Pharmacogenetic Studies on Attention Deficit Hyperactivity Disorder

Background: The science of pharmacogenetics seeks to identify patterns of genetic variation that will direct individually tailored treatment regimens and enhance long-term adherence. Attention deficit hyperactivity disorder (ADHD), characterized by inattention, hyperactivity and impulsivity, is an early onset, highly heritable, clinically heterogeneous, long-term impairing disorder with tremendous impact on individuals, families, and societies. It affects 5-10% of school-aged children worldwide (7.5% in Taiwan) and 2-4% of adults. Although the efficacy of medications for ADHD is well demonstrated in clinical trials, substantial numbers of patients fail to remain on therapy, and there is tremendous variability in tolerability and treatment acceptance. An understanding of genetic predictors of ADHD medication response is likely to influence future clinical treatments, inform research on treatment-resistant ADHD patients, and identify patients at increased risk for significant treatment related adverse events. Although interest in ADHD pharmacogenetics is encouraging, conflicting results in previous studies may reflect genetic heterogeneity and differences in phenotype, and medication response in ADHD children likely results from the combined effects of several potential genes. In addition, the categorical measure of treatment effects and retrospective study design may not have been sensitive enough to pick up statistically significant differences in treatment response based on genotype. Further prospective studies including quantitative measures of medication response are warranted.

Specific Aims:

1. to assess the specific genetic moderators of methylphenidate and atomoxetine response using repeated outcome measurements;
2. to examine the association between genetic polymorphisms and medication effects on the neuropsychological functions;
3. to identify the gene-gene interactions in pharmacogenetics for ADHD. Subjects and Methods: We will recruit 160 drug-naïve ADHD patients and 80 matched normal controls, aged 7-18. The patients will be randomly assigned to two treatment groups, the OROS-methylphenidate group (n=80) and the atomoxetine group (n=80), respectively. After complete assessment at baseline and administration of either OROs-methylphenidate or atomoxetine, patients with ADHD will be reassessed at Week 2, 4, 8, 12, 16, and 24 mainly for vital signs, behavioral symptoms, and psychosocial functions evaluations using the SNAP-IV, YSR, CBCL, CGI-ADHD-S, CGI-ADHD-I, SAICA, and Family APGAR-C. Neuropsychological tests, including CPT, Time Perception Tasks, and CANTAB, will be performed at Week 4 and 16. The DNA will be collected, and the candidate genes (DAT1, DRD4, DRD5, SLC6A2, and SLC6A4) hypothesized to influence medication effects or individual risks for ADHD will be genotyped.

Anticipated Results: We anticipate that this study will delineate the pharmacogenetics for ADHD by determining the association between medication response and genetic variants in a Taiwanese sample. The findings of different approaches to identify the effects of genotypes on the drug response in this study should help us to extend our understanding of the genetic basis of ADHD. Development of individualized medication regimens based on patient genetic variability might lead to optimized symptom reduction, improved tolerability, and concomitant improvements in patient adherence. Conversely, patients with increased genetic risk for treatment failure or significant adverse effects could be spared exposure to certain compounds that are of unlikely benefit. Pharmacogenetics also has a potential role in the development of new compounds for ADHD therapy. The use of genetic screening in dosing will provide a model for future drug development, in which outcome variability is assessed in genetic subgroups and not merely on the basis of treatment assignment.