Dopaminergic and noradrenergic gene polymorphisms and response to methylphenidate in korean children with attention-deficit/hyperactivity disorder: is there an interaction?
OBJECTIVE
We aimed to investigate the independent and interaction effects of dopamine transporter gene (DAT1), dopamine D4 receptor gene (DRD4), alpha-2A adrenergic receptor gene (ADRA2A), and norepinephrine transporter gene (NET1), with regard to treatment response to methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD).


METHODS
The participants of the study were 103 children and adolescents (ages 9.1±2.1 years) diagnosed as having ADHD according to American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria. They were enrolled in an 8-week, open-label trial of MPH. The good responder group was defined as subjects having an ≥50% decrease in the ADHD Rating Scale-IV (ADHD-RS) total score from the baseline, and at the same time a Clinical Global Impressions-Improvement Scale (CGI-I) score of 1 or 2, both at the 8th week of MPH treatment. Multivariate stepwise logistic regression was performed to examine the independent and interaction effects of genotypes on the dichotomized MPH treatment response.


RESULTS
Significant interaction effects on MPH response were detected between the genotypes of the DRD4 variable number of tandem repeat (VNTR) polymorphisms and those of either the ADRA2A DraI or the NET1 -3081(A/T) polymorphisms; significant interaction effects were also detected between the genotypes of the ADRA2A DraI polymorphisms and those of either the NET1 G1287A or the NET1 -3081(A/T) polymorphisms (Nagelkerke R(2)=0.40). No significant independent effect of a genotype was detected according to the stepwise logistic regression results.


CONCLUSIONS
The results suggest that genes involved in the dopaminergic and noradrenergic systems might interact to form important predictors of short-term response to MPH.
Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.
Soon-Beom
SB
Hong
Jae-Won
JW
Kim
Soo-Churl
SC
Cho
Min-Sup
MS
Shin
Boong-Nyun
BN
Kim
Hee-Jeong
HJ
Yoo
D044466:Asian People; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D002648:Child; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004298:Dopamine / Q000235:genetics* / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007361:Intelligence Tests; D016015:Logistic Models; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D018598:Minisatellite Repeats / Q000235:genetics; D009483:Neuropsychological Tests; D009638:Norepinephrine / Q000235:genetics* / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics; D016896:Treatment Outcome
C547768:ADRA2A protein, human; D000697:Central Nervous System Stimulants; C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; C099763:NET1 protein, human; D015513:Oncogene Proteins; D018341:Receptors, Adrenergic, alpha-2; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4; D008774:Methylphenidate; D004298:Dopamine; D009638:Norepinephrine