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.

双相情感障碍（BD）是一种常见、严重、慢性且危及生命的疾病。 锂功效的发现彻底改变了双相情感障碍患者的治疗，二十多年后，锂仍然是治疗的支柱。 据一项估计，锂的使用通过降低相关医疗成本和恢复生产力，在最近一年内为美国节省了 40 亿美元，这突显了锂对更广泛社会的影响。然而，尽管锂是精神病学最重要的治疗方法之一，但其作用机制仍有待充分阐明。 此外，越来越多的证据表明，大量患者对锂疗法反应不佳，估计有 20% 至 40% 的患者未能对锂表现出足够的治疗反应。 诸如此类的研究表明了未来研究的两个重要且与临床高度相关的方向：首先，需要更好地识别可能对锂治疗有反应的患者，其次，有必要开发更有效的治疗方案。锂治疗功效最广泛接受的假说是肌醇耗尽假说。 该假说认为，锂会导致大脑关键区域的肌醇 (mI) 相对消耗，正是这种磷酸肌醇第二信使系统主要前体的消耗最终产生了治疗效果。 尽管肌醇消耗假说很有吸引力，但从未在双相情感障碍患者中进行过研究。 因此，显然需要确定锂是否会降低 BD 患者关键脑区 mI 的水平，以及对锂引起的 CNS mI 降低的易感性的个体差异是否是决定对锂治疗效果的抵抗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波谱 (MRS) 技术来确定锂治疗是否会改变人脑中的局部 mI 浓度。 此外，该研究还将确定大脑 mI 水平的变化是否与锂的抗抑郁作用的反应有关。 这项研究不仅有可能促进识别最有可能对锂治疗产生反应的患者，而且还可能促进新型治疗药物的开发。