Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder.
Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder.
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DOI：
10.1038/s41380-020-0769-6
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发表时间：
2021-09
影响因子：
11
通讯作者：
Vasudevan SR
中科院分区：
文献类型：
--
作者：
Sanghani HR;Jagannath A;Humberstone T;Ebrahimjee F;Thomas JM;Churchill GC;Cipriani A;Attenburrow MJ;Perestenko OV;Cowley SA;Cader MZ;Peirson SN;Harrison PJ;Foster RG;Goodwin GM;Vasudevan SR
双相情感障碍是一种与情绪不稳定相关的慢性神经精神疾病，患者表现出明显的睡眠和昼夜节律异常。目前，双相情感障碍的病理生理学仍然难以捉摸，但锂治疗仍然作为基准药物疗法，对大多数（但不是所有）患者起到有效的情绪稳定剂的作用。有充分证据表明，锂可以引起生物钟的周期延长和幅度增强。基于此，我们试图研究锂是否对双相情感障碍患者细胞系的昼夜节律产生不同的影响，以及至关重要的是，锂对生物钟的影响是否是其情绪稳定作用的基础。我们分析了双相情感障碍患者来源的成纤维细胞 (n = 39) 的昼夜节律及其对锂和其他三种时间调节剂的反应。在这里，我们显示，相对于对照组（n = 23），患者表现出更广泛的昼夜节律分布（p < 0.05），并且周期较长的患者服用更广泛的药物，表明锂的有效性较低。一致的是，周期较长的患者成纤维细胞对锂以及其他表型锂的时间调节剂表现出柔和的昼夜节律反应。这些结果表明，锂以患者特定的方式对昼夜节律系统产生不同的影响，其影响取决于患者的昼夜节律表型。我们还发现，锂诱导的小鼠行为变化可以通过针对生物钟的药物调节昼夜节律系统来模拟，而功能失调的生物钟会消除这种反应。因此，时间调节化合物为新的治疗范例提供了一条有前途的途径。这些发现经过更大规模的验证，可以促进实施个性化的情绪稳定方法。
Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium’s effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient’s circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.
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影响因子：
--
作者：
Gossan, Nicole;Zeef, Leo;Hensman, James;Hughes, Alun;Bateman, John F.;Rowley, Lynn;Little, Christopher B.;Piggins, Hugh D.;Rattray, Magnus;Boot-Handford, Raymond P.;Meng, Qing-Jun
通讯作者：
Meng, Qing-Jun
影响因子：
6.8
作者：
Carr O;Saunders KEA;Bilderbeck AC;Tsanas A;Palmius N;Geddes JR;Foster R;De Vos M;Goodwin GM
通讯作者：
Goodwin GM
影响因子：
17.7
作者：
Harmer, Catherine J.;O'Sullivan, Ursula;Cowen, Philip J.
通讯作者：
Cowen, Philip J.
DOI：
10.1073/pnas.0707772105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Brown, Steven A.;Kunz, Dieter;Kramer, Achim
通讯作者：
Kramer, Achim
DOI：
10.1073/pnas.0811410106
发表时间：
2008-12-30
影响因子：
11.1
作者：
Hirota, Tsuyoshi;Lewis, Warren G.;Kay, Steve A.
通讯作者：
Kay, Steve A.