Background: The efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder (ADHD) shows wide between-study variability, which yields heterogeneous results in meta-analysis. The reasons for this variability have not been comprehensively investigated.
Objectives: To determine the influence of treatment-related covariates of methylphenidate for adults with ADHD by means of meta-analysis. Clinical and methodological moderators and clinical trial reporting quality were also collected to control for their potential confounding effect.
Methods: We searched for randomized, placebo-controlled clinical trials investigating the efficacy of methylphenidate for adults with ADHD. The study outcome was the efficacy of methylphenidate for reducing ADHD symptom severity. Treatment-related covariates included dose, type of drug-release formulation (formulations with a continuous drug release vs those with a non-continuous drug release), dose regimen (fixed vs flexible) and treatment length. Clinical (presence of co-morbid substance use disorders [SUD]) and methodological (design and rater) covariates were also collected, in addition to clinical trial reporting quality. The standardized mean difference (SMD) was calculated for each study. The analysis of the influence of methylphenidate effect modifiers was performed by means of random-effects meta-regression.
Results: Eighteen studies were included. Dose, type of formulation and SUD appeared to modify the efficacy of methylphenidate in the bivariate analysis. These variables were included in a multivariate meta-regression, which showed that methylphenidate, at an average dose of 57.4 mg/day, delivered by means of non-continuous-release formulations, had a moderate effect on ADHD symptoms compared with placebo (SMD 0.57–0.58). A dose-response relationship was found, indicating that efficacy could be increased by SMD 0.11–0.12 for every 10 mg increment of methylphenidate. Continuous-release formulations and co-morbid SUD appeared to reduce the efficacy of methylphenidate. Nevertheless, the effect of treatment formulation may have been confounded by co-morbid SUD, since all studies using this continuous-release formulation were conducted in dual ADHD-SUD patients. No residual heterogeneity was found.
Conclusions: This study shows that methylphenidate improves ADHD symptoms in adults in a dose-dependent fashion. The efficacy of methylphenidate appears to be reduced in patients with co-morbid SUD. It is unclear whether methylphenidate efficacy is influenced by the type of formulation, because the effect of this covariate is confounded by that of co-morbid SUD.
This study was funded by grants from the Departament de Salut de la Generalitat de Catalunya, the Agència de Gestió d’Ajuts Universitaris i de Recerca de la Generalitat de Catalunya for Research groups of the Generalitat de Catalunya 2009–2013 SGR 1554 and by la Obra Social “la Caixa” and the Departament de Salut de la Generalitat de Catalunya Programa “PAI-TLP-La Caixa 2009” and “PAI-TLP-La Caixa 2010”.
Dr Xavier Castells, Dr Rosa Bosch and Dr Mariana Nogueira have received lecture fees for participating in conferences organized by Janssen-Cilag. Dr Josep Antoni Ramos-Quiroga and Dr Miguel Casas have received lecture fees for participating in conferences organized by Janssen-Cilag, Laboratios Rubió and Lilly, and consulting fees from Janssen-Cilag. Dr David Rigau and Dr Xavier Vidal report no competing interests.
Kessler RC, Adler L, Ames M, et al. The prevalence and effects of adult attention deficit/hyperactivity disorder on work performance in a nationally representative sample of workers. J Occup Environ Med 2005; 47: 565–72PubMedCrossRefGoogle Scholar
Biederman J, Faraone SV, Spencer T, et al. Patterns of psychiatric comorbidity, cognition, and psychosocial functioning in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1993; 150: 1792–8PubMedGoogle Scholar
Biederman J, Monuteaux MC, Mick E, et al. Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Psychol Med 2006; 36: 167–79PubMedCrossRefGoogle Scholar
Young S, Toone B, Tyson C. Comorbidity and psychosocial profile in adults with attention deficit hyperactivity disorder. Pers Individ Diff 2003; 35: 743–55CrossRefGoogle Scholar
Barkley RA, Gordon M. Research on comorbidity, adaptive functioning, and cognitive impairments in adults with ADHD: implication for a clinical practice. In: Goldstein S, Ellison AT, editors. Clinician’s guide to adult ADHD: assessment and intervention. San Diego (CA): Academic Press, 2002: 43–69CrossRefGoogle Scholar
Pliszka S, AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007; 46: 894–921PubMedCrossRefGoogle Scholar
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. Psychopharmacology (Berl) 2008; 197: 1–11CrossRefGoogle Scholar
Koesters M, Becker T, Kilian R, et al. Limits of meta-analysis: methylphenidate in the treatment of adult attention-deficit hyperactivity disorder. J Psychopharmacol 2008; 23: 733–44PubMedCrossRefGoogle Scholar
Mészáros A, Czobor P, Bálint S, et al. Pharmacotherapy of adult attention deficit hyperactivity disorder (ADHD): a meta-analysis. Int J Neuropsychopharmacol 2009; 12: 1137–47PubMedCrossRefGoogle Scholar
Solanto MV. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 1998; 94: 127–52PubMedCrossRefGoogle Scholar
Faraone SV, Spencer T, Aleardi M, et al. Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacol 2004; 24: 24–9PubMedCrossRefGoogle Scholar
Swanson J, Gupta S, Guinta D, et al. Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. Clin Pharmacol Ther 1999; 66: 295–305PubMedCrossRefGoogle Scholar
Swanson J. Compliance with stimulants for attention-deficit/hyperactivity disorder: issues and approaches for improvement. CNS Drugs 2003; 17: 117–31PubMedCrossRefGoogle Scholar
Ramos-Quiroga JA, Bosch R, Castells X, et al. Effect of switching drug formulations from immediate-release to extended-release OROS methylphenidate: a chart review of Spanish adults with attention-deficit hyperactivity disorder. CNS Drugs 2008; 22: 603–11PubMedCrossRefGoogle Scholar
Swanson J, Volkow N. Pharmacokinetic and pharmaco-dynamic properties of methylphenidate in humans. In: Solanto MV, Arnsten AFT, Castellanos FX, editors. Stimulant drugs and ADHD: basic and clinical neuroscience. New York: Oxford University Press, Inc., 2001: 259–82Google Scholar
Modi NB, Lindemulder B, Gupta SK. Single- and multiple-dose pharmacokinetics of an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl) formulation. J Clin Pharmacol 2000; 40: 379–88PubMedCrossRefGoogle Scholar
Biederman J, Spencer T, Wilens T. Evidence-based pharmacotherapy for attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol 2004; 7: 77–97PubMedCrossRefGoogle Scholar
Döpfner M, Gerber WD, Banaschewski T, et al. Comparative efficacy of once-a-day extended-release methylphenidate, two-times-daily immediate-release methylphenidate, and placebo in a laboratory school setting. Eur Child Adolesc Psychiatry 2004; 13 Suppl. 1:I93–101PubMedGoogle Scholar
Jensen PS, Arnold LE, Swanson JM, et al. 3-Year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry 2007; 46: 989–1002PubMedCrossRefGoogle Scholar
Kooij JJ, Burger H, Boonstra AM, et al. Efficacy and safety of methylphenidate in 45 adults with attention-deficit/ hyperactivity disorder: a randomized placebo-controlled double-blind cross-over trial. Psychol Med 2004; 34: 973–82PubMedCrossRefGoogle Scholar
Faraone SV, Biederman J, Spencer TJ, et al. Comparing the efficacy of medications for ADHD using meta-analysis. Med Gen Med 2006; 8: 4Google Scholar
Jüni P, Altman DG, Egger M. Assessing the quality of clinical trials. In: Egger M, Davey Smith G, Altman DG, editors. Systematic reviews in health care: meta analysis in context. London: BMJ Publishing Group, 2001: 87–108CrossRefGoogle Scholar
Wender PH. Attention-deficit hyperactivity disorder in adults. New York: Oxford University Press, 1995Google Scholar
Ding YS, Fowler JS, Volkow ND, et al. Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain. Psychopharmacology (Berl) 1997; 131: 71–8CrossRefGoogle Scholar
Ding YS, Gatley SJ, Thanos PK, et al. Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration. Synapse 2004; 53: 168–75PubMedCrossRefGoogle Scholar
Markowitz JS, Patrick KS. Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter? J Clin Psychopharmacol 2008; 28(3 Suppl. 2): S54–61PubMedCrossRefGoogle Scholar
Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12PubMedCrossRefGoogle Scholar
Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions, version 5.0.0 (updated February 2008). The Cochrane Collaboration, 2008 [online]. Available from URL: http://www.cochrane-handbook.org/ [Accessed 2010 Jun 7]
Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med 2000; 19: 3127–31PubMedCrossRefGoogle Scholar
Adler LA, Zimmerman B, Starr HL, et al. 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 2009; 29: 239–47PubMedCrossRefGoogle Scholar
Biederman J, Mick E, Surman C, et al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 2006; 59: 829–35PubMedCrossRefGoogle Scholar
Bouffard R, Hechtman L, Minde K, et al. The efficacy of 2 different dosages of methylphenidate in treating adults with attention-deficit hyperactivity disorder. Can J Psychiatry 2003; 48: 546–54PubMedGoogle Scholar
Carpentier PJ, de Jong CA, Dijkstra BA, et al. A controlled trial of methylphenidate in adults with attention deficit/ hyperactivity disorder and substance use disorders. Addiction 2005; 100: 1868–74PubMedCrossRefGoogle Scholar
Jain U, Hechtman L, Weiss M, et al. Efficacy of a novel biphasic controlled-release methylphenidate formula in adults with attention-deficit/hyperactivity disorder: results of a double-blind, placebo-controlled crossover study. J Clin Psychiatry 2007; 68: 268–77PubMedCrossRefGoogle Scholar
Kuperman S, Perry PJ, Gaffney GR, et al. Bupropion SR vs methylphenidate vs placebo for attention deficit hyperactivity disorder in adults. Ann Clin Psychiatry 2001; 13: 129–34PubMedGoogle Scholar
Levin FR, Evans SM, Brooks DJ, et al. Treatment of methadone-maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo. Drug Alcohol Depend 2006; 81: 137–48PubMedCrossRefGoogle Scholar
Levin FR, Evans SM, Brooks DJ, et al. Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo. Drug Alcohol Depend 2007; 87: 20–9PubMedCrossRefGoogle Scholar
Mattes JA, Boswell L, Oliver H. Methylphenidate effects on symptoms of attention deficit disorder in adults. Arch Gen Psychiatry 1984; 41: 1059–63PubMedCrossRefGoogle Scholar
Medori R, Ramos-Quiroga JA, Casas M, et al. A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 2008; 63: 981–9PubMedCrossRefGoogle Scholar
Reimherr FW, Williams ED, Strong RE, et al. 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 2007; 68: 93–101PubMedCrossRefGoogle Scholar
Rösler M, Fischer R, Ammer R, et al. A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder. Eur Arch Psychiatry Clin Neurosci 2009; 259: 120–9PubMedCrossRefGoogle Scholar
Schubiner H, Saules KK, Arfken CL, et al. Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol 2002; 10: 286–94PubMedCrossRefGoogle Scholar
Spencer T, Wilens T, Biederman J, et al. A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1995; 52: 434–43PubMedCrossRefGoogle Scholar
Spencer T, Biederman J, Wilens T, et al. A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 456–63PubMedCrossRefGoogle Scholar
Spencer TJ, Adler LA, McGough JJ, et al., Adult ADHD Research Group. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/ hyperactivity disorder. Biol Psychiatry 2007; 61: 1380–7PubMedCrossRefGoogle Scholar
Tenenbaum S, Paull JC, Sparrow EP, et al. An experimental comparison of Pycnogenol and methylphenidate in adults with attention-deficit/hyperactivity disorder (ADHD). J Atten Disord 2002; 6: 49–60PubMedCrossRefGoogle Scholar
Wender PH, Reimherr FW, Wood D, et al. A controlled study of methylphenidate in the treatment of attention deficit disorder, residual type, in adults. Am J Psychiatry 1985; 142: 547–52PubMedGoogle Scholar
Mariani JJ, Levin FR. Treatment strategies for co-occurring ADHD and substance use disorders. Am J Addict 2007; 16 Suppl. 1: 45–54PubMedCrossRefGoogle Scholar
González MA, Pentikis HS, Anderl N, et al. Methylphenidate bioavailability from two extended-release formulations. Int J Clin Pharmacol Ther 2002 Apr; 40(4): 175–84PubMedGoogle Scholar
Markowitz JS, Straughn AB, Patrick KS, et al. Pharmacokinetics of methylphenidate after oral administration of two modified-release formulations in healthy adults. Clin Pharmacokinet 2003; 42(4): 393–401PubMedCrossRefGoogle Scholar
Reiz JL, Donnelly GA, Michalko K. Comparative bioavailability of single-dose methylphenidate from a multilayer-release bead formulation and an osmotic system: a two-way crossover study in healthy young adults. Clin Ther 2008; 30: 59–69PubMedCrossRefGoogle Scholar