Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

中文翻译：

---

时间型和细胞昼夜节律预测双相情感障碍患者对锂维持治疗的临床反应。

躁郁症（BD）是一种与昼夜节律异常相关的严重情绪障碍。BD的风险由基因编码，并且与维持昼夜节律的系统重叠。锂是治疗BD的有效情绪稳定剂，但只有少数患者对单药治疗完全有效。目前，我们假设与锂无反应者（Li-NR）相比，锂反应性BD患者（Li-R）在计时型和细胞昼夜节律方面表现出特征差异。从一项前瞻性，多中心，锂单药治疗的临床研究中选择患者，我们研究了193例Li-R和Li-NR BD患者的昼夜节律功能的维度，即早晚偏好（刻板型）。从59个患者捐赠者的子集中，我们使用生物发光报告分子（Per2-luc）在5天内纵向测量了皮肤成纤维细胞中的昼夜节律。然后，我们估计了昼夜节律参数（幅度，周期，相位）以及锂对Li-R和Li-NR供体细胞中的节律的药理作用。与Li-NRs相比，Li-Rs的表型有所不同，早晨的水平更高。晚上的表型与基线时情绪升高的症状有关，包括抑郁，躁狂和失眠。Li-Rs的电池更有可能表现出较短的昼夜节律，周期与相位之间的线性关系以及锂的周期缩短效应。IP3信号通路中常见的遗传变异可能解释了锂对细胞节律的影响中的一些个体差异。