Export

The Expert Committee, after evaluation, declines to list the medicine proposed in the application.
The Model List of Essential Medicines reports reasons that Committee Members have identified for denying listing.
Rejected
Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected Rejected
ATC codes: N06BA04
EMLc
Indication
Attention deficit hyperactivity disorder ICD11 code: 6A05
INN
Methylphenidate
Medicine type
Chemical agent
List type
Core
Formulations
Oral > Solid: 10 mg immediate-release ; 20 mg immediate-release
EML status history
Application rejected in 2019 (TRS 1021)
Sex
All
Age
Also recommended for children
Therapeutic alternatives
The recommendation is for this specific medicine
Patent information
Patents have expired in most jurisdictions
Expert Committee recommendation
The Committee did not recommend the addition of methylphenidate to the complementary list of the EML and EMLc for the treatment of attention-deficit hyperactivity disorder (ADHD) due to concerns regarding the quality and interpretation of the evidence for benefits and harms.
Background
The application requested the inclusion of methylphenidate on the complementary list of the EML and EMLc for the treatment of attention-deficit hyperactivity disorder (ADHD). Methylphenidate had not previously been considered for inclusion on the Model List.
Public health relevance
The mental disorders that methylphenidate is approved to treat have a high global disease burden. In 2010, mental neurological and substance use disorders accounted for 10.4% of global disability-adjusted life years (DALYs) and 28.5% of years of life lost due to disability, illness, or premature death (YLDs), making them the leading cause of YLDs (1). The Global Burden of Disease Study 2010 (GBD 2010) is the first to include conduct disorder (CD) and attention-deficit hyperactivity disorder (ADHD) for burden quantification (2). Globally, CD was responsible for 5.75 million YLDs/DALYs with ADHD responsible for a further 491 500 (3). Collectively, CD and ADHD accounted for 0.80% of total global YLDs and 0.25% of total global DALYs (3). The prevalence of ADHD is a controversial issue with varying estimates across populations, using different diagnostic criteria and reporting. A 2015 systematic review and meta-analysis of 175 studies reporting point prevalence estimates of ADHD estimated the pooled prevalence to be 7.2% (95%CI 6.7% to 7.8%) (4). A 2007 systematic review and meta-regression analysis of 102 studies (171 756 subjects) investigating the prevalence rates of ADHD/HD worldwide found large variability of ADHD/HD prevalence rates worldwide resulting mainly from methodological differences across studies. When adjusted for methodological differences, prevalence rate variability was only detected between studies conducted in North America and those conducted in Africa and the Middle East (5).
Benefits
A literature review undertaken by the applicants included 28 studies and review articles as evidence for the comparative effectiveness of methylphenidate for the treatment of ADHD versus placebo or other stimulants (6–15), versus secondline non-stimulant therapies (16–25), and in patients with ADHD comorbid with other conditions (26–31) in children, adolescents and adults. The large majority of the trials and reviews were conducted in children and adolescents and were of short duration (three months). Summaries of the findings of the included trials were presented. Based on this review, the applicants concluded that in the treatment of ADHD, methylphenidate has shown similar efficacy to amphetamine-based drugs with varying results on different psychometric scales. Some individual studies have demonstrated superiority of methylphenidate over amphetaminebased medicines, some have found superiority of amphetamine-based medicines over methylphenidate, and others have shown no difference between the two treatments. Given the currently available evidence, it has not been demonstrated that one stimulant is more efficacious than any other at a population level. In the comparison of methylphenidate with non-stimulant medications for treatment of ADHD, non-stimulant medications appear to have a lower efficacy though some studies show equivalent efficacy with atomoxetine. The application stated that methylphenidate is effective in reducing fatigue in palliative care patients when compared to placebo and that there is also evidence of methylphenidate being effective in reducing symptoms in patients with ADHD comorbid with oppositional defiant disorder and aggression. No assessment was made in the application regarding the quality of the evidence or confidence in the estimates of benefit.
Harms
A literature review undertaken by the applicants included 29 studies and review articles as evidence for the comparative safety of methylphenidate for the treatment of ADHD versus placebo (6, 32–34), versus other stimulants and nonstimulants (9, 11, 12, 14, 16–19, 21, 35–38), and in patients with ADHD comorbid with other conditions (26, 27, 30, 39–43). The large majority of the trials and reviews were conducted in children and adolescents and were of short duration. Summaries of the findings of the included trials were presented. Based on this review, the applicants concluded that there is considerable overlap in the adverse event profiles of methylphenidate- and amphetaminebased ADHD medications. Both have been associated with insomnia and appetite suppression as the most common adverse events. Overall, studies suggest that the frequency and severity of adverse events may be somewhat greater with amphetamine-based products. In comparison to other non-stimulant medications, methylphenidate was associated with less sleeping problems and higher tolerability. No assessment was made in the application regarding the quality of the evidence or confidence in the estimates of harm. As methylphenidate is a controlled Schedule II substance under the 1971 Convention on Psychotropic Substances, the application addressed the issue of potential misuse. Methylphenidate-specific misuse data generally mimic results of studies looking at stimulant medication misuse in general. While there are limited data on malingering specifically for methylphenidate, studies of malingering for stimulants in general are likely generally applicable (44). Overall, the misuse of methylphenidate raises legitimate safety concerns for overdose and drug interactions with other medications or nonmedical use drugs, particularly since illicit users are generally unaware of these issues and often use methylphenidate with other recreational drugs. However, studies suggest that amphetamine-based drugs are being used more often than methylphenidate for non-medical use, particularly in immediate-release formulations (45–48).
Additional evidence
A 2014 Cochrane systematic review of immediate-release methylphenidate for treatment of adults with ADHD was withdrawn in 2016 following failure by the authors to satisfactorily address a number of criticisms of the methodology used and conclusions drawn (49, 50). A commentary on the withdrawn review summarized the criticisms, which primarily focussed on the methodological flaws and “misleading conclusions that gave a false sense of certainty of the benefits and the absence of harms, when this in fact could not be concluded” (51).
Cost / cost effectiveness
The median buyer price of immediate release methylphenidate 10 mg, according to the International Medical Products Price Guide is US$ 0.067 per tablet/ capsule (53). A literature review undertaken by the applicants included 11 articles as evidence for the comparative cost-effectiveness of methylphenidate (54–65). Summaries of economic evaluations of methylphenidate for ADHD were presented, and the application concluded that the identified literature favoured methylphenidate as cost-effective or cost-neutral relative to stimulant and non-stimulant treatments. The Committee considered that while methylphenidate appeared to be low cost and affordable, no conclusions could be drawn regarding the cost-effectiveness of the medicine given the considerable uncertainty in the estimates of benefit and harms.
WHO guidelines
The 2016 WHO mhGAP intervention guide for mental, neurological and substance use disorders in non-specialized health settings (version 2.0) includes a recommendation to refer children (aged 6 years and above with a diagnosis of ADHD in whom other treatment approaches have failed) to a specialist for methylphenidate treatment (52).
Availability
Methylphenidate immediate release tablets are available internationally in innovator and generic brands.
Other considerations
Public comments on the application were received from Professor Ole Jakob Storebø and Dr Christian Gluud, authors of a 2015 Cochrane systematic review of methylphenidate use in children and adolescents (6) included in the application. They expressed concern in relation to limitations in the reporting and summary of the evidence in the application, with particular regard to the quality of the evidence, duration of trials, misplacement of evidence, and suspected selective biases. They stated that their assessment of the evidence supporting methylphenidate for ADHD (and other disorders) was more critical than that of the applicants, noting that the high risk of bias in the randomized trials likely overestimates positive intervention effects and underestimates risk of harms.
1. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382(9904):1575–86. 2. Erskine HE, Ferrari AJ, Nelson P, Polanczyk GV, Flaxman AD, Vos T et al. Epidemiological modelling of attention-deficit/hyperactivity disorder and conduct disorder for the Global Burden of Disease Study 2010. J Child Psychol Psychiatry. 2013;54(12):1263–74. 3. Erskine HE, Ferrari AJ, Polanczyk GV, Moffitt TE, Murray CJ, Vos T et al. The global burden of conduct disorder and attention-deficit/hyperactivity disorder in 2010. J Child Psychol Psychiatry. 2014;55(4):328–36. 4. Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics. 2015;135(4):e994–1001. 5. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164(6):942–8. 6. Storebo OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev. 2015(11):CD009885. 7. Bental B, Tirosh E. The effects of methylphenidate on word decoding accuracy in boys with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2008;28(1):89–92. 8. Flintoff MM, Barron RW, Swanson JM, Ledlow A, Kinsbourne M. Methylphenidate increases selectivity of visual scanning in children referred for hyperactivity. J Abnorm Child Psychol. 1982;10(2):145–61. 9. Arnold LE, Christopher J, Huestis R, Smeltzer DJ. Methylphenidate vs dextroamphetamine vs caffeine in minimal brain dysfunction: controlled comparison by placebo washout design with Bayes' analysis. Arch Gen Psychiatry. 1978;35(4):463–73. 10. Weiss G, Minde K, Douglas V, Werry J, Sykes D. Comparison of the effects of chlorpromazine, dextroamphetamine and methylphenidate on the behaviour and intellectual functioning of hyperactive children. Can Med Assoc J. 1971;104(1):20–5. 11. Luan R, Mu Z, Yue F, He S. Efficacy and Tolerability of Different Interventions in Children and Adolescents with Attention Deficit Hyperactivity Disorder. Front Psychiatry. 2017;8:229. 12. Li Y, Gao J, He S, Zhang Y, Wang Q. An Evaluation on the Efficacy and Safety of Treatments for Attention Deficit Hyperactivity Disorder in Children and Adolescents: a Comparison of Multiple Treatments. Mol Neurobiology. 2017;54(9):6655–69. 13. Hanwella R, Senanayake M, de Silva V. Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis. BMC Psychiatry. 2011;11:176. 14. Wang Y, Zheng Y, Du Y, Song DH, Shin YJ, Cho SC et al. Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Aust N Z J Psychiatry. 2007;41(3):222–30. 15. Pelham WE, Gnagy EM, Chronis AM, Burrows-MacLean L, Fabiano GA, Onyango AN et al. A comparison of morning-only and morning/late afternoon Adderall to morning-only, twice-daily, and three times-daily methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics. 1999;104(6):1300–11. 16. Padilha S, Virtuoso S, Tonin FS, Borba HHL, Pontarolo R. Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis. Eur Child Adolesc Psychiatry. 2018;27(10):1335–45. 17. Davari-Ashtiani R, Shahrbabaki ME, Razjouyan K, Amini H, Mazhabdar H. Buspirone versus methylphenidate in the treatment of attention deficit hyperactivity disorder: a double-blind and randomized trial. Child Psychiatry Hum Dev. 2010;41(6):641–8. 18. Salehi B, Imani R, Mohammadi MR, Fallah J, Mohammadi M, Ghanizadeh A et al. Ginkgo biloba for attention-deficit/hyperactivity disorder in children and adolescents: a double blind, randomized controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(1):76–80. 19. Arabgol F, Panaghi L, Hebrani P. Reboxetine versus methylphenidate in treatment of children and adolescents with attention deficit-hyperactivity disorder. Eur Child Adolesc Psychiatry. 2009;18(1):53–9. 20. Mohammadi MR, Ghanizadeh A, Alaghband-Rad J, Tehranidoost M, Mesgarpour B, Soori H. Selegiline in comparison with methylphenidate in attention deficit hyperactivity disorder children and adolescents in a double-blind, randomized clinical trial. J Child Adolesc Psychopharmacol. 2004;14(3):418–25. 21. Buitelaar JK, van der Gaag RJ, Swaab-Barneveld H, Kuiper M. Pindolol and methylphenidate in children with attention-deficit hyperactivity disorder. Clinical efficacy and side-effects. J Child Psychol Psychiatry. 1996;37(5):587–95. 22. Conners CK, Taylor E. Pemoline, methylphenidate, and placebo in children with minimal brain dysfunction. Arch Gen Psychiatry. 1980;37(8):922–30. 23. Rapoport JL, Quinn PO, Bradbard G, Riddle KD, Brooks E. Imipramine and methylphenidate treatments of hyperactive boys. A double-blind comparison. Arch Gen Psychiatry. 1974;30(6): 789–93. 24. Peterson K, McDonagh MS, Fu R. Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis. Psychopharmacol. 2008;197(1):1–11. 25. Barnes JJ, O’Connell RG, Nandam LS, Dean AJ, Bellgrove MA. Monoaminergic modulation of behavioural and electrophysiological indices of error processing. Psychopharmacol. 2014;231(2):379–92. 26. Osland ST, Steeves TD, Pringsheim T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev.. 2018;6:CD007990. 27. Correia Filho AG, Bodanese R, Silva TL, Alvares JP, Aman M, Rohde LA. Comparison of risperidone and methylphenidate for reducing ADHD symptoms in children and adolescents with moderate mental retardation. J Am Acad Child Adolesc Psychiatry. 2005;44(8):748–55. 28. Sturman N, Deckx L, van Driel ML. Methylphenidate for children and adolescents with autism spectrum disorder. Cochrane Database Syst Rev.. 2017;11:CD011144. 29. Golubchik P, Weizman A. The effect of methylphenidate treatment on suspiciousness in children with ADHD alone or comorbid with ODD. Int J Psychiatry Clin Pract. 2018;22(2):109–14. 30. Masi G, Manfredi A, Nieri G, Muratori P, Pfanner C, Milone A. A Naturalistic Comparison of Methylphenidate and Risperidone Monotherapy in Drug-Naive Youth With Attention-Deficit/ Hyperactivity Disorder Comorbid With Oppositional Defiant Disorder and Aggression. J Clin Psychopharmacol. 2017;37(5):590–4. 31. Ruthirakuhan MT, Herrmann N, Abraham EH, Chan S, Lanctot KL. Pharmacological interventions for apathy in Alzheimer's disease. Cochrane Database Syst Rev.. 2018;5:CD012197. 32. Storebo OJ, Pedersen N, Ramstad E, Kielsholm ML, Nielsen SS, Krogh HB et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies. Cochrane Database Syst Rev. 2018;5:CD012069. 33. Pottegard A, Hallas J, Andersen JT, Lokkegaard EC, Dideriksen D, Aagaard L et al. First-trimester exposure to methylphenidate: a population-based cohort study. J Clin Psychiatry. 2014;75(1): e88–93. 34. Sobanski E, Schredl M, Kettler N, Alm B. Sleep in adults with attention deficit hyperactivity disorder (ADHD) before and during treatment with methylphenidate: a controlled polysomnographic study. Sleep. 2008;31(3):375–81. 35. Joseph A, Ayyagari R, Xie M, Cai S, Xie J, Huss M et al. Comparative efficacy and safety of attentiondeficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison. Eur Child Adolesc Psychiatry. 2017;26(8):875–97. 36. Hennissen L, Bakker MJ, Banaschewski T, Carucci S, Coghill D, Danckaerts M et al. Cardiovascular Effects of Stimulant and Non-Stimulant Medication for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis of Trials of Methylphenidate, Amphetamines and Atomoxetine. CNS drugs. 2017;31(3):199–215. 37. Safer DJ. Relative cardiovascular safety of psychostimulants used to treat attention-deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 1992;2(4):279–90. 38. Liang EF, Lim SZ, Tam WW, Ho CS, Zhang MW, McIntyre RS et al. The Effect of Methylphenidate and Atomoxetine on Heart Rate and Systolic Blood Pressure in Young People and Adults with Attention-Deficit Hyperactivity Disorder (ADHD): Systematic Review, Meta-Analysis, and MetaRegression. Int J Environ Res Public Health. 2018;15(8). 39. Jasper BW, Conklin HM, Lawford J, Morris EB, Howard SC, Wu S et al. Growth effects of methylphenidate among childhood cancer survivors: a 12-month case-matched open-label study. Pediatr Blood Cancer. 2009;52(1):39–43. 40. Wang LJ, Shyu YC, Yuan SS, Yang CJ, Yang KC, Lee TL et al. Attention-deficit hyperactivity disorder, its pharmacotherapy, and the risk of developing bipolar disorder: A nationwide populationbased study in Taiwan. J Psychiatr Res. 2016;72:6–14. 41. Mannuzza S, Klein RG, Truong NL, Moulton JL, 3rd, Roizen ER, Howell KH et al. Age of methylphenidate treatment initiation in children with ADHD and later substance abuse: prospective follow-up into adulthood. Am J Psychiatry. 2008;165(5):604–9. 42. Steinhausen HC, Bisgaard C. Substance use disorders in association with attention-deficit/ hyperactivity disorder, co-morbid mental disorders, and medication in a nationwide sample. Eur Neuropsychopharmacol. 2014;24(2):232–41. 43. Bushe CJ, Savill NC. Suicide related events and attention deficit hyperactivity disorder treatments in children and adolescents: a meta-analysis of atomoxetine and methylphenidate comparator clinical trials. Child Adolesc Psychiatry Ment Health. 2013;7:19. 44. Clemow DB. Misuse of Methylphenidate. In: Nielsen S, Bruno R, Schenk S, editors. Non-medical and illicit use of psychoactive drugs Current Topics in Behavioral Neurosciences. 34. Cham: Springer; 2015. 45. Mao AR, Babcock T, Brams M. ADHD in adults: current treatment trends with consideration of abuse potential of medications. J Psychiatr Pract. 2011;17(4):241–50. 46. Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ. Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration. Pharmacotherapy. 2006;26(10):1501–10. 47. Harstad E, Levy S. Attention-deficit/hyperactivity disorder and substance abuse. Pediatrics. 2014;134(1):e293–301. 48. Berman SM, Kuczenski R, McCracken JT, London ED. Potential adverse effects of amphetamine treatment on brain and behavior: a review. Mol Psychiatry. 2009;14(2):123–42. 49. Epstein T, Patsopoulos NA, Weiser M. Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev. 2014(9):CD005041. 50. Epstein T, Patsopoulos NA, Weiser M. WITHDRAWN: Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev. 2016(5):CD005041. 51. Boesen K, Saiz LC, Erviti J, Storebo OJ, Gluud C, Gotzsche PC et al. The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder. Evid Based Med. 2017;22(4):143–7. 52. mhGAP intervention guide for mental, neurological and substance use disorders in non-specialized health settings (Version 2.0). Geneva: World Health Organization; 2016. Available from https:// apps.who.int/iris/bitstream/handle/10665/250239/9789241549790-eng.pdf?sequence=1, accessed 29 September 2019. 53. International Medical Products Price Guide. Arlington: Management Sciences for Health; 2015. Available from http://mshpriceguide.org/en/single-drug-information/?DMFId=928&searchYe ar=2015, accessed 29 September 2019. 54. Maia CR, Stella SF, Wagner F, Pianca TG, Krieger FV, Cruz LN et al. Cost-utility analysis of methylphenidate treatment for children and adolescents with ADHD in Brazil. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 2016;38(1):30–8. 55. Catala-Lopez F, Ridao M, Sanfelix-Gimeno G, Peiro S. Cost-effectiveness of pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: qualitative synthesis of scientific evidence. Revista de psiquiatria y salud mental. 2013;6(4):168–77. 56. Wu EQ, Hodgkins P, Ben-Hamadi R, Setyawan J, Xie J, Sikirica V et al. Cost effectiveness of pharmacotherapies for attention-deficit hyperactivity disorder: a systematic literature review. CNS drugs. 2012;26(7):581–600. 57. Miller A, Lee S, Raina P, Klassen A, Zupancic J, Olsen L. A review of therapies for attentiondeficit/hyperactivity disorder. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1998. Available from https://www.cadth.ca/review-therapies-attentiondeficithyperactivity-disorder-0, accessed 29 September 2019. 58. Marchetti A, Magar R, Lau H, Murphy EL, Jensen PS, Conners CK et al. Pharmacotherapies for attention-deficit/hyperactivity disorder: expected-cost analysis. Clinical Ther. 2001;23(11): 1904–21. 59. Cottrell S, Tilden D, Robinson P, Bae J, Arellano J, Edgell E et al. A modeled economic evaluation comparing atomoxetine with stimulant therapy in the treatment of children with attentiondeficit/hyperactivity disorder in the United Kingdom. Value Health. 2008;11(3):376–88. 60. King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G et al. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents. Health Technol Assess. 2006;10(23):iii-iv, xiii–146. 61. Jensen PS, Garcia JA, Glied S, Crowe M, Foster M, Schlander M et al. Cost-effectiveness of ADHD treatments: findings from the multimodal treatment study of children with ADHD. Am J Psychiatry. 2005;162(9):1628-36. 62. Matza LS, Paramore C, Prasad M. A review of the economic burden of ADHD. Cost Eff Resour Alloc. 2005;3:5. 63. Narayan S, Hay J. Cost effectiveness of methylphenidate versus AMP/DEX mixed salts for the first-line treatment of ADHD. Expert Rev Pharmacoecon Outcomes Res. 2004;4(6):625–34. 64. Donnelly M, Haby MM, Carter R, Andrews G, Vos T. Cost-effectiveness of dexamphetamine and methylphenidate for the treatment of childhood attention deficit hyperactivity disorder. Aust N Z J Psychiatry. 2004;38(8):592–601. 65. Gilmore A, Milne R. Methylphenidate in children with hyperactivity: review and cost-utility analysis. Pharmacoepidemiology Drug Saf. 2001;10(2):85–94.