Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.15 Adverse events: palpitations Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 ADHD symptoms (self‐rated) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 6.2 Overall dropout Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 6.3 Dropouts due to adverse events Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
