Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder

Abstract

IMPORTANCE 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. OBJECTIVES 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. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS Treatment with either methylphenidate or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE 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. TRIAL REGISTRATION identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.

White Matter by Diffusion MRI Following Methylphenidate Treatment: A Randomized Control Trial in Males with Attention-Deficit/Hyperactivity Disorder

“…Our study protocol (Appendix E1 [online]) contains several pieces of evidence supporting the view that the expected differences will lead to standardized effect sizes of at least 1.25, including the DTI assessments we report here. Our findings on dopamine function (assessed by using pharmacologic MRI) have been reported elsewhere (8).…”

“…The effect of age and MPH treatment on white matter structure was assessed by means of diffusion-tensor imaging (DTI) at baseline and at the end of the trial, after a 1-week washout in week 18 to ensure drug clearance (the half-life of MPH is 2-3 hours). The primary outcome measure of ePOD-MPH was to report on the modification by age of MPH treatment on the outgrowth of the dopamine system by using pharmacologic MRI, and second primary outcome measures included DTI for white matter assessment (8).…”

Stimulant medication to treat attention-deficit/hyperactivity disorder

“…34 The trials focused on training parents of young children using approaches such as the Webster-Stratton Incredible Years and New Forest Parenting Package. The outcomes showed improved oppositional behaviour in children, but did not appear to improve core ADHD symptoms substantially.…”

Methylphenidate challenge test in adults with attention deficit/hyperactivity disorder (ADHD): Clinical effects and their predictors

“…More recently, stimulants, such as MPH, have been recommended as first-line treatment for adult ADHD in the National Institute for Health and Clinical Excellence (NICE) guidelines (NICE, 2008). MPH appears to reduce symptoms of inattention, hyperactivity, and impulsivity in up to 70% of adults with ADHD (Asherson, 2005;Schrantee et al, 2016).…”

“…The extent of acute post-MPH challenge amplitude increase of at least 30% of an evoked potential predicted with an 81% accuracy a later favorable response to stimulants in children with ADHD (Young, Perros, Price, & Sadler, 1995). The search for predictors of later response may prove to be frustrating, since the brain response to MPH differs between adults and children, in that adults show stronger decreases in cortical cerebral blood flow while only children show decreased cerebral blood flow in the thalamus (Schrantee et al, 2016).…”