Brain Advance Access originally published online on June 7, 2006
Brain 2006 129(8):2038-2046; doi:10.1093/brain/awl147
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Dopamine transporter genotype influences the physiological response to medication in ADHD
1 Division of Neurology Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA 2 Division of Pediatrics Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA 3 Mental Health Care Line Veterans Administration Medical Center, Cincinnati, OH, USA 4 Department of Psychiatry, University of Cincinnati Cincinnati, OH, USA 5 Brain Stimulation Unit, National Institute of Neurological Disorders and Stroke Bethesda, MD, USA
Correspondence to: Donald L. Gilbert, MD, MS, Cincinnati Children's Hospital Medical Center, Division of Neurology, ML #2015, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA E-mail: d.gilbert{at}cchmc.org
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.
Key Words: ADHD; TMS; Tourette syndrome; children; motor cortex
Abbreviations: ADHD, attention deficit hyperactivity disorder; ATX, atomoxetine; DAT1, dopamine transporter; ICF, intracortical facilitation; SICI, short interval cortical inhibition; TMS, transcranial magnetic stimulation; VNTR, variable number of tandem repeats; MEP, motor-evoked potential; MPH, methylphenidate
Received December 7, 2005. Revised May 5, 2006. Accepted May 8, 2006.
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