Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder
Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder
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DOI：
10.1038/s41386-018-0273-8
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发表时间：
2019-02-01
影响因子：
7.6
通讯作者：
Kelsoe, John R.
中科院分区：
文献类型：
--
作者：
McCarthy, Michael J.;Wei, Heather;Kelsoe, John R.
双相情感障碍(BD)是一种与昼夜节律异常相关的严重情绪障碍。BD的风险是遗传编码的，并与维持昼夜节律的系统重叠。锂是治疗BD的一种有效的情绪稳定剂，但只有一小部分患者对单一疗法完全有效。目前，我们假设锂盐敏感的BD患者(LI-R)与锂盐无反应者(LI-NR)相比，在时型和细胞昼夜节律方面会表现出不同的特征。我们从锂单一疗法的前瞻性、多中心临床试验中选择患者，考察了193名LI-R和LI-NR型BD患者的昼夜节律功能维度的早晚喜好(时型)。从59名患者捐赠者的子集中，我们使用生物发光报告器(PER2-LUC)纵向测量了皮肤成纤维细胞的昼夜节律超过5天。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供体细胞节律的药理作用。与Li-NRs相比，Li-Rs表现出不同的时型，具有更高的晨度水平。晚间时型与基线时情绪症状增加有关，包括抑郁、躁狂和失眠。来自Li-Rs的细胞更有可能表现出较短的昼夜节律周期，周期和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影响的一些个体差异。我们的结论是，昼夜节律可能影响维持治疗BD时对锂的反应。
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.