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

辛伐他汀加锂治疗双相抑郁症的体外和体内研究

• 批准号: 8244180
• 负责人: STEPHEN J HAGGARTY
• 金额: $ 26.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244180
• 关键词: Acute; Adverse effects; Antidepressive Agents; Biological Assay; Bipolar Depression; Bipolar Disorder; Blood - brain barrier anatomy; Cell model; Cells; Central Nervous System Diseases; Chronic; Clinic; Clinical; Clinical Trials; Coenzyme A; Dementia; Development; Disease; Disease remission; Double-Blind Method; Enrollment; Exhibits; FDA approved; Fibroblasts; Fluoxetine; Functional disorder; Future; Glycogen Synthase Kinase 3; In Vitro; Individual; Investigation; Lithium; Mental Depression; Modeling; Montgomery and Asberg depression rating scale; Mood stabilizers; Moods; Morbidity - disease rate; Neuronal Plasticity; Neurons; Outcome; Outpatients; Oxidoreductase; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Placebo Control; Placebos; Randomized; Recruitment Activity; Resources; Rodent; Safety; Screening procedure; Signal Pathway; Signal Transduction; Simvastatin; Swimming; Testing; Time; Work; base; depressive symptoms; disorder later incidence prevention; drug development; efficacy trial; experience; high throughput screening; hypercholesterolemia; in vivo; induced pluripotent stem cell; inhibitor/antagonist; mortality; nerve stem cell; neurogenesis; novel; population based; pre-clinical; research study; response; single episode major depressive disorder; standard care

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. PUBLIC HEALTH RELEVANCE: Bipolar depression is frequently chronic and disabling, and the need for new treatments is acute. The proposed investigation will investigate the potential efficacy of a novel treatment with well-established safety. At the same time, it will help to validate a cell-based model useful for identification of future bipolar depression treatments.

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很大影响。虽然多种药物已被证明对治疗这些发作有效，但大多数患者的症状未能完全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作用机制的研究可能会提供新的治疗目标。我们小组和其他人的工作强烈表明 Wnt/GSK3 信号传导与锂的作用机制有关，锂仍然是双相抑郁症和预防复发的一线治疗方法。因此，我们在神经元细胞中利用基于高通量细胞的筛选来识别在对 Wnt/GSK3 信号传导的影响方面与锂表现出潜在加和或协同作用的化合物。在 F.D.A. 批准的具有适合长期使用的安全性的活性药物中，我们发现了多种他汀类药物与 Wnt3a 治疗具有协同作用，并且与锂治疗显示出进一步的相加作用，其中包括辛伐他汀，它是已知能够穿过血脑屏障的最有效的他汀类药物之一。我们已验证 3-羟基-3甲基戊二酰辅酶 A (HMG-CoA) 还原酶为相关靶标。他汀类药物尚未在双相情感障碍的治疗中得到直接检验。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还表明，他汀类药物可能与抑郁症状的统计显着减少以及不良精神结果可能性的降低有关。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，抑郁症状有所减轻。我们现在建议对辛伐他汀作为锂盐的附加治疗方案，对重度抑郁发作的 I 型双相情感障碍门诊患者进行一项随机、双盲、安慰剂对照、概念验证研究。与此同时，我们将收集成纤维细胞并衍生诱导多能干细胞 (iPSC) 和神经元祖细胞 (NP)。然后，在使用或不使用锂和辛伐他汀治疗的情况下，将在基于细胞的测定中对患者特异性 iPSC 衍生的 NP 细胞中 Wnt 信号通路的功能进行量化，以便能够检查 Wnt/GSK3 信号传导与抑郁症状改善程度之间的关联。这些实验预计将成为开发新的双相药物疗法的关键的第一步。通过根据对 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，并尝试使用患者特异性神经元细胞模型将这些反应关联起来，我们提出的研究将为 Wnt/GSK3 信号转导在调节双相情感障碍和抑郁症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表型良好、源自患者的细胞资源，这些资源可应用于未来锂类药物高通量筛选的研究。 公共卫生相关性：双相抑郁症通常是慢性且致残的，迫切需要新的治疗方法。拟议的调查将调查一种具有良好安全性的新型治疗方法的潜在疗效。同时，它将有助于验证基于细胞的模型，该模型可用于识别未来双相抑郁症的治疗方法。