Effects of Extended-Release Methylphenidate on Dopamine and Norepinephrine Transporters in Adults With Attention-Deficit/Hyperactivity Disorder: A Longitudinal Dual-Tracer PET Study

Abstract

Aim: Attention-deficit/hyperactivity disorder (ADHD) is associated with dysregulation of dopamine and norepinephrine neurotransmission. Extended-release methylphenidate (MPH), a first-line treatment for ADHD, modulates these systems. However, its specific effects on the dopamine transporter (DAT) and norepinephrine transporter (NET) are inadequately characterized. This study evaluated the effects of MPH on DAT and NET binding in adults with ADHD and examined the relationship between transporter binding and cognitive improvement. Methods: This longitudinal dual-tracer positron emission tomography (PET) study used [18F]-FEPE2I for DAT imaging and (S,S)-[18F]- FMeNER-D2 for NET imaging. PET imaging and cognitive assessments were conducted on 21 adults with ADHD before MPH treatment, and 12 of these participants were reevaluated after achieving treatment stabilization. Results: MPH treatment significantly decreased DAT binding in the caudate and putamen and NET binding in the thalamus and pons. Improvements in attention and multitasking abilities were observed. Baseline NET binding in the pons was higher in individuals with ADHD than in controls, and higher baseline DAT binding in the putamen predicted improvement in sustained attention. However, changes in DAT and NET binding did not correlate with cognitive improvement. Blood concentration analysis revealed that even at MPH blood levels that resulted in high DAT occupancy in the striatum, NET occupancy in the thalamus remained moderate. Conclusions: MPH simultaneously reduced DAT and NET binding in ADHD, enhanced dopamine and norepinephrine transmission, and improved cognitive function. The differential occupancy of DAT and NET suggests distinct contributions to the therapeutic effects of MPH.