Lithium, circadian rhythm, and bipolar disorder

五十多年来，情绪稳定剂锂已经证明了它在预防躁狂复发和 对双相情感障碍患者来说，自杀比其他任何药物都要多。然而，只有一小部分患者受益于 锂治疗，完全的好处可能在几个月内不会明显，而锂有不利的，有时 有毒的，副作用。因此，一种简单、快速和可靠的方法来预测哪些患者将表现出 对锂的治疗反应是必要的，可以在治疗前使用。在这项提案中， 锂对外周细胞(成纤维细胞)情绪稳定和昼夜节律表达的影响 在锂敏感和锂不敏感的双相情感障碍患者中相互关联，以确定 人外周细胞昼夜节律表达可用于预测临床锂敏感性 双相情感障碍患者。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。 至少一些形式的双相情感障碍，如锂影响昼夜节律的表达，以及预定的睡眠觉醒 周期和长时间的黑暗稳定了情绪波动。此外，使用外设的可行性 最近的一项研究报告了细胞决定人类昼夜节律的表达。找到了 双相情感障碍患者血细胞中的几个生理因素受到影响，这可能是 外周细胞和昼夜节律输出可用于锂响应性的诊断分析。 我们目前建议的一个目标是建立一种可以监测昼夜节律的检测系统 使用具有昼夜节律报告和实时生物发光监测的人成纤维细胞，并测试 假设可以使用人类外周细胞预测临床对锂的反应。因此，具体来说 目标是：(1)建立和优化一种可以监测昼夜节律的筛选方法 以及(2)检验锂对昼夜生物发光有不同影响的假设 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，我们希望 建立一种检测方法，在药物治疗前预先筛查患者的锂反应，并在未来 研究，剖析双相情感障碍的机制，特别是从锂的观点 敏感度和昼夜节律产生。模型和检测系统也应在介质中使用 高通量筛选治疗锂敏感和耐药双相情感障碍患者的新药 无序。

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.