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| 題名: | N-METHYLGLYCINE(SARCOSINE)用於憂鬱症之治療 |
| 作者: | 藍先元(Lane,Hsien-Yuan) |
| 貢獻者: | 醫學院醫學系學士班精神醫學科 |
| 日期: | 2006-12-19 |
| 上傳時間: | 2009-09-01 16:25:15 (UTC+8) |
| 摘要: | 背景：憂鬱症（major depressive disorder）是一個複雜而多因子的疾病，無法以單一基因或環境因素解釋其病因，目前尚缺乏可靠的生物標記。傳統的抗鬱劑，都是針對單胺類神經遞質作調節，但療效仍有侷限，作用發生速度慢，且對認知功能的改善亦未有令人滿意的效果，故透過其他神經傳導系統的治療方式正在積極開發中，glutamate receptor也是其中一個重點，其亞型N-methyl-D-aspartate (NMDA)受體在記憶、學習上均扮演重要的角色，NMDA受體促進劑已被嘗試作為精神分裂症的輔助治療，已知其相當安全，且除了對活性、負性症狀有幫助外，其中有一種NMDA受體促進劑sarcosine（也是一種內源性glycine transporter抑制劑）還能改善精神分裂症患者常見的憂鬱症狀（Lane et al [藍等] Arch Gen Psychiatry 2005 [SCI影響係數11.2]）；動物實驗也發現glycine transporter-I抑制劑能夠減緩大鼠的憂鬱及焦慮情形。最近我們在前驅的開放性研究中，亦發現sarcosine單一治療能快速地改善憂鬱症患者的症狀，且無明顯副作用。所以，sarcosine是否與現有的抗鬱劑具有同樣、甚至更好、更快速、更安全的療效，並提供更好的認知功能效果，值得探索。近年來基因mRNA表現量的變化與精神疾患的關係漸受重視，有研究發現憂鬱症患者週邊淋巴球DRD4受體之mRNA較之正常人為低，而CREB mRNA表現與正常人無異，但會隨著藥物治療而變化。然而，大部分的候選基因仍尚未有系統性之研究。我們設計此一研究，期望能了解sarsosine的抗鬱效果，憂鬱症患者白血球中與NMDA功能有關基因之mRNA表現情形，及其與藥物療效的關係。方法：本研究為11個月之前瞻性研究，我們將收案60名憂鬱症患者(符合DSM-IV診斷標準)，年齡介於18-55歲。我們將評估其憂鬱嚴重度(24項漢氏憂鬱量表)、自殺意念強度(貝氏自殺量表)，隨機給予一種常用的抗鬱劑citalopram（最具專一性的血清色素回收抑制劑 [SSRI]）(20-60 mg/day)或sarcosine (0.5-2.0 g/day)，治療期間每兩週評估一次以上項目，治療前後分別施測認知功能(記憶廣度、段落記憶、Wisconsin卡片分類測驗)。實驗室方面，在治療前後測定SHMT2、AMT、PSAT1、ASCT1、serine racemase等與glycine及其他胺基酸代謝或NMDA功能相關之基因於週邊白血球之mRNA (以realtime RTQ-PCR測定)表現量。我們將比較SSRI與sarcosine的療效、安全性、對認知功能的影響，也將由臨床特徵、認知功能表現、特定基因在週邊白血球之mRNA表現量等諸多變項中，找尋對於sarcosine反應較佳的預測因子。
Background: Major depressive disorder is a complex disease and can not be attributed to any single genetic or environmental factor. At present there is no reliable biological marker for clinical use. Most currently available antidepressants aiming at monoamine neurotransmission exhibit limited efficacy and cognitive effects. Novel therapies via manipulating other neurotransmission (e.g. glutamate receptor) are being developed. N-methyl-D-aspartate (NMDA), one subtype of glutamate receptors, plays an important role in learning and memory. NMDA enhancing agents (e.g. N-methylglycine) has been studied as adjunctive therapy of schizophrenia, and has shown satisfactory safety profile. N-methylglycine (sarcosine) not only benefited positive and negative symptoms but also improved depressive symptoms commonly seen in schizophrenic patients. From the pilot study, we found that sarcosine (500 mg/d) could improve the symptoms/signs of depressive patients rapidly, in aspects of mood, energy, appetite and concentration. Therefore, it deserves further study whether sarcosine has equal effectiveness with current antidepressants, and even better cognitive effects.In recent years, the relationships between mRNA expression and psychiatric diseases have gained more attention. It is considered that mRNA could reflect the interactions of the genes and the environment. For example, mRNA of DRD4 gene in peripheral lymphocytes was lower in major depressive patients than in healthy subjects. Thereis no difference of mRNA of CREB in patients and in healthy subjects, but it changed with medical treatment. Most candidate genes have not been investigated systemically. Hence, this study aim to understand the mRNA expression of NMDA-related genes in peripheral white cells in major depressive patients, and which relationships with clinical efficacy.Methods:This is a eleven month, prospective study project. We will enroll 60 patients (fulfilled the DSM-IV criteria of major depressive disorder), aged within 18-55. We will evaluate the severity of depression (with 24-item Hamilton Depression Rating Scale), cognitive functioning (Digit Span, Episodic Memory, Wisconsin Card Sorting Test), and the intensity of suicidal ideation (with Beck Suicide Scale). Those with strong suicidal ideations will be excluded. Citalopram (20-60 mg/d), sarcosine (0.5-2.0 g/d) or placebo will be given with a randomized, double blind manner. All subjects will be evaluated again after six-week treatment. Besides, mRNA of SHMT2, AMT, PSAT1, ASCT1, and serine racemase in peripheral white cells will be measured by realtime RT-PCR before and after treatment, respectively. We will compare citalopram and sarcosine in aspects of efficacy, safety and cognitive effects, and also search for the predictors for sarcosine responders among the clinical characteristics, cognitive performance, and gene expression. |
| 顯示於類別: | [醫學系] 研究計畫
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