Background: Methylphenidate (MPH) is highly effective in treating attention-deficit/hyperactivity disorder (ADHD). However, not much is known about its effect on the development of human brain white matter (WM). Purpose: To determine whether MPH modulates WM microstructure in an age-dependent fashion in a randomized double-blind placebo-controlled trial (Effects of Psychotropic Medication on Brain Development-Methylphenidate, or ePOD-MPH) among ADHD referral centers between October 13, 2011, and June 15, 2015, by using diffusion-tensor imaging (DTI). Materials and Methods: In this prospective study (NTR3103 and NL34509.000.10), 50 stimulant treatment-naive boys and 49 young adult men diagnosed with ADHD (all types) according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria were randomized to undergo treatment with MPH or placebo for 16 weeks. Before and 1 week after treatment cessation, study participants underwent MRI, including DTI. The outcome measure was change in fractional anisotropy (FA), which was assessed in three regions of interest (ROIs), as well as in a voxel-based analysis in brain WM. Data were analyzed by using intentionto- treat linear mixed models for ROI analysis and a permutation-based method for voxel-based analysis with family-wise error correction. Results: Fifty boys (n = 25 MPH group, n = 25 placebo group; age range, 10-12 years) and 48 men (n = 24 MPH group, n = 24 placebo group; age range, 23-40 years) were included. ROI analysis of FA yielded no main effect of time in any of the conditions. However, voxel-based analysis revealed significant (P , .05) time-by-medication-by-age interaction effects in several association tracts of the left hemisphere, as well as in the lateral aspect of the truncus of the corpus callosum, due to greater increase in FA (standardized effect size, 5.25) in MPH-treated boys. Similar changes were not present in boys receiving a placebo, nor in adult men. Conclusion: Four months of treatment with methylphenidate affects specific tracts in brain white matter in boys with attentiondeficit/ hyperactivity disorder. These effects seem to be age dependent, because they were not observed in adults treated with methylphenidate.

IMPORTANCE Although numerous children receivemethylphenidate 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 flowresponse 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 receivemethylphenidate 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.