Dopamine Transporter Genotype and Response to Methyphenidate Treatment in Children with ADHD

Maryam Ajikobi1,2, Weam Fageera1,2, , Sarojini M. Sengupta1,3, Natalie Grizenko1,3, and Ridha Joober1,2,3

1. Douglas Mental Health University Institute, Montreal, Quebec, Canada; 2. Department of Human Genetics, McGill University, Montreal, Quebec, Canada; 3. Department of Psychiatry, McGill University, Montreal, Quebec, Canada

Background: Stimulant medications such as methylphenidate (MPH) are the most frequently used efficient medication for ADHD. MPH functions primarily by inhibiting the dopamine transporter (DAT) a protein accountable for the reuptake of dopamine from the synapse into presynaptic terminals. Most genetic association studies with ADHD have investigated the 40-bp variable number tandem repeats (VNTR) polymorphism in the 3’-untranslated region (UTR) of the DAT1, but these investigations reported heterogeneous findings. Given these previous findings, it is plausible to investigate the effect of these SLC6A3 polymorphisms and in a larger sample to better understand the unexplained variability in response to MPH treatment in children with ADHD.

Methods: Four hundred and sixty Caucasian children with ADHD (6-12 years) were assessed using the Conner’s Global index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of their treatment to MPH (0.5mg/kg/day) using a 2-week double-blind placebo-controlled crossover trial. In addition to the 3’UTR VNTR polymorphism we also explored the role of five other single nucleotide polymorphisms (SNPs) namely: DAT1exon9, DAT1int9, DAT1Intron8 VNTR, rs463379 and rs460000 in modulating short term therapeutic response to MPH in this extended sample of children with ADHD.

Results: Children were genotyped for the DAT1 polymorphisms, as specified by a substantial genotype, a treatment two-way interaction. In our previous report we observed a significant genotype by treatment interaction for the 3’UTR VNTR CGI-Parents. We re-investigate using an independent sample and found no association with the treatment response for the 3’UTR VNTR and the other SNPs.

Conclusions: Results from this study revealed no association between the DAT1 genotypes in the gene by treatment response to methylphenidate and behavioral dimension of children with ADHD.

Key words: ADHD; Dopamine transporter; Methylphenidate; Pharmacogenetics 3’-UTR VNTR.