Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity

methylphenidate; SPECT; DRD4; DAT1 ABSTRACT Purpose: Attention-deficit/hyperactivity disorder (ADHD) and sub- stance use disorders (SUDs) are highly comorbid and may share a genetic vulnerabil- ity. Methylphenidate (MPH), a dopamine transporter (DAT) blocker, is an effective drug for most ADHD patients. Although dopamine D4 receptor (DRD4) and dopamine transporter (DAT1) genes have a role in both disorders, little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs. The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs. Methods: Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with (Tc 99m )TRODAT-1 at baseline and after three weeks on MPH. Caudate and putamen DAT binding potential was calculated. Comparisons on DAT changes were made according to the subjects' genotype. Results: The combina- tion of both DRD4 7-repeat allele (7R) and homozygosity for the DAT1 10-repeat allele (10/10) was significantly associated with a reduced DAT change after MPH treatment in right and left caudate and putamen, even adjusting the results for potential con- founders (P � 0.02; R 2 from 0.50 to 0.56). Conclusions: In patients with ADHD/ SUDs, combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy. This might be important for clinical trials, in terms of better understanding individual variability in treatment response. Synapse 65:154-159, 2011. V V C 2010 Wiley-Liss, Inc.