Pharmacogenetic predictors of methylphenidate dose-response in attention-deficit/hyperactivity disorder

Abstract

Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response.

Method: Eighty-nine stimulant-naive children with ADHD 7 to 11 years old participated in a randomized, double-blind, crossover trial of long-acting MPH. Parents and teachers assessed each child's response on placebo and three MPH dosage levels using the Vanderbilt ADHD rating scales. Children were genotyped for polymorphisms in the 3' untranslated region of dopamine transporter (DAT), exon 3 on dopamine receptor D(4) (DRD4), codon 158 on catechol-O-methyltransferase, and the adrenergic α(2A)-receptor promoter. Linear mixed models evaluated gene, dose (milligrams per kilogram per day), and gene-by-dose effects on inattentive and hyperactive-impulsive domain outcomes.

Results: The most statistically significant gene-by-dose interactions were observed on hyperactive-impulsive symptoms for DRD4 and DAT polymorphisms, with participants lacking the DAT 10-repeat allele showing greater improvements in symptoms with increasing dose compared with 10-repeat carriers (p = .008) and those lacking the DRD4 4-repeat allele showing less improvement across MPH doses compared with 4-repeat carriers (p = 0.02).

Conclusions: This study suggests that DAT and DRD4 polymorphisms may be associated with individual variability in MPH dose-response, although further research in larger samples is required to confirm these findings and their clinical utility.

Clinical trial registration information: Response Variability in Children with Attention-Deficit/Hyperactivity Disorder (ADHD); http://www.clinicaltrials.gov; NCT01238822.

Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Dopamine transporter (DAT)*Dose Effects on Parent- and Teacher-Rated Hyperactive-Impulsive Scores. Note: Participants with no copies of the 10-repeat (10R) allele had greater reduction in symptoms as methylphenidate dose increased compared with 10R carriers. The 0 mg/kg/day dose corresponds to the placebo condition. OROS = osmotic-release oral system.

Figure 2

Dopamine receptor D4 (DRD4)*Dose Effects on Parent- and Teacher-Rated Hyperactive-Impulsive Scores. Note: Participants with no copies of the 4-repeat (4R) allele experienced less reduction in symptoms as methylphenidate dose increased compared with 4R carriers. The 0 mg/kg/day dose corresponds to the placebo condition. OROS = osmotic-release oral system