Elsevier

Biological Psychiatry

Volume 68, Issue 9, 1 November 2010, Pages 854-860
Biological Psychiatry

Archival Report
Clinically Relevant Doses of Methylphenidate Significantly Occupy Norepinephrine Transporters in Humans In Vivo

https://doi.org/10.1016/j.biopsych.2010.06.017Get rights and content

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 (BPND) in the thalamus and other NET-rich regions.

Results

BPND 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.

Section snippets

Subjects

We recruited six women and five men with no current medical problems and no psychiatric history, including ADHD. Medical and psychiatric history, review of systems, the structured interview for the DSM (17), and a physical examination were performed by a board-certified psychiatrist (JH). Laboratory tests and electrocardiogram were used to rule out any unknown medical condition. All subjects were stimulant-naive, with no history of exposure to amphetamines, cocaine, ecstasy, or MPH. Urine drug

Demographic and Radiotracer Characteristics

The mean age was 34 ± 8 years, and the mean body mass index was 28 ± 5 kg/m2. Radiotracer characteristics are summarized in Table 1. MPH was well tolerated, and only one subject experienced transient anxiety after the 40-mg dose. The 75- and 195-min plasma levels of the active enantiomer d-threo-MPH were 1.5 ± 1.2 and .6 ± .4 ng/mL (2.5 mg), 3.1 ± 3 and 2.8 ± 1.7 ng/mL (10 mg), and 22.9 ± 13.9 and 15 ± 4.4 ng/mL (40 mg), respectively. For correlation between plasma levels of d-threo-MPH and MPH

MPH Occupancy of NET

This is the first in vivo study in humans showing that clinically relevant doses of MPH occupy significant levels of NET. Although MPH has been used for the treatment of ADHD for decades, the exact mechanism of action is unclear. Stimulants enhance synaptic concentrations of DA and NE, d-amphetamine by increasing catecholamine release, and MPH by inhibiting catecholamine reuptake. Currently, it is believed that MPH's therapeutic effects in ADHD are due mostly to its DAT inhibition; however,

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