The Protein Kinase C Inhibitor Tamoxifen in Acute Mania

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% BD患者的死因。锂作为一种情绪稳定剂的功效的发现已经彻底改变了BD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物化学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提供了描述BD的潜在病理生理学的可能性;然而，神经药理学研究中固有的一个主要问题是难以将治疗相关性归因于任何观察到的生化发现。一种强有力的方法是鉴定共同的生化靶标，其被属于相同治疗类别的药物（例如情绪稳定剂）修饰，但当以“治疗相关”范例（即，长期给药后观察到的效应，但在突然停药后仍持续存在）。在这种情况下，值得注意的是，具有不同化学结构的丙戊酸（VPA）和锂属于相同的治疗类别，并对蛋白激酶C（PKC）产生相当大的抑制作用。PKC信号通路显然是两种结构高度不同的抗躁狂剂-锂和VPA-作用的靶点。锂和VPA对PKC信号传导的这些影响是否具有临床意义？因此，有一个明确的需要调查的潜在疗效的直接PKC抑制剂治疗急性躁狂症。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？），一种合成的非甾体类抗雌激素，已广泛用于治疗乳腺癌。TAM？对PKC的抑制作用是显著的。最近，我们的小组进行了第一个开放标签的研究与TAM在急性躁狂症。在这项研究中，TAM导致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PKC抑制是情绪稳定药物治疗作用机制的一部分这一假设。该提议源自并建立在我们发表的TAM在急性躁狂症中的开放标签研究（Bebchuk等人，2000年）。然而，TAM单药治疗急性躁狂症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 - 65岁的男性或女性患者，诊断为躁狂或混合型I型双相情感障碍（伴或不伴精神病特征），将随机接受双盲治疗，接受TAM（20-140 mg/天）或安慰剂，持续3周。在此急性期后，患者将接受开放标签TAM或临床指征治疗。大约50例急性躁狂症患者将入组本研究。研究期间将获得生化指标。

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.