Dopamine receptor 4 (DRD4) 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetic study.
OBJECTIVE
Genetic polymorphisms of the dopamine neurotransmitter system have been identified in attention deficit hyperactivity disorder (ADHD). Since stimulant medications act through this system, we sought to determine if the 48 base pair VNTR polymorphism (7- repeat allele) of dopamine receptor gene DRD4 predicts methylphenidate responsiveness.


METHODS
Forty-five children, aged 7-15 years, with ADHD, confirmed by NIMH-DISC-IV, participated in this prospective pharmacogenetic study. Subjects received increasing methylphenidate doses based on serial Conners' Global Index-Parent assessments. Doses to obtain a 10-point improvement and normalization (T-score, 60) were determined. Blood and buccal screening for DRD4 7R was correlated with outcomes.


RESULTS
Mean dose for a 10-point CGI-P improvement with DRD4 7R (n=20) was 30 mg (1.00 mg/kg) versus 20 mg (0.49 mg/kg) without 7R (n=25) (log rank=13.69; df=1; p=0.0002). Mean dose for CGI-P normalization for children with 7R was 47 mg (1.70 mg/kg) of methylphenidate versus 31 mg (0.79 mg/kg) of methylphenidate without 7R (log rank=14.17; df=1; p=0.0002). ADHD symptom normalization at < or =50 mg methylphenidate was achieved in 58% with 7R versus 95% without (log rank=9.45; df=1; p=0.002).


CONCLUSIONS
Children with ADHD possessing the DRD4 7R allele require higher doses of methylphenidate for symptom improvement and symptom normalization. This pharmacogenetic study demonstrates that the 7-repeat allele of the DRD4 gene VNTR polymorphism correlates with treatment outcomes.
Hamarman
Stephanie
S
Department of Psychiatry, Stanley S. Lamm Institute for Child Neurology and Developmental Medicine, Brooklyn, New York 11201, USA. Sharmarman@chpnet.org
Fossella
John
J
Ulger
Celal
C
Brimacombe
Michael
M
Dermody
James
J
D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage*; D018598:Minisatellite Repeats / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050638:Receptors, Dopamine D4; D016896:Treatment Outcome
D000697:Central Nervous System Stimulants; C493599:DRD4 protein, human; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D008774:Methylphenidate