2012-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658144摘要：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，因此若能找出與ADHD藥物治療反應相關的生物標記將對臨床治療具有很大的助益。然而要偵測中樞神經的生物標記(如正子造影)是非常有侵襲性並且昂貴的檢查，但過去的研究已經顯示周邊血液中神經化學物質的mRNA表現量可以反應腦中神經化學物質的濃度，因此找出與ADHD藥物反應相關的周邊血液之生物標記是應當進行的研究方向。目的：1. 檢驗周邊血液中多巴胺標記(DAT1, DRD1, DRD2, DRD3, DRD4, DRD5)之mRNA表現量與ADHD症狀的關係；2. 檢驗周邊血液中多巴胺標記之mRNA表現量與ADHD神經認知功能之內在表現型的關係；3. 找出methylphenidate對ADHD症狀治療效果相關的多巴胺標記；4. 找出methylphenidate對ADHD神經認知功能之內在表現型治療效果相關的多巴胺標記。個案與方法：本研究預計將收集120位7-18歲未曾使用過藥物治療的ADHD病患，這些病患將接受methylphenidate治療，在十二週的治療期間內將會規則地評估藥物的療效(第0, 2, 4, 8,和12週)。主要的療效評估工具為ADHDRS與CGI-ADHD-S，其他評估療效的量化工具則包含SNAP-IV、CBCL、CGI-ADHD-I、SAICA、以及Family APGAR，另外也將施行神經心理測驗，包含魏氏兒童智力測驗、持續注意力測驗、和劍橋神經心理學自動化測驗，同時我們將收集所有受試者的血液樣本，並分析與藥物療效相關的多巴胺標記(DAT1、DRD1、DRD2、DRD3、DRD4、DRD5)之mRNA表現量。預期結果：本研究將找出能預測methylphenidate在症狀與神經認知功能療效之周邊多巴胺標記，找出能預測藥物反應的多巴胺標記將對未來ADHD的個人化治療具有重要的臨床意義，因為可以讓臨床醫師事先預測哪些病患將會從與多巴胺相關的藥物中獲得最大的療效。使用mRNA篩檢來決定使用藥物的方式可提供未來藥物發展的新模式，因為可根據不同的周邊多巴胺標記，而非只是不同的藥物，來評估療效之間的差異性。此外，找出與藥物療效相關的周邊多巴胺標記也將能幫助我們進一步了解ADHD的病理生理機轉。<br> Abstract: Background: 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 variabilityin tolerability and treatment acceptance. It is of great interest to identify biomarkers relating tomedication response in ADHD. However, the procedure for obtaining central markers such asPET scan is invasive and expensive. Previous studies have found that mRNA expression ofneurochemical markers in circulating blood can reflect the neurochemical levels in the brain.Further studies to identify peripheral biomarkers related to medication response in ADHD arewarranted.Specific Aims:1. to examine the relationship between peripheral mRNA expression levels of dopaminemarkers (DAT1, DRD1, DRD2, DRD3, DRD4, and DRD5) and symptomatology of ADHD;2. to examine the relationship between peripheral mRNA expression levels of dopaminemarkers and neurocognitive endophenotypes of ADHD;3. to identify the specific dopamine markers of methylphenidate effects on the symptomatologyof ADHD;4. to identify the specific dopamine markers of methylphenidate effects on the neurocognitiveendophenotypes of ADHD.Subjects and Methods: We will recruit 120 drug-naïve ADHD patients, aged 7-18 in this3-year project. The patients will receive methylphenidate, and the medication response will beassessed regularly within 12-week treatment period (Week 0, 2, 4, 8, and 12). The primaryefficacy measure is the ADHDRS and CGI-ADHD-S. The secondary measures include theSNAP-IV, CBCL, CGI-ADHD-I, SAICA, and Family APGAR. Neuropsychological testing,including WISC-III, CPT, and CANTAB, will be performed. The blood sample will becollected, and the mRNA expression levels of dopamine markers (DAT1, DRD1, DRD2,DRD3, DRD4, and DRD5) hypothesized to influence medication effects risks for ADHD willbe analyzed.Anticipated Results: Our study will identify peripheral dopamine biomarkers that can predictindividual variability in symptomatology and neurocognitive functions following treatmentwith methylphenidate. The ability of peripheral biomarkers to predict response tomethylphenidate administration can have important implications for personalizing thetreatment for ADHD, allowing clinicians to predict which patients will receive greatestbenefit from dopaminergic medications. The use of mRNA screening in dosing will provide amodel for future drug development, in which outcome variability is assessed in subgroups ofperipheral dopamine markers and not merely on the basis of treatment assignment. In addition,the findings of such approaches to identify the peripheral biomarkers on the drug response inthis study should help us to extend our understanding of the pathophysiological mechanism ofADHD.注意力不足過動症症狀學神經認知功能之內在表現型藥物反應Attention-deficit/hyperactivity disordersymptomatologyneurocognitive endophenotypemedication response