title: Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system.
  
  
  OBJECTIVE
  To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function.
  
  
  METHODS
  A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status.
  
  
  METHODS
  Treatment with either methylphenidate or a matched placebo for 16 weeks.
  
  
  METHODS
  Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses.
  
  
  RESULTS
  Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03).
  
  
  CONCLUSIONS
  We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up.
  
  
  BACKGROUND
  identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands2Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands3Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Schrantee
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands4d'Arc (Dutch Autism and Attention-Deficit/Hyperactivity Disorder Research Center), Department of Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Hyke G H
authors.initials: HG
authors.lastname: Tamminga
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands2Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Cheima
authors.initials: C
authors.lastname: Bouziane
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands5Department of Child and Adolescent Psychiatry, Triversum, Alkmaar, the Netherlands.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Bottelier
authors.affiliation: Biomedical Imaging Group Rotterdam, Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands7Biomedical Imaging Group Rotterdam, Department of Radiology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Bron
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands2Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Henk-Jan M M
authors.initials: HJ
authors.lastname: Mutsaerts
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: Institute of Psychology, Department of Social Sciences, University of Oslo, Oslo, Norway.
authors.forename: Inge R
authors.initials: IR
authors.lastname: Groote
authors.affiliation: Institute of Psychology, Leiden University, Leiden, the Netherlands11Department of Radiology, Leids Universitair Medisch Centrum, Leiden, the Netherlands.
authors.forename: Serge A R B
authors.initials: SA
authors.lastname: Rombouts
authors.affiliation: Department of Child and Adolescent Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands13De Bascule Academic Center for Child and Adolescent Psychiatry, Amsterdam, the Netherlands.
authors.forename: Ramon J L
authors.initials: RJ
authors.lastname: Lindauer
authors.affiliation: Biomedical Imaging Group Rotterdam, Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Klein
authors.affiliation: Biomedical Imaging Group Rotterdam, Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands14Department of Imaging Physics, Faculty of Applied Sciences, Delft University of Technology, Delft, the Netherlands.
authors.forename: Wiro J
authors.initials: WJ
authors.lastname: Niessen
authors.affiliation: Clinical Research Unit, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Brent C
authors.initials: BC
authors.lastname: Opmeer
authors.affiliation: Department of Child and Adolescent Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands13De Bascule Academic Center for Child and Adolescent Psychiatry, Amsterdam, the Netherlands.
authors.forename: Frits
authors.initials: F
authors.lastname: Boer
authors.affiliation: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lucassen
authors.affiliation: Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Andersen
authors.affiliation: d'Arc (Dutch Autism and Attention-Deficit/Hyperactivity Disorder Research Center), Department of Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Hilde M
authors.initials: HM
authors.lastname: Geurts
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands2Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands3Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Reneman
mesh_terms: D000328:Adult; D000367:Age Factors; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D001921:Brain / Q000098:blood supply* / Q000187:drug effects*; D002648:Child; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004311:Double-Blind Method; D006179:Gyrus Cinguli / Q000098:blood supply / Q000187:drug effects; D006801:Humans; D008134:Long-Term Care; D008279:Magnetic Resonance Imaging; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D009415:Nerve Net / Q000098:blood supply / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects; D013788:Thalamus / Q000098:blood supply / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D011954:Receptors, Dopamine; D008774:Methylphenidate; D004298:Dopamine