Treatment discontinuation with methylphenidate in adults with attention deficit hyperactivity disorder: a meta-analysis of randomized clinical trials
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Attention deficit hyperactivity disorder (ADHD) in adulthood is increasingly diagnosed and treated. Methylphenidate is frequently advocated as a first-line pharmacological treatment.
The aim of our study was to compare all-cause discontinuation rate of methylphenidate and its pharmaceutical presentations with placebo in adults with ADHD.
This was a systematic review and meta-analysis of randomized controlled trials comparing methylphenidate with placebo in adults with ADHD. All-cause treatment discontinuation was the primary endpoint. The efficacy in reducing ADHD symptoms and safety were the secondary endpoints.
Twelve studies (2,496 patients) met the inclusion criteria. Four racemic methylphenidate and one dexmethylphenidate presentations were investigated. The rate of all-cause treatment discontinuation was greater with methylphenidate than with placebo, but this difference was not statistically significant [odds ratio (OR) 1.19, 95 % confidence interval (95 % CI) 0.82–1.74, P = 0.37, I2 = 64 %] This finding reached the conventional threshold of statistical significance after one outlier study was excluded (OR 1.44, 95 % CI 1.14–1.82, P = 0.002, I2 = 0). Methylphenidate was more efficacious than placebo for reducing ADHD symptoms and it was associated with a higher proportion of patients dropping out due to adverse effects.
Despite reducing ADHD symptoms, methylphenidate showed no advantage over placebo in terms of treatment discontinuation. More attention should be given in the future to the endpoint “all-cause treatment discontinuation” when making regulatory decisions and developing clinical guidelines involving the treatment of ADHD in adulthood.
KeywordsAttention deficit hyperactivity disorder Adulthood Methylphenidate All-cause treatment discontinuation Meta-analysis
- 15.Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA) (2011) Canadian ADHD practice guidelines, 3rd edn. CADDRA, TorontoGoogle Scholar
- 17.National Institute for Health and Clinical Excellence (NICE) (2008) Attention deficit hyperactivity disorder. Diagnosis and management of ADHD in children, young people and adults. Clinical guidelines CG72, September 2008. NICE, LondonGoogle Scholar
- 18.Nutt DJ, Fone K, Asherson P, Bramble D, Hill P, Matthews K, Morris KA, Santosh P, Sonuga-Barke E, Taylor E, Weiss M, Young S, British Association for Psychopharmacology (2007) Evidence-based guidelines for management of attention-deficit/hyperactivity disorder in adolescents in transition to adult services and in adults: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 21:10–41PubMedCrossRefGoogle Scholar
- 21.Treceño C, Martín Arias LH, Sáinz M, Salado I, García Ortega P, Velasco V, Jimeno N, Escudero A, Velasco A, Carvajal A (2012) Trends in the consumption of attention deficit hyperactivity disorder medications in Castilla y León (Spain): changes in the consumption pattern following the introduction of extended release methylphenidate. Pharmacoepidemiol Drug Saf. 21(4):435–41Google Scholar
- 24.Graham J, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Dittmann RW, Döpfner M, Hamilton R, Hollis C, Holtmann M, Hulpke-Wette M, Lecendreux M, Rosenthal E, Rothenberger A, Santosh P, Sergeant J, Simonoff E, Sonuga-Barke E, Wong IC, Zuddas A, Steinhausen HC, Taylor E, European Guidelines Group (2011) European guidelines on managing adverse effects of medication for ADHD. Eur Child Adolesc Psychiatry 20:17–37PubMedCrossRefGoogle Scholar
- 28.Egger M, Dickersin K, Davey Smith D (2007) Problems and limitations in conducting systematic reviews. In: Egger M, Davey Smith D, Altman DG (eds) Systematic reviews in healthcare. Meta-analysis in context. BMJ Publishing Group, London, pp 43–68Google Scholar
- 30.McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ (2006) Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry 163:1531–1541PubMedCrossRefGoogle Scholar
- 33.Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223PubMedCrossRefGoogle Scholar
- 34.Banaschewski T, Coghill D, Santosh P, Zuddas A, Asherson P, Buitelaar J, Danckaerts M, Döpfner M, Faraone SV, Rothenberger A, Sergeant J, Steinhausen HC, Sonuga-Barke EJ, Taylor E (2006) Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline. Eur Child Adolesc Psychiatry 15:476–495PubMedCrossRefGoogle Scholar
- 35.European Medicine Agency (EMA): Guideline on the clinical investigation of medicinal products for the treatment of attention deficit hyperactivity disorder (ADHD). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/08/WC500095686.pdf. Accessed 2 Nov 2011
- 37.Higgins JPT, Green S (2011) Strategies for addressing heterogeneity. Cochrane Handbook for Systematic Reviews of interventions Version 5.1.0. (updated March 2011). The Cochrane Collaboration Available from www.cochrane-handbook.org
- 39.The Nordic Cochrane Centre (2011) Review Manager (RevMan), ver. 5.1 (computer program). The Nordic Cochrane Centre, The Cochrane Collaboration, CopenhagenGoogle Scholar
- 40.StataCorp LP (2007) STATA ver. 10 (computer program). STataCorp LP, College Station, TXGoogle Scholar
- 41.Adler LA, Zimmerman B, Starr HL, Silber S, Palumbo J, Orman C, Spencer T (2009) Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose escalation study. J Clin Psychopharmacol 29:239–247PubMedCrossRefGoogle Scholar
- 42.Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Harpold T, Dunkel S, Dougherty M, Aleardi M, Spencer T (2006) A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 59:829–835, Erratum in: Biol Psychiatry 2007; 61:1402PubMedCrossRefGoogle Scholar
- 43.Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Kotarski M, Spencer T (2010) A randomized, 3-phase, 34-week, double-blind, long-term efficacy study of osmotic-release oral system-methylphenidate in adults with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol 30:549–553PubMedCrossRefGoogle Scholar
- 44.Casas M, Rösler M, Sandra Kooij JJ, Ginsberg Y, Ramos-Quiroga JA, Heger S, Berwaerts J, Dejonckheere J, van der Vorst E, Schäuble B (2011) Efficacy and safety of prolonged-release OROS methylphenidate in adults with attention deficit/hyperactivity disorder: A 13-week, randomized, double-blind, placebo-controlled, fixed-dose study. World J Biol Psychiatry. doi:10.3109/15622975.2011.600333
- 46.Medori R, Ramos-Quiroga JA, Casas M, Kooij JJ, Niemelä A, Trott GE, Lee E, Buitelaar JK (2008) A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatr 63:981–989CrossRefGoogle Scholar
- 47.Reimherr FW, Williams ED, Strong RE, Mestas R, Soni P, Marchant BK (2007) A double-blind, placebo-controlled, crossover study of osmotic release oral system methylphenidate in adults with ADHD with assessment of oppositional and emotional dimensions of the disorder. J Clin Psychiatry 68:93–101PubMedCrossRefGoogle Scholar
- 51.Spencer T, Biederman J, Wilens T, Doyle R, Surman C, Prince J, Mick E, Aleardi M, Herzig K, Faraone S (2005) A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 57:456–463PubMedCrossRefGoogle Scholar
- 53.Schubiner H, Saules KK, Arfken CL, Johanson CE, Schuster CR, Lockhart N, Edwards A, Donlin J, Pihlgren E (2002) Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol 10:286–294PubMedCrossRefGoogle Scholar
- 54.Winhusen TM, Somoza EC, Brigham GS, Liu DS, Green CA, Covey LS, Croghan IT, Adler LA, Weiss RD, Leimberger JD, Lewis DF, Dorer EM (2010) Impact of attention-deficit/hyperactivity disorder (ADHD) treatment on smoking cessation intervention in ADHD smokers: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 71:1680–1688PubMedCrossRefGoogle Scholar
- 56.Wilens TE, Biederman J, Lerner M, Concerta Study Group (2004) Effects of once-daily osmotic-release methylphenidate on blood pressure and heart rate in children with attention-deficit/hyperactivity disorder: results from a one-year follow-up study. J Clin Psychopharmacol 24:36–41PubMedCrossRefGoogle Scholar