Comparison of the Inhibitory and Excitatory Effects of ADHD Medications Methylphenidate and Atomoxetine on Motor Cortex

Abstract

Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in healthy adults, both stimulant and nonstimulant medications for ADHD decrease cortical inhibition and increase cortical facilitation. Cortical inhibition, shown previously to be abnormal in ADHD, may play a key role producing behavioral pathology.

Atomoxetine treatment of ADHD in Tourette Syndrome: Reduction in motor cortex inhibition correlates with clinical improvement

“…This reduction seems surprising, but is consistent with other healthy-adult studies of psychostimulants and of the SNRI reboxetine (Gilbert et al, 2006a). In children with ADHD, the effects on SICI of single doses of atomoxetine are more variable and may depend on dopamine transporter genotypes or on TS phenotypes (Gilbert et al, 2006b).…”

“…Comparison with prior cohorts-The first-visit, pre-treatment SICI ratio in this cohort appeared to be lower than the SICI ratio in our prior single-dose study (Gilbert et al, 2006b), and closer to the baseline, pre-dose SICI in our study of healthy adults (Gilbert et al, 2006a). Therefore, we were concerned that this cohort might be atypical in some way and that the ATXassociated changes in SICI might not be generalizable.…”

“…We have previously found consistent correlations between reductions in SICI and ADHD symptom severity in TS (Gilbert et al, 2004a. Moreover, many studies show that SICI changes in response to dopamine agonists, stimulants, and norepinephrine reuptake inhibitors (Gilbert et al, 2006a,Gilbert et al, 2006b,Ilic et al, 2003,Kirschner et al, 2003,Moll et al, 2000,Ziemann et al, 1997. Most of these pharmaco-physiological studies have measured effects of single doses in healthy adults.…”

“…We also assessed another pTMS measure, intracortical facilitation. Although ICF is not linked to ADHD, it is sensitive to effects of norepinephrine reuptake inhibitors (Gilbert et al, 2006a,Herwig et al, 2002,Plewnia et al, 2002. We report a novel result which may relate to ATX's mechanism of action in treating ADHD symptoms in TS.…”

“…The location was recorded and the coil stabilized with a wall-mounted clamp to increase consistency across pTMS sessions. As described in our previous studies (Gilbert et al, 2006a,Gilbert et al, 2006b, and consistent with convention, the resting motor threshold (RMT) was determined by increasing the coil stimulation intensity by increments of 10% of maximum stimulator output until a robust MEP was elicited. Then the intensity was decreased by 1% repeatedly until the lowest intensity able to produce MEPs of at least 50 uV on 5 out of 10 consecutive trials of stimulation was identified.…”