Objective: Methylphenidate is effective in reducing ADHD symptoms in the short term, but long–term benefits are inconsistent, possibly due to the development of tolerance. Moreover, little is known about its sustained effects on brain functional connectivity. We examined whether a 4–month methylphenidate treatment leads to sustained alterations in resting–state functional connectivity, and whether acute brain responses to methylphenidate decrease after treatment, as a potential marker of neurobiological tolerance. Method: This is a secondary analysis of the ePOD–MPH RCT in which 50 boys and 49 men with ADHD were randomized to methylphenidate or placebo. Resting–state fMRI data were collected before, and one week after, a 4–month treatment period. At both visits, participants were scanned before and after an acute oral methylphenidate challenge. We computed whole–brain and default mode network (DMN) global efficiency, and DMN–whole–brain connectivity strength. Results: In adults, methylphenidate (but not placebo) led to sustained increases in whole–brain efficiency (p=0.01) and DMN–whole-brain connectivity strength (p=0.03). No significant effects were observed in children (all p>0.17). Exploratory analyses indicated that whole-brain efficiency increases related to decreasing cognitive performance in methylphenidate–treated children, but improving performance in placebo-treated children, suggesting treatment–dependent moderation (p<0.01). Acute connectivity responses remained stable in adults across visits (all p>0.15), but increased in children, regardless of treatment (all p<0.04). Conclusion: Four months of methylphenidate treatment led to sustained functional connectivity changes in adults with ADHD, without evidence of neurobiological tolerance. These findings emphasize the importance of studying longer treatment durations, considering that methylphenidate treatments typically span multiple years.

The authors have declared no competing interest.

NTR3103

This study was funded by the ZonMW open grant (project number: 09120012110091). The ePOD-MPH trial was funded by a research grant awarded to LR by the Academic Medical Center, University of Amsterdam, and 11.32050.26ERA-NET PRIOMEDCHILD FP 6(EU). JC received funding from the NIH grants R01MH119091 and R01MH136041.

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 study was approved on March 24, 2011 by the Central Committee on Research Involving Human Subjects (NL34509.000.10)

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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data produced in the present study are not openly available due to privacy restrictions and are available from the corresponding author on reasonable request and execution of a data use agreement.