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

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References

Referencias de los estudios incluidos en esta revisión

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Barkley 2000 {published data only}

Barkley RA, Connor DF, Kwasnik D. Challenges to determining adolescent medication response in an outpatient clinical setting: comparing Adderall and methylphenidate for ADHD. Journal of Attention Disorders 2000;4(2):102‐13. [DOI: 10.1177/108705470000400204]

Biederman 2002 {published data only}

Biederman J, Lopez FA, Boellner SW, Chandler MC. A randomized, double‐blind, placebo‐controlled, parallel‐group study of SLI381 (Adderall XR) in children with attention‐deficit/hyperactivity disorder. Pediatrics 2002;110(2):258‐66.

Biederman 2007a {published data only}

Biederman J, Boellner SW, Childress A, Lopez FA, Krishnan S, Zhang Y. Lisdexamfetamine dimesylate and mixed amphetamine salts extended‐release in children with ADHD: a double‐blind, placebo‐controlled, crossover analogue classroom study. Biological Psychiatry 2007;62(9):970‐6. [PUBMED: 17631866]

Biederman 2007b {published data only (unpublished sought but not used)}

Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP‐104) in children with attention‐deficit/hyperactivity disorder: a phase III, multicenter, randomized, double‐blind, forced‐dose, parallel‐group study. Clinical Therapeutics 2007;29(3):450‐63. [PUBMED: 17577466]

Borcherding 1990 {published data only (unpublished sought but not used)}

Borcherding BG, Keysor CS, Rapoport JL, Elia J, Amass J. Motor/vocal tics and compulsive behaviors on stimulant drugs: is there a common vulnerability?. Psychiatry Research 1990;33(1):83‐94. [PUBMED: 2217661]
Elia J, Borcherding BG, Potter WZ, Mefford IN, Rapoport JL, Keysor CS. Stimulant drug treatment of hyperactivity: biochemical correlates. Clinical Pharmacaology and Therapeutics 1990;48(1):57‐66. [DOI: 10.1038/clpt.1990.118]
Elia J, Borcherding BG, Rapoport JL, Keysor CS. Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true nonresponders?. Psychiatry Research 1991;36(2):141‐55. [PUBMED: 2017529]
Elia J, Welsh PA, Gullotta CS, Rapoport JL. Classroom academic performance: improvement with both methylphenidate and dextroamphetamine in ADHD boys. Journal of Child Psychology and Psychiatry 1993;34(5):785‐804. [DOI: 10.1111/j.1469‐7610.1993.tb01071.x]

Childress 2015 {published data only}

Childress AC, Brams M, Culter AJ, Kollins SH, Northcutt J, Padilla A, et al. The efficacy and safety of evekeo, racemic amphetamine sulfate, for treatment of attention‐deficit/hyperactivity disorder symptoms: a multicenter, dose‐optimized, double‐blind, randomized, placebo‐controlled crossover laboratory classroom study. Journal of Child and Adolescent Psychopharmacology 2015;25(5):402‐14. [DOI: 10.1089/cap.2014.0176]

Coghill 2013 {published data only}

Banachewski T, Soutullo C, Lecendreux M, Johnson M, Zuddas A, Hodgkins P, et al. Health‐related quality of life and functional outcomes from a randomized, controlled study of lisdexamfetamine dimesylate in children and adolescents with attention deficit hyperactivity disorder. CNS Drugs 2013;27(10):829‐40. [DOI: 10.1007/s40263‐013‐0095‐5]
Coghill D, Banaschewski T, Lecendreux M, Soutullo C, Johnson M, Zuddas A, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention‐deficit/hyperactivity disorder. European Neuropsychopharmacology 2013;23(10):1208‐18. [DOI: 10.1016/j.euroneuro.2012.11.012]
Coghill DR, Banaschewski T, Lecendreux M, Zuddas A, Dittmann RW, Otero IH, et al. Efficacy of lisdexamfetamine dimesylate throughout the day in children and adolescents with attention‐deficit/hyperactivity disorder: results from a randomized, controlled trial. European Child and Adolescent Psychiatry 2014;23(2):61‐8. [PUBMED: 23708466]

Donnelly 1989 {published data only (unpublished sought but not used)}

Donnelly M, Rapoport JL, Ismond DR. Fenfluramine treatment of childhood attention deficit disorder with hyperactivity: a preliminary report. Psychopharmacology Bulletin 1986;22(1):152‐4.
Donnelly M, Rapoport JL, Potter WZ, Oliver J, Keysor CS, Murphy DL. Fenfluramine and dextroamphetamine treatment of childhood hyperactivity: clinical and biochemical findings. Archives of General Psychiatry 1989;46(3):205‐12. [DOI: 10.1001/archpsyc.1989.01810030011002]

Findling 2011 {published data only}

Findling RL, Childress AC, Cutler AJ, Gasior M, Hamdani M, Ferreira‐Cornwell MC, et al. Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention‐deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 2011;50(4):395‐405. [PUBMED: 21421179]

Giblin 2011 {published data only (unpublished sought but not used)}

Giblin GM, Strobel AL. Effect of lisdexamphetamine dimesylate on sleep in children with ADHD. Journal of Attention Disorders 2011;15(6):491‐8. [DOI: 10.1177/1087054710371195]

Gillberg 1997 {published data only}

Gillberg C, Melander H, Knorring AL, Janols LO, Thernlund G, Hagglof B, et al. Long‐term stimulant treatment of children with attention‐deficit hyperactivity disorder symptoms: a randomized, double‐blind, placebo‐controlled trial. Archives of General Psychiatry 1997;54(9):857‐64. [PUBMED: 9294377]

James 2001 {published data only}

James RS, Sharp WS, Bastain TM, Lee PP, Walter JM, Czarnolewski M, et al. Double‐blind, placebo‐controlled study of single‐dose amphetamine formulations in ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 2001;40(11):1268‐76. [PUBMED: 11699800]

Manos 1999 {published data only}

Manos MJ, Short EJ, Findling RL. Differential effectiveness of methylphenidate and Adderall in school‐age youths with attention‐deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 1999;38(7):813‐9. [PUBMED: 10405498]

McCracken 2003 {published data only}

McCracken JT, Biederman J, Greenhill LL, Swanson JM, McGough JJ, Spencer TJ, et al. Analog classroom assessment of a once‐daily mixed amphetamine formulation, SLI381 (Adderall XR), in children with ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 2003;42(6):673‐83. [PUBMED: 12921475]

Nemzer 1986 {published data only}

Nemzer ED, Arnold E, Votolato NA, McConnell H. Amino acid supplementation as therapy for attention deficit disorder. Journal of the American Academy of Child Psychiatry 1986;25(4):509‐13.

Pliszka 2000 {published data only}

Pliszka SR, Browne RG, Olvera RL, Wynne SK. A double‐blind, placebo‐controlled study of Adderall and methylphenidate in the treatment of attention‐deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 2000;39(5):619‐26. [DOI: 10.1097/00004583‐200005000‐00016]

Ramtvedt 2013 {published data only}

Ramtvedt BE, Aabech HS, Sundet K. Minimizing adverse events while maintaining clinical improvement in a pediatric attention‐deficit/hyperactivity disorder crossover trial with dextroamphetamine and methylphenidate. Journal of Child and Adolescent Psychopharmacology 2014;24(3):130‐9. [DOI: 10.1089/cap.2013.0114]
Ramtvedt BE, Røinås E, Aabech HS, Sundet KS. Clinical gains from including both dextroamphetamine and methylphenidate in stimulant trials. Journal of Child and Adolescent Psychopharmacology 2013;23(9):597‐604. [DOI: 10.1089/cap.2012.0085]

Sharp 1999 {published data only (unpublished sought but not used)}

Sharp WS, Walter JM, Marsh WL, Ritchie GF, Hamburger SD, Castellanos FX. ADHD in girls: clinical comparability of a research sample. Journal of the American Academy of Child and Adolescent Psychiatry 1999;38(1):40‐7. [PUBMED: 9893415]

Shekim 1986 {published data only}

Shekim WO, Bylund DB, Alexson J, Glaser RD, Jones SB, Hodges K, et al. Platelet MAO and measures of attention and impulsivity in boys with attention deficit disorder and hyperactivity. Psychiatry Research 1986;18(2):179‐88. [DOI: 10.1016/0165‐1781(86)90029‐6]

Short 2004 {published data only}

Short EJ, Manos MJ, Findling RL, Schubel EA. A prospective study of stimulant response in preschool children: insights from ROC analyses. Journal of the American Academy of Child and Adolescent Psychiatry 2004;43(3):251‐9. [DOI: 10.1097/00004583‐200403000‐00005]

Spencer 2006a {published data only}

Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attention‐deficit/hyperactivity disorder in adolescent patients: a 4‐week, randomized, double‐blind, placebo‐controlled, parallel‐group study. Clinical Therapeutics 2006;28(2):266‐79. [DOI: 10.1016/j.clinthera.2006.02.011]

Swanson 1998a {published data only (unpublished sought but not used)}

Swanson JM, Wigal S, Greenhill LL, Browne R, Waslik B, Lerner M, et al. Analog classroom assessment of Adderall (R) in children with ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 1998;37(5):519‐26.

Wigal 2009a {published data only}

Wigal SB, Kollins SH, Childress AC, Squires L, for the 311 Study Group. A 13‐hour laboratory school study of lisdexamfetamine dimesylate in school‐aged children with attention‐deficit/hyperactivity disorder. Child and Adolescent Psychiatry and Mental Health 2009;3(1):17. [DOI: 10.1186/1753‐2000‐3‐17]

Referencias de los estudios excluidos de esta revisión

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Akhondzadeh 2003 {published data only}

Akhondzadeh S, Tavakolian R, Davari‐Ashtiani R, Arabgol F, Amini H. Selegiline in the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial. Progress in Neuro‐Psychopharmacology & Biological Psychiatry 2003;27(5):841‐5. [DOI: 10.1016/S0278‐5846(03)00117‐9]

Alexandris 1968 {published data only}

Alexandris A, Lundell FW. Effect of thioridazine, amphetamine and placebo on the hyperkinetic syndrome and cognitive area in mentally deficient children. Canadian Medical Association Journal 1968;98(2):92‐6.

Arnold 2011 {published data only}

Arnold LE, Disilvestro RA, Bozzolo D, Bozzolo H, Crowl L, Fernandez S, et al. Zinc for attention‐deficit/hyperactivity disorder: placebo‐controlled double‐blind pilot trial alone and combined with amphetamine. Journal of Child and Adolescent Psychopharmacology 2011;21(1):1‐19. [PUBMED: 21309695]

Biederman 2006 {published data only}

Biederman J, Wigal SB, Spencer TJ, McGough JJ, Mays DA. A post hoc subgroup analysis of an 18‐day randomized controlled trial comparing the tolerability and efficacy of mixed amphetamine salts extended release and atomoxetine in school‐age girls with attention‐deficit/hyperactivity disorder. Clinical Therapeutics 2006;28(2):280‐93. [DOI: 10.1016/j.clinthera.2006.02.008]

Biederman 2008 {published data only}

Biederman J, Seidman LJ, Petty CR, Fried R, Doyle AE, Cohen DR, et al. Effects of stimulant medication on neuropsychological functioning in young adults with attention‐deficit/hyperactivity disorder. Journal of Clinical Psychiatry 2008;69(7):1150‐6.

Boellner 2010 {published data only}

Boellner SW, Stark JG, Krishnan S, Zhang Y. Pharmacokinetics of lisdexamfetamine dimesylate and its active metabolite, d‐amphetamine, with increasing oral doses of lisdexamfetamine dimesylate in children with attention‐deficit/hyperactivity disorder: a single‐dose, randomized, open‐label, crossover study. Clinical Therapeutics 2010;32(2):252‐64. [PUBMED: 20206783]

Brown 2010 {published data only}

Brown TE, Landgraf JM. Improvements in executive function correlate with enhanced performance and functioning and health‐related quality of life: evidence from 2 large, double‐blind, randomized, placebo‐controlled trials in ADHD. Postgraduate Medicine 2010;122(5):42‐51. [PUBMED: 20861587]

Denhoff 1971 {published data only}

Denhoff E, Davids A, Hawkins R. Effects of dextroamphetamine on hyperkinetic children: a controlled double blind study. Journal of Learning Disabilities 1971;4(9):491‐8. [DOI: 10.1177/002221947100400906]

Donner 2007 {published data only}

Donner R, Michaels MA, Ambrosini PJ. Cardiovascular effects of mixed amphetamine salts extended release in the treatment of school‐aged children with attention‐deficit/hyperactivity disorder. Biological Psychiatry 2007;61(5):706‐12. [DOI: 10.1016/j.biopsych.2006.05.002]

Efron 1997 {published data only}

Efron D, Jarman F, Barker M. Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double‐blind, crossover trial. Pediatrics 1997;100(4):662‐6. [PUBMED: 9310521]

Findling 2009 {published data only}

Findling RL, Ginsberg LD, Jain R, Gao J. Effectiveness, safety, and tolerability of lisdexamfetamine dimesylate in children with attention‐deficit/hyperactivity disorder: an open‐label, dose‐optimization study. Journal of Child and Adolescent Psychopharmacology 2009;19(6):649‐62. [PUBMED: 20035583]

Greenhill 2003 {published data only}

Greenhill LL, Swanson JM, Steinhoff K, Fried J, Posner K, Lerner M, et al. A pharmacokinetic/pharmacodynamic study comparing a single morning dose of Adderall to twice‐daily dosing in children with ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 2003;42(10):1234‐41. [PUBMED: 14560174]

Kamien 1998 {published data only}

Kamien M. The use of an N‐of‐1 randomised clinical trial in resolving therapeutic doubt. The case of a patient with an 'attention disorder'. Australian Family Physician 1998;27 Suppl 2:S103‐5.

Lopez 2008 {published data only}

Lopez FA, Ginsberg LD, Arnold V. Effect of lisdexamfetamine dimesylate on parent‐rated measures in children aged 6 to 12 years with attention‐deficit/hyperactivity disorder: a secondary analysis. Postgraduate Medicine 2008;120(3):89‐102. [DOI: 10.3810/pgm.2008.09.1910]

McGough 2005 {published data only}

McGough JJ, Biederman J, Wigal SB, Lopez FA, McCracken JT, Spencer T, et al. Long‐term tolerability and effectiveness of once‐daily mixed amphetamine salts (Adderall XR) in children with ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 2005;44(6):530‐8. [DOI: 10.1097/01.chi.0000157550.94702.a2]

Najib 2009 {published data only}

Najib J. The efficacy and safety profile of lisdexamfetamine dimesylate, a prodrug of d‐amphetamine, for the treatment of attention‐deficit/hyperactivity disorder in children and adults. Clinical Therapeutics 2009;31(1):142‐76. [DOI: 10.1016/j.clinthera.2009.01.015]

Nikles 2006 {published data only}

Nikles CJ, Mitchell GK, Del Mar CB, Clavarino A, McNairn N. An n‐of‐1 trial service in clinical practice: testing the effectiveness of stimulants for attention‐deficit/hyperactivity disorder. Pediatrics 2006;117(6):2040‐6.

Quintana 2007 {published data only}

Quintana H, Cherlin EA, Duesenberg DA, Bangs ME, Ramsey JL, Feldman PD, et al. Transition from methylphenidate or amphetamine to atomoxetine in children and adolescents with attention‐deficit/hyperactivity disorder ‐ a preliminary tolerability and efficacy study. Clinical Therapeutics 2007;29(6):1168‐77. [DOI: 10.1016/j.clinthera.2007.06.017]

Scheffer 2005 {published data only}

Scheffer RE, Kowatch RA, Carmody T, Rush AJ. Randomized, placebo‐controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. American Journal of Psychiatry 2005;162(1):58‐64. [PUBMED: 15625202]

Sleator 1974 {published data only}

Sleator EK, Von Neumann A, Sprague RL. Hyperactive children: a continuous long‐term placebo‐controlled follow‐up. JAMA 1974;229(3):316‐7. [DOI: 10.1001/jama.1974.03230410040022.]

Spencer 2005 {published data only}

Spencer TJ, Biederman J, Wilens TE. Efficacy and tolerability of long‐term, open‐label, mixed amphetamine salts extended release in adolescents with ADHD. CNS Spectrums 2005;10 Suppl 15:14‐21. [DOI: 10.1017/S1092852900014103]

Spencer 2006b {published data only}

Spencer TJ, Abikoff HB, Connor DF, Biederman J, Pliszka SR, Boellner S, et al. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of oppositional defiant disorder with or without comorbid attention‐deficit/hyperactivity disorder in school‐aged children and adolescents: a 4‐week, multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled, forced‐dose‐escalation study. Clinical Therapeutics 2006;28(3):402‐18. [DOI: 10.1016/j.clinthera.2006.03.006]

Turgay 2010 {published data only}

Turgay A, Ginsberg L, Sarkis E, Jain R, Adeyi B, Gao J, et al. Executive function deficits in children with attention‐deficit/hyperactivity disorder and improvement with lisdexamfetamine dimesylate in an open‐label study. Journal of Child and Adolescent Psychopharmacology 2010;20(6):503‐11. [DOI: 10.1089/cap.2009.0110]

Wigal 2009b {published data only}

Wigal SB, Kollins SH, Childress AC, Squires L, for the 311 Study Group. A 13‐hour laboratory school study of lisdexamfetamine dimesylate in school‐aged children with attention‐deficit/hyperactivity disorder. Child and Adolescent Psychiatry and Mental Health 2009;3(1):17. [DOI: 10.1186/1753‐2000‐3‐17]

Wigal 2010a {published data only}

Wigal SB, Kollins SH, Childress AC, Adeyi B. Efficacy and tolerability of lisdexamfetamine dimesylate in children with attention‐deficit/hyperactivity disorder: sex and age effects and effect size across the day. Child and Adolescent Psychiatry and Mental Health 2010;4:32. [DOI: 10.1186/1753‐2000‐4‐32]

Wigal 2010b {published data only}

Wigal T, Brams M, Gasior M, Gao J, Squires L, Giblin J, et al. Randomized, double‐blind, placebo‐controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention‐deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design. Behavioral and Brain Functions 2010;6:34. [DOI: 10.1186/1744‐9081‐6‐34]

Referencias de los estudios en espera de evaluación

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Glos 1973 {published data only}

Glos J. Amphetamines in the treatment of hyperactive and unstable children. Ceskoslovenska Pediatrie 1973;28(10):559‐60.

Itil 1974 {published data only}

Itil TM, Simeon J. Proceedings: computerized EEG in the prediction of outcome of drug treatment in hyperactive childhood behavior disorders. Psychopharmacology Bulletin 1974;10(4):36. [PUBMED: 4610619]

Fanton 2009 {published data only}

Fanton J, Waslick B, Harvey E. The 49th Annual National Institute of Mental Health (NIMH) New Clinical Drug Evaluation Unit (NCDEU) meeting Hollywood, Florida, June 29‐July 2, 2009: posters most relevant to child and adolescent psychopharmacology. Journal of Child and Adolescent Psychopharmacology2009; Vol. 19, issue 6:786.

NCT01711021 {published data only}

NCT01711021. A randomized, double‐blind, placebo‐controlled, crossover, laboratory classroom study to evaluate the safety and efficacy of d‐amphetamine transdermal drug delivery system (d‐ATS) compared to placebo in children and adolescents with ADHD. http://clinicaltrials.gov/ct2/show/record/NCT01711021 (accessed 11 February 2014).

AHRQ 1999

Agency for Health Care Policy and Research. Diagnosis of attention‐deficit/hyperactivity disorder. Summary: technical review: number 3. www.ahrq.gov/clinic/epcsums/adhdsutr.htm (accessed 1 May 2012).

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Anderson SW, Bechara A, Damasio H, Tranel D, Damasio AR. Impairment of social and moral behavior related to early damage in human prefrontal cortex. Natural Neuroscience 1999;2(11):1032‐7.

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Buck ML. Amphetamines in the treatment of attention‐deficit/hyperactivity disorder. Pediatric Pharmacotherapy 2002;8(3):1‐3.

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Cohen J. Statistical Power Analysis in Behavioral Sciences. 2nd Edition. Hillsdale, NJ: Lawrence Erlbaum Associates Inc, 1988.

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Conners CK. Conners’ Abbreviated Symptom Questionnaire: Parent Version, Teacher Version Manual. Toronto: Multi‐Health Systems, 1990.

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DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale—IV: Checklists, Norms, and Clinical Interpretation. New York: The Guilford Press, 1998:186‐201.

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The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Salum 2012

Salum GA, Patrick DL, Isolan LR, Manfro GG, Fleck MP. Youth Quality of Life Instrument‐Research version (YQOL‐R): psychometric properties in a community sample [Youth Quality of Life Instrument‐Research version (YQOL‐R): propriedades psicométricas em uma amostra comunitária]. Journal of Pediatrics 2012;88(5):443‐8. [PUBMED: 22850664]

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Schulz KF, Altman DG, Moher D, for the CONSORT Group. Research Methods & Reporting: CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials. BMJ 2010;340:c332. [DOI: 10.1136/bmj.c332]

Sterne 2013

Sterne JAC. Why the Cochrane risk of bias tool should not include funding source as a standard item [editorial]. Cochrane Database of Systematic Reviews2013, issue 12:1. [DOI: 10.1002/14651858.ED000076]

Swanson 1998b

Swanson J, Wigal S, Greenhill L, Browne R, Waslick B, Lerner M, et al. Objective and subjective measures of the pharmacodynamic effects of Adderall in the treatment of children with ADHD in a controlled laboratory classroom setting. Psychopharmacoly Bulletin 1998;34(1):55‐60. [PUBMED: 9564199]

Swanson 2007

Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos GA, Volkow N, et al. Etiologic subtypes of attention‐deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychology Reviews 2007;17(1):39‐59. [PUBMED: 17318414]

The Medical Letter 2007

The Medical Letter Online. Lisdexamfetamine dimesylate (Vyvanase) for ADHD. The Medical Letter on Drugs and Therapeutics 2007;49(1265):58‐9.

Varni 1998

Varni JW, Katz ER, Seid M, Quiggins DJ, Friedman‐Bender A. The Pediatric Quality of Life Inventory‐32 (PedsQL‐32): reliability and validity. Cancer 1998;82(6):1184‐96. [PUBMED: 9506367]

Wechsler 1991

Wechsler D. Wechsler Intelligence Scale for Children. San Antonio, TX: The Psychological Corporation, 1991.

Wigal 1999

Wigal T, Swanson JM, Regino R, Lerner MA, Soliman I, Steinoff K, et al. Stimulant medications for the treatment of ADHD: efficacy and limitations. Mental Retardation and Development Disabilities Research Reviews 1999;5(3):215‐24.

Williamson 2012

Williamson PR, Clarke M. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative: its role in improving Cochrane Reviews [editorial]. Cochrane Database of Systematic Reviews2012, issue 4. [DOI: 10.1002/14651858.ED000041]

Referencias de otras versiones publicadas de esta revisión

Jump to:

Punja 2012

Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles CJ, et al. Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database of Systematic Reviews 2012, Issue 7. [DOI: 10.1002/14651858.CD009996]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Barkley 2000

Methods

Randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: per protocol

Participants

Sample size: 46* children/adolescents with an ADHD diagnosis according to the DSM‐IV criteria
Dropouts: NR
Psychiatric comorbid conditions: NR
Age range: 12 years to 17 years
Mean age (SD): 14 (NR) years
Sex: 30 (86%) males
ADHD subtype: NR

Interventions

Five interventions (all 46 children/adolescents participated in each of the five interventions):

  1. Mixed amphetamine salts (short acting), 5 mg, twice a day, (n = 46)

  2. Mixed amphetamine salts (short acting), 10 mg, twice a day, (n = 46)

  3. Methylphenidate, 5 mg, twice a day, (n = 46)

  4. Methylphenidate, 10 mg, twice a day, (n = 46)

  5. Placebo (n = 46)

Duration: 35 days (5 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (parents and teachers)

  2. Clinical impression, assessed with Clinical Global Impressions ‐ Improvement scale

  3. Adverse events

Other outcomes:

  1. Oppositional defiant disorder symptom severity, assessed with an oppositional defiant disorder rating scale (not specified)

  2. Assessment attention and impulsivity, as measured by the Conners' Continuous Performance Test

  3. Response inhibition and interference control, assessed with the Stroop Word ‐ Color Association Test

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university
Study funding: pharmaceutical industry
*Clinical characteristics were only reported on children/adolescents who started the trial (n = 35)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Only data for completers included in analysis. For one of the primary outcomes, only 37% of randomized children/adolescents included in analysis

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not adequately described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Biederman 2002

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, parallel‐group trial
Country: United States
Number of study sites: 47

Statistical methods: modified ITT (last observation carried forward)

Participants

Sample size: 584* children/adolescents with an ADHD diagnosis according to DSM‐IV criteria
Dropouts: 75
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 8.6 (1.7) years
Sex: 434 (77%) males
ADHD subtype: 28 (5%) hyperactive ‐ impulsive; 12 (2%) inattentive; 523 (93%) combined

Interventions

Four interventions (584 children/adolescents participated in one of four interventions):

  1. Mixed amphetamine salts (long acting), 10 mg/day, (n = 129)

  2. Mixed amphetamine salts (long acting), 20 mg/day (10 mg/day for week 1 with forced dose escalation to 20 mg/day in weeks 2 to 3), (n = 121)

  3. Mixed amphetamine salts (long acting), 30 mg/day (10 mg/day in week 1, 20 mg/day in week 2, 30 mg/day in week 3), (n = 124)

  4. Placebo (n = 210)

Duration: 21 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners Global Index, teacher‐ and parent‐rated

  2. Clinician impression, assessed with Clinical Global Impressions ‐ Improvement scale

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who experienced at least one adverse event

  5. Number of participants who dropped out due to any adverse event

  6. Adverse events

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliations: university
Study funding: pharmaceutical industry

*Clinical characteristics are only provided on those children included in the primary efficacy analysis (n = 563)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Moderate attrition (13%). Reasons for attrition reported and 96% of randomized children/adolescents included in primary analysis

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Biederman 2007a

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States
Number of study sites: 4
Statistical methods: modified ITT (all randomized children/adolescents who had at least one post‐randomization score on primary outcome measure)

Participants

Sample size: 52 children/adolescents with an ADHD diagnosis according to the DSM‐IV‐TR criteria
Dropouts: 2
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9.1 (1.7) years
Sex: 33 (64%) males
ADHD subtypes: 52 (100%) combined

Interventions

Three interventions (all 52 children/adolescents participated in each of the three interventions):

  1. Mixed amphetamine salts (long acting), either 10 mg/day, 20 mg/day or 30 mg/day (determined by dose optimisation period), (n = 52)*

  2. Lisdexamphetamine (long acting), either 30 mg/day, 50 mg/day or 70 mg/day (determined by dose optimisation period), (n = 52)

  3. Placebo (n = 52)

Duration: 21 days (3 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with the attention subscale (investigator) of the Swanson, Kotkin, Agler, M‐Flynn and Pelham scale

  2. Academic performance, assessed with Permanent Product Measure of Performance scale

  3. Clinical impression, assessed with Clinical Global Impressions ‐ Severity and Clinical Global Impressions ‐ Improvement scales

  4. Retention: number of participants who completed the study

  5. Adverse events

Other outcomes:

  1. Conduct problems, assessed with deportment subscale of the Swanson, Kotkin, Agler, M‐Flynn and Pelham (SKAMP) scale

  2. Vital signs (blood pressure, pulse)

Notes

ClinicalTrials.gov identifier: NCT00557011
Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*Mixed amphetamine salts ‐ extended release was randomly chosen to represent the amphetamine group in this study for binary outcomes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Low risk

Method of allocation concealment involved pre‐packaged, serially‐numbered drug kits, in which the next participant enrolled received the next available drug kit. Drug kits prepared by a third party

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Although the primary analysis only included trial completers, attrition was low at 4%

Selective reporting (reporting bias)

Low risk

Data provided on all outcomes listed in the registered protocol. Study appears to be free of selective reporting

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Biederman 2007b

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, parallel‐group trial
Country: United States
Number of study sites: 40
Statistical methods: modified ITT (children/adolescents who had baseline and at least one post‐randomization primary efficacy measure, last observation carried forward)

Participants

Sample size: 290 children/adolescents with an ADHD diagnosis according to the DSM‐IV‐TR criteria
Dropouts: 60
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9 (1.8) years
Sex: 201 (69%) males
ADHD subtype: 12 (4%) hyperactive ‐ impulsive; 278 (96%) combined

Interventions

Four interventions (290 children/adolescents participated in one of four interventions):

  1. Lisdexamphetamine (long acting), 30 mg/day, (n = 71)

  2. Lisdexamphetamine (long acting), 50 mg/day (30 mg/day for week 1 with forced dose escalation to 50 mg/day for weeks 2 to 4), (n = 74)

  3. Lisdexamphetamine (long acting), 70 mg/day (30 mg/day for week 1 with forced dose escalation to 50 mg/day for week 2 and 70 mg/day for weeks 3 to 4), (n = 73)

  4. Placebo (n = 72)

Duration: 28 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version, and the Conners' Parent Rating Scale‐Revised: Short Form

  2. Clinical impression, assessed with Clinical Global Impression ‐ Severity and Clinical Global Impressions ‐ Improvement scales

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who experienced at least one adverse event

  5. Number of participants who dropped out due to any adverse event

  6. Adverse events

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university
Study funding: pharmaceutical industry
*The authors reported their results of parent ratings of hyperactivity/impulsivity and inattention on the ADHD Rating Scale, Fourth Version, as well as total ADHD symptom scores on the Conners' Parent Rating Scale ‐ Revised as bar graphs. We sought to extract relevant data using graphic digitizer software but this gave implausible results. Consequently, this data could not be included in the meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence generated by a computer program

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Moderate attrition (21%). However, 98% of randomized children/adolescents included in primary analysis. Reasons for dropouts provided

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo are described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Borcherding 1990

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States
Number of study sites: 1
Statistical methods: ITT (all randomized children/adolescents are included in the analysis, with any missing data imputed with the group mean value)

Participants

Sample size: 46 children/adolescents with an ADHD diagnosis according to DSM‐III criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, conduct disorder, reading developmental disorder, arithmetic disorder, dysthymic disorder
Age range: 6 years to 12 years
Mean age (SD): 8.6 (1.7) years
Sex: 46 (100%) males
ADHD subtype: NR

Interventions

Three interventions (all 46 children/adolescents participated in each of the three interventions):

  1. Dextroamphetamine (short acting), weight‐based dosing increasing each week (children < 30 kg (66 lbs) received 10, 25, and 40 mg/day, twice a day; children/adolescents > 30 kg (66 lbs) received 15, 30, and 45 mg/day, twice a day), (n = 46)

  2. Methylphenidate hydrochloride, weight‐based dosing increasing each week (children < 30 kg (66 lbs) received 25, 40, and 70 mg/day, twice a day; children/adolescents > 30 kg (66 lbs) received 30, 50, and 90 mg/day, twice a day), (n = 46)

  3. Placebo (n = 46)

Duration: 63 days (3 x 21‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Teacher Rating Scale ‐ Short Form* and Conners' Parent Rating Scale ‐ Long Form

  2. Clinical impression, assessed with Clinical Global Impressions ‐ Improvement scale

  3. Academic performance, assessed with: the Barnell Loft, Ltd, Developing Key Concepts in Math test

  4. Retention: proportion of participants who completed the trial

  5. Adverse events

Other outcomes:

  1. Nervous habits/mannerisms, compulsive acts and obsessive thinking assessed with Children's Psychiatric Rating Scale

  2. Urine biochemistry

  3. Plasma biochemistry

  4. Renal clearance

  5. Cognitive ratings, assessed with Conners' Continuous Performance Test

Notes

ClinicalTrials.gov identifier: not available
Authors' affiliation: National Institute of Mental Health
Study funding: NR

Outcomes were presented across four publications with varying sample sizes
*Unpublished data on the ADHD symptoms as rated by the Conners' Teacher Rating Scale ‐ Short Form were sought on three separate occasions but were not obtained

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

This study has four associated publications, and all reports have varying numbers of participants. Upon communication with the corresponding author of these reports, it was confirmed that the numbers of participants vary in the four publications due to missing data and dropouts. Reasons for missing data not provided

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Unclear risk

No information on the validity of the primary outcome measure provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Childress 2015

Methods

Multi‐center, randomized, double‐blinded, placebo‐controlled, cross‐over trial
Countries: United States
Number of study sites: 7
Statistical methods: modified ITT (all randomized children/adolescents who took at least one dose of the study medication, and had at least one post‐randomization score on primary outcome measure)

Participants

Sample size: 97 children/adolescents with an ADHD diagnosis according to DSM‐IV‐TR criteria
Dropouts: 2
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9.6 (1.86) years
Sex: 59 (60.8%) males
ADHD subtype: 0 (0%) hyperactive ‐ impulsive; 18 (18.6%) inattentive; 79 (81.4%) combined

Interventions

Two interventions (all 97 children/adolescents participated in both interventions):

  1. Mixed amphetamine salts (short acting), dose determined by dose optimisation period (mean (SD) dose: 23.4 (8.18) mg/day), (n = 97)

  2. Placebo (n = 97)

Duration: 14 days (2 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with the combined (investigator/research personnel) and attention subscales of the Swanson, Kotkin, Agler, M‐Flynn and Pelham (SKAMP) scale

  2. Academic performance, assessed with Permanent Product Measure of Performance

  3. Retention: proportion of participants who completed the trial

  4. Adverse events

Notes

ClinicalTrials.gov identifier: NCT01986062
Authors' affiliation: pharmaceutical industry
Study funding: pharmaceutical industry

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence generated using an interactive web‐based response system

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Very low attrition (2%)

Selective reporting (reporting bias)

Low risk

Data provided on all outcomes listed in the registered protocol. Study appears to be free of selective reporting

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Coghill 2013

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, parallel‐group trial
Countries: Belgium, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, Sweden, UK
Number of study sites: 48
Statistical methods: modified ITT (last observation carried forward)

Participants

Sample size: 336* children/adolescents with an ADHD diagnosis according to DSM‐IV‐TR criteria
Dropouts: 140
Psychiatric comorbid conditions: ODD
Age range: 6 years to 17 years
Mean age (SD): 10.9 (2.8)
Sex: 268 (81%) male
ADHD subtype: 10 (3%) hyperactive‐impulsive; 53 (16%) inattentive; 268 (80.7%) combined; 1 (0.3%) NR

Interventions

Three interventions (336 children/adolescents participated in one of three interventions):

  1. Lisdexampehtamine (long acting), varying doses at either 30, 50, or 70 mg/day, (n = 113)

    1. Mean (SD) dose across participants: 53.8 (15.6) mg/day

  2. Osmotic release oral system methylphenidate, varying doses at either 18, 36, or 59 mg/day, (n = 112)

    1. Mean (SD) dose across participants: 45.4 (12.7) mg/day

  3. Placebo (n = 111)

Duration: 49 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (investigator), and Conners' Parent Rating Scale ‐ Revised

  2. Clinical impression, assessed with Clinical Global Impression ‐ Severity and Clinical Global Impression ‐ Improvement scales

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who dropped out due to lack of efficacy

  5. Number of participants who dropped out due to any adverse event

  6. Adverse events

Notes

ClinicalTrials.gov identifier: NCT00763971
Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
Outcomes were presented across three publications

*Clinical characteristics were only reported on those who received at least one dose of the intervention to which they were randomized (n = 332)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Low risk

Study utilized an interactive voice/web response system, which automatically generated a unique randomization number for each child/adolescent

Incomplete outcome data (attrition bias)
All outcomes

High risk

High attrition (58%). 14 (4%) children/adolescents excluded from the efficacy analysis with no reasons provided

Selective reporting (reporting bias)

High risk

Outcomes listed in the registered protocol are not reported in any of the three publications

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo are described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment is not described
Donnelly 1989

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: ITT

Participants

Sample size: 20 children/adolescents with an ADHD diagnosis according to DSM‐III criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, conduct disorder, mental learning disorder, language disorder
Age range: NR
Mean age (SD): 8 (2) years
Sex: 20 (100%) males
ADHD subtype: NR

Interventions

Three interventions (all 20 children/adolescents participated in each of the three interventions):

  1. Dextroamphetamine (short acting), weight‐based dose, 0.5 mg/kg/day, twice a day, (n = 20)

  2. Fenfluramine hydrochloride, weight‐based dosing increasing each week (0.6 mg/kg/day, 1.3 mg/kg/day, 2.0 mg/kg/day), twice a day, (n = 20)

  3. Placebo (n = 20)

Duration: 63 days (3 x 21‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Teacher Rating Scale ‐ Short Form

  2. Clinical impression, assessed with Clinical Global Impression scale*

  3. Adverse events

Other outcomes:

  1. Vigiliance/attention and impulsivity, assessed with Conners' Continuous Performance Test

  2. Motor activity, assessed with activity monitor

  3. Biochemical and platelet measures (urine and plasma)

  4. Measures of prolactin

Notes

ClinicalTrials identifier: not available

Authors' affiliation: university and National Institute of Mental Health
Study funding: NR

Donnelly 1986 is a pilot study of Donnelly 1989 and therefore have overlapping data

*Unpublished data on the Clinical Global Impression scale sought on three separate occasions but not obtained

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All recruited children/adolescents included in analyses. Only one dropout, with reasons provided

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Unclear risk

No information on the validity of the primary outcome measure provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Findling 2011

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, parallel‐group trial
Country: United States
Number of study sites: 45
Statistical methods: modified ITT (last observation carried forward)

Participants

Sample size: 314 children/adolescents with an ADHD diagnosis according to DSM‐IV‐TR criteria
Dropouts: 52
Psychiatric comorbid conditions: NR
Age range: 13 years to 17 years
Mean age (SD): 14.6 (1.31) years
Sex: 249 (79%) males
ADHD subtype: 203 (65%) combined

Interventions

Four interventions (312 children/adolescents participated in one of four interventions):

  1. Lisdexamphetamine (long acting), 30 mg/day, (n = 78*)

  2. Lisdexamphetamine (long acting), 50 mg/day (30 mg/day for week 1 with forced dose escalation to 50 mg/day for weeks 2 to 4), (n = 77*)

  3. Lisdexamphetamine, long acting, 70 mg/day (30 mg/day for week 1 with forced dose escalation to 50 mg/day for week 2 and 70 mg/day for weeks 3 to 4), (n = 78*)

  4. Placebo (n = 79)

Duration: 28 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (clinician ratings)

  2. Clinical impression, assessed with Clinical Global Impression ‐ Severity and Clinical Global Impression ‐ Improvement scales

  3. Quality of life, assessed with Youth Quality of Life ‐ Research Version (YQOL‐R)

  4. Retention: proportion of participants who completed the trial

  5. Number of participants who dropped out due to lack of efficacy

  6. Number of participants who experienced at least one adverse event

  7. Number of participants who dropped out due to any adverse event

  8. Adverse events

Notes

ClinicalTrials.gov identifier: NCT00735371

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*Numbers are based on participants included in the safety analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence generated by a web‐based computer system

Allocation concealment (selection bias)

Low risk

Allocation concealment ensured using the web‐based computer system and third party, which serially numbered treatment bottles for each participant

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Moderate attrition (16%). However, 98% of randomized children/adolescents included in primary efficacy analysis. Reasons for dropouts provided

Selective reporting (reporting bias)

Low risk

Data provided on all outcomes listed in the registered protocol. Study appears to be free of selective reporting

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Giblin 2011

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, parallel‐group trial
Country: United States

Number of study sites: 1
Statistical methods: modified ITT (all randomized children/adolescents who had both a baseline and a post‐randomization primary outcome assessment)

Participants

Sample size: 24 children/adolescents with an ADHD diagnosis according to DSM‐IV‐TR criteria
Dropouts: 0
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9.65 (2.2) years
Sex: 10 (42%) males
ADHD subtype: NR

Interventions

Four interventions (24 children/adolescents participated in one of four interventions):

  1. Lisdexamphetamine (long acting), 30 mg/day, (n = 3)

  2. Lisdexamphetamine, (long acting), 50 mg/day, (n = 11)

  3. Lisdexamphetamine, (long acting), 70 mg/day, (n = 2)

  4. Placebo (n = 8)

Duration: 28 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (investigator) and Conners' Parent Rating Scale ‐ Revised: Short Form*

  2. Clinical impression, assessed with Clinical Global Impression ‐ Severity scale

  3. Adverse events

Other outcomes:

  1. Sleep onset latency, assessed with polysomnography

  2. Wake time after sleep onset, assessed with polysomnography and actigraphy

  3. Number awakenings after sleep onset, assessed with polysomnography

  4. Total sleep time, assessed with polysomnography and actigraphy

  5. Sleep efficiency, assessed with actigraphy

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: private organization and pharmaceutical industry
Study funding: pharmaceutical industry
*Unpublished data sought on both outcome measures on three separate occasions but not obtained

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Incomplete outcome data not addressed; number of completers not reported

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Gillberg 1997

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, parallel‐group trial
Country: Sweden
Number of sites: 4
Statistical methods: modified ITT (for inclusion into the analysis at least two measurements had to be available, with the last observation carried forward)

Participants

Sample size: 62 children/adolescents with an ADHD diagnosis according to DSM‐III‐R criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, conduct disorder, anxiety, autistic disorder, pervasive development disorder, motor tic disorder, Tourette syndrome, mild mental retardation
Age range: 6 years to 11 years
Mean age (SD): 9 (1.6) years
Sex: 52 (84%) males
ADHD subtype: NR

Interventions

Two interventions (62 children/adolescents participated in one of two interventions):

  1. Mixed amphetamine salts (short acting), dosage was titrated from 10 mg/day, twice a day, to a maximum of 60 mg/day, twice a day, (n = 32)

  2. Placebo (n = 30)

Duration: 365 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Teacher Rating Scale and Conners' Parent Rating Scale

  2. Adverse events

Other outcomes:

  1. Depression, assessed with the Birleson Depression Self‐Rating Scale

  2. Mood, assessed with the McGrath Test

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry and public funds

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Moderate attrition (14%). However, all dropouts occurred prior to randomization. Reasons for dropout provided. All randomized children/adolescents included in primary analysis

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
James 2001

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: per protocol

Participants

Sample size: 35 children/adolescents with an ADHD diagnosis according to DSM‐IV criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, anxiety, enuresis, dysthymic disorder, learning disorder
Age range: 6.9 years to 12.2 years
Mean age (SD): 9.1 (1.5) years
Sex: 21 (60%) males
ADHD subtype: 35 (100%) combined

Interventions

4 interventions:*

  1. Dextroamphetamine (short acting)*

  2. Dextroamphetamine spansules (long acting)*

  3. Mixed amphetamine salts (long acting)*

  4. Placebo

Duration: 56 days (4 x 14‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Teacher Rating Scale and Conners' Parent Rating Scale

  2. Academic performance, assessed with a 5‐minute timed math task

  3. Adverse events

Other outcomes:

  1. Motor activity, assessed with an actometer

Notes

ClinicalTrial.gov identifier: not available

Authors' affiliation: National Insitute of Mental Health
Study funding: NR
*Doses were individualized and based on age, weight, prior medication experience and symptom severity (overall mean dose range: 7.8 mg/day to 12.8 mg/day)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Low attrition (7%), and reasons provided. All dropouts occurred prior to randomization. All randomized children/adolescents completed the trial and included in primary analysis

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Manos 1999

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: unclear

Participants

Sample size: 84 children/adolescents with an ADHD diagnosis according to DSM‐IV criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, anxiety, mood disorder, learning disability
Age range: 5 years to 17 years
Mean age (SD): 10.1 (NR) years
Sex: 66 (79%) males
ADHD subtypes: 38 (45%) inattentive; 46 (55%) combined

Interventions

Two conditions (84 children/adolescents participated in one of two conditions):

  1. Mixed amphetamine salts (short acting), (42 children/adolescents participated in each of the following four interventions):

    1. 5 mg/day, once daily

    2. 10 mg/day, once daily

    3. 15 mg/day, once daily

    4. Placebo

  2. 2. Methylphenidate (42 children/adolescents participated in each of the following four interventions):

    1. 5 mg/day, twice a day

    2. 10 mg/day, twice a day

    3. 15 mg/day, twice a day

    4. Placebo

Children/adolescents received either the four mixed amphetamine salt OR methylphenidate conditions (determined by his or her physician) in a randomly assigned sequence
Duration: 28 days (4 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Abbreviated Symptoms Questionnaire ‐ Parent Version and Conners' Abbreviated Symptoms Questionnaire ‐ Teacher Version

  2. Adverse events

Other outcomes:

  1. Concentration in school, assessed with School Situations Questionnaire ‐ Revised

Notes

ClinicalTrial.gov identifier: not available

Authors' affiliations: university
Study funding: public funds

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Low risk

A third party pharmacist prepared individually sealed bottles dated by week

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Study did not describe if any children/adolescents dropped out from the trial

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo are described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Clinician, teacher and parent (outcome assessors) were blinded to treatment order
McCracken 2003

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States
Number of study sites: 4
Statistical methods: modified ITT

Participants

Sample size: 51 children/adolescents with an ADHD diagnosis according to DSM‐IV criteria
Dropouts: 4
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9.5 (1.9) years
Sex: 44 (86%) males
ADHD subtypes: 1 (2%) hyperactive ‐ impulsive; 50 (98%) combined

Interventions

Five interventions (all 51 children/adolescents participated in each of the five interventions):

  1. Mixed amphetamine salts (short acting), 10 mg, once a day, (n = 51)

  2. Mixed amphetamine salts (long acting), 10 mg, once a day, (n = 51)

  3. Mixed amphetamine salts (long acting), 20 mg, once a day*, (n = 51)

  4. Mixed amphetamine salts (long acting), 30 mg, once a day, (n = 51)

  5. Placebo (n = 51)

Duration: 35 days (5 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with the attention subscale (investigator ratings) of the Swanson, Kotkin, Agler, M‐Flynn and Pelham (SKAMP) scale

  2. Academic performance, assessed with Permanent Product Measure of Performance

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who dropped out due to any adverse event

  5. Adverse events

Other outcomes:

  1. Conduct problems, assessed with the deportment subscale of the Swanson, Kotkin, Agler, M‐Flynn and Pelham (SKAMP) scale

Notes

ClinicalTrial.gov identifier: not available
Authors' affiliation: university
Study funding: pharmaceutical industry
*We randomly chose mixed amphetamine salts (long acting), given at 20 mg/day, to represent the amphetamine group in this study for binary outcomes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Low attrition (4%) and reasons provided. All randomized children/adolescents included in primary analysis

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Nemzer 1986

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: NR

Participants

Sample size: 14 children/adolescents with an ADHD diagnosis according to DSM‐III criteria

Dropouts: NR
Psychiatric comorbid conditions: NR
Age range: 7 years to 12 years
Mean age (SD): 9.36 (NR) years
Sex: 11 (79%) males
ADHD subtype: NR

Interventions

Four interventions (all 14 children/adolescents participated in each of the four interventions):

  1. Dextroamphetamine (short acting), weight‐based dosing (children < 32 kg (70.5 lbs) received 5 mg/day, twice a day; children/adolescents > 32 kg (70.5 lbs) received 10 mg/day), twice a day, (n = 14)

  2. Tyrosine supplement, 140 mg/kg/day, (n = 14)

  3. Tryptophan supplement, 100 mg/kg/day, (n = 14)

  4. Placebo (n = 14)

Duration: 28 days (4 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Parent Rating Scale and Conners' Teacher Rating Scale

  2. Academic performance, assessed with Wechsler Intelligence Scale for Children ‐ Revised

  3. Adverse events

Other outcomes:

  1. Tyrosine serum levels

  2. Tryptophan serum levels

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university
Study funding: NR

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Dropouts not discussed

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo are described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Pliszka 2000

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, parallel‐group trial
Country: United States

Number of study sites: 1
Statistical methods: modified ITT (last observation carried forward)

Participants

Sample size: 59* children/adolescents with an ADHD diagnosis according to the Diagnostic Interview Schedule for Children
Dropouts: 5
Psychiatric comorbid disorders: oppositional defiant disorder, conduct disorder, anxiety
Age range: 6 years to 10 years
Mean age (SD): 8.2 (1.6) years
Sex: NR
ADHD subtype: NR

Interventions

Three interventions (58 children/adolescents participated in one of three interventions):

  1. Mixed amphetamine salts (short acting), weight‐based, titrated dosing (maximum dose for children < 27.2 kg (60 lbs) was 15 mg/day; maximum daily dose for children/adolescents > 27.2 kg (60 lbs) was 30 mg/day), (n = 20)

  2. Methylpehnidate, weight‐based, titrated dosing (maximum dose for children < 27.2 kg (60 lbs) was 25 mg/day; maximum daily dose for children/adolescent > 27.2 kg (60 lbs) was 50 mg/day), (n = 20)

  3. Placebo (n = 18)

Duration: 21 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with IOWA (inattention/overactivity with aggression) Conners' Teacher Rating Scale and Conners' Parent Global Index

  2. Clinical impression, assessed with Clinical Global Impressions ‐ Improvement scale

  3. Number of participants who dropped out due to any adverse event

  4. Adverse events

Other outcomes:

  1. Agression/defiance, assessed with Conners' Teacher Rating Scale

Notes

ClinicalTrials.gov identifier: not available

Author's affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*1 participant dropped out before the end of the study, and was not accounted for in the participant characteristic description (data only provided on 58 participants)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Low attrition (10%), and reasons provided. All randomized children/adolescents included in primary analysis

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo are described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Ramtvedt 2013

Methods

Multi‐center, randomized, placebo‐controlled, cross‐over trial
Country: Norway
Number of study sites: 4
Statistical methods: unclear

Participants

Sample size: 36* children/adolescents with an ADHD diagnosis according to DMS‐IV‐TR criteria
Dropouts: 0
Psychiatric comorbid disorders: oppositional defiant disorder, anxiety/depression, learning disability
Age range: 9 years to 14 years
Mean age (SD): 11.4 (1.4) years
Sex: 29 (81%) males
ADHD subtype: 10 (28%) inattentive; 1 (3%) hyperactive ‐ impulsive; 25 (69%) combined

Interventions

Three interventions (all 36 children/adolescents participated in each of the three interventions):

  1. Dextroamphetamine (short acting), 5 mg twice a day in week 1; 10 mg twice a week in week 2, (n = 36)

  2. Methylphenidate (short acting): 10 mg three times a day in week 1; 15 mg twice a day, 10 mg once daily in week 2, (n = 36)

  3. Placebo (n = 36)

Duration: 42 days (3 x 14‐day treatment periods)

Outcomes

Relevant outcomes:

  1. Improvement of ADHD symptoms, assessed with a 21‐item ADHD questionnaire developed for the study by parents and teachers**

  2. Adverse events

Other outcomes:

  1. Inattention, assessed with Conners' Continuous Performance Test

  2. Motor activity, assessed with Conners' Continuous Performance Test

Notes

ClinicalTrials.gov identifier: NCT01220440
Authors' affiliation: university and hospital
Study funding: public funds
Outcomes were presented across two publications

*Data only provided on those children/adolescents who completed the trial; no information provided regarding number of children/adolescents randomized
**Data is presented as an aggregate score of parent and teacher ratings and therefore could not be incorporated into the meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Primary analysis only included a subset of completers without any reason provided. No information on non‐completers provided

Selective reporting (reporting bias)

High risk

Although the registered protocol stated that they would collect adverse events using the Side‐Effects Rating Scale, this was not reported in the published manuscript

Other bias

Unclear risk

No information on the validity of the primary outcome measure provided

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Interventions and placebo were not identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Sharp 1999

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: ITT (missing data were imputed using group means)

Participants

Sample size: 32* children/adolescents with an ADHD diagnosis according to DSM‐IV criteria
Dropouts: 1
Psychiatric comorbid disorders: oppositional defiant disorder, conduct disorder, depression, separation anxiety, specific phobias, tic disorder, enuresis, reading disorder
Age range: 6.2 years to 12.7 years
Mean age (SD): 8.9 (1.7) years
Sex: 0 (0%) males
ADHD subtype: 32 (100%) combined

Interventions

Three interventions (all 32 children/adolescents participated in each of the three interventions):

  1. Dextroamphetamine (short acting), weight‐based dosing and increasing over time (mean doses of 0.23 mg/kg/day, 0.43 mg/kg/day, and 0.64 mg/kg/day, twice a day for weeks 1, 2, and 3 respectively), (n = 32)

  2. Methylphenidate, weight‐based dosing and increasing over time (mean doses of 0.45 mg/kg/day, 0.85 mg/kg/day, and 1.28 mg/kg/day, once daily for weeks 1, 2, and 3 respectively), (n = 32)

  3. Placebo (n = 32)

Duration: 63 days (3 x 21‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Parent Rating Scale and Conners' Teacher Rating Scale**

  2. Clinician impression, assessed with Clinical Global Impressions ‐ Severity and Clinical Global Impressions ‐ Improvement scales

  3. Retention: proportion of participants who completed the trial

  4. Adverse events

Notes

ClinicalTrial.gov identifier: not available

Authors' affiliation: university and National Institute for Mental Health
Study funding: NR

*Clinical characteristics were presented on 42 children/adolescents, 10 of whom participated in a separate pilot program
**Unpublished data on the ADHD core symptoms sought on three separate occasions but not obtained

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Moderate attrition (14%), with reasons provided

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo are described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Shekim 1986

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: NR

Participants

Sample size: 22 children/adolescents with an ADHD diagnosis according to DSM‐III criteria
Dropouts: NR
Psychiatric comorbid disorders: 0
Age range: 6 years to 12 years
Mean age (SD): 9.75 (2.08) years
Sex: 22 (100%) males
ADHD subtype: NR

Interventions

Two interventions (all 22 children/adolescents participated in both interventions):

  1. Dextroamphetamine (short acting), weight‐based at 0.3 mg/kg twice a day, and titrated upwards during trial period, (n = 22)

  2. Placebo (n = 22)

Duration: 28 days (2 x 14‐day treatment periods)

Outcomes

Relevant outcomes:

  1. Academic performance, assessed with Wide Range Achievement Test ‐ math subset

Other outcomes:

  1. Wide Range Achievement Test ‐ spelling and reading subsets

  2. Monoamine oxidase activity

  3. Attention and impulsivity, assessed with Conners' Contininuous Performance Test

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university
Study funding: public funds

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Reasons for exclusions from the analysis not provided. Methods of analysis not described. Number of individuals included in the analyses not reported

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Short 2004

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: per protocol

Participants

Sample size: 34* children/adolescents with an ADHD diagnosis according to DSM‐IV criteria
Dropouts: NR
Psychiatric comorbid conditions: NR
Age range: 3 years to 5.9 years
Mean age (SD): 5.3 (NR) years
Sex: 24 (85%) males
ADHD subtype: 5 (17%) inattentive; 23 (83%) hyperactive ‐ impulsive or combined

Interventions

Two conditions (28 children/adolescents participated in one of two conditions)*:

  1. Amphetamine:

    1. Mixed amphetamine salts (short acting), 5 mg/day, once daily

    2. Mixed amphetamine salts (short acting), 10 mg/day, once daily

    3. Mixed amphetamine salts (short acting), 15 mg/day, once daily

    4. Placebo

  2. Methylphenidate:

    1. Methylphenidate, 5 mg/day, twice a day

    2. Methylphenidate, 10 mg/day, twice a day

    3. Methylphenidate, 15 mg/day, twice a day

    4. Placebo

Amphetamine or methylphenidate determined by a physician
Duration: 28 days (4 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Parent Rating Scale‐short form and Conners' Teacher Rating Scale‐short form**

  2. Adverse events

Notes

ClinicalTrial.gov identifier: not available

Authors' affiliations: university
Study funding: public funds
*Clinical characteristics only presented on children/adolescents included in analysis (n = 28)
**The authors did not separate the two active interventions (amphetamine and methylphenidate) in their analysis. We contacted the authors on three occasions to obtain the data on amphetamines only, but we received no response, and therefore outcomes could not be included in the meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not sufficiently described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Reasons for attrition not described. In addition, six participants were dropped from the analysis, and their last data point was not carried forward

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors blinded to order of trial interventions
Spencer 2006a

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, parallel‐group trial
Country: United States
Number of study sites: NR
Statistical methods: modified ITT (those with at least one post‐baseline primary efficacy assessment)

Participants

Sample size: 287* children/adolescents with an ADHD diagnosis according to DSM‐IV‐TR criteria
Dropouts: 52
Psychiatric comorbid conditions: NR
Age range: 13 years to 16 years
Mean age (SD): 14.2 (1.2) years
Sex: 182 (66%) males
ADHD subtypes: 114 (41%) inattentive; 7 (2.5%) hyperactive‐impulsive; 157 (56.5%) combined

Interventions

Five interventions (287 children/adolescents participated in one of five interventions):

  1. Mixed amphetamine salts (long acting), 10 mg/day, once daily, (n = 56)

  2. Mixed amphetamine salts (long acting), 20 mg/day, once daily (10 mg/day for week 1 with forced dose escalation to 20 mg/day for weeks 2 to 4), (n = 56)

  3. Mixed amphetamine salts (long acting), 30 mg/day, once daily (10 mg/day for week 1, with forced dose escalation to 20 mg/day for week 2, and 30 mg/day for weeks 3 to 4), (n = 58)

  4. Mixed amphetamine salts (long‐acting), 40 mg/day, once daily (10 mg/day for week 1, with forced dose escalation to 20 mg/day for week 2, 30 mg/day for week 3, and 40 mg/day for week 4), (n = 63)

  5. Placebo (n = 54)

Duration: 28 days (4 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (clinician ratings)

  2. Clinical impression, assessed with Clinical Global Impression ‐ Severity and Clinical Global Impression ‐ Improvement scales

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who dropped out due to any adverse event

  5. Adverse events

Other outcomes:

  1. Vital signs

  2. Body weight

Notes

ClinicalTrials.gov Identifier: NCT00507065

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*Clinical characteristics only provided on the study's ITT population (n = 278)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Low attrition (10%), and reasons provided. Only 3% of children/adolescents excluded from analysis due to no post‐baseline primary efficacy assessment

Selective reporting (reporting bias)

Low risk

Data provided on all outcomes listed in the registered protocol. Study appears to be free of selective reporting

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of participants and personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Swanson 1998a

Methods

Single‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States

Number of study sites: 1
Statistical methods: unclear

Participants

Sample size: 33 children/adolescents with an ADHD diagnosis according to DSM‐IV criteria
Dropouts: 3
Psychiatric comorbid conditions: NR
Age range: 7 years to 14 years
Mean age (SD): 10.58 (1.81) years
Sex: 26 (79%) males
ADHD subtypes: NR

Interventions

Six interventions (all 33 children/adolescents participated in each of the six interventions):

  1. Mixed amphetamine salts (short acting), 5 mg/day, once daily, (n = 33)

  2. Mixed amphetamine salts (short acting), 10 mg/day, once daily, (n = 33)

  3. Mixed amphetamine salts (short acting), 15 mg/day, once daily, (n = 33)

  4. Mixed amphetamine salts (short acting), 20 mg/day, once daily, (n = 33)

  5. Methylphenidate (dose determined by physician), (n = 33)

  6. Placebo (n = 33)

Duration: 49 days (6 x 7‐day treatment periods defined by the six medication conditions above, plus an extra seven‐day period to provide an opportunity to make‐up any missed weeks)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with the attention subscale (teacher ratings)* of the Swanson, Kotkin, Agler, M‐Flynn and Pelham (SKAMP) scale

  2. Academic performance, assessed with Permanent Product Measure of Performance*

  3. Retention: proportion of randomized participants who completed the trial

Other outcomes:

  1. Conduct problems, assessed with the deportment subscale of the Swanson, Kotkin, Agler, M‐Flynn and Pelham (SKAMP) scale

Notes

ClinicalTrials identifier: not available

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*Unpublished data on outcomes sought on three separate occasions but not obtained

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Low attrition (8%), but reasons for dropout not provided, and only 88% of children/adolescents contributed to primary analysis

Selective reporting (reporting bias)

Unclear risk

Study protocol not available and the possibility of reporting bias could not be assessed

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described
Wigal 2009a

Methods

Multi‐center, randomized, double‐blind, placebo‐controlled, cross‐over trial
Country: United States
Number of study sites: 7
Statistical methods: modified ITT (children/adolescents who received at least one dose of study medication, with at least one post‐randomization measurement of the primary efficacy variable ‐ last observation carried forward)

Participants

Sample size: 117* children/adolescents with an ADHD diagnosis according to DSM‐IV‐TR criteria
Dropouts: 6
Psychiatric comorbid disorders: NR
Age range: 6 years to 12 years
Mean age (SD): 10.1 (1.5) years
Sex: 98 (76%) males
ADHD subtypes: NR

Interventions

Two interventions (all 117 children/adolescents participated in both interventions):

  1. Lisdexamphetamine (long acting), either 30 mg/day, 50 mg/day or 70 mg/day (determined by dose optimisation period), (n = 117)

  2. Placebo (n = 117)

Duration: 14 days (2 x 7‐day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (clinician ratings)

  2. Academic performance, assessed with Permanent Product Measure of Performance

  3. Clinical impression, assessed with Clinical Global Impression ‐ Severity and Clinical Global Impressions ‐ Improvement scales

  4. Retention: number of participants who completed the study

  5. Number of participants who experienced at least one adverse event

  6. Number of participants who dropped out due to an adverse event

  7. Adverse events

Notes

ClinicalTrials.gov Identifier: NCT00500149

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry

*Clinical characteristics provided on 129 children/adolescents first enrolled into an open‐label dose‐optimisation phase. Of these, 117 children/adolescents randomized to the double‐blind phase

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Low attrition (9%), and reasons provided; 97% of randomized children/adolescents included in primary analysis. Four individuals not included due to no post‐baseline efficacy measure

Selective reporting (reporting bias)

Unclear risk

Data provided on all outcomes listed in the registered protocol. However, also reported on additional outcomes not listed in protocol

Other bias

Low risk

Study appears to be free of other biases

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo described as identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not described

ADHD: attention deficit hyperactivity disorder.
DSM‐III: Diagnostic and Statistical Manual of Mental Disorders, Third Edition.
DSM‐III‐R: Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised.
DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
DSM‐IV‐TR: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.
ITT: intention‐to‐treat.
NR: not reported.

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Akhondzadeh 2003

No placebo comparison assessed

Alexandris 1968

ADHD diagnosis not confirmed using formal diagnostic criteria

Arnold 2011

No direct amphetamine ‐ placebo comparison

Biederman 2006

Not a randomized controlled trial

Biederman 2008

Not a randomized controlled trial

Boellner 2010

Not a randomized controlled trial

Brown 2010

Not a randomized controlled trial

Denhoff 1971

ADHD diagnosis not confirmed using formal diagnostic criteria

Donner 2007

Not a randomized controlled trial

Efron 1997

No placebo comparison assessed

Findling 2009

Not a randomized controlled trial

Greenhill 2003

No placebo comparison assessed

Kamien 1998

Study design was a series of multiple, cross‐over, randomized controlled trials; our review included only single, cross‐over, randomized controlled trials

Lopez 2008

Not a randomized controlled trial

McGough 2005

Not a randomized controlled trial

Najib 2009

Not a randomized controlled trial

Nikles 2006

Study design was a series of multiple, cross‐over, randomized controlled trials; our review included only single, cross‐over, randomized controlled trials

Quintana 2007

Not a randomized controlled trial

Scheffer 2005

Included children/adolescents who had comorbid bipolar disorder and were treated with mood stabilizers (divalproex sodium)

Sleator 1974

Not a randomized controlled trial

Spencer 2005

Not a randomized controlled trial

Spencer 2006b

ADHD diagnosis not confirmed using formal diagnostic criteria

Turgay 2010

Not a randomized controlled trial

Wigal 2009b

Not a randomized controlled trial

Wigal 2010a

Not a randomized controlled trial

Wigal 2010b

Study participants were adults with ADHD

ADHD: attention deficit hyperactivity disorder.

Characteristics of studies awaiting assessment [ordered by study ID]

Jump to:

Glos 1973

Methods

Double‐blind, controlled trial*

Participants

Sample size: 20 hyperactive children**
Mean age: 9.4 years

Interventions

Amphetamine and placebo

Outcomes

Notes

*Information on whether or not the trial was randomized is necessary for inclusion into this review
**Information on whether participants were diagnosed with ADHD and according to formal diagnostic criteria is necessary for inclusion into this review. Since we were unable to contact the author due to lack of contact information, we are unable to classify this study as either included or excluded

Itil 1974

Methods

Double‐blind, three‐way study design

Participants

Children with hyperactivity

Interventions

Thioridazine, dextroamphetamine and placebo

Outcomes

Global behavior evaluation

Notes

Only abstract available. Detailed outcome data not in abstract. Unsure:

  1. If treatments were randomized

  2. If participants had a formal diagnosis of ADHD

  3. Of the ages of the participants included

Author has been contacted three times but no response received as yet

ADHD: attention deficit hyperactivity disorder.

Characteristics of ongoing studies [ordered by study ID]

Jump to:

Fanton 2009

Trial name or title

Effectiveness of an extended‐release stimulant medication in treating preschool children with attention deficit hyperactivity disorder

Methods

Six‐week, placebo‐controlled, cross‐over trial

Participants

Children aged 3 years to 6 years with ADHD

Interventions

Mixed amphetamine salts (long acting) and placebo

Outcomes

Primary

  1. Composite parent and teacher Conners' Rating Scale score

  2. Tolerance of extended‐release mixed amphetamine salts

Secondary

  1. Clinical Global Impression ‐ Improvement Scale score

Starting date

June 2008

Contact information

Dr. John Fanton, Baystate Medical Center

Notes

Clinicaltrials.gov identifier: NCT00712699. States that recruitment period ended in August 2010. However, no results have been published as yet. Currently, only abstract available

NCT01711021

Trial name or title

A randomized, double‐blind, placebo‐controlled, cross‐over, laboratory, classroom study to evaluate the safety and efficacy of d‐amphetamine transdermal drug delivery system (d‐ATS) compared to placebo in children and adolescents with ADHD

Methods

Two‐week, double‐blind, randomized cross‐over trial

Participants

Children and adolescents aged 6 years to 17 years with ADHD

Interventions

D‐Amphetamine Transdermal System and placebo patch

Outcomes

Primary

  1. Change in ADHD symptoms using the Swanson, Kotkin, Agler, M‐Flynn, and Pelham (SKAMP) scale

Starting date

October 2012

Contact information

Dr. James Waxmonsky (affiliation not stated)

Notes

ClinicalTrials.gov identifier: NCT01711021. States that recruitment period ended in March 2013. However, no results have been published as yet. No abstract available

ADHD: attention deficit hyperactivity disorder.

Data and analyses

Open in table viewer
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]
Analysis 1.1
Comparison 1 Amphetamines versus placebo, Outcome 1 Total ADHD symptom score ‐ parent ratings.

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

2 Hyperactivity/impulsivity ‐ parent ratings Show forest plot

2

132

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

‐0.54 [‐0.89, ‐0.19]
Analysis 1.2
Comparison 1 Amphetamines versus placebo, Outcome 2 Hyperactivity/impulsivity ‐ parent ratings.

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

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]
Analysis 1.3
Comparison 1 Amphetamines versus placebo, Outcome 3 Total ADHD symptom score ‐ teacher ratings.

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

4 Hyperactivity/impulsivity ‐ teacher ratings Show forest plot

1

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

Subtotals only
Analysis 1.4
Comparison 1 Amphetamines versus placebo, Outcome 4 Hyperactivity/impulsivity ‐ teacher ratings.

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

5 Inattention ‐ teacher ratings Show forest plot

1

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

Subtotals only
Analysis 1.5
Comparison 1 Amphetamines versus placebo, Outcome 5 Inattention ‐ teacher ratings.

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

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]
Analysis 1.6
Comparison 1 Amphetamines versus placebo, Outcome 6 Total ADHD symptom score ‐ clinician ratings.

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

7 Hyperactivity/impulsivity ‐ clinician ratings Show forest plot

3

813

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

‐0.75 [‐1.28, ‐0.23]
Analysis 1.7
Comparison 1 Amphetamines versus placebo, Outcome 7 Hyperactivity/impulsivity ‐ clinician ratings.

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

8 Inattention ‐ clinician ratings Show forest plot

3

813

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

‐0.78 [‐1.26, ‐0.30]
Analysis 1.8
Comparison 1 Amphetamines versus placebo, Outcome 8 Inattention ‐ clinician ratings.

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

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

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

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]
Analysis 1.10
Comparison 1 Amphetamines versus placebo, Outcome 10 Hyperactivity/impulsivity ‐ investigator/research personnel ratings.

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

11 Inattention ‐ investigator/research personnel ratings Show forest plot

4

634

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

‐0.73 [‐1.42, ‐0.04]
Analysis 1.11
Comparison 1 Amphetamines versus placebo, Outcome 11 Inattention ‐ investigator/research personnel ratings.

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

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]
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 12 Proportion of responders (Clinical Global Impression ‐ Improvement; CGI ‐ I).

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

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

14 Academic performance Show forest plot

8

826

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

0.56 [0.39, 0.73]
Analysis 1.14
Comparison 1 Amphetamines versus placebo, Outcome 14 Academic performance.

Comparison 1 Amphetamines versus placebo, Outcome 14 Academic performance.

15 Quality of life Show forest plot

1

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

Subtotals only
Analysis 1.15
Comparison 1 Amphetamines versus placebo, Outcome 15 Quality of life.

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

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

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

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]
Analysis 1.17
Comparison 1 Amphetamines versus placebo, Outcome 17 Proportion of participants experiencing decreased appetite.

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

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]
Analysis 1.18
Comparison 1 Amphetamines versus placebo, Outcome 18 Proportion of participants experiencing insomnia/trouble sleeping.

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

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]
Analysis 1.19
Comparison 1 Amphetamines versus placebo, Outcome 19 Proportion of participants experiencing abdominal pain.

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

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]
Analysis 1.20
Comparison 1 Amphetamines versus placebo, Outcome 20 Proportion of participants experiencing nausea/vomiting.

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

21 Proportion of participants experiencing headaches Show forest plot

9

2091

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.75, 1.16]
Analysis 1.21
Comparison 1 Amphetamines versus placebo, Outcome 21 Proportion of participants experiencing headaches.

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

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]
Analysis 1.22
Comparison 1 Amphetamines versus placebo, Outcome 22 Proportion of participants experiencing anxiety/nervousness.

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

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]
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 23 Proportion of participants who experienced at least one adverse event.

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

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

Open in table viewer
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]
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 1 Total ADHD symptom score ‐ parent ratings.

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]
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 2 Proportion of responders (CGI ‐ I).

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]
Analysis 2.3
Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 3 Academic performance.

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

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]
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 4 Retention: proportion of participants who completed the trial.

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]
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 5 Proportion of participants who dropped out/withdrew due to an adverse event.

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]
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 6 Proportion of participants experiencing decreased appetite.

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]
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 7 Proportion of participants experiencing insomnia/trouble sleeping.

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]
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 8 Proportion of participants experiencing abdominal pain.

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]
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 9 Proportion of participants experiencing headaches.

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

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

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]
Open in table viewer
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]
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 1 Total ADHD symptom score ‐ parent ratings.

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]
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 2 Proportion of responders (CGI ‐ I).

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]
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 3 Academic performance.

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]
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 4 Retention: proportion of participants who completed the trial.

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]
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 5 Proportion of participants experiencing decreased appetite.

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

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

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]
Open in table viewer
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]
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 1 Total ADHD symptom score ‐ parent ratings.

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]
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 2 Proportion of responders (CGI ‐ I).

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]
Analysis 4.3
Comparison 4 Subgroup analysis 3: Funding source, Outcome 3 Academic performance.

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

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]
Open in table viewer
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]
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 1 Total ADHD symptom score ‐ parent ratings.

2 Hyperactivity/impulsivity ‐ parent ratings Show forest plot

2

132

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

‐0.54 [‐0.89, ‐0.19]
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 2 Hyperactivity/impulsivity ‐ parent ratings.

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]
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 3 Total ADHD symptom score ‐ teacher ratings.

4 Hyperactivity/impulsivity ‐ teacher ratings Show forest plot

1

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

Subtotals only
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 4 Hyperactivity/impulsivity ‐ teacher ratings.

5 Inattention ‐ teacher ratings Show forest plot

1

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

Subtotals only
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 5 Inattention ‐ teacher ratings.

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]
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 6 Total ADHD symptom score ‐ clinician ratings.

7 Hyperactivity/impulsivity ‐ clinician ratings Show forest plot

3

813

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

‐0.74 [‐0.90, ‐0.58]
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 7 Hyperactivity/impulsivity ‐ clinician ratings.

8 Inattention ‐ clinician ratings Show forest plot

3

813

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

‐0.77 [‐0.94, ‐0.61]
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 8 Inattention ‐ clinician ratings.

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]
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 9 Total ADHD symptom score ‐ investigator/research personnel ratings.

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]
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 10 Hyperactivity/impulsivity ‐ Investigator/research personnel ratings.

11 Inattention ‐ investigator/research personnel ratings Show forest plot

4

634

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

‐0.76 [‐0.93, ‐0.60]
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 11 Inattention ‐ investigator/research personnel ratings.

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

9

2207

Risk Ratio (M‐H, Fixed, 95% CI)

3.11 [2.68, 3.61]
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 12 Proportion of responders (CGI ‐ I).

13 CGI ‐ S score Show forest plot

2

86

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

‐0.71 [‐1.15, ‐0.27]
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 13 CGI ‐ S score.

14 Quality of life Show forest plot

1

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

Subtotals only
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 14 Quality of life.

15 Academic performance Show forest plot

8

826

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

0.59 [0.45, 0.73]
Analysis 5.15
Comparison 5 Sensitivity analysis 1: Fixed‐effect model, Outcome 15 Academic performance.

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

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]
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 16 Retention: proportion of participants who completed the trial.

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]
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 17 Proportion of participants who experienced at least one adverse event.

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]
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 18 Proportion of participants who dropped out/withdrew due to an adverse event.

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]
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 19 Proportion of participants experiencing decreased appetite.

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]
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 20 Proportion of participants experiencing insomnia/trouble sleeping.

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]
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 21 Proportion of participants experiencing abdominal pain.

22 Proportion of participants experiencing headaches Show forest plot

9

2091

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.76, 1.18]
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 22 Proportion of participants experiencing headaches.

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]
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 23 Proportion of participants experiencing anxiety/nervousness.

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

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

Study flow diagram
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Figure 1

Study flow diagram

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Comparison 1 Amphetamines versus placebo, Outcome 5 Inattention ‐ teacher ratings.
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Analysis 1.5

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

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

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

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

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

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Comparison 1 Amphetamines versus placebo, Outcome 8 Inattention ‐ clinician ratings.
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Analysis 1.8

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

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

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

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

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

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

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

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

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

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

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

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Comparison 1 Amphetamines versus placebo, Outcome 14 Academic performance.
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Analysis 1.14

Comparison 1 Amphetamines versus placebo, Outcome 14 Academic performance.

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Comparison 1 Amphetamines versus placebo, Outcome 15 Quality of life.
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Analysis 1.15

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Comparison 4 Subgroup analysis 3: Funding source, Outcome 3 Academic performance.
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Analysis 4.3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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.

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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
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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
Navigate to table in Review
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
Navigate to table in Review
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
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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
Navigate to table in Review
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
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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
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