부산대학교 도서관

Atomoxetine is a specific inhibitor of the norepinephrine transporter (NET) that has demonstrated efficacy in the treatment of children with attention-deficit hyperactivity disorder (ADHD). We investigated whether polymorphisms in the NET/SLC6A2 gene may influence atomoxetine response in ADHD. Two independent cohorts of 160 and 105 ADHD children treated for 6 weeks with atomoxetine (0.5–1.8 mg/kg per day) were genotyped on CYP2D6, which metabolizes atomoxetine, and 108 single nucleotide polymorphisms in the NET/SLC6A2 gene. Response was defined as a minimum decrease of 25% in ADHD Rating Scale IV-Parent Version and a Clinical Global Impression-Severity (CGI-S) score less than or equal to 2 at week 6. Interindividual response was independent of the genetic variants of CYP2D6. Significant (p<0.05) associations between 20 NET/SLC6A2 single nucleotide polymorphisms (SNPs) and clinical efficacy in atomoxetine responders, compared with non-responders, were observed. The genomic region across exons 4 to 9 of NET/SLC6A2, where 36 SNPs have been genotyped, was associated with treatment response in both cohorts (p<0.01, odds ratio=2.2 and p=0.026, odds ratio=6.3, respectively), in the combined cohort (p<0.01, odds ratio=1.83), and in the subgroup of Caucasians only (p=0.02, odds ratio=1.8). Clinical efficacy of atomoxetine treatment in ADHD shows potential dependence upon a series of genetic polymorphisms of its mechanistic target, the norepinephrine transporter. Taking into account the high heritability of ADHD, the significance of the present finding and replication of a similar haplotype allele sequence result in an independent cohort, it is suggested that further assessment of this region could be useful in determining response to atomoxetine in ADHD.Neuropsychopharmacology (2009) 34, 2135–2142; doi:10.1038/npp.2009.39; published online 22 April 2009 [ABSTRACT FROM AUTHOR]