Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo.
BACKGROUND
Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood. The mechanism of action of methylphenidate, the most common treatment for attention deficit hyperactivity disorder, is unclear. In vitro, the affinity of methylphenidate for the norepinephrine transporter (NET) is higher than that for the dopamine transporter (DAT). The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylphenidate in vivo in humans.


METHODS
We used (S,S)-[¹¹C] methylreboxetine ([¹¹C]MRB) to determine the effective dose 50 (ED₅₀) of methylphenidate for NET. In a within-subject design, healthy subjects (n = 11) received oral, single-blind placebo and 2.5, 10, and 40 mg of methylphenidate 75 min before [¹¹C]MRB injection. Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph. The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable (BP(ND)) in the thalamus and other NET-rich regions.


RESULTS
BP(ND) was reduced by methylphenidate in a dose-dependent manner in thalamus and other NET-rich regions. The global ED₅₀ was estimated to be .14 mg/kg; therefore, the average clinical maintenance dose of methylphenidate (.35-.55 mg/kg) produces 70% to 80% occupancy of NET.


CONCLUSIONS
For the first time in humans, we demonstrate that oral methylphenidate significantly occupies NET at clinically relevant doses. The ED₅₀ is lower than that for DAT (.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of methylphenidate in attention-deficit/hyperactivity disorder.
Hannestad
Jonas
J
Department of Psychiatry, Yale PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Gallezot
Jean-Dominique
JD
Planeta-Wilson
Beata
B
Lin
Shu-Fei
SF
Williams
Wendol A
WA
van Dyck
Christopher H
CH
Malison
Robert T
RT
Carson
Richard E
RE
Ding
Yu-Shin
YS
D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects*; D049268:Positron-Emission Tomography / Q000379:methods; D011869:Radioligand Assay / Q000379:methods; D000077593:Reboxetine
D000697:Central Nervous System Stimulants; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C524178:O-methyl reboxetine; D008774:Methylphenidate; D000077593:Reboxetine