2/2-Prevention of Relapse & Recurrence of Bipolar Depression

描述(由申请人提供)：这笔赠款的主题是双相I型(BP I)重度抑郁发作(MDE)的复发，现在被认为是一个主要的精神健康问题。复发性BP I MDE是一种没有令人满意的治疗方法的疾病，其治疗仍然是临床医生面临的挑战。到目前为止，BP I MDE的初始和长期治疗一直基于未经验证的实践指南。这些指南建议在BP I MDE的初始治疗期间限制抗抑郁药物(AD)的使用，并在长期治疗期间完全避免AD的使用。然而，没有经验证据表明，情绪稳定剂(MS)单一疗法在预防BP I MDE复发方面优于MS+AD联合疗法。也没有证据表明长期的多发性硬化症加阿尔茨海默病治疗会导致更多的躁狂发作。我们提出的证据表明，在BP I MDE的长期治疗中，AD引起的躁狂被高估了，长期使用MS加AD治疗在预防BP I MDE复发方面可能优于单独使用MS治疗。在这个应用中，我们会问：“与单一锂治疗相比，锂加氟西汀联合治疗是否能减少MDE的复发和复发？”为了回答这个问题，BP I MDE患者将接受为期8周的锂加氟西汀联合治疗。继续巩固治疗4周后情况良好的应答者将被随机分成两组：(I)锂加氟西汀联合治疗，或(Ii)单独锂治疗(在氟西汀逐渐减少和停止治疗后)，再治疗50周。我们假设长期的锂加氟西汀治疗将导致较少的MDE复发和复发比锂单一治疗。我们还会问：“在持续治疗期间，锂加氟西汀联合治疗与单一锂治疗相比，综合征和亚综合征躁狂、躁狂和混合状态转换的相对安全性、耐受性和频率是多少？”为了回答这个问题，我们将测量：症状和亚症状躁狂、躁狂和混合状态转换的频率、严重程度和持续时间；治疗紧急不良事件的频率、严重程度和持续时间；停止治疗的频率；首次症状和亚症状转换事件的发病时间；每个症状和亚症状转化事件的首次治疗干预时间；以及自杀意念事件增加的发病时间。我们假设，锂加氟西汀治疗将导致类似频率的综合征和亚症状转换事件，以及类似频率的治疗-紧急不良事件。我们进一步假设，与锂联合氟西汀治疗相比，锂联合氟西汀治疗将导致较少的自杀意念事件和较少的研究中断。我们认为，这项试验的结果可能会对目前治疗BP I MDE的实践指南产生重要的公共卫生影响。 公共卫生相关性：此应用程序符合PA-07-092的公共卫生意图，该意图寻求“支持治疗、预防或康复精神障碍患者的协作性干预试验。”这是一种相互关联的协作赠款机制，允许在两个或更多地点之间使用共同的协议，以增加样本规模并加快患者招募。现场的主要调查人员已经建立了“跨现场协调、质量控制、数据管理、统计分析和报告的机制”。这笔赠款采用最先进的临床治疗和结果衡量标准，以确定双相I(BP I)重度抑郁发作(MDE)的最佳长期治疗方案。这项研究的结果可能为预防BP I MDE的复发和复发提供新的信息，并可能对当前BP I MDE的实践指南产生重要的公共卫生影响。这项研究的结果也可能为未来BP I障碍的试验提供新的研究假设。

DESCRIPTION (provided by applicant): The subject of this grant, recurrence of Bipolar I (BP I) major depressive episode (MDE), is now recognized as a major mental health problem. Recurrent BP I MDE is a disorder with no satisfactory therapy, and its treatment remains a challenge to clinicians. To date, initial and long-term therapy of BP I MDE has been based on un-validated practice guidelines. These guidelines recommend limiting antidepressant drug (AD) use during initial therapy of BP I MDE, and completely avoiding AD use during long-term therapy. There is, however, no empirical evidence to suggest that mood stabilizer (MS) monotherapy is superior to combined MS plus AD therapy in preventing recurrent BP I MDE. Nor is there evidence to suggest that long-term MS plus AD therapy results in more manic switch episodes. We present evidence that AD-induced mania during long-term therapy of BP I MDE has been over-estimated, and that long-term use of MS plus AD therapy may be superior to MS therapy alone in preventing recurrent BP I MDE. In this application, we will ask: "Does continuation therapy with combined lithium plus fluoxetine result in fewer MDE relapses and recurrences vs. lithium monotherapy?" To answer this question, patients with BP I MDE will receive combined lithium plus fluoxetine therapy for 8 weeks. Responders who stay well for an additional 4 weeks of consolidation therapy will then be randomized to double-blind continuation therapy with either (i) combined lithium plus fluoxetine, or (ii) lithium alone (following fluoxetine taper and discontinuation) for an additional 50 weeks. We hypothesize that long-term lithium plus fluoxetine therapy will result in fewer MDE relapses and recurrences vs. lithium monotherapy. We will also ask: "What is the relative safety, tolerability, and frequency of syndromal and sub-syndromal manic, hypomanic, and mixed state conversions during continuation treatment with combined lithium plus fluoxetine vs. lithium monotherapy?" To answer this question, we will measure: the frequency, severity, and duration of syndromal and sub-syndromal manic, hypomanic, and mixed state conversions; frequency, severity, and duration of treatment-emergent adverse events; frequency of treatment discontinuation; time to onset of first syndromal and sub-syndromal conversion event; time to first treatment intervention of each syndromal and sub-syndromal conversion event; and, time to onset of increase in suicidal ideation event. We hypothesize that lithium plus fluoxetine therapy will result in a similar frequency of syndromal and sub-syndromal conversion events, and a similar frequency of treatment- emergent adverse events. We further hypothesize that lithium plus fluoxetine therapy will result in fewer suicide ideation events and fewer study discontinuations vs. lithium monotherapy. We believe that the results of this trial may have an important public health impact on the current practice guidelines for treating BP I MDE. PUBLIC HEALTH RELEVANCE: This application comports with the public health intent of PA-07-092 which seeks to "support collaborative intervention trials in the treatment, prevention, or rehabilitation of those with mental disorders." This is a linked collaborative grant mechanism that allows for the use of a common protocol among two or more sites in order to increase sample size and accelerate patient recruitment. The principal investigators of the sites have an established "mechanism for cross-site coordination, quality control, data management, statistical analysis, and reporting." This grant employs state-of-the-art clinical therapy and outcome measures to identify the best long- term therapy of Bipolar I (BP I) major depressive episode (MDE). Results from this study may provide new information on the prevention of relapse and recurrence of BP I MDE, and may have an important public health impact on current practice guidelines for BP I MDE. Results from this study may also inform new research hypotheses for future trials in BP I disorder.