2010-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658145摘要：背景：藥物基因學的目標在於尋找與個人化治療有關的基因變異，並可提升長期的藥物遵從性。注意力不足過動症（attention-deficit/hyperactivity disorder，以下簡稱ADHD）的主要表徵包括不專心、過動和衝動，是對個人、家庭及社會具有極大衝擊之早發型、高遺傳性、臨床上異質性之神經精神疾病。世界各國在學齡兒童之盛行率約為5到10%（台灣，7.5%），在成人之盛行率約為2到4%。雖然臨床研究已經顯示藥物治療對於ADHD的成效，但仍然有許多病患無法持續接受治療，並且在藥物的耐受性與接受度方面存有許多差異。若了解ADHD基因在治療效果方面的預測因子，未來將有助於提升臨床治療、幫助藥物治療效果不佳的病患、以及事先找出可能產生藥物副作用的病患。雖然目前國際上對於ADHD藥物基因學的研究持續增加，但是仍未有一致的結果，這可能反應了ADHD患者在基因型與表現型上的異質性，並且藥物效果可能是許多基因共同作用的結果，此外過去採取二分法的測量方式以及回溯性的研究設計，可能都會導致無法偵測到有意義的基因型差異。因此本研究的設計為前瞻性的藥物試驗，以症狀、社會及認知功能多面向的工具評估療效。目的：1. 使用重覆測量的方式找出與ADHD藥物(methylphenidate和atomoxetine)治療效果相關的基因調節因子；2. 找出藥物對神經心理功能產生的反應與基因多形性之間的關聯；3. 找出和ADHD藥物療效的各個基因之間的交互作用。個案與方法：本研究預計將收集160位7-18歲未曾使用過藥物治療的ADHD患者和80位正常控制組的參與者，ADHD患者將被隨機分配至methylphenidate治療組(n=80)及atomoxetine治療組(n=80)，於用藥前、治療後第2、4、8、12、16、24週進行行為症狀及家庭、社會功能評估(包括SNAP-IV、YSR、CBCL、CGI-ADHD-S、CGI-ADHD-I、SAICA、及FamilyAPGAR-C)。於用藥前(加上魏氏兒童智力測驗)、治療後第4及16週進行神經心理學測驗評估(包括持續注意力測驗、劍橋神經心理學自動化測驗、和時間知覺電腦測驗)。我們將收集所有受試者的DNA樣本，並針對可能會影響藥物效果的相關基因(DAT1, DRD4,DRD5, SLC6A2, SLC6A4)進行鑑定。預期結果：我們預期完成本研究可以建立台灣本土的ADHD藥物基因學先導研究，並找出藥物治療效果與基因變異之間的關聯性。藉著不同的測量方式所找出不同基因型對藥物反應的作用，將會幫助我們更加了解ADHD的基因機制，未來根據病患個別的基因型所發展的個人化治療將會有效減輕病症、改善耐受性、以及增加藥物遵從度。相反地，若是病患帶有與療效不佳或顯著副作用相關的基因型，則可以避免接受沒有療效的藥物。藥物基因學在發展新的ADHD治療藥物方面也具有重要的潛力，使用基因篩檢來決定藥物劑量的方式可以提供未來藥物發展的新模式，因為可根據不同的基因型，而非只是不同的藥物，來評估療效之間的差異性。<br> Abstract: Background: The science of pharmacogenetics seeks to identify patterns of genetic variationthat will direct individually tailored treatment regimens and enhance long-term adherence.Attention deficit hyperactivity disorder (ADHD), characterized by inattention, hyperactivityand impulsivity, is an early onset, highly heritable, clinically heterogeneous, long-termimpairing disorder with tremendous impact on individuals, families, and societies. It affects5-10% of school-aged children worldwide (7.5% in Taiwan) and 2-4% of adults. Although theefficacy of medications for ADHD is well demonstrated in clinical trials, substantial numbersof patients fail to remain on therapy, and there is tremendous variability in tolerability andtreatment acceptance. An understanding of genetic predictors of ADHD medication responseis likely to influence future clinical treatments, inform research on treatment-resistant ADHDpatients, and identify patients at increased risk for significant treatment related adverse events.Although interest in ADHD pharmacogenetics is encouraging, conflicting results in previousstudies may reflect genetic heterogeneity and differences in phenotype, and medicationresponse in ADHD children likely results from the combined effects of several potentialgenes. In addition, the categorical measure of treatment effects and retrospective study designmay not have been sensitive enough to pick up statistically significant differences in treatmentresponse based on genotype. Further prospective studies including quantitative measures ofmedication response are warranted.Specific Aims:1. to assess the specific genetic moderators of methylphenidate and atomoxetine responseusing repeated outcome measurements;2. to examine the association between genetic polymorphisms and medication effects on theneuropsychological 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 matchednormal 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 oratomoxetine, patients with ADHD will be reassessed at Week 2, 4, 8, 12, 16, and 24 mainlyfor vital signs, behavioral symptoms, and psychosocial functions evaluations using theSNAP-IV, YSR, CBCL, CGI-ADHD-S, CGI-ADHD-I, SAICA, and Family APGAR-C.Neuropsychological tests, including CPT, Time Perception Tasks, and CANTAB, will beperformed 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 orindividual risks for ADHD will be genotyped.Anticipated Results: We anticipate that this study will delineate the pharmacogenetics forADHD by determining the association between medication response and genetic variants in aTaiwanese sample. The findings of different approaches to identify the effects of genotypeson the drug response in this study should help us to extend our understanding of the geneticbasis of ADHD. Development of individualized medication regimens based on patient geneticvariability might lead to optimized symptom reduction, improved tolerability, andconcomitant improvements in patient adherence. Conversely, patients with increased geneticrisk for treatment failure or significant adverse effects could be spared exposure to certaincompounds that are of unlikely benefit. Pharmacogenetics also has a potential role in thedevelopment of new compounds for ADHD therapy. The use of genetic screening in dosingwill provide a model for future drug development, in which outcome variability is assessed ingenetic subgroups and not merely on the basis of treatment assignment.注意力不足過動症藥物基因學分子基因學藥物反應Attention-deficit/hyperactivity disorderpharmacogeneticsmolecular geneticsmedication response