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How effective are drug treatments for children with ADHD at improving on-task behaviour and academic achievement in the school classroom? A systematic review and meta- analysis.

Vibhore Prasad, Ellen Brogan, Caroline A. Mulvaney, Matthew J. Grainge, Wendy Stanton, Kapil Sayal

Division of Primary Care University of Nottingham University Park Nottingham NG7 2RD E-mail: [email protected]

Dr Vibhore Prasad - NIHR Doctoral Research Fellow and Clinical Lecturer in Primary Care, Division of Primary Care, University of Nottingham

Dr Ellen Brogan – Academic Foundation Trainee, East Midlands Healthcare Workforce Deanery

Dr Caroline Mulvaney - Senior Research Fellow, School of Nursing/Division of Primary Care, University of Nottingham

Matthew J. Grainge – Division of Epidemiology and Public Health, University of Nottingham.

Wendy Stanton - Faculty Team Leader Medicine and Health Sciences, Information Services, University of Nottingham. Online Resource 2

Dr Kapil Sayal - Developmental Psychiatry, University of NottinghamOnline Resource 2: A table to summarize findings of studies not suitable for meta-analysis.

Paper details Main comparisons Main findings Significance (where stated) Ajibola and Clement Methylphenidate + non- Low-dose methylphenidate + non- 1995 contingent reinforcement contingent reinforcement no VS methylphenidate + significant effect on questions self-reinforcement VS completed compared to placebo + Ajibola, O and Clement, placebo + non-contingent non-contingent reinforcement. PW (1995) Differential reinforcement on seatwork p = 0.035 effects of completion and accuracy. High-dose methylphenidate + non- methylphenidate and contingent reinforcement self-reinforcement on significantly worsened questions attention-deficit completed compared to placebo + hyperactivity disorder. non-contingent reinforcement. p=0.001 Behavior Modification 19:2: 211-233. Low-dose methylphenidate + non- contingent reinforcement significantly worsened accuracy compared to baseline Ballinger et al. 1984 Low dose methylphenidate Methylphenidate had no significant and high-dose effect on speed or error rate in oral Ballinger, C., Varley, C., methylphenidate VS reading or for the measures of Nolen, P. (1984) Effects placebo on reading. comprehension accompanying the of methylphenidate on reading paragraph. reading in children with attention deficit disorder. No significant effect on Durrell American Journal of Analysis of Reading Difficulty. Psychiatry 141:12: 1590- 3.

Balthazor et al 1991. Methylphenidate VS Significant improvement in amount p < 0.001 placebo on reading reading comprehension attempted. Balthazor, MJ, Wagner comprehension. RK, and Pelham WE Significant improvement in amount p< 0.05 (1991) The specificity of reading comprehension attempted the effects of stimulant and accurate. medication on classroom learning-related measures of cognitive processing for attention- deficit disorder children. Journal of Abnormal Child Psychology 19:1: 35-52. Barkley et al. 1991 Methylphenidate low dose, Restricted Academic Situation (RAS) moderate dose and high (maths problems over 15 minutes): Barkley, RA, Dupaul, GJ dose VS placebo on - Number of off tasks over 15 and McMurray MB (1991) Restricted Academic minutes significantly Attention-deficit disorder Situation reduced by medication. with and without Significant increase in the hyperactivity - clinical - response to 3 dose levels accuracy of math problems of methylphenidate. completed during with Pediatrics 87:4: 519- moderate dose and high 531. dose methylphenidate. Online Resource 2

Biederman et al. 2007 Mixed amphetamine salts LDX significantly improved PERMP p< 0.0001 extended release VS attempted and correct compared to and p< Biederman, J et al (2007) lisdexamfetamine placebo. 0.0001 Lisdexamfetamine disemylate MAS significantly improved PERMP Dimesylate and Mixed (dexamfetamine) VS attempted and correct compared to p< 0.0001 Amphetamine Salts placebo on PERMP placebo. and Extended-Release in (questions attempted and p<0.0001 Children with ADHD: A correct). Double-Blind, Placebo- Controlled, Crossover Analog Classroom Study. Biological Psychiatry 62:9: 970-976 Brams et al. 2008 Dexmethylphenidate VS Dexmethylphenidate improvement Brams, M et al (2008) A placebo on maths test compared to placebo for: randomized, double- completion & accuracy. - Maths test correct (p=0.001 p<0.001 blind, crossover study of at 0.5 hours post dose and once-daily p<0.001 at all other dexmethylphenidate in timepoints); p<0.001 children with attention- - Maths test attempted deficit hyperactivity (p=0.003 at 0.5 hours post disorder: Rapid onset of dose and p<0.001 at all effect. CNS Drugs 22:8: other time points). 693-704. Brown et al. 2006 Atomoxetine VS placebo No significant main effects for the p = 0.143 on Academic Performance efficacy of atomoxetine relative to Brown, R.T., et al.(2006) Rating Scale. placebo on children’s completion of Atomoxetine in the work or level of academic management of children productivity. with ADHD: Effects on quality of life and school functioning. Clinical Pediatrics. 45:9:819-827 Douglas et al. 1986 Methylphenidate VS Arithmetic: children attempted placebo on arithmetic significantly more questions and Douglas, VI et al (1986) attempted, correct and solved more questions correctly Short-term effects of self-correction and on whilst medicated. Accuracy score methylphenidate on the spelling effort and number higher in drug condition with more cognitive, learning and correct. questions solved correctly per academic-performance minute spent on the task. of children with attention-deficit disorder Results from spelling task showed in the laboratory and the little evidence of drug effect. classroom. Journal of Child Psychology and Psychiatry and Allied Disciplines 27:2: 191- 211. Elia et al. 1993 Methylphenidate and Arithmetic attempted: dextroamphetamine VS - Significant improvement p<0.01 Elia, J et al (1993) placebo on reading and with d-AMPH compared to Classroom academic- arithmetic % attempted placebo p<0.01 performance - and % correct. - Significant improvement improvement with both p<0.05 with MPH compared to methlyphendiate and placebo dextroamphetamine in Subjects attempted ADHD boys. Journal of - Child Psychology and significantly more on d- Psychiatry and Allied AMPH than on MPH Online Resource 2

Disciplines 34:5: 785- 804. Gorman et al. 2006 Methylphenidate VS - Significant increase in p < 0.005 placebo on arithmetic children’s correct responses Gorman, EB et al (2006) performance. to arithmetic problems with Effects of methylphenidate compared methylphenidate on to placebo. subtypes of attention- - Unmedicated ADHD children deficit/hyperactivity significantly worse than disorder. Journal of the control children on American Academy of arithmetic tasks. Child and Adolescent - Medicated ADHD children Psychiatry 45:7: 808- did not differ in overall 816. performance on arithmetic tasks than control children. James et al. 2001 Adderall®, immediate- Overall medication superior to release placebo on p = 0.002 James, RS et al (2001) dextroamphetamine - Maths problems attempted p = 0.003 Double-blind, placebo- and dextroamphetamine - Maths problems correct controlled study of spansules VS placebo on p = 0.01 Individually: single-dose total responses and correct amphetamine responses to timed maths - Dextroamphetamine formulations in ADHD. task. improved maths problems p = 0.003 Journal of the American attempted compared to Academy of Child and placebo Adolescent Psychiatry - Dextroamphetamine 40:11: 1268-1276. spansules improved maths problems attempted compared to placebo. - Adderall® non-significant effect compared to placebo Klein 1991 Methylphenidate VS Methylphenidate significantly placebo on Wide Range improved Performance and Full Klein, R.G. (1991) Effects Achievement Test Scale IQ scores compared to of high methylphenidate (encompassing reading, placebo. doses on the cognitive arithmetic, spelling, oral p<0.05 performance of reading test) Methylphenidate significantly hyperactive children. improved arithmetic performance Bratislava Medical on WRAT. Journal 92:11: 534-539. No single instance of significantly worse performance for drug vs. placebo treated children was found.

McCracken et al. 2003 Adderall® (mixed Math problems attempted and p < 0.0001 amphetamine salts) and problems correct showed highly (for all McCracken, JT et al Adderall® extended significant effects of treatment measures) (2003) Analog classroom release VS placebo on (SLI381 10, 20, 30mg, Adderall® assessment of a once- PERMP (questions 10mg) versus placebo. daily mixed attempted and correct). amphetamine formulation, SLI381 (ADDERALL XR), in children with ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 42:6: 673-683. Online Resource 2

McGough et al. 2006 Methylphenidate Mean number of math problems < 0.0001 Transdermal System VS attempted significantly higher with McGough, JJ et al (2006) Placebo Transdermal MTS than PTS. A randomized, double- System on PERMP < 0.0001 blind, placebo-controlled, (questions attempted and Mean number of math problems laboratory classroom correct). correct significantly higher for with assessment of MTS than PTS. methylphenidate transdermal system in children with ADHD. J Atten Disord 9:3: 476-85. Pelham et al. 1985 Methylphenidate low dose, Methylphenidate enhanced in moderate dose and high- varying degrees the children’s Pelham, WE et al (1985) dose VS placebo on performance on reading, arithmetic, Methylphenidate and arithmetic, reading and spelling, as well as on measures children with attention comprehension, spelling deficit disorder - dose (all % attempted and % of classroom disruptiveness and on- effects on classroom correct) and on-task task behaviour. p<0.01 academic and social behaviour. - Arithmetic: significant behavior. Archives of effects of the linear p<0.0001 General Psychiatry components of dose (F[1,24] 42:10: 948-952. = 9.71 p < .01) and attempted-correct (F[1,24] = 36.8 p < .0001)” (both the number attempted and the number correct P<0.01 increased linearly as dose increased) - Reading: significant linear increase in proportion correct as a function of dose (F [1,24] = 8.55, p <0 .01) - On-task behaviour: significant effect of the linear component of dose with dose-related improvement in on-task behaviour with methylphenidate.

Pelham et al 1989 Methylphenidate Significant effect of drug on: (0.3mg/kg) VS placebo on - Timed reading attempted p<0.05 Pelham, W.E., et al on-task behaviour, - % Timed reading correct p<0.01 (1989) Comparative reading, seatwork Effects of completion and accuracy, Methylphenidate on ADD maths and spelling. Non-significant effect of drug on: Girls and ADD Boys. - % On task behaviour Journal of the American - % Seatwork completed Academy of Child & - Observed interactions Adolescent Psychiatry 28:5: 773-776. No effect of drug on: - Maths % completed or correct - Seatwork % correct - Spelling task

Rapport et al. 1985 Methylphenidate 5mg, - On-task behviour Online Resource 2

10mg and 15mg VS significantly enhanced by Rapport, MD et al (1985) placebo on % on-task methylphenidate 10- and p < 0 .05 Methylphenidate in behaviour, % seatwork 15-mg conditions compared hyperactive-children - assignments completed to placebo. differential effects of and % seatwork - On-task behaviour was also dose on academic, assignments correct. significantly increased by p< 0.05 learning and social 15-mg methylphenidate behavior. Journal of compared to 5-mg. Abnormal Child - Improvement in % academic Psychology 13:2: 227- assignments completed only p <0.05 243. significant for 15-mg methylphenidate. p <0 .05 - % academic assignments correct were significantly improved over placebo by all three drug levels.

Rapport et al. 1986 Methylphenidate Significant positive drug effect on: 5mg,10mg and 15mg VS - % on-task behaviour p<0.001 Rapport, M.D., et al placebo on % on-task p<0.05 - % assignments completed (1986) Comparing behaviour, % seatwork p<0.05 Classroom and Clinic assignments completed - % assignments correct Measures of Attention and % seatwork Academic accuracy was enhanced Deficit Disorder: assignments correct. as a function of increasing dose Differential, (linear). Idiosyncratic, and Dose- Assignments completed showed Response Effects of more gradual increase following the Methylphenidate. Journal 5-mg dose (quadratic). of Consulting and Clinical Psychology 54:3:334- 341. Rapport et al. 1987 Methylphenidate 5mg, Significant MPH effects found for: 10mg, 15mg and 20mg VS - On-task behaviour p<0.01 Rapport, M.D., et al placebo on on-task - Academic efficiency/AES, p<0.01 (1987) Attention Deficit behaviour and Academic Between-dose comparisons: Disorder and Efficiency Score. Methylphenidate: Group - On-task behaviour greater in and Single-Subject 10-, 15- and 20mg MPH p<0.01 Analyses of Dose Effects conditions than baseline, on Attention in Clinic and placebo and 5-mg Classroom Settings. - On-task also enhanced p<0.01 Journal of Clinical Child under 5-mg MPH compared Psychology 16:4:329- to both baseline and p<0.05 338. placebo and under 20-mg compared to 10mg. - Academic efficiency p<0.01 significantly enhanced in the 10-, 15- and 20mg trials relative to baseline, placebo p<0.01, and 5-mg conditions <0.05 - Academic efficiency significantly greater in 5-mg compared to both baseline and placebo .

Rapport et al. 1994 Methylphenidate 5mg, Significant main effect for drug p < 0.001 10mg, 15mg and 20mg VS condition (Wilks’ λ [5,71] = .185), Online Resource 2

Rapport, MD et al (1994) placebo, on % on-task indicating that scores on composite Attention-deficit disorder behaviour, % seatwork of the three classroom measures and methylphenidate - assignments completed changed as a function of dose. normalization rates, and % seatwork clinical effectiveness, assignments correct, p < 0.00001 and response prediction academic efficiency. Significant main effect of dose for: p < 0.00001 in 76 children. Journal of - On-task F[5,375] =78.12 the American Academy - Academic efficiency p < 0.00001 of Child and Adolescent F[5,375] = 43.46 Psychiatry 33:6: 882- - Seatwork %-complete p < 0.00001 893. (F[5,375] = 34.59) - Seatwork %-correct (F[5,375] =14.66,

Richardson et al. 1998 Methylphenidate low dose, Only significant effects were drug moderate dose and high- improved reading grade level over Richardson, E., et al dose VS placebo on tests first 14 weeks of study, and drug (1988) Effects of of reading achievement improved PIAT reading recognition. Methylphenidate Dosage and Peabody Individual in Hyperactive Reading- Achievement Test (subsets No other significant effects of drug disabled Children: II. including Reading on relevant measures. Reading Achievement. Recognition, Journal of the American Comprehension and Math) Academy of Child & Adolescent Psychiatry 27:1:78-87. Silva et al. 2005 Methylphenidate extended Significantly more maths problems p < 0.001 release VS were correct with all active Silva, R., et al (2005) methylphenidate standard treatments than placebo from hours Efficacy of two long- release VS placebo on 1 through 8. acting methylphenidate maths problems attempted p < 0.001 formulations in children and correct. Significantly more maths problems with attention- were attempted with all active deficit/hyperactivity treatments than with placebo from disorder in a laboratory hours 1 through 8 classroom setting. Journal of Child and Adolescent Psychopharmacology 15:4: 637-654. Silva et al. 2006 Methylphenidate extended Significant improvements, largest release VS placebo on effect size at 12 hours in: Silva, RR et al (2006) PERMP (questions - PERMP maths questions p < 0.001 Efficacy and duration of attempted and correct). p < 0.001 attempted effect of extended- PERMP maths questions release - dexmethylphenidate correct versus placebo in schoolchildren with attention- deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology 16:3: 239-251. Swanson et al. 1998 Adderall® (mixed Adderall® produced dose-related amphetamine salts) 5mg, improvement in PERMP attempted p < 0.001 Swanson, JM et al (1998) 10mg, 15mg and 20mg VS and PERMP correct; p < 0.001 Online Resource 2

Analog classroom placebo and VS active Methylphenidate improved number assessment control (methylphenidate). of PERMP questions attempted. of Adderall in children with Earlier peak effects for ADHD. Journal of the methylphenidate than Adderall®; American shorter duration of action for Academy of Child and methylphenidate than Adderall®. Adolescent Psychiatry 37:5: 519-526. Swanson et al. 2004 Concerta (MPH extended Overall significant improvement in p < 0.0001 release) VS Metadate (MPH PERMP scores with medication: F[2, Swanson, J.M., et al extended release) VS 260] = 21.84] (2004) A comparison of Placebo on PERMP p < 0.0001 once-daily extended- (questions attempted and release methylphenidate correct). Effect of session x medication also formulations in children significant for all measures: with attention- - Immediately post dose, deficit/hyperactivity placebo superior to either disorder in the active treatment. laboratory school (The - AM session, MCD superior to Comacs Study). CON, both superior to Pediatrics 113:3:Part 1: placebo Supplement: e206-16. - PM session MCD = CON, both still superior to placebo; - Early evening CON but not MCD superior to PLA in some measures. Wietecha et al. 2009 Methylphenidate fast Methylphenidate produced: titration VS slow titration - Significant improvements in p < 0.001 Wietecha, L.A., et al VS baseline on reading, reading and written (both (2009) Atomoxetine written language, maths language scores compared measures) Treatment in and academic grades. to baseline Adolescents with - Numerical but not p = 0.289 – Attention- 0.870 statistically significant Deficit/Hyperactivity across improvement in academic Disorder. Journal of Child subject grades. and Adolescent areas No significant improvements Psychopharmacology - 19:6. in maths scores. p = 0.569

WIgal et al. 2009 Lisdexamfetamine Lisdexamfetamine produced: dimesylate VS placebo on - Increase in PERMP P<0.0001 Wigal, SB et al (2009) A PERMP (questions attempted P<0.0001 13-hour laboratory attempted and correct). - Increase in PERMP correct school study of at all timepoints from 1.5 hours to lisdexamfetamine dimesylate in school- 13 hours post-dose. aged children with attention- deficit/hyperactivity disorder. Child and Adolescent Psychiatry and Mental Health 3:17 Worrall 1993 Methylphenidate VS Methylphenidate improved: placebo on language and - Language – effort p<0.01 Worrall, A.(1993) maths attempted and p<0.01 Online Resource 2

Evaluating the effects of correct. - Language - % attempted p<0.05 methylphenidate on the - Language - % correct p<0.01 cognitive, behavioural - Maths – effort p<0.01 and academic p<0.01 performance of A.D.D. - Maths - % attempted children in the - Maths - % correct classroom. Southern compared to placebo. African Journal of Child and Adolescent Mental Health 5:2: 96-101. Vyse and Rapport Methylphenidate 5mg, Methylphenidate significantly 1989 10mg, 15mg and 20mg VS improved: p < 0.001 placebo on on-task - On-task F(4,100) = 22.64 p < 0.01 Vyse, SA and Rapport behaviour and academic AES F(4,100) = 17.80 MD (1989) The effects of work % completed and % - methylphenidate on correct and academic - Mean percentages in all four learning in children with efficiency score (AES). active medication conditions ADDH: The stimulus were significantly higher equivalence paradigm. than those in the placebo Journal of Consulting and condition for both on-task p <0 .01 Clinical Psychology 57:3: behavior (p < 0.01) and AES 425-435. (p <0 .01)” - Increased seat-work p <0 .05 completion with20mg MPH compared to 5mg. - Increased percentage seatwork correct with 10mg and 20mg MPH compared to 5mg.