Dopamine Transporter and Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.

Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter- also commonly known as ) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 ) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Genetic variations in and were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: = 0.058, Methylphenidate [MPH]: = 0.044). There was also a trend for the 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine ( = 0.029). Participants with 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Most children with ADHD who were CYP2D6 normal metabolizers or had 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of and with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.