LITHIUM RESPONSIVE BIPOLAR DISORDER AND CNS MYO INOSITOL

锂反应性双相情感障碍和中枢神经系统肌醇

• 批准号: 2908653
• 负责人: HUSSEINI K MANJI
• 金额: $ 32.5万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2908653
• 关键词: antidepressants; biological signal transduction; bipolar depression; brain mapping; central nervous system; clinical research; drug resistance; human subject; human therapy evaluation; inositol; interview; lithium; mental disorder chemotherapy; neurochemistry; neuropsychology; nuclear magnetic resonance spectroscopy; phosphatidylinositols; second messengers

Bipolar Affective Disorder (BD) is a common, severe, chronic and life-threatening illness. The discovery of lithium's efficacy revolutionized the treatment of patients with BD, and after more than two decades, lithium continues to be the mainstay of treatment. The effect on the broader community has been highlighted by one estimation that the use of lithium saved the United States US4 billion dollars in a recent year period, by reducing associated medical costs and restoring productivity. However, despite its role as one of psychiatry's most important treatments, lithium's mechanisms of action remain to be fully elucidated. Furthermore, increasing evidence suggests that a significant number of patients respond poorly to lithium therapy, with an estimated 20 percent to 40 percent failing to show an adequate therapeutic response to lithium. Studies such as these indicate two important and highly clinically relevant directions for future research: firstly, the need to better identify patients likely to respond to lithium treatment, and secondly, the necessity to develop more effective treatment regimens. The most widely accepted hypothesis underlying lithium's therapeutic efficacy is the inositol depletion hypothesis. This hypothesis posits that lithium produces a relative depletion of myo-inositol (mI) in critical areas of brain and it is this depletion of a major precursor of the phosphoinositide second messenger system which ultimately results in its therapeutic effects. Despite the attractiveness of the inositol depletion hypothesis, it has never been investigated in BD patients. Thus, there is a clear need to determine if lithium reduces the levels of mI critical brain regions of individuals with BD, and if individual differences in susceptibility to lithium-induced CNS mI reductions represent major factors determining resistance or sensitivity to lithium's therapeutic effects. The proposed research will utilize non-invasive proton magnetic resonance spectroscopy (MRS) technology to determine if lithium treatment alters regional mI concentrations in the human brain. In addition, the research will determine if alterations in brain mI levels are associated with responsiveness to lithium's antidepressants effects. This research offers the potential not only to facilitate in the identification of patients most likely to respond to lithium treatment, but may also facilitate the development of novel therapeutic agents.

双极情感障碍（BD）是一种常见，严重，慢性和威胁生命的疾病。 锂的疗效的发现彻底改变了对BD患者的治疗，经过二十年，锂仍然是治疗的主要手段。 据估计，锂在最近一年中为美国节省了40亿美元，通过降低相关的医疗费用和恢复生产率，对更广泛的社区的影响得到了强调。然而，尽管它是精神病学最重要的治疗方法之一，但锂的作用机制仍尚待充分阐明。 此外，越来越多的证据表明，大量患者对锂治疗的反应很差，估计有20％至40％未能表现出对锂的适当治疗反应。 诸如此类的研究表明了两个重要且高度临床相关的研究方向：首先，需要更好地识别可能对锂治疗反应的患者，其次是开发更有效治疗方案的必要性。锂治疗疗效的基本假设最广泛的假设是肌醇耗竭假说。 该假设认为，锂会在大脑关键区域产生肌醇（MI）的相对耗竭，正是磷酸辛酰胺二信使系统的主要前体的耗竭最终导致其治疗作用。 尽管肌醇耗竭假说具有吸引力，但BD患者从未对其进行研究。 因此，明确需要确定锂是否降低了患有BD的个体的MI关键脑区域的水平，以及是否在锂诱导的CNS MI降低的易感性上的个体差异代表了确定对锂治疗效应的抗药性或敏感性的主要因素。 拟议的研究将利用非侵入性质子磁共振光谱（MRS）技术来确定锂处理是否改变了人脑中的区域MI浓度。 此外，研究将确定脑MI水平的改变是否与锂抗抑郁药作用的反应性有关。 这项研究不仅提供了促进最有可能对锂治疗反应的患者的潜力，而且还可能促进新型治疗剂的发展。