Extended‐release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults

Kim Boesen; Asger Sand Paludan-Müller; Peter C Gøtzsche; Karsten Juhl Jørgensen

doi:10.1002/14651858.CD012857.pub2

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Figure 1

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.

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Figure 2

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

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Figure 3

Funnel plot. Extended‐release methylphenidate versus placebo: ADHD symptoms (self‐rated).

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Figure 4

Funnel plot of comparison: 1 Extended‐release methylphenidate versus placebo ‐ primary outcomes (short and medium term), outcome: 1.8 Serious adverse events.

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Figure 5

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).

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Analysis 1.1

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 1: Days missed at work/school/training (week 13)

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Analysis 1.2

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 2: Days missed at work/school/training (weeks 13‐26)

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Analysis 1.3

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 3: Days missed at work/school/training (weeks 26‐52)

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Analysis 1.4

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 4: ADHD symptoms (self‐rated) (short‐term)

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Analysis 1.5

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 5: ADHD symptoms (self‐rated) [subgroup MD] (short‐term)

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Analysis 1.6

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 6: ADHD symptoms (self‐rated) (medium‐term)

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Analysis 1.7

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 7: ADHD symptoms (self‐rated) [LMCF data] (medium‐term)

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Analysis 1.8

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 8: Serious adverse events

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Analysis 2.1

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 1: Quality of life (self‐rated) (short‐term)

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Analysis 2.2

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 2: Quality of life (self‐rated) [subgroup MD] (short‐term)

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Analysis 2.3

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 3: Quality of life (self‐rated) (medium‐term)

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Analysis 2.4

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 4: ADHD symptoms (investigator rated) (short‐term)

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Analysis 2.5

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 5: ADHD symptoms (investigator‐rated) [subgroup MD] (short‐term)

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Analysis 2.6

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 6: ADHD symptoms (investigator‐rated) (medium‐term)

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Analysis 2.7

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 7: ADHD symptoms (investigator‐rated) [LMCF data] (medium‐term)

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Analysis 2.8

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 8: ADHD symptoms (peer‐rated) (short‐term)

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Analysis 2.9

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 9: Cardiovascular: pulse (beats per minute)

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Analysis 2.10

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 10: Cardiovascular: systolic blood pressure

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Analysis 2.11

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 11: Cardiovascular: diastolic blood pressure

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Analysis 3.1

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 1: Dropout (overall)

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Analysis 3.2

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 2: Dropout (due to adverse events)

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Analysis 3.3

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 3: Adverse events (proportion experiencing any adverse event)

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Analysis 3.4

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 4: Psychiatric adverse events (proportion of participants)

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Analysis 3.5

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 5: Weight (change in kilograms)

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Analysis 3.6

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 6: Adverse event: decreased appetite

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Analysis 3.7

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 7: Adverse event: dry mouth

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Analysis 3.8

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 8: Adverse event: headache

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Analysis 3.9

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 9: Adverse event: palpitations

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Analysis 3.10

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 10: Adverse event: insomnia

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Analysis 3.11

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 11: Adverse event: sexual dysfunction

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Analysis 3.12

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 12: Adverse event: anxiety

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Analysis 3.13

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 13: Adverse event: depression

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Analysis 3.14

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 14: Adverse event: irritability

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Analysis 3.15

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 15: Adverse event: feeling jittery

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Analysis 3.16

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 16: Adverse event: agitation

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Analysis 3.17

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 17: Adverse event: aggression

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Analysis 4.1

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 1: Overall dropout rate: psychiatric comorbidity (subgroup analysis)

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Analysis 4.2

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 2: Overall dropout rate: 'enriched design' (subgroup analysis)

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Analysis 4.3

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 3: Overall dropout rate: withdrawal effects (subgroup analysis)

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Analysis 4.4

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 4: Overall dropout rate: funding (subgroup analysis)

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Analysis 4.5

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 5: Proportion experiencing any adverse event: psychiatric comorbidity (subgroup analysis)

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Analysis 4.6

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 6: Proportion experiencing any adverse event: withdrawal effects (subgroup analysis)

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Analysis 4.7

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 7: Proportion experiencing any adverse event: funding (subgroup analysis)

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Analysis 4.8

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 8: Proportion experiencing any adverse event: dropout rates (sensitivity analysis)

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Analysis 5.1

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 1: ADHD symptoms (self‐rated)

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Analysis 5.2

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 2: Serious adverse events

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Analysis 5.3

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 3: Adverse event: initial insomnia

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Analysis 5.4

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 4: Weight

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Analysis 5.5

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 5: ADHD symptoms (investigator‐rated)

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Analysis 5.6

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 6: Overall dropout

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Analysis 5.7

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 7: Adverse events (AE): proportion experiencing any AE

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Analysis 5.8

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 8: Adverse events (leading to dropout)

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Analysis 5.9

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 9: Adverse event: headache

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Analysis 5.10

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 10: Adverse event: decreased appetite

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Analysis 5.11

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 11: Adverse event: irritability

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Analysis 5.12

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 12: Adverse event: dry mouth

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Analysis 5.13

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 13: Adverse event: decreased libido

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Analysis 5.14

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 14: Adverse event: feeling jittery

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Analysis 5.15

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 15: Adverse events: palpitations

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Analysis 6.1

Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 1: ADHD symptoms (self‐rated)

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Analysis 6.2

Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 2: Overall dropout

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Analysis 6.3

Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 3: Dropouts due to adverse events

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Summary of findings 1. Extended‐release methylphenidate compared to placebo for ADHD

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Extended‐release methylphenidate compared to placebo for ADHD
Patient or population: adults diagnosed with ADHD Setting: outpatient setting Intervention: extended‐release methylphenidate Comparison: placebo
Outcomes	Risk with placebo	Risk with extended‐release methylphenidate	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
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 (2.11 fewer to 1.81 more)	‐	409 (1 RCT)	⊕⊝⊝⊝ Very low^a,b	‐
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 (0.43 lower to 0.30 lower)	‐	3799 (16 RCTs)	⊕⊝⊝⊝ Very low^a,b	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 (0.85 to 2.43)	4078 (14 RCTs)	⊕⊝⊝⊝ Very low^a,b	‐
	12 per 1000	17 per 1000 (10 to 30)	RR1.43 (0.85 to 2.43)	4078 (14 RCTs)	⊕⊝⊝⊝ Very low^a,b	‐
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 (6 RCTs)	⊕⊝⊝⊝ Very low^a,b	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 (0.49 lower to 0.36 lower)	‐	4183 (18 RCTs)	⊕⊝⊝⊝ Very low^a,b	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 (0.48 lower to 0.14 lower)	‐	1005 (3 RCTs)	⊕⊝⊝⊝ Very low^a,b	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 (1.19 to 1.37)	4214 (14 RCTs)	⊕⊝⊝⊝ Very low^a,b	‐
	641 per 1000	814 per 1000 (763 to 878)	RR1.27 (1.19 to 1.37)	4214 (14 RCTs)	⊕⊝⊝⊝ Very low^a,b	‐
*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). ADHD: Attention deficit hyperactivity disorder; CI: Confidence interval; RCT: Randomised controlled trial; RR: Risk ratio; SD: Standard deviation; SMD: Standardised mean difference.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect
^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. ^bWe downgraded two levels due to indirectness; 19 of 21 trials had limited generalisability due to strict inclusion of allowed psychiatric comorbidity; 19 of 21 trials used an 'enriched design' thereby excluding potential participants with previous poor response to methylphenidate; and 16 of 21 trials were at risk of being confounded by withdrawal effects since participants were asked to stop concurring CNS stimulant use prior to randomisation. In addition, 18 of 21 trials had a short follow‐up between 2 to 13 weeks.

Summary of findings 1. Extended‐release methylphenidate compared to placebo for ADHD

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Comparison 1. Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term)

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]

Comparison 1. Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term)

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Comparison 2. Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term)

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]

Comparison 2. Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term)

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Comparison 3. Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term)

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]

Comparison 3. Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term)

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Comparison 4. Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses

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]

Comparison 4. Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses

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Comparison 5. Extended‐release methylphenidate versus atomoxetine

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

Comparison 5. Extended‐release methylphenidate versus atomoxetine

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Comparison 6. Extended‐release methylphenidate versus bupropion

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

Comparison 6. Extended‐release methylphenidate versus bupropion

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