| 摘要: | 研究背景：N-methyl-D- aspartate (NMDA)受體功能低下已被認為與精神分裂症的病理機轉有關。一系列的研究發現：數種能促進NMDA受體傳導的內生性胺基酸(例如：glycine、 D-cycloserine、D-serine、sarcosine等)，作為精神分裂症輔助治療能夠改善臨床症狀，尤其是負性症狀，而且它們皆具有優良的安全性。Sarcosine(一種內生性glycine transporter I抑制劑))被認為是當中最具療效者(Lane et al, Arch Gen Psychiatry 2005)。我們最近也進行sarcosine單獨治療急性發作精神分裂症患者的開放性試驗，發現sarcosine對於部份患者有良好的療效。然而到目前為止，此類研究均限於短期(六週)試驗，且著重在精神症狀的評估，目前唯一較長期的是D-cycloserine六個月的輔助治療試驗，但並未見正面的結果。其他NMDA受體促進劑(特別是sarcosine)是否能改善精神分裂症患者長期的預後，尚未明確。再者，目前仍未明瞭哪些患者適合使用NMDA 促進劑？這些問題均需更進一步的臨床試驗，更完整地分析生物及臨床因子方能解答。此外，目前診斷精神分裂症仍端賴現象學觀察，而缺乏可靠的生物標記，由於活體腦組織取得不易，近年來，週邊淋巴球已被當作大腦基因表現的」探針」。例如，精神分裂症患者的某些基因在週邊血液mRNA表現量異於常人；憂鬱症患者之CREB基因表現會隨著抗鬱劑治療而改變。透過NCBI之UniGene資料庫 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unigene)，我們已找出182個同時在大腦及週邊淋巴球有mRNA表現的基因，期望可以從中找出精神分裂症的生物標記。在本研究中，我們將進行一較長期(六個月)的sarcosine輔助治療，瞭解其對臨床症狀、認知功能及生活品質的效益。此外，我們亦將測定在週邊白血球之mRNA表現，及相關胺基酸之血清濃度，以找尋NMDA受體促進劑臨床療效的生物預測因子。研究方法：本案為三年期計畫，預計收集120位服用適當劑量risperidone(一廣泛使用的第二代抗精神病劑)之精神分裂症患者，其病情呈現穩定但仍有顯著負性症狀(負性症狀量表 [Scale for Assessment of Negative Symptoms，SANS]總分高於40分)，以隨機雙盲方式分成二組，分別在既有的用藥加上sarcosine (2克/日；n=60)或安慰劑(n=60)，為期26週。我們將在第0、2、4、6、10、14、18、22、26週進行評估，項目包括精神症狀 (SANS, Positive and Negative Syndrome Scale, Clinical Global Impression, Global Assessment of Function)、生活品質、副作用等，並在進入研究之前（baseline）、第6週及研究結束時，施行認知功能測驗(包括連續注意力測驗、 Wisconsin卡片分類測驗、河內塔、段落記憶及記憶廣度測驗)。實驗室方面，我們將以real-time RT-PCR量測週邊白血球與NMDA功能相關的基因之mRNA表現，以HPLC量測血清中數種內生性胺基酸 (sarcosine、glycine、 D-serine等與NMDA受體功能相關者) 濃度，我們將比較其在治療前、治療6週與治療結束後的變化，並探究其與臨床表現的可能相關性。我們將分析sarcosine作為長程輔助治療對臨床症狀、生活品質及認知功能的影響，並找尋對於能夠預測臨床療效的實驗室工具。預期結果：我們預期，精神分裂症患者接受連續26週的sarcosine輔助治療，對於減輕臨床症狀（特別是負性症狀）、改善認知功能與生活品質方面將明顯優於安慰劑。數種涉及NMDA受體功能的基因(如SHMT2、AMT、PSAT1、ASCT1、serine racemase等)表現及血清胺基酸濃度，將與臨床反應相關。此外，臨床上負性症狀及認知缺損較明顯的患者，可能對於NMDA促進劑的反應較佳。本研究將進一步驗證精神分裂症之NMDA受體假說，並探索NMDA促進劑的臨床實用價值及療效預測因子。
Background: Hypofunction of N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Serial studies revealed that, several endogenous amino acids which enhance NMDA receptor neurotransmission (e.g. glycine, D-cycloserine, D-serine, sarcosine) could improve clinical manifestations, particularly negative symptoms, as adjuvant therapy for schizophrenia. Moreover, they all yielded excellent safety profiles. Sarcosine (an endogenous glycine transporter I inhibitor) has been suggested to be the most efficacious agent among them (Lane et al, Arch Gen Psychiatry, 2005). We have also conducted an open trial of sarcosine monotherapy in acutely exacerbated schizophrenia patients, and found that a portion of subjects responded well. To date, most of these studies, however, were short-term (6-week) trials and focused on merely symptomatology. Only one study on D-cycloserine extended to 6 months, but yielded a negative result. It has not yet been explored whether other NMDA agents, especially sarcosine (perhaps the most efficacious one), could improve the long-term outcome of schizophrenic patients. In addition, how to identify the patients suitable for NMDA enhancers and how to predict the clinical response of NMDA enhancers remain to be clarified. Currently, diagnosis and treatment response of schizophrenia stands on behavioral phenomenon, without a reliable biological marker. Recently, peripheral white cells have been viewed as 「probes」 of gene expression of brains because of the unavailability of brain tissue in vivo. For example, it has been shown that schizophrenic patients had abnormal mRNA expression of some genes in peripheral blood. Expressions of the CREB gene in depressed patients changed with antidepressant treatment. We have found 182 genes which transcript mRNA in both brains and peripheral blood lymphocytes via the UniGene system (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unigene). Among them we may identify biological markers for schizophrenia and its response predictors. In this proposed project, we will conduct a longer-term (6-month) sarcosine adjuvant treatment to explore its effects on clinical symptomatology, cognitive function, and life quality in patients with schizophrenia. In addition, we will also measure the mRNA expression of NMDA-related genes in peripheral white cells and the concentrations of relevant amino acids in serum. We look forward to uncovering biological predictors for clinical response of this NMDA enhancer. Methods: This is a 3-year proposal. We will recruit 120 schizophrenic patients who remain clinically stable under optimal treatment of risperidone (a commonly used second-generation antipsychotic agent) but still show predominantly negative symptoms (score of Scale for Assessment of Negative Symptoms higher than 40). They will be randomly assigned into two treatment groups in a double-blind manner: sarcosine (2 g/d, n=60) and placebo (n=60), and receive treatment for consecutive 26 weeks. We will do clinical measurements at week 0, 2, 4, 6, 10, 14, 18, 22, 26 during the trial, including symptomatology (Positive and Negative Syndrome Scale, Clinical Global Impression, Global Assessment of Function), quality of life, and side effects. At the beginning, week 6 and the end of the trial, we will measure cognitive functioning (Continuous Performance Test, Wisconsin Card Sorting Test, Tower of Hanoi, Logical Memory and Digit Span Test). In our laboratory, we will measure mRNA expression in peripheral white cells with real-time RT-PCR, and serum amino acids (involving NMDA neurotransmission, e.g. sarcosine, D-serine, glycine etc.) with HPLC. We will examine the difference of before-treatment, after 6-week treatment, and after-treatment, and its relationships with clinical manifestation. We will analyze the effects of sarcosine on life quality and cognitive function as a mid-to-long term adjuvant therapy, and search a laboratory tool which can predict clinical response. Expected Results: We expect that 26-week sarcosine adjuvant therapy will be more efficacious than placebo in reducing negative symptoms and in improving cognitive functions and quality of life of schizophrenic patients. The mRNA expressions of several genes which are involved in NMDA neurotransmission (e.g. SHMT2, AMT, PSAT1, ASCT1, serine racemase, etc) and serum levels of amino acids will be relate to clinical response. Patients with predominantly negative symptoms and cognitive deficits may respond better to sarcosine. The results will lend supports to the NMDA hypothesis of schizophrenia, elucidate the role of sarcosine for schizophrenia treatment, and identify response predictors of the NMDA enhancer. |
