In vitro and in vivo study of simvastatin plus lithium in bipolar depression

描述(由申请人提供)：严重的抑郁发作对双相情感障碍的发病率和死亡率有很大影响。虽然多种药物已证明对这些发作的治疗有效，但大多数患者并未达到完全症状缓解或难以耐受这些药物。对已知对双相情感障碍有效的治疗的作用机制的研究可能提供新的治疗靶点。我们小组和其他人的工作强烈表明WNT/GSK3信号与锂的作用机制有关，锂仍然是治疗双相抑郁和预防复发的一线药物。因此，我们在神经细胞中利用高通量细胞筛选来识别在Wnt/GSK3信号转导方面显示出与锂潜在相加或协同作用的化合物。在FDA批准的安全性与长期使用相适应的活性药物中，我们发现了多种他汀类药物，它们与WNT3a治疗具有协同作用，并与锂治疗显示出进一步的相加作用，包括辛伐他汀，这是已知的能够穿越血脑屏障的最有效的他汀类药物之一。我们验证了3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶为相关靶点。他汀类药物尚未被直接用于双相情感障碍的治疗。最近的一项啮齿动物研究发现，有证据表明他汀类药物可以增强氟西汀的抗抑郁作用。有趣的是，多项基于人群的研究也表明，他汀类药物可能与抑郁症状的统计显著减少和不良精神后果的可能性降低有关。另一项检查他汀类药物治疗痴呆症的研究表明，与安慰剂相比，抑郁症状有所减少。我们现在建议进行一项随机、双盲、安慰剂对照的概念验证研究，将辛伐他汀作为门诊双相I型障碍患者在严重抑郁发作时对锂的附加治疗。同时，我们将收集成纤维细胞，并获得诱导多能干细胞(IPSCs)和神经前体细胞(NP)。然后，在锂和辛伐他汀治疗和不使用锂和辛伐他汀治疗的情况下，患者特定的IPSC来源的NP细胞中Wnt信号通路的功能将被量化，以检验Wnt/GSK3信号与抑郁症状改善幅度之间的关联。预计这些实验将成为开发新的双极药物疗法的关键的第一步。通过基于对Wnt/GSK3信号通路的影响来预测双相情感障碍辅助治疗的益处，并尝试使用患者特定的神经细胞模型来关联这些反应，我们拟议的研究将提供一项关键测试，以检验Wnt/GSK3信号在调节双相情感障碍和抑郁症的神经可塑性中的重要性。至少，这些研究还将为未来锂反应和双相情感障碍的研究提供表型良好的患者来源的细胞资源，可应用于未来高通量筛选类锂药物的研究。

DESCRIPTION (provided by applicant): Major depressive episodes contribute substantially to morbidity and mortality in bipolar disorder. While multiple medications have demonstrated efficacy for treating these episodes, a majority of patients do not reach complete symptomatic remission or have difficulty tolerating these medications. Studies of the mechanism of action of treatments known to be effective in bipolar may provide new treatment targets. Work by our group and others strongly implicates Wnt/GSK3 signaling in the mechanism of action of lithium, which remains a first-line treatment for bipolar depression as well as prevention of recurrence. We therefore have utilized high-throughput cell-based screening in neuronal cells to identify compounds that showed potential additivity or synergy with lithium in terms of effects on Wnt/GSK3 signaling. Among the active F.D.A.-approved drugs with safety profiles compatible with long-term use, we identified multiple statins that acted synergistically with Wnt3a treatment and show further additivity with lithium treatment, including simvastatin, one of the most potent statins known to be capable of crossing the blood-brain barrier. We have validated 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase as the relevant target. Statins have not been directly examined in the treatment of bipolar disorder. A recent rodent study found evidence that a statin augmented the antidepressant-like effects with fluoxetine. Intriguingly, multiple population-based studies also suggest that statins may be associated with a statistically significant decrease in depressive symptoms, and a decrease in the likelihood of adverse psychiatric outcomes. Another study examining statin treatment of dementia indicated a decrease in depressive symptoms compared to placebo. We now propose to conduct a randomized, double-blind, placebo-controlled, proof-of-concept investigation of simvastatin as add-on treatment to lithium in outpatients with bipolar I disorder in a major depressive episode. In parallel, we will collect fibroblasts and derive induced pluripotent stem cells (iPSCs) and neuronal progenitor (NP) cells. The function of the Wnt signaling pathway in patient-specific iPSC-derived NP cells will then be quantified in cell-based assays, with and without treatment with lithium and simvastatin, to enable examination of the association between Wnt/GSK3 signalling and magnitude of improvement in depressive symptoms. These experiments are expected to serve as a crucial first step in the development of new bipolar pharmacotherapies. By predicting the benefit of an adjunctive therapy for bipolar disorder based upon its effects on Wnt/GSK3 signaling pathway and attempting to correlate these responses using patient-specific neuronal cell models, our proposed study will provide a critical test of the importance of Wnt/GSK3 signaling in regulating neuroplasticity in bipolar disorder and depression. At a minimum, these studies will also provide a well-phenotyped, patient-derived cellular resource for future investigation of lithium response and bipolar disorder that can be applied in future studies toward high-throughput screening for lithium-like drugs.