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Anfetaminas para el trastorno de déficit de atención e hiperactividad (TDAH) en niños y adolescentes

Appendices

Appendix 1. CENTRAL search strategy

1. exp Amphetamines/
2. (amphetamine$ or dexamphetamine$ or methamphetamine$ or dextroamphetamine$ or lisdexamphetamine$ or vyvanase$ or Dexedrin3 or desoxyn$ or adderall$).mp.
3. Central Nervous System Stimulants/
4. 1 or 2 or 3
5. exp Attention Deficit Disorder with Hyperactivity/
6. Child Behavior Disorders/
7. adhd.tw.
8. addh.tw.
9. adhs.tw.
10. "ad/hd".tw.
11. hyperactiv$.tw.
12. hyper‐activ$.tw.
13. overactiv$.tw.
14. over‐activ$.tw.
15. hyperkinesis/
16. hyperkin$.tw.
17. hyper‐kin$.tw.
18. hkd.tw.
19. (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
20. (attention$ adj3 (deficit$ or disorder$ or dysfunc$)).tw.
21. (behav$ adj3 (dysfunc$ or disorder$)).tw.
22. (impulsiv$ or inattentiv$ or inattention$).tw.
23. disruptiv$.tw.
24. or/5‐23
25. exp child/
26. adolescent/
27. (adoles$ or teen$ or youth$ or young people or young person$).tw.
28. (child$ or toddler$ or preschool$ or pre‐school or schoolchild$ or schoolgirl$ or schoolboy$ or girl$ or boy$).tw.
29. Pediatrics/
30. p?ediatric$.tw.
31. or/25‐30
32. 4 and 24 and 31

Appendix 2. Ovid MEDLINE search strategy

1. exp Amphetamines
2. (amphetamine$ or dexamphetamine$ or methamphetamine$ or dextroamphetamine$ or lisdexamphetamine$ or vyvanase$ or Dexedrin3 or desoxyn$ or adderall$).mp.
3. Central Nervous System Stimulants/
4. 1 or 2 or 3
5. exp Attention Deficit Disorder with Hyperactivity/
6. Child Behavior Disorders/
7. adhd.tw.
8. addh.tw.
9. adhs.tw
10. "ad/hd".tw.
11. hyperactiv$.tw.
12. hyper‐activ$.tw.
13. overactiv$.tw.
14. over‐activ$.tw.
15. hyperkinesis/
16. hyperkin$.tw.
17. hyper‐kin$.tw.
18. hkd.tw.
19. (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
20. (attention$ adj3 (deficit$ or disorder$ or dysfunc$)).tw.
21. (behav$ adj3 (dysfunc$ or disorder$)).tw.
22. (impulsiv$ or inattentiv$ or inattention$).tw.
23. disruptiv$.tw.
24. or/5‐23
25. exp child/
26. adolescent/
27. (adoles$ or teen$ or youth$ or young people or young person$).tw.
28. (child$ or toddler$ or preschool$ or pre‐school or schoolchild$ or schoolgirl$ or schoolboy$ or girl$ or boy$).tw.
29. Pediatrics/
30. p?ediatric$.tw.
31. or/25‐30
32. 4 and 24 and 31
33. randomized controlled trial.pt.
34. controlled clinical trial.pt.
35. randomi#ed.ab.
36. placebo$.ab.
37. drug therapy.fs.
38. randomly.ab.
39. trial.ab.
40. groups.ab.
41. or/33‐40
42. exp animals/ not humans.sh.
43. 41 not 42
44. 32 and 43

Lines 33 to 43 are the Cochrane highly sensitive search strategy for identifying randomized trials in MEDLINE (Ovid version) (Lefebvre 2011).

Appendix 3. Embase search strategy

1. exp amphetamine/
2. (amphetamine$ or dexamphetamine$ or methamphetamine$ or dextroamphetamine$ or lisdexamphetamine$ or vyvanase$ or Dexedrin3 or desoxyn$ or adderall$).mp.
3. central stimulant agent/
4. 1 or 2 or 3
5. exp attention deficit disorder/
6. behavior disorder/
7. adhd.tw.
8. addh.tw.
9. adhs.tw.
10. "ad/hd".tw.
11. hyper‐activ$.tw.
12. hyperactiv$.tw.
13. overactiv$.tw.
14. over‐activ$.tw.
15. hyperkinesia/
16. hyperkin$.tw.
17. hyper‐kin$.tw.
18. hkd.tw.
19. (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
20. (attention$ adj3 (deficit$ or disorder$ or dysfunc$)).tw.
21. (behav$ adj3 (dysfunc$ or disorder$)).tw.
22. (impulsiv$ or inattentiv$ or inattention$).tw.
23. disruptiv$.tw.
24. or/5‐23
25. child/
26. adolescent/
27. (adoles$ or teen$ or youth$ or young people or young person$).tw.
28. (child$ or toddler$ or preschool$ or pre‐school or schoolchild$ or schoolgirl$ or schoolboy$ or girl$ or boy$).tw.
29. pediatrics/
30. p?ediatric$.tw.
31. or/25‐30
32. 4 and 24 and 31
33. randomized controlled trial/
34. controlled clinical trial/
35. randomi#ed.ab.
36. placebo$.ab.
37. drug therapy/
38. randomly.ab.
39. trial.ab.
40. single blind procedure/
41. double blind procedure/
42. or/33‐41
43. exp animal/ not human.sh.
44. 42 not 43

Appendix 4. PsycINFO search strategy

1. exp amphetamine/
2. (amphetamine$ or dexamphetamine$ or methamphetamine$ or dextroamphetamine$ or lisdexamphetamine$ or vyvanase$ or Dexedrin3 or desoxyn$ or adderall$).mp.
3. exp attention deficit disorder/
4. behavior disorder/
5. adhd.tw.
6. addh.tw.
7. adhs.tw.
8. "ad/hd".tw.
9. hyper‐activ$.tw.
10. hyperactiv$.tw.
11. overactiv$.tw.
12. over‐activ$.tw.
13. hyperkin$.tw.
14. hyper‐kin$.tw.
15. hkd.tw.
16. (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
17. (attention$ adj3 (deficit$ or disorder$ or dysfunc$)).tw.
18. (behav$ adj3 (dysfunc$ or disorder$)).tw.
19. (impulsiv$ or inattentiv$ or inattention$).tw.
20. disruptiv$.tw.
21. (adoles$ or teen$ or youth$ or young people or young person$).tw.
22. (child$ or toddler$ or preschool$ or pre‐school or schoolchild$ or schoolgirl$ or schoolboy$ or girl$ or boy$).tw.
23. pediatrics/
24. p?ediatric$.tw.
25. randomi#ed.ab.
26. placebo$.ab.
27. drug therapy/
28. randomly.ab.
29. trial.ab.
30. (doubl$ adj blind$).mp.
31. (singl$ adj blind$).mp.
32. 1 or 2
33. or/3‐20
34. or/21‐24
35. 32 and 33 and 34
36. or/25‐31
37. exp animals/ not humans.sh.
38. 36 not 37
39. 35 and 38

Appendix 5. Proquest Dissertations and Theses search strategy

Advanced search
(attention deficit disorder OR attention deficit hyperactivity disorder OR hyperactivity) AND all(amphetamine OR adderall) AND all(children OR youth OR adolescent)

Appendix 6. Networked Digital Library of Theses and Dissertations search strategy

Attention Deficit Hyperactivity Disorder AND amphetamine AND (child OR youth OR adolescent)

Appendix 7. ClinicalTrials.gov search strategy

Advanced search
Conditions: Attention Deficit Hyperactivity Disorder OR ADHD OR Attention Deficit Disorder OR ADD
Interventions: amphetamine OR dexamphetamine OR methamphetamine OR dextroamphetamine OR lisdexamphetamine OR vyvanase OR dexedrine OR adderall
Study results: All studies
Age group: Child

Appendix 8. Risk of bias domains

Domain

Description

Judgement

Random sequence generation

The method used to generate the allocation sequence is described in sufficient detail so as to assess whether it should have produced comparable groups.

What is the risk of selection bias due to inadequate generation of a randomized sequence?

Allocation concealment

The method used to conceal the allocation sequence is described in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.

What is the risk of selection bias due to inadequate concealment of allocations prior to assignment?

Blinding of participants and personnel

The measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received and any information relating to whether the intended blinding was effective.

What is the risk of performance bias due to knowledge of the allocated interventions by participants and personnel during the study?

Blinding of outcome assessment

The measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received and any information relating to whether the intended blinding was effective.

What is the risk of detection bias due to knowledge of the allocated interventions by outcome assessors?

Incomplete outcome data

Assessment of the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis.

What is the risk of attrition bias due to amount, nature, or handling of incomplete outcome data?

Selective outcome reporting

Attempts made to assess the possibility of selective outcome reporting by investigators.

What is the risk of reporting bias due to selective outcome reporting?

Other sources of bias

Assessment of other sources of bias in other domains not covered by the tool, including validity of outcome measures utilized.

What is the risk of bias due to problems not covered elsewhere in the table?

Study flow diagram
Figures and Tables -
Figure 1

Study flow diagram

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

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

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.1 Total ADHD symptom score ‐ parent ratings.
Figures and Tables -
Figure 3

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.1 Total ADHD symptom score ‐ parent ratings.

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.3 Total ADHD symptom score ‐ teacher ratings.
Figures and Tables -
Figure 4

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.3 Total ADHD symptom score ‐ teacher ratings.

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.23 Proportion of participants who experienced at least one adverse event.
Figures and Tables -
Figure 5

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.23 Proportion of participants who experienced at least one adverse event.

Forest plot of comparison: 2 Subgroup analysis 1: Type of amphetamine, outcome: 2.6 Proportion of participants experiencing decreased appetite.
Figures and Tables -
Figure 6

Forest plot of comparison: 2 Subgroup analysis 1: Type of amphetamine, outcome: 2.6 Proportion of participants experiencing decreased appetite.

Comparison 1 Amphetamines versus placebo, Outcome 1 Total ADHD symptom score ‐ parent ratings.
Figures and Tables -
Analysis 1.1

Comparison 1 Amphetamines versus placebo, Outcome 1 Total ADHD symptom score ‐ parent ratings.

Comparison 1 Amphetamines versus placebo, Outcome 2 Hyperactivity/impulsivity ‐ parent ratings.
Figures and Tables -
Analysis 1.2

Comparison 1 Amphetamines versus placebo, Outcome 2 Hyperactivity/impulsivity ‐ parent ratings.

Comparison 1 Amphetamines versus placebo, Outcome 3 Total ADHD symptom score ‐ teacher ratings.
Figures and Tables -
Analysis 1.3

Comparison 1 Amphetamines versus placebo, Outcome 3 Total ADHD symptom score ‐ teacher ratings.

Comparison 1 Amphetamines versus placebo, Outcome 4 Hyperactivity/impulsivity ‐ teacher ratings.
Figures and Tables -
Analysis 1.4

Comparison 1 Amphetamines versus placebo, Outcome 4 Hyperactivity/impulsivity ‐ teacher ratings.

Comparison 1 Amphetamines versus placebo, Outcome 5 Inattention ‐ teacher ratings.
Figures and Tables -
Analysis 1.5

Comparison 1 Amphetamines versus placebo, Outcome 5 Inattention ‐ teacher ratings.

Comparison 1 Amphetamines versus placebo, Outcome 6 Total ADHD symptom score ‐ clinician ratings.
Figures and Tables -
Analysis 1.6

Comparison 1 Amphetamines versus placebo, Outcome 6 Total ADHD symptom score ‐ clinician ratings.

Comparison 1 Amphetamines versus placebo, Outcome 7 Hyperactivity/impulsivity ‐ clinician ratings.
Figures and Tables -
Analysis 1.7

Comparison 1 Amphetamines versus placebo, Outcome 7 Hyperactivity/impulsivity ‐ clinician ratings.

Comparison 1 Amphetamines versus placebo, Outcome 8 Inattention ‐ clinician ratings.
Figures and Tables -
Analysis 1.8

Comparison 1 Amphetamines versus placebo, Outcome 8 Inattention ‐ clinician ratings.

Comparison 1 Amphetamines versus placebo, Outcome 9 Total ADHD symptom score ‐ investigator/research personnel ratings.
Figures and Tables -
Analysis 1.9

Comparison 1 Amphetamines versus placebo, Outcome 9 Total ADHD symptom score ‐ investigator/research personnel ratings.

Comparison 1 Amphetamines versus placebo, Outcome 10 Hyperactivity/impulsivity ‐ investigator/research personnel ratings.
Figures and Tables -
Analysis 1.10

Comparison 1 Amphetamines versus placebo, Outcome 10 Hyperactivity/impulsivity ‐ investigator/research personnel ratings.

Comparison 1 Amphetamines versus placebo, Outcome 11 Inattention ‐ investigator/research personnel ratings.
Figures and Tables -
Analysis 1.11

Comparison 1 Amphetamines versus placebo, Outcome 11 Inattention ‐ investigator/research personnel ratings.

Comparison 1 Amphetamines versus placebo, Outcome 12 Proportion of responders (Clinical Global Impression ‐ Improvement; CGI ‐ I).
Figures and Tables -
Analysis 1.12

Comparison 1 Amphetamines versus placebo, Outcome 12 Proportion of responders (Clinical Global Impression ‐ Improvement; CGI ‐ I).

Comparison 1 Amphetamines versus placebo, Outcome 13 Clinical Global Impression ‐ Severity (CGI ‐ S) score.
Figures and Tables -
Analysis 1.13

Comparison 1 Amphetamines versus placebo, Outcome 13 Clinical Global Impression ‐ Severity (CGI ‐ S) score.

Comparison 1 Amphetamines versus placebo, Outcome 14 Academic performance.
Figures and Tables -
Analysis 1.14

Comparison 1 Amphetamines versus placebo, Outcome 14 Academic performance.

Comparison 1 Amphetamines versus placebo, Outcome 15 Quality of life.
Figures and Tables -
Analysis 1.15

Comparison 1 Amphetamines versus placebo, Outcome 15 Quality of life.

Comparison 1 Amphetamines versus placebo, Outcome 16 Retention: proportion of participants who completed the trial.
Figures and Tables -
Analysis 1.16

Comparison 1 Amphetamines versus placebo, Outcome 16 Retention: proportion of participants who completed the trial.

Comparison 1 Amphetamines versus placebo, Outcome 17 Proportion of participants experiencing decreased appetite.
Figures and Tables -
Analysis 1.17

Comparison 1 Amphetamines versus placebo, Outcome 17 Proportion of participants experiencing decreased appetite.

Comparison 1 Amphetamines versus placebo, Outcome 18 Proportion of participants experiencing insomnia/trouble sleeping.
Figures and Tables -
Analysis 1.18

Comparison 1 Amphetamines versus placebo, Outcome 18 Proportion of participants experiencing insomnia/trouble sleeping.

Comparison 1 Amphetamines versus placebo, Outcome 19 Proportion of participants experiencing abdominal pain.
Figures and Tables -
Analysis 1.19

Comparison 1 Amphetamines versus placebo, Outcome 19 Proportion of participants experiencing abdominal pain.

Comparison 1 Amphetamines versus placebo, Outcome 20 Proportion of participants experiencing nausea/vomiting.
Figures and Tables -
Analysis 1.20

Comparison 1 Amphetamines versus placebo, Outcome 20 Proportion of participants experiencing nausea/vomiting.

Comparison 1 Amphetamines versus placebo, Outcome 21 Proportion of participants experiencing headaches.
Figures and Tables -
Analysis 1.21

Comparison 1 Amphetamines versus placebo, Outcome 21 Proportion of participants experiencing headaches.

Comparison 1 Amphetamines versus placebo, Outcome 22 Proportion of participants experiencing anxiety/nervousness.
Figures and Tables -
Analysis 1.22

Comparison 1 Amphetamines versus placebo, Outcome 22 Proportion of participants experiencing anxiety/nervousness.

Comparison 1 Amphetamines versus placebo, Outcome 23 Proportion of participants who experienced at least one adverse event.
Figures and Tables -
Analysis 1.23

Comparison 1 Amphetamines versus placebo, Outcome 23 Proportion of participants who experienced at least one adverse event.

Comparison 1 Amphetamines versus placebo, Outcome 24 Proportion of participants who dropped out/withdrew due to an adverse event.
Figures and Tables -
Analysis 1.24

Comparison 1 Amphetamines versus placebo, Outcome 24 Proportion of participants who dropped out/withdrew due to an adverse event.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 1 Total ADHD symptom score ‐ parent ratings.
Figures and Tables -
Analysis 2.1

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 1 Total ADHD symptom score ‐ parent ratings.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 2 Proportion of responders (CGI ‐ I).
Figures and Tables -
Analysis 2.2

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 2 Proportion of responders (CGI ‐ I).

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 3 Academic performance.
Figures and Tables -
Analysis 2.3

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 3 Academic performance.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 4 Retention: proportion of participants who completed the trial.
Figures and Tables -
Analysis 2.4

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 4 Retention: proportion of participants who completed the trial.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 5 Proportion of participants who dropped out/withdrew due to an adverse event.
Figures and Tables -
Analysis 2.5

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 5 Proportion of participants who dropped out/withdrew due to an adverse event.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 6 Proportion of participants experiencing decreased appetite.
Figures and Tables -
Analysis 2.6

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 6 Proportion of participants experiencing decreased appetite.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 7 Proportion of participants experiencing insomnia/trouble sleeping.
Figures and Tables -
Analysis 2.7

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 7 Proportion of participants experiencing insomnia/trouble sleeping.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 8 Proportion of participants experiencing abdominal pain.
Figures and Tables -
Analysis 2.8

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 8 Proportion of participants experiencing abdominal pain.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 9 Proportion of participants experiencing headaches.
Figures and Tables -
Analysis 2.9

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 9 Proportion of participants experiencing headaches.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 10 Proportion of participants experiencing nausea/vomiting.
Figures and Tables -
Analysis 2.10

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 10 Proportion of participants experiencing nausea/vomiting.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 1 Total ADHD symptom score ‐ parent ratings.
Figures and Tables -
Analysis 3.1

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 1 Total ADHD symptom score ‐ parent ratings.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 2 Proportion of responders (CGI ‐ I).
Figures and Tables -
Analysis 3.2

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 2 Proportion of responders (CGI ‐ I).

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 3 Academic performance.
Figures and Tables -
Analysis 3.3

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 3 Academic performance.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 4 Retention: proportion of participants who completed the trial.
Figures and Tables -
Analysis 3.4

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 4 Retention: proportion of participants who completed the trial.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 5 Proportion of participants experiencing decreased appetite.
Figures and Tables -
Analysis 3.5

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 5 Proportion of participants experiencing decreased appetite.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 6 Proportion of participants experiencing abdominal pain.
Figures and Tables -
Analysis 3.6

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 6 Proportion of participants experiencing abdominal pain.

Comparison 4 Subgroup analysis 3: Funding source, Outcome 1 Total ADHD symptom score ‐ parent ratings.
Figures and Tables -
Analysis 4.1

Comparison 4 Subgroup analysis 3: Funding source, Outcome 1 Total ADHD symptom score ‐ parent ratings.

Comparison 4 Subgroup analysis 3: Funding source, Outcome 2 Proportion of responders (CGI ‐ I).
Figures and Tables -
Analysis 4.2

Comparison 4 Subgroup analysis 3: Funding source, Outcome 2 Proportion of responders (CGI ‐ I).

Comparison 4 Subgroup analysis 3: Funding source, Outcome 3 Academic performance.
Figures and Tables -
Analysis 4.3

Comparison 4 Subgroup analysis 3: Funding source, Outcome 3 Academic performance.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 1 Total ADHD symptom score ‐ parent ratings.
Figures and Tables -
Analysis 5.1

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 1 Total ADHD symptom score ‐ parent ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 2 Hyperactivity/impulsivity ‐ parent ratings.
Figures and Tables -
Analysis 5.2

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 2 Hyperactivity/impulsivity ‐ parent ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 3 Total ADHD symptom score ‐ teacher ratings.
Figures and Tables -
Analysis 5.3

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 3 Total ADHD symptom score ‐ teacher ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 4 Hyperactivity/impulsivity ‐ teacher ratings.
Figures and Tables -
Analysis 5.4

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 4 Hyperactivity/impulsivity ‐ teacher ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 5 Inattention ‐ teacher ratings.
Figures and Tables -
Analysis 5.5

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 5 Inattention ‐ teacher ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 6 Total ADHD symptom score ‐ clinician ratings.
Figures and Tables -
Analysis 5.6

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 6 Total ADHD symptom score ‐ clinician ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 7 Hyperactivity/impulsivity ‐ clinician ratings.
Figures and Tables -
Analysis 5.7

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 7 Hyperactivity/impulsivity ‐ clinician ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 8 Inattention ‐ clinician ratings.
Figures and Tables -
Analysis 5.8

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 8 Inattention ‐ clinician ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 9 Total ADHD symptom score ‐ investigator/research personnel ratings.
Figures and Tables -
Analysis 5.9

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 9 Total ADHD symptom score ‐ investigator/research personnel ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 10 Hyperactivity/impulsivity ‐ Investigator/research personnel ratings.
Figures and Tables -
Analysis 5.10

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 10 Hyperactivity/impulsivity ‐ Investigator/research personnel ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 11 Inattention ‐ investigator/research personnel ratings.
Figures and Tables -
Analysis 5.11

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 11 Inattention ‐ investigator/research personnel ratings.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 12 Proportion of responders (CGI ‐ I).
Figures and Tables -
Analysis 5.12

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 12 Proportion of responders (CGI ‐ I).

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 13 CGI ‐ S score.
Figures and Tables -
Analysis 5.13

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 13 CGI ‐ S score.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 14 Quality of life.
Figures and Tables -
Analysis 5.14

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 14 Quality of life.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 15 Academic performance.
Figures and Tables -
Analysis 5.15

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 15 Academic performance.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 16 Retention: proportion of participants who completed the trial.
Figures and Tables -
Analysis 5.16

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 16 Retention: proportion of participants who completed the trial.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 17 Proportion of participants who experienced at least one adverse event.
Figures and Tables -
Analysis 5.17

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 17 Proportion of participants who experienced at least one adverse event.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 18 Proportion of participants who dropped out/withdrew due to an adverse event.
Figures and Tables -
Analysis 5.18

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 18 Proportion of participants who dropped out/withdrew due to an adverse event.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 19 Proportion of participants experiencing decreased appetite.
Figures and Tables -
Analysis 5.19

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 19 Proportion of participants experiencing decreased appetite.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 20 Proportion of participants experiencing insomnia/trouble sleeping.
Figures and Tables -
Analysis 5.20

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 20 Proportion of participants experiencing insomnia/trouble sleeping.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 21 Proportion of participants experiencing abdominal pain.
Figures and Tables -
Analysis 5.21

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 21 Proportion of participants experiencing abdominal pain.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 22 Proportion of participants experiencing headaches.
Figures and Tables -
Analysis 5.22

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 22 Proportion of participants experiencing headaches.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 23 Proportion of participants experiencing anxiety/nervousness.
Figures and Tables -
Analysis 5.23

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 23 Proportion of participants experiencing anxiety/nervousness.

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 24 Proportion of participants experiencing nausea/vomiting.
Figures and Tables -
Analysis 5.24

Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 24 Proportion of participants experiencing nausea/vomiting.

Amphetamines compared with placebo for attention deficit hyperactivity disorder in children and adolescents

Patient or population: children or adolescents with ADHD

Settings: Beligum, France, Germany, Hungary, Italy, Netherlands, Norway, Poland, Spain, Sweden, United Kingdom, United States

Intervention: amphetamines (i.e. dexamphetamine, lisdexamphetamine, mixed amphetamine salts)

Comparison: placebo

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

Amphetamine

Total ADHD symptom score ‐ parent ratings (ADHD Rating Scale, Fourth Version; Conners' Rating Scale; Conners' Global Index; Conners' Abbreviated Symptom Questionnaire)

Follow‐up: 7 to 49 days

The mean total score in the intervention groups was 0.57 standard deviations lower (‐0.86 to ‐0.27)

SMD ‐0.57 (‐0.86 to ‐0.27)

1247
(7)

⊕⊝⊝⊝
Very low1,2,3

Moderate effect**

Total ADHD symptom score ‐ teacher ratings (ADHD Rating Scale, Fourth Version; Conners' Rating Scale; Conners' Global Index; Conners' Abbreviated Symptom Questionnaire)

Follow‐up: 7 to 35 days

The mean total score in the intervention groups was 0.55 standard deviations lower (‐0.83 to ‐0.27)

SMD ‐0.55 (‐0.83 to ‐0.27)

745
(5)

⊕⊕⊝⊝
Low1,2

Moderate effect**

Total ADHD symptom score ‐ clinician ratings (ADHD Rating Scale, Fourth Version)

Follow‐up: 7 to 28 days

The mean total score in the intervention groups was 0.84 standard deviations lower (‐1.32 to ‐0.36)

SMD ‐0.84 (‐1.32 to ‐0.36)

813
(3)

⊕⊝⊝⊝
Very low1,2,3

Large effect**

Proportion of responders (Clinical Global Impressions ‐ Improvement (CGI‐I) scale)

187 per 1000

605 per 1000

RR 3.36

(2.48 to 4.55)

2207
(9)

⊝⊝⊝⊝
Very low1,2,3,4

Academic performance (Permanent Product Measure of Performance; Wechsler Intelligence Scale for Children ‐ Revised; Barnell Lot, Ltd Math Test; Wide Range Achievement Test)

Follow‐up: 7 to 21 days

The mean score in the intervention groups was 0.51 standard deviations higher (0.31 to 0.70)

SMD 0.56 (0.39 to 0.73)

826
(8)

⊕⊕⊝⊝
Low1,2

Moderate effect**

Retention: proportion of participants who completed the trial

825 per 1000

864 per 1000

RR 1.03
(0.97 to 1.10)

2381
(11)

⊕⊝⊝⊝
Very low1,2,3

Proportion of participants who experienced at least 1 adverse event

366 per 1000

582 per 1000

RR 1.30

(1.18 to 1.44)

1742
(6)

⊕⊕⊝⊝
Low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in the footnotes. The corresponding risk (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).
**Magnitude of effect sizes have been defined according to Cohen 1988 (< 0.2 = small, 0.5 to 0.8 = moderate, > 0.8 = large)

ADHD: Attention deficit hyperactivity disorder; CI: Confidence interval; GRADE: Grades of recommendation, assessment, development and evaluation; RR: Risk ratio; SMD: Standardized 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.

1Downgraded one level due to the majority of studies included in this outcome having a high risk of bias.
2 Downgraded one level due to this outcome including comparisons of different amphetamine derivatives and release formulations.
3Downgraded one level due to presence of significant statistical heterogeneity (I² > 50%).
4Downgraded one level due to wide 95% CI indicating that the intervention effect for this outcome is highly variable.

Figures and Tables -
Table 1. Protocol decisions not used in this review

Types of outcome measures

Primary outcomes

Multiple perspectives (i.e. teacher, parent, clinician) are considered the gold standard when assessing the core symptoms of ADHD. As such, we will not favor one perspective over another. In the event that reports do not agree with one another, for example, teacher reports disagree with parent reports on the improvement of core symptoms, this may be quite telling about how a child’s environment impacts their ADHD given the varying demands between a school environment and home environment. This will be interpreted accordingly in the discussion.

Secondary outcomes

We will assess 'parental stress' as a secondary outcome.

Measures of treatment effect

Dichotomous outcome data

When a single study has utilized more than one measure to assess the same construct (e.g. ADHD core symptoms as assessed by teacher‐rated ADHD‐RS‐IV and teacher ratings of the Conners’ ADHD Rating Scale), treatment effects will be averaged across outcome measures in order to arrive at a single treatment effect for use in the meta‐analysis.

Continuous outcome data

For continuous outcomes, where the same rating scale has been used for all studies, we will calculate mean differences.

Unit of analysis issues

Cross‐over trials

For meta‐analyses that use that use a mean difference, we will compute standard deviations for the cross‐over trials taking into account correlation. If correlation coefficients are not available, we will impute them from other studies or use 0.5 as a conservative estimate (Follman 1992).

For cross‐over trials where carry‐over is thought to be a problem, where no washout period is present, or when only data from the first period are available, we will analyze data from the first period only.

Studies with multiple time points

In studies where results are presented for several periods of follow‐up, we will analyze each outcome at each point in a separate meta‐analysis with other comparable studies taking measures at a similar time frame post‐randomization. Time frames will reflect short‐term (up to six months), medium‐term (between 6 months and 12
months), and long‐term (over 12 months) outcomes.

Assessment of reporting biases

For each primary meta‐analysis in which we have identified a sufficient number of studies (n ≥ 10) for inclusion, we will draw funnel plots in order to assess the possibility of publication bias.

Subgroup analysis and investigation of heterogeneity

We will conduct the following subgroup analyses.

  1. Presence of comorbidities (i.e. oppositional defiant disorder, conduct disorder, or both) versus no comorbid conditions.

  2. ADHD subtype: inattentive type versus hyperactive‐impulsive type versus combined type

Sensitivity analysis

We will conduct the following sensitivity analyses.

  1. Based on the risk of bias assessment of the studies: we will restrict each outcome meta‐analysis to those studies with a low risk of bias. A study is defined as having a low risk of bias if all domains of the risk of bias tool score a low risk of bias.

  2. Based on publication status: unpublished versus published studies.

  3. Missing data: we will conduct a sensitivity analysis of the imputed standard deviation versus a lower imputed standard deviation.

ADHD: attention deficit hyperactivity disorder.
ADHD‐RS‐IV: Attention Deficit Hyperactivity Rating Scale, Fourth Version.

Figures and Tables -
Table 1. Protocol decisions not used in this review
Table 2. ADHD core symptom outcome measures by study

Outcome

Outcome measure (respondent)

Studies

Measure used in meta‐analysis

Inattention

ADHD Rating Scale, Fourth Version (parent ratings)

Biederman 2007b

No (data presented in an unusable format)

ADHD Rating Scale, Fourth Version (clinician ratings)

Findling 2011

Yes

Spencer 2006a

Yes

Wigal 2009a

Yes

ADHD Rating Scale, Fourth Version (investigator/research personnel ratings)

Coghill 2013

Yes

Conners’ Rating Scale (parent ratings)

Borcherding 1990

Yes

Gillberg 1997

No (only study that included long‐term data)

Conners’ Rating Scale (teacher ratings)

Gillberg 1997

No (only study that included long‐term data)

IOWA Conners’ Rating Scale

Pliszka 2000

Yes

SKAMP scale (teacher ratings)

Swanson 1998a

No (data not available)

SKAMP scale (investigator/research personnel ratings)

Biederman 2007a

Yes

McCracken 2003

Yes

Hyperactivity/impulsivity

ADHD Rating Scale, Fourth Version (parent ratings)

Biederman 2007b

No (data presented in an unusable format)

ADHD Rating Scale, Fourth Version (clinician ratings)

Findling 2011

Yes

Spencer 2006a

Yes

Wigal 2009a

Yes

ADHD Rating Scale, Fourth Version (investigator/research personnel ratings)

Coghill 2013

Yes

Conners’ Rating Scale (parent ratings)

Gillberg 1997

No (only study that included long‐term data)

James 2001

Yes

Conners’ Rating Scale (teacher ratings)

Gillberg 1997

No (only study that included long‐term data)

James 2001

Yes

Total core symptom score

ADHD Rating Scale, Fourth Version (parent ratings)

Barkley 2000

Yes

Biederman 2007b

Yes

ADHD Rating Scale, Fourth Version (teacher ratings)

Barkley 2000

Yes

ADHD Rating Scale, Fourth Version (clinician ratings)

Findling 2011

Yes

Spencer 2006a

Yes

Wigal 2009a

Yes

ADHD Rating Scale, Fourth Version (investigator/research personnel ratings)

Coghill 2013

Yes

Giblin 2011

No (no data available)

Conners’ Rating Scale (parent ratings)

Biederman 2007b

No (data presented in an unusable format)

Coghill 2013

Yes

Giblin 2011

No (data not available)

Gillberg 1997

No (only study that included long‐term data)

Nemzer 1986

Yes

Sharp 1999

No (data not available)

Short 2004

No (data presented in an unusable format)

Conners’ Rating Scale (teacher ratings)

Borcherding 1990

No (no data available)

Donnelly 1989

Yes

Gillberg 1997

No (only study that included long‐term data)

Nemzer 1986

Yes

Sharp 1999

No (data not available)

Short 2004

No (data presented in an unusable format)

Conners’ Global Index (parent ratings)

Biederman 2002

Yes

Pliszka 2000

Yes

Conners’ Global Index (teacher ratings)

Biederman 2002

Yes

Conners’ Abbreviated Symptom Questionnaire (parent ratings)

Manos 1999

Yes

Conners’ Abbreviated Symptom Questionnaire (teacher ratings)

Manos 1999

Yes

ADHD Questionnaire (developed within study) (parent ratings)

Ramtvedt 2013

No (data presented in an unusable format)

ADHD Questionnaire (developed within study) (teacher ratings)

Ramtvedt 2013

No (data presented in an unusable format)

SKAMP scale (investigator/research personnel ratings)

Childress 2015

Yes

ADHD: attention deficit hyperactivity disorder.
IOWA: inattention/overactivity with aggression.
SKAMP: Swanson, Kotkin, Agler, M‐Flynn and Pelham scale.

Figures and Tables -
Table 2. ADHD core symptom outcome measures by study
Comparison 1. Amphetamines versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total ADHD symptom score ‐ parent ratings Show forest plot

7

1247

Std. Mean Difference (IV, Random, 95% CI)

‐0.57 [‐0.86, ‐0.27]

2 Hyperactivity/impulsivity ‐ parent ratings Show forest plot

2

132

Std. Mean Difference (IV, Random, 95% CI)

‐0.54 [‐0.89, ‐0.19]

3 Total ADHD symptom score ‐ teacher ratings Show forest plot

5

745

Std. Mean Difference (IV, Random, 95% CI)

‐0.55 [‐0.83, ‐0.27]

4 Hyperactivity/impulsivity ‐ teacher ratings Show forest plot

1

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

5 Inattention ‐ teacher ratings Show forest plot

1

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

6 Total ADHD symptom score ‐ clinician ratings Show forest plot

3

813

Std. Mean Difference (IV, Random, 95% CI)

‐0.84 [‐1.32, ‐0.36]

7 Hyperactivity/impulsivity ‐ clinician ratings Show forest plot

3

813

Std. Mean Difference (IV, Random, 95% CI)

‐0.75 [‐1.28, ‐0.23]

8 Inattention ‐ clinician ratings Show forest plot

3

813

Std. Mean Difference (IV, Random, 95% CI)

‐0.78 [‐1.26, ‐0.30]

9 Total ADHD symptom score ‐ investigator/research personnel ratings Show forest plot

3

630

Std. Mean Difference (IV, Random, 95% CI)

‐1.15 [‐1.87, ‐0.44]

10 Hyperactivity/impulsivity ‐ investigator/research personnel ratings Show forest plot

2

280

Std. Mean Difference (IV, Random, 95% CI)

‐1.46 [‐1.83, ‐1.08]

11 Inattention ‐ investigator/research personnel ratings Show forest plot

4

634

Std. Mean Difference (IV, Random, 95% CI)

‐0.73 [‐1.42, ‐0.04]

12 Proportion of responders (Clinical Global Impression ‐ Improvement; CGI ‐ I) Show forest plot

9

2207

Risk Ratio (M‐H, Random, 95% CI)

3.36 [2.48, 4.55]

13 Clinical Global Impression ‐ Severity (CGI ‐ S) score Show forest plot

2

86

Std. Mean Difference (IV, Random, 95% CI)

‐0.86 [‐1.72, ‐0.01]

14 Academic performance Show forest plot

8

826

Std. Mean Difference (IV, Random, 95% CI)

0.56 [0.39, 0.73]

15 Quality of life Show forest plot

1

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

16 Retention: proportion of participants who completed the trial Show forest plot

11

2381

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.97, 1.10]

17 Proportion of participants experiencing decreased appetite Show forest plot

11

2467

Risk Ratio (M‐H, Random, 95% CI)

6.31 [2.58, 15.46]

18 Proportion of participants experiencing insomnia/trouble sleeping Show forest plot

10

2429

Risk Ratio (M‐H, Random, 95% CI)

3.80 [2.12, 6.83]

19 Proportion of participants experiencing abdominal pain Show forest plot

10

2155

Risk Ratio (M‐H, Random, 95% CI)

1.44 [1.03, 2.00]

20 Proportion of participants experiencing nausea/vomiting Show forest plot

6

1579

Risk Ratio (M‐H, Random, 95% CI)

1.63 [1.04, 2.56]

21 Proportion of participants experiencing headaches Show forest plot

9

2091

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.75, 1.16]

22 Proportion of participants experiencing anxiety/nervousness Show forest plot

5

1088

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.78, 1.93]

23 Proportion of participants who experienced at least one adverse event Show forest plot

6

1742

Risk Ratio (M‐H, Random, 95% CI)

1.30 [1.18, 1.44]

24 Proportion of participants who dropped out/withdrew due to an adverse event Show forest plot

9

2160

Risk Ratio (M‐H, Random, 95% CI)

1.60 [0.86, 2.98]

Figures and Tables -
Comparison 1. Amphetamines versus placebo
Comparison 2. Subgroup analysis 1: Type of amphetamine

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total ADHD symptom score ‐ parent ratings Show forest plot

7

1247

Std. Mean Difference (IV, Random, 95% CI)

‐0.57 [‐0.86, ‐0.27]

1.1 Dexamphetamine

1

28

Std. Mean Difference (IV, Random, 95% CI)

‐0.60 [‐1.36, 0.16]

1.2 Lisdexamphetamine

2

486

Std. Mean Difference (IV, Random, 95% CI)

‐0.72 [‐1.59, 0.14]

1.3 Mixed amphetamine salts

4

733

Std. Mean Difference (IV, Random, 95% CI)

‐0.44 [‐0.63, ‐0.24]

2 Proportion of responders (CGI ‐ I) Show forest plot

9

2205

Risk Ratio (M‐H, Random, 95% CI)

3.38 [2.51, 4.55]

2.1 Dexamphetamine

1

64

Risk Ratio (M‐H, Random, 95% CI)

5.4 [2.38, 12.25]

2.2 Lisdexamphetamine

4

1065

Risk Ratio (M‐H, Random, 95% CI)

3.62 [2.04, 6.41]

2.3 Mixed amphetamine salts

4

1076

Risk Ratio (M‐H, Random, 95% CI)

2.72 [2.14, 3.45]

3 Academic performance Show forest plot

8

826

Std. Mean Difference (IV, Random, 95% CI)

0.56 [0.39, 0.73]

3.1 Dexamphetamine

4

208

Std. Mean Difference (IV, Random, 95% CI)

0.40 [0.12, 0.67]

3.2 Lisdexamphetamine

1

226

Std. Mean Difference (IV, Random, 95% CI)

0.78 [0.51, 1.05]

3.3 Mixed amphetamine salts

3

392

Std. Mean Difference (IV, Random, 95% CI)

0.56 [0.29, 0.84]

4 Retention: proportion of participants who completed the trial Show forest plot

10

2364

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.99, 1.12]

4.1 Dexamphetamine

1

64

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.95, 1.12]

4.2 Lisdexamphetamine

4

1084

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.92, 1.42]

4.3 Mixed amphetamine salts

5

1216

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.96, 1.11]

5 Proportion of participants who dropped out/withdrew due to an adverse event Show forest plot

9

2161

Risk Ratio (M‐H, Random, 95% CI)

1.61 [0.86, 2.98]

5.1 Dexamphetamine

1

92

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 71.78]

5.2 Lisdexamphetamine

4

1085

Risk Ratio (M‐H, Random, 95% CI)

2.03 [0.70, 5.91]

5.3 Mixed amphetamine salts

4

984

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.53, 3.06]

6 Proportion of participants experiencing decreased appetite Show forest plot

10

2273

Risk Ratio (M‐H, Random, 95% CI)

6.20 [2.44, 15.71]

6.1 Dexamphetamine

1

68

Risk Ratio (M‐H, Random, 95% CI)

1.41 [0.95, 2.11]

6.2 Lisdexampheatmine

4

1081

Risk Ratio (M‐H, Random, 95% CI)

9.83 [5.08, 19.02]

6.3 Mixed amphetamine salts

5

1124

Risk Ratio (M‐H, Random, 95% CI)

6.42 [1.56, 26.52]

7 Proportion of participants experiencing insomnia/trouble sleeping Show forest plot

10

2429

Risk Ratio (M‐H, Random, 95% CI)

3.80 [2.12, 6.83]

7.1 Dexamphetamine

1

68

Risk Ratio (M‐H, Random, 95% CI)

2.14 [1.41, 3.26]

7.2 Lisdexamphetamine

4

1081

Risk Ratio (M‐H, Random, 95% CI)

5.91 [2.84, 12.29]

7.3 Mixed amphetamine salts

5

1280

Risk Ratio (M‐H, Random, 95% CI)

3.34 [1.25, 8.96]

8 Proportion of participants experiencing abdominal pain Show forest plot

10

2155

Risk Ratio (M‐H, Random, 95% CI)

1.44 [1.03, 2.00]

8.1 Dexamphetamine

1

68

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.27, 1.67]

8.2 Lisdexamphetamine

3

769

Risk Ratio (M‐H, Random, 95% CI)

1.29 [0.76, 2.19]

8.3 Mixed amphetamine salts

6

1318

Risk Ratio (M‐H, Random, 95% CI)

1.69 [1.17, 2.45]

9 Proportion of participants experiencing headaches Show forest plot

9

2063

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.75, 1.16]

9.1 Dexamphetamine

1

68

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.42, 2.36]

9.2 Lisdexamphetamine

5

1077

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.73, 1.57]

9.3 Mixed amphetamine salts

3

918

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.64, 1.14]

10 Proportion of participants experiencing nausea/vomiting Show forest plot

6

1579

Risk Ratio (M‐H, Random, 95% CI)

1.63 [1.04, 2.56]

10.1 Dexamphetamine

1

68

Risk Ratio (M‐H, Random, 95% CI)

1.67 [0.68, 4.07]

10.2 Lisdexamphetamine

4

927

Risk Ratio (M‐H, Random, 95% CI)

1.48 [0.61, 3.61]

10.3 Mixed amphetamine salts

1

584

Risk Ratio (M‐H, Random, 95% CI)

1.84 [1.04, 3.27]

Figures and Tables -
Comparison 2. Subgroup analysis 1: Type of amphetamine
Comparison 3. Subgroup analysis 2: Type of amphetamine release formulation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total ADHD symptom score ‐ parent ratings Show forest plot

7

1247

Std. Mean Difference (IV, Random, 95% CI)

‐0.57 [‐0.86, ‐0.27]

1.1 Long acting

3

1049

Std. Mean Difference (IV, Random, 95% CI)

‐0.61 [‐1.08, ‐0.13]

1.2 Short acting

4

198

Std. Mean Difference (IV, Random, 95% CI)

‐0.52 [‐0.82, ‐0.23]

2 Proportion of responders (CGI ‐ I) Show forest plot

9

2105

Risk Ratio (M‐H, Random, 95% CI)

3.31 [2.44, 4.49]

2.1 Long acting

6

1662

Risk Ratio (M‐H, Random, 95% CI)

3.55 [2.63, 4.79]

2.2 Short acting

3

443

Risk Ratio (M‐H, Random, 95% CI)

2.89 [1.39, 6.02]

3 Academic performance Show forest plot

8

826

Std. Mean Difference (IV, Random, 95% CI)

0.56 [0.39, 0.73]

3.1 Long acting

4

494

Std. Mean Difference (IV, Random, 95% CI)

0.59 [0.36, 0.81]

3.2 Short acting

4

332

Std. Mean Difference (IV, Random, 95% CI)

0.48 [0.15, 0.81]

4 Retention: proportion of participants who completed the trial Show forest plot

10

2364

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.99, 1.12]

4.1 Long acting

6

1756

Risk Ratio (M‐H, Random, 95% CI)

1.11 [1.00, 1.24]

4.2 Short acting

4

608

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.95, 1.01]

5 Proportion of participants experiencing decreased appetite Show forest plot

10

2271

Risk Ratio (M‐H, Random, 95% CI)

6.18 [2.44, 15.63]

5.1 Long acting

8

2165

Risk Ratio (M‐H, Random, 95% CI)

7.67 [3.33, 17.65]

5.2 Short acting

2

106

Risk Ratio (M‐H, Random, 95% CI)

1.58 [0.69, 3.62]

6 Proportion of participants experiencing abdominal pain Show forest plot

10

2155

Risk Ratio (M‐H, Random, 95% CI)

1.44 [1.03, 2.00]

6.1 Long acting

7

1855

Risk Ratio (M‐H, Random, 95% CI)

1.49 [1.10, 2.02]

6.2 Short acting

3

300

Risk Ratio (M‐H, Random, 95% CI)

2.54 [0.30, 21.39]

Figures and Tables -
Comparison 3. Subgroup analysis 2: Type of amphetamine release formulation
Comparison 4. Subgroup analysis 3: Funding source

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total ADHD symptom score ‐ parent ratings Show forest plot

7

1247

Std. Mean Difference (IV, Random, 95% CI)

‐0.57 [‐0.86, ‐0.27]

1.1 Industry

5

1135

Std. Mean Difference (IV, Random, 95% CI)

‐0.53 [‐0.89, ‐0.16]

1.2 Public

1

84

Std. Mean Difference (IV, Random, 95% CI)

‐0.75 [‐1.20, ‐0.31]

1.3 Not reported

1

28

Std. Mean Difference (IV, Random, 95% CI)

‐0.60 [‐1.36, 0.16]

2 Proportion of responders (CGI ‐ I) Show forest plot

9

2210

Risk Ratio (M‐H, Random, 95% CI)

3.37 [2.50, 4.53]

2.1 Industry

8

2146

Risk Ratio (M‐H, Random, 95% CI)

3.24 [2.39, 4.40]

2.2 Not reported

1

64

Risk Ratio (M‐H, Random, 95% CI)

5.4 [2.38, 12.25]

3 Academic performance Show forest plot

8

826

Std. Mean Difference (IV, Random, 95% CI)

0.56 [0.39, 0.73]

3.1 Industry

5

688

Std. Mean Difference (IV, Random, 95% CI)

0.64 [0.46, 0.81]

3.2 Public

1

44

Std. Mean Difference (IV, Random, 95% CI)

‐0.01 [‐0.60, 0.59]

3.3 Not reported

2

94

Std. Mean Difference (IV, Random, 95% CI)

0.47 [0.06, 0.88]

Figures and Tables -
Comparison 4. Subgroup analysis 3: Funding source
Comparison 5. Sensitivity analysis 1: Fixed‐effect model

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total ADHD symptom score ‐ parent ratings Show forest plot

7

1247

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.52 [‐0.64, ‐0.40]

2 Hyperactivity/impulsivity ‐ parent ratings Show forest plot

2

132

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.54 [‐0.89, ‐0.19]

3 Total ADHD symptom score ‐ teacher ratings Show forest plot

5

745

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.47 [‐0.62, ‐0.32]

4 Hyperactivity/impulsivity ‐ teacher ratings Show forest plot

1

Std. Mean Difference (IV, Fixed, 95% CI)

Subtotals only

5 Inattention ‐ teacher ratings Show forest plot

1

Std. Mean Difference (IV, Fixed, 95% CI)

Subtotals only

6 Total ADHD symptom score ‐ clinician ratings Show forest plot

3

813

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.84 [‐1.01, ‐0.68]

7 Hyperactivity/impulsivity ‐ clinician ratings Show forest plot

3

813

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.74 [‐0.90, ‐0.58]

8 Inattention ‐ clinician ratings Show forest plot

3

813

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.77 [‐0.94, ‐0.61]

9 Total ADHD symptom score ‐ investigator/research personnel ratings Show forest plot

3

630

Std. Mean Difference (IV, Fixed, 95% CI)

‐1.08 [‐1.25, ‐0.91]

10 Hyperactivity/impulsivity ‐ Investigator/research personnel ratings Show forest plot

2

280

Std. Mean Difference (IV, Fixed, 95% CI)

‐1.50 [‐1.76, ‐1.23]

11 Inattention ‐ investigator/research personnel ratings Show forest plot

4

634

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.76 [‐0.93, ‐0.60]

12 Proportion of responders (CGI ‐ I) Show forest plot

9

2207

Risk Ratio (M‐H, Fixed, 95% CI)

3.11 [2.68, 3.61]

13 CGI ‐ S score Show forest plot

2

86

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.71 [‐1.15, ‐0.27]

14 Quality of life Show forest plot

1

Std. Mean Difference (IV, Fixed, 95% CI)

Subtotals only

15 Academic performance Show forest plot

8

826

Std. Mean Difference (IV, Fixed, 95% CI)

0.59 [0.45, 0.73]

16 Retention: proportion of participants who completed the trial Show forest plot

10

2364

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [1.04, 1.12]

17 Proportion of participants who experienced at least one adverse event Show forest plot

6

1742

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [1.20, 1.47]

18 Proportion of participants who dropped out/withdrew due to an adverse event Show forest plot

9

2160

Risk Ratio (M‐H, Fixed, 95% CI)

1.95 [1.08, 3.51]

19 Proportion of participants experiencing decreased appetite Show forest plot

11

2467

Risk Ratio (M‐H, Fixed, 95% CI)

5.57 [4.03, 7.68]

20 Proportion of participants experiencing insomnia/trouble sleeping Show forest plot

10

2429

Risk Ratio (M‐H, Fixed, 95% CI)

3.91 [2.82, 5.41]

21 Proportion of participants experiencing abdominal pain Show forest plot

10

2155

Risk Ratio (M‐H, Fixed, 95% CI)

1.57 [1.18, 2.08]

22 Proportion of participants experiencing headaches Show forest plot

9

2091

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.76, 1.18]

23 Proportion of participants experiencing anxiety/nervousness Show forest plot

5

1088

Risk Ratio (M‐H, Fixed, 95% CI)

1.21 [0.94, 1.56]

24 Proportion of participants experiencing nausea/vomiting Show forest plot

6

1579

Risk Ratio (M‐H, Fixed, 95% CI)

1.72 [1.20, 2.46]

Figures and Tables -
Comparison 5. Sensitivity analysis 1: Fixed‐effect model