Lithium, circadian rhythm, and bipolar disorder

50多年来，情绪稳定剂锂已被证明在预防躁狂复发方面有效， 双相情感障碍患者自杀率高于其他任何药物。然而，只有一部分患者受益于 锂治疗，充分的好处可能几个月不明显，锂有不利，有时 有毒副作用因此，一种简单、快速和可靠的检测方法来预测哪些患者将表现出 需要对锂的治疗反应，锂可以在治疗前应用。在本提案中， 锂对外周细胞（成纤维细胞）中情绪稳定和昼夜节律表达的影响将 在锂敏感型和锂不敏感型双相情感障碍患者中相关，以确定是否 人外周细胞中的昼夜节律表达可用于预测临床锂敏感性， 躁郁症患者有令人信服的证据表明，在at的发病机制中存在昼夜节律成分。 至少某些形式的双相情感障碍，例如，锂影响昼夜节律表达， 周期和长时间的黑暗会稳定情绪波动。此外，使用外围设备的可行性 在最近的一项研究中，已经报道了用细胞来确定人体的昼夜节律表达。找到了 在双相情感障碍患者中，血细胞中的几种生理因素受到影响， 外周细胞和昼夜输出可用于锂反应性的诊断测定。 我们目前建议的一个目标是建立一个测定系统，通过该系统可以监测昼夜节律 使用人成纤维细胞与昼夜节律报告和真实的时间生物发光监测，并测试 假设锂的临床反应可以使用人外周细胞预测。因此，具体 目的：（1）建立和优化一种监测昼夜节律的筛选方法 在人外周细胞中，和（2）测试锂差异影响昼夜节律Bmall生物发光的假设 锂敏感和锂不敏感患者成纤维细胞的节律。 通过测试锂对人类外周细胞昼夜节律表达的影响，我们期望 在药物治疗之前建立一种检测方法来预先筛选患者对锂的反应性， 研究，剖析双相情感障碍的机制，特别是从锂的角度来看， 敏感性和昼夜节律的产生。该模型和测定系统也应该是有用的， 高通量筛选治疗锂盐敏感和耐药双相情感障碍患者的新药 disorder.

For over fifty years, the mood stabilizer lithium has proven its efficacy in preventing recurrence of mania and suicide in bipolar patients more than any other drug. However, only a sub-population of patients benefit from lithium treatment, full benefits may not be apparent for several months, and lithium has adverse, sometimes toxic, side effects. Therefore, a simple, rapid and reliable assay to predict which patients will show a therapeutic response to lithium, which can be applied prior to treatment, is needed. In this proposal, the effects of lithium on mood stabilization and circadian rhythm expression in peripheral cells (fibroblasts) will be correlated in lithium-responsive and lithium-insensitive bipolar disorder patients, to determine whether circadian rhythm expression in human peripheral cells can be used to predict clinical lithium sensitivity in bipolar disorder patients. There is compelling evidence for a circadian component in the pathogenesis of at least some forms of bipolar disorder, e.g., lithium affects circadian rhythm expression, and scheduled sleepwake cycles and prolonged darkness stabilize mood swings. In addition, the feasibility of using peripheral cells to determine circadian rhythm expression in humans has been reported in a recent study. Having found that several physiological factors in blood cells are affected in bipolar disorder patients, it is probable that peripheral cells and circadian output can be used for a diagnostic assay for lithium responsiveness. A goal of our present proposal is to establish an assay system by which circadian rhythms can be monitored using human fibroblasts with a circadian reporter and real time bioluminescence monitoring, and to test the hypothesis that clinical response to lithium can be predicted using human peripheral cells. Therefore, specific aims will be: (1) To establish and optimize a screening method by which circadian rhythms can be monitored in human peripheral cells, and (2) to test the hypothesis that lithium differentially affects circadian Bmallbioluminescence rhythms in fibroblasts of lithium-responsive and lithium-insensitive patients. By testing the effects of lithium on circadian rhythm expression in human peripheral cells, we expect to establish an assay to pre-screen patients for lithium responsiveness prior to drug treatment, and, in future studies, to dissect the mechanisms responsible for bipolar disorder, particularly from the viewpoint of lithium sensitivity and circadian rhythm generation. The model and assay system should also be useful in medium to high throughput screening for new drugs to treat both lithium-responsive and -resistant patients with bipolar disorder.