精神分裂症之NMDA受體功能低下假說

The Hypothesis of NMDA Receptor Hypofunction for Schizophrenia

精神分裂症是屬於多因子所造成的疾病，包括多基因遺傳及環境影響等因素，且此疾病 具有特殊的症狀及神經認知缺損。認知功能缺損比起正性症狀更能決定病人的生活品質、整 體功能及預後。雖然致病機轉目前尚不明確，廣泛的研究正在進行中。在各種機轉中，最受 矚目之一的假說為NMDA 受體功能障礙。此文章主要回顧了臨床上使用抗精神病藥物治療 核心症狀之侷限及面臨病情和治療策略需要概念重建的趨勢。NMDA 受體之模型在製藥產 業革命性的發展中扮演了關鍵性的角色，因為除了傳統的單胺(monoamine) 模型外，一組新 的藥物標靶即將崛起。基因及臨床研究對於探討調控glutamate 系統，尤其是NMDA/glycine 的部位，為NMDA 受體功能低下的假說陸續提供了前瞻性的證據。「NMDA 促進劑」，不 管是單一或合併抗精神病藥物使用，皆能在臨床前及早期臨床試驗中有效地改善難治型精神 分裂症病人的精神症狀，尤其是負性症狀及認知功能缺損。此發現將使NMDA 促進劑在治 療精神分裂症的藥物研發上展露新契機。

Schizophrenia, a multifactorial mental disorder with polygenic inheritance as well as environmental infl uences, encompasses a characteristic group of symptoms and neurocognitive defi cits. Cognitive function, a major determinant of quality of life and overall function in schizophrenia, contributes more to the prognosis of the disease than positive symptoms, such as delusions or hallucinations. Although its exact etiological mechanisms remain relatively unknown, extensive studies are ongoing to explore. Among them, one of the primary causal factors is dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews the clinical limitations of current antipsychotics in treating the core symptoms of schizophrenia and the trend in the reconceptualization of the disease nature and treatment modalities. The NMDA receptor model plays a critical role in the revolution of pharmaceutical industry as a new set of drug targets in addition to those based on the traditional monoaminergic models is proposed. The evidence of NMDA receptor hypofunction in schizophrenia is accumulating from the investigations on the modulation of glutamatergic system, particularly the intrinsic NMDA/glycine site, through genetic research and various clinical trials. A group of “NMDA-enhancing agents,” being used either as adjuncts to typical/atypical antipsychotics or as monotherapy, in schizophrenic patients, particularly those with refractory negative and cognitive symptoms, offer effi cacy in preclinical and early clinical trials. Novel therapeutic agents acting as NMDA enhancers show promise as the next wave of drug development for schizophrenia.