The Protein Kinase C Inhibitor Tamoxifen in Acute Mania

蛋白激酶 C 抑制剂他莫昔芬治疗急性躁狂症

• 批准号: 6982748
• 负责人: HUSSEINI K MANJI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6982748
• 关键词: acute disease /disorder; biochemistry; bipolar depression manic phase; clinical trials; drug screening /evaluation; enzyme mechanism; human subject; human therapy evaluation; kinase inhibitor; lithium; mental disorder chemotherapy; patient oriented research; pharmacokinetics; protein kinase C; tamoxifen; valproate

Bipolar Disorder (BD) is a common, severe, chronic and often life-threatening illness. Suicide is the cause of death in 10-20% of individuals with BD. The discovery of lithium's efficacy as a mood-stabilizing agent has since revolutionized the treatment of patients with BD. However, approximately 50% of patients do not respond fully to lithium, and the biochemical basis for lithium's antimanic and mood-stabilizing actions remains to be fully elucidated. Elucidation of the mechanism(s) by which lithium stabilizes an underlying dysregulation of limbic and limbic-associated function also offers the potential to delineate the underlying pathophysiology of BD; however, a major problem inherent in neuropharmacologic research is the difficulty in attributing therapeutic relevance to any observed biochemical finding. One powerful approach is to identify common biochemical targets, which are modified by drugs belonging to the same therapeutic class (e.g. mood-stabilizing agents) but possessing distinct chemical structures when administered in a "therapeutically relevant" paradigm (i.e., effects which are observed upon chronic drug administration, and yet persist beyond abrupt drug discontinuation). In this context, it is noteworthy that both valproic acid (VPA) and lithium, with different chemical structures, belong to the same therapeutic class and cause considerable inhibition of protein kinase C (PKC). The PKC signaling pathway is clearly a target for the actions of two structurally highly dissimilar antimanic agents -- lithium and VPA. Do these effects of lithium and VPA on PKC signaling have any clinical relevance? There is thus a clear need to investigate the potential efficacy of a direct PKC inhibitor in the treatment of acute mania. There is currently only one relatively selective PKC inhibitor available for human use- Tamoxifen. Tamoxifen (TAM; NOLVADEX?), a synthetic nonsteroidal antiestrogen, has been widely used in the treatment of breast cancer. TAM?s potent inhibitory effects on PKC are striking. Recently, our group conducted the first open-label study with TAM in acute mania. In this study, TAM resulted in a significant decrease in manic symptoms within a short period of time (3-7 days). The overarching goal of this proposal is to test the hypothesis that PKC inhibition is part of the mechanism of the therapeutic effect of mood stabilizing drugs. The proposal derives from and builds on our published open-label study of TAM in acute mania (Bebchuk et al., 2000). However, the efficacy of TAM monotherapy in acute mania has only been reported in an open-label study and has not yet been evaluated in a randomized, double blind, placebo-controlled study. Male or female patients, ages 18 to 65, with a diagnosis of bipolar I disorder manic or mixed (with or without psychotic features), will be randomized to double-blind treatment to receive either TAM (20-140 mg/day) or placebo, for a period of 3 weeks. Following this acute period, the patients will receive either open-label TAM or treatment as clinically indicated. Approximately 50 patients with acute mania will be enrolled in the study. Biochemical measures will be obtained during the study.

双相情感障碍（BD）是一种常见的、严重的、慢性的、经常危及生命的疾病。自杀是10-20%双相障碍患者死亡的原因。锂作为情绪稳定剂的功效的发现彻底改变了双相障碍患者的治疗。然而，大约50%的患者对锂没有完全反应，锂的抗躁狂和情绪稳定作用的生化基础仍有待充分阐明。阐明锂稳定边缘和边缘相关功能潜在失调的机制也为描述双相障碍的潜在病理生理学提供了可能；然而，神经药理学研究中固有的一个主要问题是难以将任何观察到的生化发现归因于治疗相关性。一种强有力的方法是确定共同的生化靶点，这些靶点被属于同一治疗类别的药物（例如情绪稳定剂）所改变，但在“治疗相关”范式下使用时具有不同的化学结构（即，在慢性药物施用中观察到的效果，但在突然停药后仍持续存在）。在这种情况下，值得注意的是，丙戊酸（VPA）和锂具有不同的化学结构，属于同一治疗类别，并且对蛋白激酶C （PKC）具有相当大的抑制作用。PKC信号通路显然是两种结构高度不同的抗狂躁剂——锂和VPA作用的靶标。锂和VPA对PKC信号的影响是否有临床意义？因此，明确需要研究直接PKC抑制剂治疗急性躁狂症的潜在疗效。目前只有一种相对选择性的PKC抑制剂可用于人类-他莫昔芬。他莫昔芬（Tamoxifen； NOLVADEX?）是一种合成的非甾体类抗雌激素药物，已被广泛应用于乳腺癌的治疗。TAM吗?其对PKC的有效抑制作用是惊人的。最近，我们的小组进行了首次开放标签的研究，TAM在急性躁狂。在本研究中，TAM可在短时间内（3-7天）显著减轻躁狂症状。