Association between long-term stimulant treatment and the functional brain response to methylphenidate in adolescents and adults with attention-deficit/hyperactivity disorder

Background: Stimulant medication is commonly used by children and adolescents with attention-deficit/hyperactivity disorder (ADHD), however its long-lasting effects on the developing brain remain unclear. In a previous randomized controlled trial (RCT) we found that short-term stimulant treatment influences the functional brain response to an acute methylphenidate-challenge in an age-dependent manner, in line with animal studies suggesting persisting effects on brain development. Methods: In this 4-year naturalistic follow-up of the initial RCT, we investigated the long-term age-dependent effects of stimulant treatment on the functional brain response to methylphenidate in male children and adults with ADHD (n = 56; adolescents aged 10–17 years, adults aged 23–43 years). At baseline and 4-year follow-up, we used pharmacological MRI to estimate relative cerebral blood flow (rCBF) before a single-dose methylphenidate-challenge (resting rCBF) and the rCBF-response to a single-dose methylphenidate-challenge. Linear mixed models were constructed to evaluate the effect of stimulant medication use, age and visit on resting rCBF and rCBF-response. Results: We found no evidence for long-term age-dependent effects of stimulant treatment, suggesting that our previously identified short-term effects may be transient. We did identify age-dependent associations between rCBF-response in the medial prefrontal cortex and stimulant treatment, which were already present before treatment initiation but were unrelated to ADHD symptom severity. Moreover, rCBF-response was associated with dopamine D1 receptor distributions in adolescents only. Conclusions: The identified age-dependent associations may potentially be mediated by changes in dopamine- and noradrenaline-related functioning, and may hold predictive value for extent of stimulant medication use after ADHD diagnosis in children and adolescents.