Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial
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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.
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In pre-pubertal children, exposure to methylphenidate produces an enduring increase in methylphenidate-stimulated blood flow in the striatum and thalamus, with no significant change observed in adult-exposed subjects.
“Moreover, in pre-pubertal children exposure to methylphenidate produces an enduring increase in methylphenidate-stimulated blood flow in the STR and thalamus, with no significant change observed in adult-exposed subjects (Schrantee et al., 2016).”
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- Authors
- Schrantee, A., Tamminga, H. G. H., Bouziane, C., Bottelier, M. A., Bron, E. E., Mutsaerts, H.-J. M. M., Zwinderman, A. H., Groote, I. R., Rombouts, S. A. R. B., Lindauer, R. J. L., Klein, S., Niessen, W. J., Opmeer, B. C., Boer, F., Lucassen, P. J., Andersen, S. L., Geurts, H. M., & Reneman, L.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Erasmus MC (NL)
- University of Oslo (NO)
- Leiden University (NL)
- 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
- University of Amsterdam (NL)
- Harvard University (US)
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2016-09-01
- Volume
- 73
- Issue
- 9
- Pages
- 955
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC5267166
- OpenAlex
- W2484812056
- Cited by
- 77
- References
- 43
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 9 · 2020: 7 · 2019: 15 · 2018: 4 · 2017: 7 · 2016: 1
- FWCI
- 7.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion, other-oa)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Universiteit van Amsterdam
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institute of Mental Health (R01MH091114)
- National Institute on Drug Abuse (R01DA026485, R01DA015403)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- methylphenidate, attention deficit hyperactivity disorder, dopaminergic system, age-dependent effects, cerebral blood flow, striatum, thalamus, developing brain, children, adults, pharmacological MRI
- MeSH terms
- Adult, Age Factors, Attention Deficit Disorder with Hyperactivity, Brain, Child, Corpus Striatum, Dopamine, Double-Blind Method, Gyrus Cinguli, Humans, Long-Term Care, Magnetic Resonance Imaging, Male, Methylphenidate, Nerve Net, Receptors, Dopamine, Regional Blood Flow, Thalamus, Treatment Outcome
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