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、严重、慢性且常常危及生命的疾病。自杀是 10-20% BD 患者的死亡原因。锂作为情绪稳定剂的功效的发现彻底改变了双相情感障碍患者的治疗。然而，大约 50% 的患者对锂没有完全反应，并且锂的抗躁狂和稳定情绪作用的生化基础仍有待充分阐明。阐明锂稳定边缘系统和边缘系统相关功能的潜在失调的机制也有可能描述 BD 的潜在病理生理学；然而，神经药理学研究固有的一个主要问题是很难将治疗相关性归因于任何观察到的生化发现。一种有效的方法是识别常见的生化靶标，这些靶标可以被属于同一治疗类别的药物（例如情绪稳定剂）修饰，但在“治疗相关”范例中给药时具有不同的化学结构（即，在治疗中观察到的效果）长期用药，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) 和锂虽然具有不同的化学结构，但属于同一治疗类别，并且对蛋白激酶 C (PKC) 具有显着的抑制作用。 PKC 信号通路显然是两种结构高度不同的抗躁狂剂（锂和 VPA）作用的目标。锂和 VPA 对 PKC 信号传导的这些影响是否有任何临床意义？因此，显然需要研究直接 PKC 抑制剂在治疗急性躁狂症中的潜在功效。目前只有一种相对选择性的PKC抑制剂可供人类使用——他莫昔芬。他莫昔芬（TAM；NOLVADEX？）是一种合成的非甾体抗雌激素，已广泛用于乳腺癌的治疗。 TAM 对 PKC 的有效抑制作用是惊人的。最近，我们小组进行了第一个 TAM 治疗急性躁狂症的开放标签研究。在这项研究中，TAM 使躁狂症状在短时间内（3-7 天）显着减少。 该提案的总体目标是检验以下假设：PKC 抑制是情绪稳定药物治疗作用机制的一部分。该提案源自并建立在我们已发表的关于急性躁狂症中 TAM 的开放标签研究（Bebchuk 等，2000）的基础上。然而，TAM 单药治疗急性躁狂的疗效仅在开放标签研究中报告，尚未在随机、双盲、安慰剂对照研究中进行评估。 年龄 18 至 65 岁、诊断为躁狂或混合型双相情感障碍（有或没有精神病特征）的男性或女性患者将被随机分配至双盲治疗组，接受 TAM（20-140 毫克/天）或安慰剂，为期 3 周。在此急性期之后，患者将接受开放标签 TAM 或临床指示的治疗。大约 50 名急性躁狂患者将参加该研究。在研究期间将获得生化测量值。