Responsivity of the striatal dopamine system to methylphenidate – a within-subject I-123-ß-CIT-SPECT study in children and adolescents with Attention-Deficit/Hyperactivity Disorder

Background Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight in how effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning. Methods Thirteen adolescent male patients (9-16 years) with diagnosis of ADHD according to DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-ß-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in on and off-MPH status balanced for order across participants. A virtual-reality continuous-performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH. Results On-MPH status was associated with a highly significant decrease (−27,6%) of striatal DAT BP as compared to off-MPH (t=4.93, p<0.001). More pronounced decrease in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r=0.68, p=0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings off-MPH (Pearson r=0.56, p=0.04). In further exploratory analysis in left vs. right striatal sub-regions, stronger decrease in DAT BP in the right caudate nucleus was weakly associated with improved performance in the continuous-performance test (Pearson r= - 0.54, p=0.07). Conclusion Our findings corroborate previous reports from mainly adult samples that MPH reduces striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity. More speculatively, regional specific responsivity of DAT BP to MPH may reflect treatment response with respect to cognitive functioning. However, implications from this small patient sample should be treated with caution and warrant replication. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by a grant from the Interdisciplinary Centre of Clinical Research at the Medical Faculty of the University of Wuerzburg (Untersuchungen des Dopamin-Transporters mittels TC-99m-TRODAT-1-SPECT bei Jugendlichen mit ADHS) and by the German Research Foundation (DFG) as part of KFO 125 Attention Deficit/Hyperactivity Syndrome (ADHD): Molecular Pathogenesis and Endophenotypes in the Course of Treatment, project number 5397423. HCA is supported by a Clinician Scientist Program at the Interdisciplinary Centre of Clinical Research at the Medical Faculty of the University of Wuerzburg. LD is supported by the IFB Adiposity Diseases, Federal Ministry of Education and Research (BMBF), Germany, GN: 01EO150 and the German Research Foundation (DFG) as part of the Collaborative Research Centre 265 Losing and Regaining Control over drug intake (402170461, Project A02). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics commitee of the medical faculty of the University of Wuerzburg and the German Federal Office for Radiation Protection gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. All data produced in the present study are available upon reasonable request to the authors.