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


METHODS
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.


BACKGROUND
Response Variability in Children with Attention-Deficit/Hyperactivity Disorder (ADHD); http://www.clinicaltrials.gov; NCT01238822.
University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. tanya.froehlich@cchmc.org
Tanya E
TE
Froehlich
Jeffery N
JN
Epstein
Todd G
TG
Nick
Maria S
MS
Melguizo Castro
Mark A
MA
Stein
William B
WB
Brinkman
Amanda J
AJ
Graham
Joshua M
JM
Langberg
Robert S
RS
Kahn
D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics; D002394:Catechol O-Methyltransferase / Q000235:genetics; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002648:Child; D018592:Cross-Over Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005838:Genotype; D006801:Humans; D008774:Methylphenidate / Q000494:pharmacology*; D018895:Microsatellite Repeats / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D010919:Placebos; D011110:Polymorphism, Genetic; D011569:Psychiatric Status Rating Scales; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics; D014888:Wechsler Scales
D000697:Central Nervous System Stimulants; C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D010919:Placebos; D018341:Receptors, Adrenergic, alpha-2; D050638:Receptors, Dopamine D4; D008774:Methylphenidate; D002394:Catechol O-Methyltransferase