Dopamine-related genotypes and the dose-response effect of methylphenidate on eating in attention-deficit/hyperactivity disorder youths.
OBJECTIVE
There are individual differences in the effects of methylphenidate (MPH), a dopamine (DA) transport inhibitor, on appetite in children with attention-deficit/hyperactivity disorder (ADHD). One potential moderating factor is variation in brain DA activity, which is influenced by dopamine-related genes: the DA transporter (DAT) (SLC6A3), the DA D2 receptor (DRD2), and the DA D4 receptor (DRD4) genes. The purpose of this study was to explore the relationship between dopamine-related gene polymorphisms and food consumption in ADHD children receiving varying doses of MPH.


METHODS
In a randomized, within-subject, double-blind design, 58 ADHD children (ages 6-12 years) received placebo, 0.15, 0.3, or 0.6 mg/kg of MPH three times daily over 9 weeks. Observations of percent lunch consumed as a function of dopamine-related genotypes and MPH dose were analyzed using mixed effects regression models.


RESULTS
A significant dose-response reduction in eating was observed across all genotypes (p < 0.001). There was an interaction of DAT SLC6A3 and DRD2 genotypes and dose, because 9/9 DAT children showed a stronger effect of dose when compared with the 9/10 and 10/10 children (p < 0.001) and DRD2 A2/A2 children showed a stronger effect of dose when compared with A1/A1 and A1/A2 children combined (p = 0.007). There was no significant interaction of dose by DRD4 genotype.


CONCLUSIONS
Lunch consumption decreased as a function of MPH dose. DA-related genotypes associated with greater brain DA signaling moderated the influence of drug on consumption. These results provide information relevant to predicting which children are likely to experience the greatest appetite suppression when taking MPH.
Leddy
John J
JJ
State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, USA. leddy@buffalo.edu
Waxmonsky
James G
JG
Salis
Robert J
RJ
Paluch
Rocco A
RA
Gnagy
Elizabeth M
EM
Mahaney
Patrick
P
Erbe
Richard
R
Pelham
William E
WE
Epstein
Leonard H
LH
D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics; D001921:Brain / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004435:Eating / Q000187:drug effects*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology* / Q000627:therapeutic use; D018598:Minisatellite Repeats; D011110:Polymorphism, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D015431:Weight Loss / Q000187:drug effects
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; C493214:SLC6A3 protein, human; D008774:Methylphenidate; D004298:Dopamine