Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)

Ole Jakob Storebø; Erica Ramstad; Helle B. Krogh<sup>a</sup>; 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

doi:10.1002/14651858.CD009885.pub2

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Figure 1

Flow chart.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

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Figure 4

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).

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Figure 5

Trial Sequential Analysis: serious adverse events.

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Figure 6

Trial Sequential Analysis: non‐serious adverse events.

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Analysis 1.1

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 1 All parallel‐group trials and first‐period cross‐over trials.

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Analysis 1.2

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 2 Subgroup analysis: types of scales.

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Analysis 1.3

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 3 Medication status: medication naive versus not medication naive.

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Analysis 1.4

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 4 Subgroup analysis: duration of treatment.

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Analysis 1.5

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 5 Subgroup analysis: dose.

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Analysis 1.6

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 6 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials.

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Analysis 1.7

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 7 Subgroup analysis: trials with cohort selection bias of all participants compared with trials without cohort selection bias of all participants.

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Analysis 1.8

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 8 ADHD symptoms, cross‐over trial (endpoint data).

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Analysis 1.9

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 9 ADHD symptoms, cross‐over trials (endpoint data), subgroup analysis: dose.

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Analysis 1.10

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 10 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data).

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Analysis 1.11

Comparison 1 Teacher‐rated ADHD symptoms, Outcome 11 All parallel‐group trials and cross‐over trials: risk of bias.

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Analysis 2.1

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 1 All parallel‐group trials and first‐period cross‐over trials.

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Analysis 2.2

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 2 Subgroup analysis: types of scales.

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Analysis 2.3

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 3 Subgroup analysis: duration of treatment.

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Analysis 2.4

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 4 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials.

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Analysis 2.5

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 5 Subgroup analysis: trials with cohort selection bias of all participants compared with trials without cohort selection bias of all participants.

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Analysis 2.6

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 6 Subgroup analysis: dose.

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Analysis 2.7

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 7 ADHD symptoms, cross‐over trials (endpoint data), subgroup analysis: risk of bias.

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Analysis 2.8

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 8 ADHD symptoms, cross‐over trials (endpoint data), subgroup analysis: dose.

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Analysis 2.9

Comparison 2 Independent assessor‐rated ADHD symptoms, Outcome 9 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data).

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Analysis 3.1

Comparison 3 Parent‐rated ADHD symptoms, Outcome 1 All parallel‐group trials and first‐period cross‐over trials.

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Analysis 3.2

Comparison 3 Parent‐rated ADHD symptoms, Outcome 2 Subgroup analysis: types of scales.

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Analysis 3.3

Comparison 3 Parent‐rated ADHD symptoms, Outcome 3 Subgroup analysis: duration of treatment.

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Analysis 3.4

Comparison 3 Parent‐rated ADHD symptoms, Outcome 4 Subgroup analysis: dose.

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Analysis 3.5

Comparison 3 Parent‐rated ADHD symptoms, Outcome 5 Medication status: medication naive versus not medication naive.

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Analysis 3.6

Comparison 3 Parent‐rated ADHD symptoms, Outcome 6 Subgroup analysis: trials with cohort selection bias of all participants compared with trials without cohort selection bias of all participants.

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Analysis 3.7

Comparison 3 Parent‐rated ADHD symptoms, Outcome 7 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials.

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Analysis 3.8

Comparison 3 Parent‐rated ADHD symptoms, Outcome 8 ADHD symptoms, cross‐over trials (endpoint data).

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Analysis 3.9

Comparison 3 Parent‐rated ADHD symptoms, Outcome 9 ADHD symptoms, cross‐over trials (endpoint data), subgroup analysis: dose.

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Analysis 3.10

Comparison 3 Parent‐rated ADHD symptoms, Outcome 10 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data).

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Analysis 4.1

Comparison 4 Additional subgroup analyses of ADHD symptoms: parallel‐group trials and first‐period cross‐over trials, Outcome 1 Comparision of raters.

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Analysis 4.2

Comparison 4 Additional subgroup analyses of ADHD symptoms: parallel‐group trials and first‐period cross‐over trials, Outcome 2 Age.

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Analysis 4.3

Comparison 4 Additional subgroup analyses of ADHD symptoms: parallel‐group trials and first‐period cross‐over trials, Outcome 3 Comorbidity versus no comorbidity.

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Analysis 4.4

Comparison 4 Additional subgroup analyses of ADHD symptoms: parallel‐group trials and first‐period cross‐over trials, Outcome 4 Subtypes ADHD: ADHD Rating Scale (parent‐, teacher‐ or independent assessor‐rated).

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Analysis 4.5

Comparison 4 Additional subgroup analyses of ADHD symptoms: parallel‐group trials and first‐period cross‐over trials, Outcome 5 Cross‐over trials: first‐period data versus endpoint data (parent‐, independent assessor‐ and teacher‐rated).

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Analysis 5.1

Comparison 5 Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 1 Number of serious adverse events (SAE).

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Analysis 5.2

Comparison 5 Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 2 Nervous system.

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Analysis 5.3

Comparison 5 Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 3 Digestive system: gastrointestinal disorders.

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Analysis 5.4

Comparison 5 Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 4 Urinary system: kidney infection.

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Analysis 5.5

Comparison 5 Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 5 Circulatory and respiratory systems: asthma.

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Analysis 5.6

Comparison 5 Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 6 Immune system: cyst rupture.

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Analysis 5.7

Comparison 5 Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 7 Other: drug toxicity.

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Analysis 6.1

Comparison 6 Number of serious adverse events: cross‐over trials (endpoint data), Outcome 1 Number of serious adverse events (SAE).

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Analysis 6.2

Comparison 6 Number of serious adverse events: cross‐over trials (endpoint data), Outcome 2 Hallucinations/psychosis.

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Analysis 7.1

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 1 Total number of non‐serious adverse events.

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Analysis 7.2

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 2 Subgroup analysis: total number of non‐serious adverse events according to dose.

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Analysis 7.3

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 3 Nervous system.

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Analysis 7.4

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 4 Digestive system.

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Analysis 7.5

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 5 Circulatory and respiratory systems.

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Analysis 7.6

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 6 Skeletal and muscular systems.

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Analysis 7.7

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 7 Immune system.

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Analysis 7.8

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 8 Height.

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Analysis 7.9

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 9 Weight.

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Analysis 7.10

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 10 BMI.

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Analysis 7.11

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 11 Vital signs.

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Analysis 7.12

Comparison 7 Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 12 Other.

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Analysis 8.1

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 1 Total number of non‐serious adverse events.

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Analysis 8.2

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 2 Subgroup analysis: total number of non‐serious adverse events according to dose.

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Analysis 8.3

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 3 Nervous system.

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Analysis 8.4

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 4 Digestive system.

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Analysis 8.5

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 5 Urinary system: urinary incontinence.

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Analysis 8.6

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 6 Skeletal and muscular system: somatic complaints.

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Analysis 8.7

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 7 Immune system.

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Analysis 8.8

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 8 Skin.

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Analysis 8.9

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 9 Vital signs.

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Analysis 8.10

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 10 Height (cm).

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Analysis 8.11

Comparison 8 Number of non‐serious adverse events: cross‐over trials (endpoint data), Outcome 11 Weight.

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Analysis 9.1

Comparison 9 Teacher‐rated general behaviour, Outcome 1 All parallel‐group trials and first‐period cross‐over trials: risk of bias.

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Analysis 9.2

Comparison 9 Teacher‐rated general behaviour, Outcome 2 Subgroup analysis: types of scales.

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Analysis 9.3

Comparison 9 Teacher‐rated general behaviour, Outcome 3 Subgroup analysis: dose.

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Analysis 9.4

Comparison 9 Teacher‐rated general behaviour, Outcome 4 Subgroup analysis: duration of treatment.

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Analysis 9.5

Comparison 9 Teacher‐rated general behaviour, Outcome 5 Subgroup analysis: parallel‐group trials versus first‐period cross‐over trials.

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Analysis 9.6

Comparison 9 Teacher‐rated general behaviour, Outcome 6 General behaviour, cross‐over trials (endpoint data).

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Analysis 9.7

Comparison 9 Teacher‐rated general behaviour, Outcome 7 Subgroup analysis: general behaviour, cross‐over trials (endpoint data): risk of bias.

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Analysis 9.8

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).

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Analysis 10.1

Comparison 10 Independent assessor‐rated general behaviour, Outcome 1 General behaviour, cross‐over trials (endpoint data).

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Analysis 10.2

Comparison 10 Independent assessor‐rated general behaviour, Outcome 2 Subgroup analysis: general behaviour, cross‐over trials (endpoint data): risk of bias.

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Analysis 10.3

Comparison 10 Independent assessor‐rated general behaviour, Outcome 3 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (independent assessor‐rated) compared with cross‐over trials (endpoint data).

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Analysis 11.1

Comparison 11 Parent‐rated general behaviour, Outcome 1 All parallel‐group trials and first‐period cross‐over trials.

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Analysis 11.2

Comparison 11 Parent‐rated general behaviour, Outcome 2 Subgroup analysis: risk of bias.

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Analysis 11.3

Comparison 11 Parent‐rated general behaviour, Outcome 3 Subgroup analysis: types of scales.

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Analysis 11.4

Comparison 11 Parent‐rated general behaviour, Outcome 4 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials.

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Analysis 11.5

Comparison 11 Parent‐rated general behaviour, Outcome 5 Subgroup analysis: duration of treatment.

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Analysis 11.6

Comparison 11 Parent‐rated general behaviour, Outcome 6 Subgroup analysis: dose.

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Analysis 11.7

Comparison 11 Parent‐rated general behaviour, Outcome 7 General behaviour, cross‐over trials (endpoint data).

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Analysis 11.8

Comparison 11 Parent‐rated general behaviour, Outcome 8 Subgroup analysis: general behaviour, cross‐over trials (endpoint data): risk of bias.

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Analysis 11.9

Comparison 11 Parent‐rated general behaviour, Outcome 9 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (parent‐rated) compared with cross‐over trials (endpoint data).

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Analysis 12.1

Comparison 12 Additional subgroup analyses of general behaviour: parallel‐group trials and first‐period cross‐over trials, Outcome 1 Comparisions of raters.

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Analysis 12.2

Comparison 12 Additional subgroup analyses of general behaviour: parallel‐group trials and first‐period cross‐over trials, Outcome 2 Comorbidity versus no comorbidity.

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Analysis 12.3

Comparison 12 Additional subgroup analyses of general behaviour: parallel‐group trials and first‐period cross‐over trials, Outcome 3 Cross‐over trials: first‐period data versus endpoint data (teacher‐, parent‐, and independent assessor‐rated).

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Analysis 13.1

Comparison 13 Quality of life: parallel‐group trials and first‐period cross‐over trials, Outcome 1 Subgroup analysis: types of scales.

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Summary of findings for the main comparison. Methylphenidate compared with placebo or no intervention for ADHD

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 Settings: out‐patient clinic, in‐patient hospital ward and summer school Intervention: methylphenidate Comparison: placebo or no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo or no intervention	Methylphenidate
ADHD symptoms: all parallel‐group trials and first‐period cross‐over trials ADHD Rating Scale (Teacher‐rated) Average study duration: 74.8 days		Mean ADHD symptom score in the intervention groups corresponds to a mean difference of 9.6 (95% CI 11.25 to 8.00) on ADHD Rating Scale	SMD ‐0.77 (‐0.90 to ‐0.64)	1698 (19 studies)	⊕⊝⊝⊝ Very low^a,b	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, Schedule for Non‐adaptive and Adaptive Personality (SNAP) ‐ Teacher, Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS)). The effect size has been translated on to the ADHD Rating Scale from the SMD
Total number of serious adverse events	Trial population		RR 0.98 (0.44 to 2.22)	1532 (9 studies)	⊕⊝⊝⊝ Very low^a,c	‐
	16 per 1000	16 per 1000 (7 to 36)
Total number of non‐serious adverse events	Trial population		RR 1.29 (1.10 to 1.51)	3132 (21 studies)	⊕⊝⊝⊝ Very low^a,b	‐
	408 per 1000	526 per 1000 (448 to 615)
General behaviour: all parallel‐group trials and first‐period cross‐over trials General behaviour rating scales (Teacher‐rated)		Mean general behaviour score in the intervention groups was 0.87 standard mean deviations lower (95% CI 1.04 to 0.71 lower)	SMD ‐0.87 (‐0.71 to ‐1.04)	668 (5 studies)	⊕⊝⊝⊝ Very low^a,d	‐
Quality of life (Parent‐rated)		Mean quality of life score in the intervention groups corresponds to a mean difference of 8.0 (95% CI 5.49 to 10.46) on the Child Health Questionnaire	SMD 0.61 (0.42 to 0.80)	514 (3 studies)	⊕⊝⊝⊝ Very low^a,e	‐
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; RR: Risk ratio; SMD: Standardised mean difference
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^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). ^bDowngraded one level due to inconsistency: moderate statistical heterogeneity. ^c Downgraded one level due to imprecision: wide confidence intervals. ^dDowngraded one level due to indirectness: children's general behavior was assessed by different types of rating scales with different focus on behavior. e Downgraded one level due to indirectness: children's quality of life was assessed by their parents.

Summary of findings for the main comparison. Methylphenidate compared with placebo or no intervention for ADHD

Ir a la tabla de la revisión

Table 1. ADHD symptoms ‐ rating scales

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	Conners 1997a
Abbreviated Symptom Questionnaire, including ASQ Teacher and ASQ Parent	ASQ	Conners 1995
Academic Performance Rating Scale	APRS	DuPaul 1991a
The ADD/H Comprehensive Teacher Rating Scale	ACTeRS	Ullmann 1984
ADHD/ODD Rating Scale, Parent‐ and Teacher‐Rated	ADHD‐RS	Barkley 1998
ADHD Rating Scale, including ADHD Rating Scale Parent and Teacher Ratings	ADHD‐RS	DuPaul 1991a
ADHD Rating Scale‐IV, including ADHD Rating Scale‐IV Parent and Teacher Versions	ADHD‐RS‐IV	DuPaul 1991a
Brief Psychiatric Rating Scale for Children	BPRS	Gale 1986
Child Attention Problems Rating Scale	CAP	Achenbach 1986
Child Attention Profile	CAP	Barkley 1988b
Child Behavior Rating Form	NCBHF	Aman 1996
Child Symptom Inventory	CSI	Gadow 1994
Children’s Psychiatric Rating Scale	CPRS	Pfefferbaum‐Levine 1983
Conners’ Abbreviated Hyperactivity Questionnaire	C‐HI	Conners 1997a
Conners’ Abbreviated Questionnaire	ASQ	Conners 1995
Conners’ Abbreviated Parent Teacher Questionnaire	APTQ	Rowe 1997
Conners’ Abbreviated Rating Scale	ABRS	Conners 1997a
Conners’ Abbreviated Symptom Questionnaire	ASQ	Conners 1995
Conners Abbreviated Symptom Questionnaire for Parents	ASQ‐Parent	Conners 1995
Conners’ Abbreviated Symptom Questionnaire for Teachers	ASQ‐Teacher	Conners 1997a
Conners’ Abbreviated Teacher Rating Scale	ABTRS	Conners 2001
Conners’ ADHD/DSM‐IV Scales Adolescent	CADS‐A	Conners 1997b
Conners’ ADHD/DSM‐IV Scales Parent	CADS–P, CADS‐P DSM‐IV	Conners 1997a
Conners’ ADHD/DSM‐IV Scale Teacher, including Inattentive and Hyperactive‐Impulsive subscales	CADS‐T, CADS‐T DSM‐IV	Conners 1997a
Conners’ Rating Scale ‐ Revised, Parent and Teacher: Hyperactivity and Conduct Factors score	CPRS‐R and CTRS‐R	Goyette 1978
Conners’ Hyperactivity Index, Parent and Teacher, including abbreviated versions	CPRS/CTRS‐Hyperactivity index	Conners 1997a
Conners’ Hyperkinesis Index	‐	Milich 1980
Conners, Loney and Milich Scale	CLAM	Milich 1980
Conners’ Parent and Teacher Rating Scale ‐ Revised, Short Form	CRS‐R:S	Conners 1997a
Conners’ Parent Rating Scale, including abbreviated versions	CPRS	Conners 1998b
Conners’ Parent Rating Scale ‐ Revised	CPRS‐R	Conners 1997a
Conners’ Parent Rating Scale ‐ Revised, Short Form	CPRS‐R:S	Conners 1997a
Conners’ Parent Rating Scale ‐ Revised, Long Version	CPRS‐R:L	Conners 1997a
Conners’ Rating Scale ‐ Revised	CRS‐R	Conners 1997a
Conners’ Short Form Rating Scale, Parent and Teacher	‐	Conners 1997a
Conners’ Teacher Rating Scale	CTRS	Conners 1998a
Conners’ Teacher Rating Scale ‐ Revised, Long Version	CTRS‐R:L	Conners 1998a
Diagnostic and Statistical Manual of Mental Disorders Total	DSM‐IV	APA 1994
Diagnostiksystem für Psychische Störungen im Kindes ‐ und Jugendalter nach ICD‐10 und DSM‐IV, Parental Questionnaire of ADHD symptoms	DISYPS	Döpfner 2000
Fremdbeurteilungsbogen für Hyperkinetische Störungen	FBB‐HKS	Döpfner 2008
German Teacher’s report on ADHD symptoms	FBB‐HKS of the DISYPS	Döpfner 2000
Hyperactivity Index of the Revised Conners Parent and Teacher Rating Scales	‐	Goyette 1978
IOWA Conners Parent Rating Scale, including abbreviated versions	IOWA CPRS	Loney 1982
IOWA Conners Teacher Rating Scale, including abbreviated versions	IOWA CTRS	Loney 1982
IOWA Conners Teacher Rating Scale, Inattention/Overactivity (I/O) and Oppositional/Defiant (O/D) subscales	IOWA‐I/O and O/D subscales	Loney 1982
IOWA Inattention/Overactivity and Aggression/Noncompliance scales ‐ Parent and Teacher rating	IOWA	Loney 1982
Lehrer‐Fragenbogen von Steinhausen	LF	Steinhausen 1993
Loney’s Time on Task Scale, Hyperactivity, Attention and Aggression subscales	TOTS	Fitzpatrick 1992b
Modified Conner Scale Parent and Teacher	ACR	Conners 1997a
Mothers’ Objective Method for Subgrouping	MOMS	Loney 1984
Parent Symptom Checklist	PSC ADHD	Döpfner 2000
Parental Account of Children’s Symptoms	PACS	Chen 2006
Restricted Academic Situation Scale	RASS	Fischer 1998
Schedule for Affective Disorders and Schizophrenia	K‐SADS/ K‐SADS‐E for diagnosis	Chambers 1985
Schedule for Non‐adaptive and Adaptive Personality	SNAP	Clark 1993; Clark 1996
Swanson, Nolan, and Pelham ‐ IV SNAP‐ADHD Rating scale	SNAP‐ADHD	Swanson 1992
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)	Wigal 1998; Murray 2009
Teacher Self‐control Rating Scale	SCRS	Kendall 1979
Turgay ‐ DSM‐IV Scale, Parent	T‐DSM‐IV Scale, Parent	Turgay 1994; Ercan 2001
Turgay ‐ DSM‐IV Scale, Teacher	T‐DSM‐IV Scale, Teacher	Turgay 1994; Ercan 2001
Teacher Hyperactivity Index	THI	Achenbach 1991b
Teacher Symptom Checklist	TSC	Döpfner 2000
Vanderbilt ADHD Rating Scale	VADP(T)RS	Wolraich 2003
Wender Utah Rating Scale	WURS	Ward 1993
Wide Range Achievement Test	WRAT‐4	Wilkinson 2006
Wide Range Achievement Test Revised	WRAT‐R	Woodcock 2001
ADD/H: Attention deficit disorder with hyperactivity. ADHD: Attention deficit hyperactivity disorder. DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. ODD: Oppositional defiant disorder.

Table 1. ADHD symptoms ‐ rating scales

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Table 2. Table 2: General behaviour rating scales

Name of scale	Abbreviation	Reference
Achenbach Child Behaviour Checklist	CBCL	Achenbach 1991a
Achenbach’s Teacher Report	ATRF	Achenbach 1991b; Achenbach 2001
ADHD Rating Scale	ADHD‐RS	DuPaul 1991a
ADHD School Observation Code	ADHD‐SOC	Gadow 1996
Barkley Scales, Disruptive Behavior Disorders Rating Scale	‐	Barkley 1991a
Child Attention Problems Scale	CAP	Barkley 1991
Child Attention Profile	CAP	Barkley 1988b
Child Behavior Checklist	CBCL	Achenbach 1991a
Child Health Questionnaire	CHQ	Landgraf 1998
Child and Adolescent Psychiatric Assessment, selected items	CAPA	Angold 1995
Children’s Psychiatric Rating Scale	CPRS	Fish 1985
Classroom Observation Code (Abikoff Classroom Observational System)	COC	Abikoff 1980
Code for Observing Social Activity	COSA	Sprafkin 1986
Conners' Child Behavior Scale	UC‐CCBS	Ladd 1996
Conners' Global Index Scale	CGI‐S	Conners 1998a
Conners’ Global Index ‐ Parent	CGI‐P	Conners 1997a
Conners' Global Index ‐ Teacher	CGI‐T	Conners 1998a
Conners', Loney and Milich Scale	CLAM	Milich 1980
Conners’ Parent Questionnaire	CPQ	Conners 1995
Conners’ Parent Rating Scale	CPRS	Conners 1998b
Conners’ Teacher Rating Scale	CTRS	Conners 1998a
Conners’ Teacher Rating Conduct Problems	‐	Miller 1997
Disruptive Behavior Disorders Rating Scale, Parent‐ and Teacher‐Rated	DBS	Mendelsohn 1978
Disruptive Behavior Disorders Rating Scale	DBD	Silva 2005b
Groninger Behaviour Observation Scale	GOO and GBO	Van der Meere 1999b
Groninger Behaviour Checklists, Parent and Teacher Versions of the abbreviated Groninger	GGGS and GGBS	Van der Meere 1999b
Hillside Behavior Rating Scale	HBRS	Gittleman‐Klein 1976
Home Situations Questionnaire	HSQ	Barkley 1987
Home Situations Questionnaire ‐ Revised	HSQ‐R	DuPaul 1992
Humphrey’s Teacher Self‐Control Rating Scale	TSCRS	Humphrey 1982
Hyperactivity Index from the Conners Revised Teacher Rating Scale	CTRS‐R‐Hyperactivity Index	Goyette 1978
Impairment Rating Scale	IRS	Fabiano 2006
Inpatient Global Rating Scale, Revised	IGRS	Conners 1985
Inpatient Global Rating Scale, Somatic factor	IGRS‐S	Conners 1985
IOWA Conners' Rating Scale, Oppositional/Defiant (O/D) subscales	IOWA‐O/D subscales	Loney 1982
Nisonger Child Behavior Rating Form	NCBRF	Aman 1996
Paired Associates Learning	PAL	Wechsler 1945
Parent Global Assessment for Improvement	PGA	McGough 2006a
Peer Conflict Scale	PCS	Marsee 2007
Personality Inventory for Children	PIC	Lachar 1986
School Situations Questionnaire	SSQ	Barkley 1987
School Situations Questionnaire ‐ Revised	SSQ‐R	DuPaul 1992
Schedule for Nonadaptive and Adaptive Personality	SNAP	Clark 1993; Clark 1996
Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Scale, Parent and Teacher	SWAN	Swanson 2006; Polderman 2007
Subjective Treatment Emergent Symptom Scale	STESS‐R	Guy 1976
Swanson, Nolan and Pelham, Fourth Edition	SNAP‐IV	Bussing 2008
Teachers Report Form	TRF	Achenbach 1991b
Telephone Interview Probe (Parent and Teacher)	TIP	Corkum 2007
Vanderbilt ADHD rating scales: Vanderbilt ADHD Diagnostic Parent Rating Scale and Vanderbilt ADHD Diagnostic Teacher Rating Scale	VADPRS and VADTRS	Wolraich 2003
Wahler, House and Stambaugh’s Ecobehavioral Assessment System	ECO	Wahler 1976
The Weekly Parent Ratings of Evening and Morning Behaviour	WREMB‐R	Kelsey 2004
Werry‐Weiss‐Peters Activity Rating Scale	WWP	Routh 1978
Woodcock‐Johnson Achievement Battery	WJ‐III Ach	Woodcock 2001
ADHD: attention deficit hyperactivity disorder.

Table 2. Table 2: General behaviour rating scales

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Table 3. Table 3: Quality of life ratings scales

Name of scale	Abbreviation	Reference
ADHD Impact Module‐Child	AIM‐C	AIM‐C 2013
Child Impact Scale and Home Impact Scale	CIS/HIS	Landgraf 2002
Child Health and Illness Profile, Child Edition: Parent Report Form	CHIP‐CE:PRF	Riley 2004
Child Health Questionnaire	CHQ‐P	Landgraf 1998
Children's Global Assessment Scale	CGAS	Shaffer 1983
Comprehensive Psychopathological Rating Scale	CPRS	Aasberg 1978
Health Utilities Index ‐ 2	HUI‐2	Torrance 1982
ADHD: attention deficit hyperactivity disorder.

Table 3. Table 3: Quality of life ratings scales

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Comparison 1. Teacher‐rated ADHD symptoms

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All parallel‐group trials and first‐period cross‐over trials Show forest plot	19	1698	Std. Mean Difference (IV, Random, 95% CI)	‐0.77 [‐0.90, ‐0.64]

1.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 High risk of bias	19	1698	Std. Mean Difference (IV, Random, 95% CI)	‐0.77 [‐0.90, ‐0.64]
2 Subgroup analysis: types of scales Show forest plot	19		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 Conners' Teacher Rating Scale (CTRS)	8	518	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.82, ‐0.47]
2.2 Abbreviated Conners' Rating Scale (ACRS) ‐ Teacher	2	105	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐1.79, 0.29]
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]
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]
2.5 Schedule for Non‐adaptive and Adaptive Personality (SNAP) ‐ Teacher	2	328	Std. Mean Difference (IV, Random, 95% CI)	‐0.61 [‐0.96, ‐0.25]
2.6 Teacher ratings of attention	1	20	Std. Mean Difference (IV, Random, 95% CI)	‐0.55 [‐1.45, 0.35]
2.7 Teacher ratings of impulsivity	1	20	Std. Mean Difference (IV, Random, 95% CI)	0.04 [‐0.83, 0.92]
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]
2.9 Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS)	1	85	Std. Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.52, ‐0.61]
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]
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]
3 Medication status: medication naive versus not medication naive Show forest plot	6	717	Std. Mean Difference (IV, Random, 95% CI)	‐0.79 [‐1.08, ‐0.50]

3.1 Medication naive	4	431	Std. Mean Difference (IV, Random, 95% CI)	‐0.63 [‐0.94, ‐0.31]
3.2 Not medication naive	2	286	Std. Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.33, ‐0.79]
4 Subgroup analysis: duration of treatment Show forest plot	19	1698	Std. Mean Difference (IV, Random, 95% CI)	‐0.77 [‐0.90, ‐0.64]

4.1 Short term (up to 6 months)	18	1445	Std. Mean Difference (IV, Random, 95% CI)	‐0.81 [‐0.94, ‐0.68]
4.2 Long term (over 6 months)	1	253	Std. Mean Difference (IV, Random, 95% CI)	‐0.47 [‐0.72, ‐0.22]
5 Subgroup analysis: dose Show forest plot	19		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 Low dose	8	493	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.82, ‐0.46]
5.2 High dose	7	688	Std. Mean Difference (IV, Random, 95% CI)	‐0.81 [‐1.08, ‐0.54]
5.3 Unknown dose	6	669	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.06, ‐0.68]
6 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials Show forest plot	19	1698	Std. Mean Difference (IV, Random, 95% CI)	‐0.77 [‐0.90, ‐0.64]

6.1 Parallel‐group trials	17	1506	Std. Mean Difference (IV, Random, 95% CI)	‐0.80 [‐0.95, ‐0.65]
6.2 First‐period cross‐over trials	2	192	Std. Mean Difference (IV, Random, 95% CI)	‐0.58 [‐0.87, ‐0.29]
7 Subgroup analysis: trials with cohort selection bias of all participants compared with trials without cohort selection bias of all participants Show forest plot	19	1698	Std. Mean Difference (IV, Random, 95% CI)	‐0.77 [‐0.90, ‐0.64]

7.1 Trials with cohort selection bias of all participants	7	994	Std. Mean Difference (IV, Random, 95% CI)	‐0.79 [‐1.01, ‐0.57]
7.2 Trials without cohort selection bias of all participants	12	704	Std. Mean Difference (IV, Random, 95% CI)	‐0.76 [‐0.93, ‐0.59]
8 ADHD symptoms, cross‐over trial (endpoint data) Show forest plot	59	5145	Std. Mean Difference (IV, Random, 95% CI)	‐0.93 [‐1.06, ‐0.80]

8.1 Low risk of bias	4	204	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.97, ‐0.30]
8.2 High risk of bias	55	4941	Std. Mean Difference (IV, Random, 95% CI)	‐0.95 [‐1.09, ‐0.82]
9 ADHD symptoms, cross‐over trials (endpoint data), subgroup analysis: dose Show forest plot	59	6821	Std. Mean Difference (IV, Random, 95% CI)	‐0.85 [‐0.96, ‐0.74]

9.1 Low dose	42	3408	Std. Mean Difference (IV, Random, 95% CI)	‐0.73 [‐0.89, ‐0.57]
9.2 High dose	36	3413	Std. Mean Difference (IV, Random, 95% CI)	‐0.98 [‐1.13, ‐0.84]
10 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data) Show forest plot	75	6344	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.01, ‐0.80]

10.1 All parallel‐group trials and first‐period cross‐over trials	19	1698	Std. Mean Difference (IV, Random, 95% CI)	‐0.77 [‐0.90, ‐0.64]
10.2 Cross‐over trials (endpoint data)	56	4646	Std. Mean Difference (IV, Random, 95% CI)	‐0.95 [‐1.09, ‐0.82]
11 All parallel‐group trials and cross‐over trials: risk of bias Show forest plot	75	6344	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.01, ‐0.80]

11.1 Low risk of bias	4	204	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.97, ‐0.30]
11.2 High risk of bias	71	6140	Std. Mean Difference (IV, Random, 95% CI)	‐0.92 [‐1.03, ‐0.81]

Comparison 1. Teacher‐rated ADHD symptoms

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Comparison 2. Independent assessor‐rated ADHD symptoms

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All parallel‐group trials and first‐period cross‐over trials Show forest plot	10	1907	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.89, ‐0.39]

1.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 High risk of bias	10	1907	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.89, ‐0.39]
2 Subgroup analysis: types of scales Show forest plot	10		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 Swanson, Kotkin, Agler, M‐Glynn and Pelham (SKAMP) Scale	1	164	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐1.04, ‐0.41]
2.2 ADHD Rating Scale (ADHD‐RS )	7	1442	Std. Mean Difference (IV, Random, 95% CI)	‐0.71 [‐1.09, ‐0.32]
2.3 Swanson, Nolan and Pelham (SNAP) Scale	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.61, ‐0.08]
2.4 Unknown	1	78	Std. Mean Difference (IV, Random, 95% CI)	‐0.94 [‐1.41, ‐0.47]
3 Subgroup analysis: duration of treatment Show forest plot	10	1907	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.89, ‐0.39]

3.1 Short term (up to 6 months)	9	1686	Std. Mean Difference (IV, Random, 95% CI)	‐0.68 [‐0.95, ‐0.40]
3.2 Long term (over 6 months)	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.61, ‐0.08]
4 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials Show forest plot	10	1907	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.89, ‐0.39]

4.1 Parallel‐group trials	7	1609	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.91, ‐0.28]
4.2 First‐period cross‐over trials	3	298	Std. Mean Difference (IV, Random, 95% CI)	‐0.76 [‐0.99, ‐0.52]
5 Subgroup analysis: trials with cohort selection bias of all participants compared with trials without cohort selection bias of all participants Show forest plot	10	1907	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.89, ‐0.39]

5.1 Trials with cohort selection bias of all participants	4	630	Std. Mean Difference (IV, Random, 95% CI)	‐0.51 [‐0.73, ‐0.29]
5.2 Trials without cohort selection bias of all participants	6	1277	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐1.11, ‐0.33]
6 Subgroup analysis: dose Show forest plot	10	1907	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.89, ‐0.39]

6.1 Low dose	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 High dose	6	1380	Std. Mean Difference (IV, Random, 95% CI)	‐0.55 [‐0.91, ‐0.20]
6.3 Unknown dose	4	527	Std. Mean Difference (IV, Random, 95% CI)	‐0.80 [‐0.98, ‐0.61]
7 ADHD symptoms, cross‐over trials (endpoint data), subgroup analysis: risk of bias Show forest plot	19	2471	Std. Mean Difference (IV, Random, 95% CI)	1.00 [‐1.16, ‐0.84]

7.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7.2 High risk of bias	19	2471	Std. Mean Difference (IV, Random, 95% CI)	1.00 [‐1.16, ‐0.84]
8 ADHD symptoms, cross‐over trials (endpoint data), subgroup analysis: dose Show forest plot	19	3874	Std. Mean Difference (IV, Random, 95% CI)	‐0.89 [‐1.02, ‐0.75]

8.1 Low dose	16	2021	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.82, ‐0.55]
8.2 High dose	12	1853	Std. Mean Difference (IV, Random, 95% CI)	‐1.13 [‐1.31, ‐0.95]
9 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data) Show forest plot	28	4215	Std. Mean Difference (IV, Random, 95% CI)	‐0.83 [‐0.98, ‐0.67]

9.1 All parallel‐group trials and first‐period cross‐over trials	10	1907	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.89, ‐0.39]
9.2 Cross‐over trials (endpoint data)	18	2308	Std. Mean Difference (IV, Random, 95% CI)	‐0.95 [‐1.13, ‐0.77]

Comparison 2. Independent assessor‐rated ADHD symptoms

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Comparison 3. Parent‐rated ADHD symptoms

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All parallel‐group trials and first‐period cross‐over trials Show forest plot	21	2187	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.82, ‐0.51]

1.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 High risk of bias	21	2187	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.82, ‐0.51]
2 Subgroup analysis: types of scales Show forest plot	21		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 Conners' Parent Rating Scale (CPRS)	7	751	Std. Mean Difference (IV, Random, 95% CI)	‐0.58 [‐0.87, ‐0.30]
2.2 ADHD Rating Scale ‐ Fourth Edition (ADHD‐RS‐IV)	2	194	Std. Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.58, ‐0.02]
2.3 Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS)	1	85	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.36, ‐0.46]
2.4 Conners’ ADHD/DSM‐IV Scales ‐ Parent (CADS‐P)	1	120	Std. Mean Difference (IV, Random, 95% CI)	‐1.26 [‐1.65, ‐0.86]
2.5 CADS‐P Inattentive subscale	1	109	Std. Mean Difference (IV, Random, 95% CI)	‐0.78 [‐1.17, ‐0.39]
2.6 CADS‐P Hyperactivity subscale	1	109	Std. Mean Difference (IV, Random, 95% CI)	‐0.93 [‐1.32, ‐0.53]
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]
2.8 Abbreviated Conners' Rating Scale (ACRS) ‐ Parent	2	121	Std. Mean Difference (IV, Random, 95% CI)	‐0.62 [‐0.99, ‐0.25]
2.9 Swanson, Nolan, and Pelham, Fourth Edition ‐ Parent (SNAP‐IV‐Parent) Scale	4	430	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.79, ‐0.40]
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]
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 Subgroup analysis: duration of treatment Show forest plot	21	2187	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.82, ‐0.51]

3.1 Short term (up to 6 months)	20	1925	Std. Mean Difference (IV, Random, 95% CI)	‐0.67 [‐0.84, ‐0.50]
3.2 Long term (over 6 months)	1	262	Std. Mean Difference (IV, Random, 95% CI)	‐0.58 [‐0.82, ‐0.33]
4 Subgroup analysis: dose Show forest plot	21	2335	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.79, ‐0.48]

4.1 Low dose	5	329	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [1.00, ‐0.07]
4.2 High dose	10	1132	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.86, ‐0.33]
4.3 Unknown dose	8	874	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐0.92, ‐0.52]
5 Medication status: medication naive versus not medication naive Show forest plot	7	795	Std. Mean Difference (IV, Random, 95% CI)	‐0.76 [‐1.05, ‐0.48]

5.1 Medication naive	4	492	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐1.03, ‐0.35]
5.2 Not medication naive	3	303	Std. Mean Difference (IV, Random, 95% CI)	‐0.88 [‐1.33, ‐0.42]
6 Subgroup analysis: trials with cohort selection bias of all participants compared with trials without cohort selection bias of all participants Show forest plot	21	2187	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.82, ‐0.51]

6.1 Trials with selection bias of all participants	10	1559	Std. Mean Difference (IV, Random, 95% CI)	‐0.68 [‐0.86, ‐0.51]
6.2 Trials without cohort selection bias of all participants	11	628	Std. Mean Difference (IV, Random, 95% CI)	‐0.62 [‐0.90, ‐0.33]
7 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials Show forest plot	21	2187	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.82, ‐0.51]

7.1 Parallel‐group trials	19	2094	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.83, ‐0.50]
7.2 First‐period cross‐over trials	2	93	Std. Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.07, ‐0.23]
8 ADHD symptoms, cross‐over trials (endpoint data) Show forest plot	41	3734	Std. Mean Difference (IV, Random, 95% CI)	‐0.78 [‐0.90, ‐0.67]

8.1 Low risk of bias	4	204	Std. Mean Difference (IV, Random, 95% CI)	‐0.54 [‐0.96, ‐0.13]
8.2 High risk of bias	37	3530	Std. Mean Difference (IV, Random, 95% CI)	‐0.81 [‐0.92, ‐0.69]
9 ADHD symptoms, cross‐over trials (endpoint data), subgroup analysis: dose Show forest plot	41	4918	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.79, ‐0.58]

9.1 Low dose	26	2272	Std. Mean Difference (IV, Random, 95% CI)	‐0.65 [‐0.82, ‐0.48]
9.2 High dose	28	2646	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐0.84, ‐0.60]
10 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data) Show forest plot	59	5861	Std. Mean Difference (IV, Random, 95% CI)	‐0.74 [‐0.83, ‐0.65]

10.1 All parallel‐group trials and first‐period cross‐over trials	21	2215	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.82, ‐0.51]
10.2 Cross‐over trials (endpoint data)	39	3646	Std. Mean Difference (IV, Random, 95% CI)	‐0.79 [‐0.90, ‐0.67]

Comparison 3. Parent‐rated ADHD symptoms

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Comparison 4. Additional subgroup analyses of ADHD symptoms: parallel‐group trials and first‐period cross‐over trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Comparision of raters Show forest plot	31	5697	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.79, ‐0.59]

1.1 Teacher‐rated	19	1689	Std. Mean Difference (IV, Random, 95% CI)	‐0.78 [‐0.93, ‐0.63]
1.2 Independent assessor‐rated	9	1829	Std. Mean Difference (IV, Random, 95% CI)	‐0.61 [‐0.87, ‐0.35]
1.3 Parent‐rated	21	2179	Std. Mean Difference (IV, Random, 95% CI)	‐0.65 [‐0.81, ‐0.50]
2 Age Show forest plot	6	1039	Std. Mean Difference (IV, Random, 95% CI)	‐0.44 [‐0.74, ‐0.14]

2.1 2 to 6 years	1	64	Std. Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.82, 0.17]
2.2 7 to 11 years	2	278	Std. Mean Difference (IV, Random, 95% CI)	‐0.59 [‐1.03, ‐0.15]
2.3 12 to 18 years	3	697	Std. Mean Difference (IV, Random, 95% CI)	‐0.38 [‐0.88, 0.12]
3 Comorbidity versus no comorbidity Show forest plot	20	2310	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐0.91, ‐0.53]

3.1 ADHD with comorbidity	18	1981	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐0.94, ‐0.51]
3.2 ADHD without comorbidity	2	329	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.92, ‐0.46]
4 Subtypes ADHD: ADHD Rating Scale (parent‐, teacher‐ or independent assessor‐rated) Show forest plot	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Combined ADHD	2	559	Std. Mean Difference (IV, Random, 95% CI)	0.65 [‐1.30, 2.60]
4.2 Inattentive ADHD	1	204	Std. Mean Difference (IV, Random, 95% CI)	‐1.31 [‐1.61, ‐1.01]
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

5.1 First‐period data	4	372	Std. Mean Difference (IV, Random, 95% CI)	‐0.64 [‐0.85, ‐0.44]
5.2 Endpoint data	4	372	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.18, ‐0.65]

Comparison 4. Additional subgroup analyses of ADHD symptoms: parallel‐group trials and first‐period cross‐over trials

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Comparison 5. Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of serious adverse events (SAE) Show forest plot	9	1532	Risk Ratio (IV, Random, 95% CI)	0.98 [0.44, 2.22]

2 Nervous system Show forest plot	6	2280	Risk Ratio (IV, Random, 95% CI)	0.87 [0.30, 2.53]

2.1 Aggression	1	303	Risk Ratio (IV, Random, 95% CI)	0.50 [0.05, 5.49]
2.2 Concussion	1	303	Risk Ratio (IV, Random, 95% CI)	0.34 [0.01, 8.17]
2.3 Loss of consciousness	1	221	Risk Ratio (IV, Random, 95% CI)	0.33 [0.01, 8.02]
2.4 Psychosis	4	712	Risk Ratio (IV, Random, 95% CI)	1.78 [0.19, 16.96]
2.5 Syncope	3	741	Risk Ratio (IV, Random, 95% CI)	1.39 [0.23, 8.47]
3 Digestive system: gastrointestinal disorders Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

4 Urinary system: kidney infection Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

5 Circulatory and respiratory systems: asthma Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

6 Immune system: cyst rupture Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

7 Other: drug toxicity Show forest plot	1	303	Risk Ratio (IV, Random, 95% CI)	0.34 [0.01, 8.17]

Comparison 5. Number of serious adverse events: parallel‐group trials and first‐period cross‐over trials

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Comparison 6. Number of serious adverse events: cross‐over trials (endpoint data)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of serious adverse events (SAE) Show forest plot	8	1721	Risk Ratio (IV, Random, 95% CI)	1.62 [0.34, 7.71]

2 Hallucinations/psychosis Show forest plot	4	187	Risk Ratio (IV, Random, 95% CI)	1.10 [0.18, 6.72]

Comparison 6. Number of serious adverse events: cross‐over trials (endpoint data)

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Comparison 7. Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total number of non‐serious adverse events Show forest plot	21	3132	Risk Ratio (IV, Random, 95% CI)	1.29 [1.10, 1.51]

2 Subgroup analysis: total number of non‐serious adverse events according to dose Show forest plot	21	3135	Risk Ratio (IV, Random, 95% CI)	1.28 [1.11, 1.49]

2.1 Low dose	2	151	Risk Ratio (IV, Random, 95% CI)	1.09 [0.82, 1.46]
2.2 High dose	10	1761	Risk Ratio (IV, Random, 95% CI)	1.22 [1.10, 1.35]
2.3 Unknown dose	10	1223	Risk Ratio (IV, Random, 95% CI)	1.37 [1.01, 1.87]
3 Nervous system Show forest plot	21		Risk Ratio (Random, 95% CI)	Subtotals only

3.1 Affective	4	390	Risk Ratio (Random, 95% CI)	2.39 [0.48, 11.96]
3.2 Aggression	2	417	Risk Ratio (Random, 95% CI)	1.16 [0.17, 7.80]
3.3 Apathy	1	59	Risk Ratio (Random, 95% CI)	0.80 [0.19, 3.33]
3.4 Confusion	2	548	Risk Ratio (Random, 95% CI)	1.01 [0.22, 4.73]
3.5 Depression	1	59	Risk Ratio (Random, 95% CI)	0.83 [0.22, 3.10]
3.6 Dizziness	3	683	Risk Ratio (Random, 95% CI)	2.50 [0.70, 8.99]
3.7 Drowsiness	4	811	Risk Ratio (Random, 95% CI)	1.27 [0.82, 1.98]
3.8 Emotional lability	1	132	Risk Ratio (Random, 95% CI)	2.41 [0.27, 21.32]
3.9 Fatigue	7	858	Risk Ratio (Random, 95% CI)	0.76 [0.36, 1.63]
3.10 Headache	17	2724	Risk Ratio (Random, 95% CI)	1.22 [0.90, 1.64]
3.11 Insomnia	3	349	Risk Ratio (Random, 95% CI)	1.31 [0.35, 4.93]
3.12 Irritability	11	1721	Risk Ratio (Random, 95% CI)	1.11 [0.77, 1.60]
3.13 Nervousness	2	362	Risk Ratio (Random, 95% CI)	2.52 [0.82, 7.76]
3.14 Pain	1	132	Risk Ratio (Random, 95% CI)	1.91 [0.21, 17.60]
3.15 Picking at skin or fingers, nail biting, lip or cheek chewing	1	316	Risk Ratio (Random, 95% CI)	1.01 [0.60, 1.70]
3.16 Sad, tearful or depressed	4	707	Risk Ratio (Random, 95% CI)	1.41 [0.86, 2.29]
3.17 Somnolence	2	173	Risk Ratio (Random, 95% CI)	0.59 [0.11, 3.11]
3.18 Trouble sleeping or sleep problems	13	2416	Risk Ratio (Random, 95% CI)	1.60 [1.15, 2.23]
3.19 Tics or nervous movements	8	1231	Risk Ratio (Random, 95% CI)	0.85 [0.26, 2.79]
3.20 Worried or anxious	3	596	Risk Ratio (Random, 95% CI)	1.37 [0.84, 2.25]
4 Digestive system Show forest plot	18		Risk Ratio (IV, Random, 95% CI)	Subtotals only

4.1 Decreased appetite	16	2962	Risk Ratio (IV, Random, 95% CI)	3.66 [2.56, 5.23]
4.2 Decreased weight	6	859	Risk Ratio (IV, Random, 95% CI)	3.89 [1.43, 10.59]
4.3 Diarrhoea	5	857	Risk Ratio (IV, Random, 95% CI)	1.07 [0.41, 2.74]
4.4 Dyspepsia	2	159	Risk Ratio (IV, Random, 95% CI)	1.80 [0.71, 4.54]
4.5 Increased appetite	1	179	Risk Ratio (IV, Random, 95% CI)	0.07 [0.00, 1.43]
4.6 Nausea	11	1995	Risk Ratio (IV, Random, 95% CI)	1.30 [0.85, 1.99]
4.7 Stomachache	13	2341	Risk Ratio (IV, Random, 95% CI)	1.30 [1.00, 1.69]
4.8 Vomiting	11	1916	Risk Ratio (IV, Random, 95% CI)	1.17 [0.76, 1.79]
5 Circulatory and respiratory systems Show forest plot	8		Risk Ratio (Random, 95% CI)	Subtotals only

5.1 ECG: prolonged QT‐interval	2	466	Risk Ratio (Random, 95% CI)	0.81 [0.13, 5.00]
5.2 ECG: tachycardia	1	245	Risk Ratio (Random, 95% CI)	1.04 [0.11, 10.18]
5.3 Cough	4	996	Risk Ratio (Random, 95% CI)	0.95 [0.41, 2.18]
5.4 Nasal congestion	2	479	Risk Ratio (Random, 95% CI)	1.19 [0.59, 2.41]
5.5 Pharyngolaryngeal pain	1	303	Risk Ratio (Random, 95% CI)	1.12 [0.59, 2.13]
5.6 Supraventricular extrasystoles	1	17	Risk Ratio (Random, 95% CI)	3.00 [0.11, 84.55]
5.7 Upper respiratory tract infection	1	217	Risk Ratio (Random, 95% CI)	1.07 [0.42, 2.76]
6 Skeletal and muscular systems Show forest plot	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only

6.1 Arthralgia	1	303	Risk Ratio (IV, Random, 95% CI)	0.67 [0.24, 1.84]
6.2 Asthenia	1	177	Risk Ratio (IV, Random, 95% CI)	0.21 [0.01, 4.25]
6.3 Back pain	1	303	Risk Ratio (IV, Random, 95% CI)	0.81 [0.39, 1.66]
6.4 Myalgia	1	303	Risk Ratio (IV, Random, 95% CI)	0.60 [0.23, 1.62]
6.5 Toothache	1	303	Risk Ratio (IV, Random, 95% CI)	1.01 [0.43, 2.35]
7 Immune system Show forest plot	7		Risk Ratio (IV, Random, 95% CI)	Subtotals only

7.1 Gastroenteritis	3	435	Risk Ratio (IV, Random, 95% CI)	4.63 [0.99, 21.72]
7.2 Influenza	3	624	Risk Ratio (IV, Random, 95% CI)	0.65 [0.20, 2.10]
7.3 Nasopharyngitis	5	979	Risk Ratio (IV, Random, 95% CI)	1.15 [0.70, 1.87]
7.4 Otitis media	1	100	Risk Ratio (IV, Random, 95% CI)	1.77 [0.17, 18.94]
7.5 Pharyngitis	2	293	Risk Ratio (IV, Random, 95% CI)	2.43 [0.49, 12.05]
7.6 Pyrexia	2	400	Risk Ratio (IV, Random, 95% CI)	1.02 [0.01, 87.72]
7.7 Rhinitis	1	132	Risk Ratio (IV, Random, 95% CI)	1.28 [0.43, 3.79]
7.8 Upper respiratory tract infection ‐ not otherwise specified (NOS)	5	917	Risk Ratio (IV, Random, 95% CI)	1.19 [0.68, 2.06]
7.9 Viral infection NOS	3	614	Risk Ratio (IV, Random, 95% CI)	0.70 [0.23, 2.15]
8 Height Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

9 Weight Show forest plot	5	805	Std. Mean Difference (IV, Random, 95% CI)	‐1.12 [‐1.55, ‐0.70]

10 BMI Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

11 Vital signs Show forest plot	9	3374	Mean Difference (IV, Random, 95% CI)	1.41 [0.30, 2.52]

11.1 Diastolic blood pressure (mmHg)	8	1067	Mean Difference (IV, Random, 95% CI)	0.94 [‐0.12, 2.01]
11.2 Systolic blood pressure (mmHg)	8	1067	Mean Difference (IV, Random, 95% CI)	‐0.05 [‐1.25, 1.16]
11.3 Pulse or heart rate (bpm)	8	1240	Mean Difference (IV, Random, 95% CI)	3.41 [0.87, 5.94]
12 Other Show forest plot	5	1815	Risk Ratio (IV, Random, 95% CI)	1.20 [0.56, 2.57]

12.1 Accidental injury	3	656	Risk Ratio (IV, Random, 95% CI)	0.99 [0.48, 2.07]
12.2 Epistasis	1	132	Risk Ratio (IV, Random, 95% CI)	4.25 [0.23, 77.22]
12.3 Excoriation	1	303	Risk Ratio (IV, Random, 95% CI)	3.52 [1.19, 10.46]
12.4 Overdose	1	221	Risk Ratio (IV, Random, 95% CI)	2.97 [0.12, 72.20]
12.5 Skin disorder (rash)	2	200	Risk Ratio (IV, Random, 95% CI)	0.52 [0.01, 26.44]
12.6 Skin laceration	1	303	Risk Ratio (IV, Random, 95% CI)	0.42 [0.15, 1.16]

Comparison 7. Number of non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials

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Comparison 8. Number of non‐serious adverse events: cross‐over trials (endpoint data)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total number of non‐serious adverse events Show forest plot	21	2072	Risk Ratio (Random, 95% CI)	1.33 [1.11, 1.58]

2 Subgroup analysis: total number of non‐serious adverse events according to dose Show forest plot	21	2859	Risk Ratio (Random, 95% CI)	1.26 [1.11, 1.44]

2.1 Low dose	16	1539	Risk Ratio (Random, 95% CI)	1.11 [0.94, 1.31]
2.2 High dose	12	1080	Risk Ratio (Random, 95% CI)	1.57 [1.22, 2.01]
2.3 Unknown dose	2	240	Risk Ratio (Random, 95% CI)	0.98 [0.51, 1.86]
3 Nervous system Show forest plot	50		Risk Ratio (Random, 95% CI)	Subtotals only

3.1 Aggression	2	589	Risk Ratio (Random, 95% CI)	0.52 [0.17, 1.60]
3.2 Agitation	1	62	Risk Ratio (Random, 95% CI)	1.18 [0.38, 3.60]
3.3 Anger	3	264	Risk Ratio (Random, 95% CI)	0.45 [0.26, 0.77]
3.4 Behavioural complaints	1	82	Risk Ratio (Random, 95% CI)	0.55 [0.35, 0.86]
3.5 Buccal or lingual movements	4	302	Risk Ratio (Random, 95% CI)	1.06 [0.62, 1.79]
3.6 Compulsive acts	1	90	Risk Ratio (Random, 95% CI)	2.57 [1.45, 4.56]
3.7 Daydreaming	3	222	Risk Ratio (Random, 95% CI)	0.66 [0.44, 0.98]
3.8 Dizziness	9	746	Risk Ratio (Random, 95% CI)	1.17 [0.89, 1.55]
3.9 Drowsiness: dull, tired, listless or sleepy	21	1350	Risk Ratio (Random, 95% CI)	0.97 [0.73, 1.28]
3.10 Euphoria	6	405	Risk Ratio (Random, 95% CI)	1.06 [0.72, 1.57]
3.11 Headache	37	3752	Risk Ratio (Random, 95% CI)	1.21 [1.01, 1.45]
3.12 Insomnia or sleep problems	31	3270	Risk Ratio (Random, 95% CI)	1.57 [1.20, 2.06]
3.13 Irritability	23	2238	Risk Ratio (Random, 95% CI)	0.92 [0.66, 1.27]
3.14 Nightmares	10	686	Risk Ratio (Random, 95% CI)	0.97 [0.66, 1.42]
3.15 Overly meticulous	1	96	Risk Ratio (Random, 95% CI)	40.77 [2.35, 706.72]
3.16 Obsessive thinking	1	90	Risk Ratio (Random, 95% CI)	2.35 [1.53, 3.62]
3.17 Picking at skin or fingers, nail biting, lip or cheek chewing	15	888	Risk Ratio (Random, 95% CI)	1.12 [0.88, 1.41]
3.18 Repetitive language	1	48	Risk Ratio (Random, 95% CI)	1.0 [0.32, 3.10]
3.19 Sad, tearful or depressed	23	1849	Risk Ratio (Random, 95% CI)	1.15 [0.94, 1.41]
3.20 Socially withdrawn ‐ decreased interaction with others	12	771	Risk Ratio (Random, 95% CI)	1.24 [0.82, 1.87]
3.21 Sleep efficiency (SEF)	2	108	Risk Ratio (Random, 95% CI)	0.48 [0.02, 14.28]
3.22 Stares a lot	9	904	Risk Ratio (Random, 95% CI)	1.03 [0.75, 1.40]
3.23 Tics or nervous movements	19	1403	Risk Ratio (Random, 95% CI)	1.33 [1.03, 1.72]
3.24 Unusual blinking	1	48	Risk Ratio (Random, 95% CI)	3.13 [0.12, 80.68]
3.25 Worried or anxious	20	1673	Risk Ratio (Random, 95% CI)	0.82 [0.60, 1.12]
4 Digestive system Show forest plot	42		Risk Ratio (Random, 95% CI)	Subtotals only

4.1 Decreased appetite or loss of appetite	35	3862	Risk Ratio (Random, 95% CI)	3.04 [2.35, 3.94]
4.2 Diarrhoea	3	402	Risk Ratio (Random, 95% CI)	0.58 [0.19, 1.74]
4.3 Dry mouth	5	342	Risk Ratio (Random, 95% CI)	1.25 [0.54, 2.90]
4.4 Dyspepsia	1	62	Risk Ratio (Random, 95% CI)	0.22 [0.02, 2.14]
4.5 Nausea	9	768	Risk Ratio (Random, 95% CI)	1.52 [1.00, 2.30]
4.6 Increased appetite	1	136	Risk Ratio (Random, 95% CI)	0.20 [0.08, 0.50]
4.7 Stomachache	33	3777	Risk Ratio (Random, 95% CI)	1.61 [1.27, 2.04]
4.8 Vomiting	4	710	Risk Ratio (Random, 95% CI)	0.90 [0.26, 3.11]
5 Urinary system: urinary incontinence Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

6 Skeletal and muscular system: somatic complaints Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

7 Immune system Show forest plot	7		Risk Ratio (IV, Random, 95% CI)	Subtotals only

7.1 Allergic rhinitis	4	475	Risk Ratio (IV, Random, 95% CI)	1.38 [0.35, 5.51]
7.2 Fever	2	91	Risk Ratio (IV, Random, 95% CI)	1.39 [0.09, 20.56]
7.3 Lymphadenitis	2	296	Risk Ratio (IV, Random, 95% CI)	3.93 [0.44, 35.11]
7.4 Pharyngolaryngeal pain	1	160	Risk Ratio (IV, Random, 95% CI)	2.0 [0.19, 21.62]
7.5 Pharyngitis	4	754	Risk Ratio (IV, Random, 95% CI)	0.71 [0.19, 2.62]
7.6 Upper respiratory tract infection	5	888	Risk Ratio (IV, Random, 95% CI)	0.61 [0.27, 1.37]
8 Skin Show forest plot	3		Risk Ratio (IV, Random, 95% CI)	Subtotals only

8.1 Rash	2	208	Risk Ratio (IV, Random, 95% CI)	0.96 [0.14, 6.41]
8.2 Skin laceration	1	167	Risk Ratio (IV, Random, 95% CI)	2.96 [0.12, 71.75]
9 Vital signs Show forest plot	14		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 Diastolic blood pressure (mmHg)	11	755	Mean Difference (IV, Random, 95% CI)	1.23 [‐0.39, 2.86]
9.2 Systolic blood pressure (mmHg)	11	755	Mean Difference (IV, Random, 95% CI)	0.53 [‐1.30, 2.36]
9.3 Pulse or heart rate (bpm)	14	939	Mean Difference (IV, Random, 95% CI)	5.06 [2.88, 7.24]
10 Height (cm) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

11 Weight Show forest plot	6	530	Std. Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.23, 0.11]

Comparison 8. Number of non‐serious adverse events: cross‐over trials (endpoint data)

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Comparison 9. Teacher‐rated general behaviour

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All parallel‐group trials and first‐period cross‐over trials: risk of bias Show forest plot	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]

1.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 High risk of bias	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]
2 Subgroup analysis: types of scales Show forest plot	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]

2.1 Conners' Global Index ‐ Teacher (CGI‐T)	1	314	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.14, ‐0.68]
2.2 Groninger Behaviour Observation Scale (GBOS)	1	43	Std. Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.46, ‐0.21]
2.3 Conners' Teacher Rating Scale ‐ Conduct problems	1	25	Std. Mean Difference (IV, Random, 95% CI)	‐0.67 [‐1.48, 0.14]
2.4 IOWA Conners' Rating Scale ‐ Oppositional/Defiant (IOWA‐O/D)	2	286	Std. Mean Difference (IV, Random, 95% CI)	‐0.86 [‐1.12, ‐0.59]
3 Subgroup analysis: dose Show forest plot	5	696	Std. Mean Difference (IV, Random, 95% CI)	‐0.85 [‐1.02, ‐0.69]

3.1 Low dose	2	71	Std. Mean Difference (IV, Random, 95% CI)	‐0.67 [‐1.16, ‐0.19]
3.2 High dose	3	466	Std. Mean Difference (IV, Random, 95% CI)	‐0.89 [‐1.08, ‐0.70]
3.3 Unknown dose	1	159	Std. Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.21, ‐0.46]
4 Subgroup analysis: duration of treatment Show forest plot	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]

4.1 Short term (up to 6 months)	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]
4.2 Long term (over 6 months)	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5 Subgroup analysis: parallel‐group trials versus first‐period cross‐over trials Show forest plot	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]

5.1 Parallel‐group trials	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]
5.2 First‐period cross‐over trials	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 General behaviour, cross‐over trials (endpoint data) Show forest plot	16	2014	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.78, ‐0.60]

6.1 Low dose	13	1110	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.72, ‐0.48]
6.2 High dose	12	904	Std. Mean Difference (IV, Random, 95% CI)	‐0.82 [‐0.95, ‐0.68]
7 Subgroup analysis: general behaviour, cross‐over trials (endpoint data): risk of bias Show forest plot	16	1308	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐0.87, ‐0.63]

7.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7.2 High risk of bias	16	1308	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐0.87, ‐0.63]
8 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (teacher‐rated) versus cross‐over trials (endpoint data) Show forest plot	21	1976	Std. Mean Difference (IV, Random, 95% CI)	‐0.79 [‐0.88, ‐0.70]

8.1 All parallel‐group trials and first‐period cross‐over trials	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]
8.2 Cross‐over trials (endpoint data)	16	1308	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐0.87, ‐0.63]

Comparison 9. Teacher‐rated general behaviour

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Comparison 10. Independent assessor‐rated general behaviour

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 General behaviour, cross‐over trials (endpoint data) Show forest plot	8	1241	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.75, ‐0.46]

1.1 Low dose	7	903	Std. Mean Difference (IV, Random, 95% CI)	‐0.56 [‐0.76, ‐0.36]
1.2 High dose	5	338	Std. Mean Difference (IV, Random, 95% CI)	‐0.71 [‐0.93, ‐0.49]
2 Subgroup analysis: general behaviour, cross‐over trials (endpoint data): risk of bias Show forest plot	8	951	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.88, ‐0.49]

2.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 High risk of bias	8	951	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.88, ‐0.49]
3 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	8	951	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.88, ‐0.49]

3.1 Parallel‐group trials and first‐period cross‐over trials	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Cross‐over trials (endpoint data)	8	951	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.88, ‐0.49]

Comparison 10. Independent assessor‐rated general behaviour

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Comparison 11. Parent‐rated general behaviour

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All parallel‐group trials and first‐period cross‐over trials Show forest plot	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]

2 Subgroup analysis: risk of bias Show forest plot	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]

2.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 High risk of bias	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]
3 Subgroup analysis: types of scales Show forest plot	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]

3.1 The Weekly Parent Ratings of Evening and Morning Behaviour (WPREMB) ‐ Revised	1	17	Std. Mean Difference (IV, Random, 95% CI)	0.50 [‐0.47, 1.47]
3.2 Conners' Global Index (CGI) ‐ Parent	2	352	Std. Mean Difference (IV, Random, 95% CI)	‐0.41 [‐0.63, ‐0.20]
3.3 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]
3.4 IOWA Conners' Rating Scale ‐ Oppositional/Defiant (IOWA‐I/O)	2	286	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐1.01, ‐0.49]
4 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials Show forest plot	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]

4.1 Parallel‐group trials	5	655	Std. Mean Difference (IV, Random, 95% CI)	‐0.51 [‐0.78, ‐0.23]
4.2 First‐period cross‐over trials	1	15	Std. Mean Difference (IV, Random, 95% CI)	‐0.86 [‐1.95, 0.23]
5 Subgroup analysis: duration of treatment Show forest plot	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]

5.1 Short term (up to 6 months)	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]
5.2 Long term (over 6 months)	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Subgroup analysis: dose Show forest plot	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]

6.1 Low dose	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 High dose	4	496	Std. Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.77, ‐0.08]
6.3 Unknown dose	2	174	Std. Mean Difference (IV, Random, 95% CI)	‐0.73 [‐1.08, ‐0.38]
7 General behaviour, cross‐over trials (endpoint data) Show forest plot	6	550	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐0.93, ‐0.56]

7.1 Low dose	5	248	Std. Mean Difference (IV, Random, 95% CI)	‐0.65 [‐0.93, ‐0.38]
7.2 High dose	4	302	Std. Mean Difference (IV, Random, 95% CI)	‐0.83 [‐1.07, ‐0.60]
8 Subgroup analysis: general behaviour, cross‐over trials (endpoint data): risk of bias Show forest plot	6	384	Std. Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.05, ‐0.63]

8.1 Low risk of bias	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
8.2 High risk of bias	6	384	Std. Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.05, ‐0.63]
9 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (parent‐rated) compared with cross‐over trials (endpoint data) Show forest plot	12	1054	Std. Mean Difference (IV, Random, 95% CI)	‐0.68 [‐0.86, ‐0.50]

9.1 All parallel‐group trials and first‐period cross‐over trials	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]
9.2 Cross‐over trials (endpoint data)	6	384	Std. Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.05, ‐0.63]

Comparison 11. Parent‐rated general behaviour

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Comparison 12. Additional subgroup analyses of general behaviour: parallel‐group trials and first‐period cross‐over trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Comparisions of raters Show forest plot	8	1338	Std. Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.86, ‐0.52]

1.1 Teacher‐rated	5	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.04, ‐0.71]
1.2 Independent assessor‐rated	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Parent‐rated	6	670	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.78, ‐0.27]
2 Comorbidity versus no comorbidity Show forest plot	7	579	Std. Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.98, ‐0.43]

2.1 ADHD with comorbidity	6	265	Std. Mean Difference (IV, Random, 95% CI)	‐0.59 [‐0.95, ‐0.23]
2.2 ADHD without comorbidity	1	314	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.14, ‐0.68]
3 Cross‐over trials: first‐period data versus endpoint data (teacher‐, parent‐, and independent assessor‐rated) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 First‐period data	1	16	Mean Difference (IV, Random, 95% CI)	‐0.81 [‐1.75, 0.13]
3.2 Endpoint data	1	14	Mean Difference (IV, Random, 95% CI)	0.14 [‐0.71, 1.00]

Comparison 12. Additional subgroup analyses of general behaviour: parallel‐group trials and first‐period cross‐over trials

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Comparison 13. Quality of life: parallel‐group trials and first‐period cross‐over trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Subgroup analysis: types of scales Show forest plot	3	514	Std. Mean Difference (IV, Random, 95% CI)	0.61 [0.42, 0.80]

1.1 Child Health Questionnaire (CHQ)	1	257	Std. Mean Difference (IV, Random, 95% CI)	0.54 [0.25, 0.83]
1.2 Children´s Global Assessment Scale (CGAS)	1	36	Std. Mean Difference (IV, Random, 95% CI)	0.79 [0.10, 1.47]
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]

Comparison 13. Quality of life: parallel‐group trials and first‐period cross‐over trials

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