Abstract
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.
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Acknowledgements
We acknowledge Ms. Shuyu Zhang of Eli Lilly and Company for sharing her statistical expertise.
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CONFLICT OF INTEREST
Both clinical trials, LYAF and LYBI, and pharmacogenetic analysis were funded by Eli Lilly and Company, Indianapolis, IN, USA. AMD, SLC, and AJA are employees of Eli Lilly and Company. AMP is a current and SLP is a former employee of BioStat Solutions that Eli Lilly and Company paid for services and other than receiving compensation from their employer, have no other conflicts of interest to report. PG received grants from Eli Lilly; honoraria from Lundbeck, Servier, UCB-Pharma and participated in advisory boards for Janssen, Servier, and Wyeth. He has a paid position from University of Paris VII. NR, CB, MH, and DPO declare no conflicts of interest.
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Ramoz, N., Boni, C., Downing, A. et al. A Haplotype of the Norepinephrine Transporter (Net) Gene Slc6a2 is Associated with Clinical Response to Atomoxetine in Attention-Deficit Hyperactivity Disorder (ADHD). Neuropsychopharmacol 34, 2135–2142 (2009). https://doi.org/10.1038/npp.2009.39
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DOI: https://doi.org/10.1038/npp.2009.39
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