Dopamine transporter genotype influences the physiological response to medication in ADHD

Abstract

Attention deficit hyperactivity disorder (ADHD) is a complex, multifactorial disorder characterized by physical hyperactivity and behavioural disinhibition. Short interval cortical inhibition (SICI), measured in motor cortex with transcranial magnetic stimulation, is reduced in ADHD and correlates with symptom severity. However, ADHD medication-induced changes in SICI vary widely among normal individuals and have not been well studied in children with ADHD. Therefore, we undertook this study to measure and compare effects of two ADHD medications, methylphenidate (MPH), a psychostimulant, and atomoxetine (ATX), a selective norepinephrine reuptake inhibitor, on SICI in children with ADHD. In addition, we wished to determine whether a genetic variation in the dopamine transporter (DAT1), a site of action of MPH, could influence the effects of MPH or ATX on SICI. We performed a randomized, double-blind, single-dose, crossover study comparing 0.5 mg/kg MPH with 1.0 mg/kg ATX in 16 children with ADHD, aged 8-17. Seven were homozygotes and 9 heterozygotes for the DAT1 variable number of tandem repeats 10-repeat allele. Medication and genotype effects on SICI were estimated with repeated measures, mixed model regression. We found that MPH and ATX had similar effects on SICI. However, medication effects differed significantly by DAT1 genotype [F(2,13) = 13.04, P = 0.0008]. Both MPH and ATX increased SICI in heterozygotes but not in 10-repeat homozygotes. In conclusion, MPH and ATX have similar effects on SICI in children with ADHD. A genetic variation in DAT1, previously linked to ADHD risk and MPH behavioural responses, influences the neurophysiological effects of both MPH and ATX.

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). To date, no published studies have assessed SICI changes and clinical ADHD responses to atomoxetine over longer time periods.…”

“…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.…”

“…Eleven subjects age 8 to 16 years (mean 12) completed the study. Some subjects had participated in a previous, single-dose study (Gilbert et al, 2006b). Diagnoses were based clinical interview, DSM-IV criteria (American Psychiatric Association, 2000), and DuPaul ADHD rating scale (ADHDRS) scores (DuPaul et al, 1998).…”

“…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.…”