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

描述（由申请人提供）：重度抑郁发作对双相情感障碍的发病率和死亡率有重要影响。虽然多种药物已经证明对治疗这些发作有效，但大多数患者没有达到症状完全缓解或难以耐受这些药物。对已知有效治疗双相情感障碍的作用机制的研究可能会提供新的治疗靶点。我们和其他人的工作强烈暗示Wnt/GSK3信号通路在锂的作用机制中，锂仍然是双相抑郁症的一线治疗方法，并预防复发。因此，我们在神经细胞中利用基于细胞的高通量筛选来鉴定在Wnt/GSK3信号传导方面与锂表现出潜在可加性或协同作用的化合物。在fda批准的具有长期使用安全性的活性药物中，我们发现了多种他汀类药物与Wnt3a治疗协同作用，并与锂治疗显示出进一步的可加性，包括辛伐他汀，已知能够穿过血脑屏障的最有效的他汀类药物之一。我们已经验证了3-羟基-3甲基戊二酰辅酶A （HMG-CoA）还原酶是相关的靶标。他汀类药物在双相情感障碍的治疗中尚未被直接检验。最近的一项啮齿动物研究发现，他汀类药物增强了氟西汀类抗抑郁药物的作用。有趣的是，多个基于人群的研究也表明，他汀类药物可能与统计上显著减少抑郁症状和减少不良精神结局的可能性有关。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，他汀类药物可以减少抑郁症状。我们现在建议进行一项随机、双盲、安慰剂对照、概念验证的研究，将辛伐他汀作为锂离子的附加治疗，用于双相I型障碍伴有重度抑郁发作的门诊患者。同时，我们将收集成纤维细胞，并获得诱导多能干细胞（iPSCs）和神经祖细胞（NP）。Wnt信号通路在患者特异性ipsc衍生的NP细胞中的功能将通过基于细胞的测定进行量化，在使用和不使用锂和辛伐他汀治疗的情况下，以检查Wnt/GSK3信号通路与抑郁症状改善程度之间的关联。这些实验预计将作为发展新的双相药物治疗的关键的第一步。基于对Wnt/GSK3信号通路的影响，通过预测双相情感障碍辅助治疗的益处，并尝试使用患者特异性神经元细胞模型将这些反应联系起来，我们提出的研究将为Wnt/GSK3信号通路在调节双相情感障碍和抑郁症的神经可塑性中的重要性提供关键测试。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良好的表型，患者来源的细胞资源，可用于未来锂类药物的高通量筛选研究。

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.