Pharmacogenetic Studies on Attention Deficit Hyperactivity Disorder
Condition: Attention Deficit Hyperactivity Disorder
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Study type: Observational

Summary: 
      The ultimate goal of this study is to find the association between specific polymorphism of
      candidate genes and medication response in attention deficit hyperactivity disorder (ADHD)
      patients. These results will lead the investigators' team: (1) to resolve controversies over
      inconsistent findings in previous pharmacogenetic studies; (2) to study the medication effect
      on the neuropsychological functions that are useful candidate endophenotypes for ADHD; (3) to
      delineate the nature and the effect of gene-gene interaction in the drug response of ADHD
      patients.
    

Detailed description: 
      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.
    

Observational model: Case-Control
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        The sample will consist of 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.
      
Biospecimen description: 
      The subjects will receive blood withdrawal. The blood sample will be used for establishing
      lymphoblastoid cell lines, which will be used for molecular genetic experiments.
    
Keywords: Attention-deficit/hyperactivity disorder; pharmacogenetics; molecular genetics; medication response