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

描述（由申请人提供）：该补助金的主题，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心理健康问题。复发性BP I MDE是一种目前尚无满意治疗的疾病，其治疗仍是临床医生面临的挑战。迄今为止，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（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）单药治疗在预防复发性BP I MDE方面上级MS + AD联合治疗。也没有证据表明长期MS加AD治疗会导致更多的躁狂转换发作。我们提出的证据表明，AD诱导的躁狂症在长期治疗BP I MDE已被高估，长期使用MS加AD治疗可能优于单用MS治疗在预防复发BP I MDE上级。在本申请中，我们会问：“与锂单药治疗相比，锂+氟西汀联合持续治疗是否会导致MDE复发和复发更少？“为了回答这个问题，BP I MDE患者将接受8周的锂联合氟西汀治疗。在另外4周巩固治疗中保持良好的应答者随后将被随机分配至双盲继续治疗，（i）锂+氟西汀联合治疗，或（ii）锂单药治疗（在氟西汀逐渐减量和停药后），持续另外50周。我们假设长期锂盐联合氟西汀治疗与锂盐单药治疗相比，MDE复发和复发率更低。我们也会问：“锂+氟西汀联合治疗与锂单药治疗持续治疗期间综合征和亚综合征躁狂、轻躁狂和混合状态转换的相对安全性、耐受性和频率如何？“为了回答这个问题，我们将测量：综合征和亚综合征躁狂、轻躁狂和混合状态转换的频率、严重程度和持续时间;治疗后出现的不良事件的频率、严重程度和持续时间;治疗中断的频率;至首次综合征和亚综合征转换事件发生的时间;至每个综合征和亚综合征转换事件首次治疗干预的时间;以及至自杀意念事件增加的发生时间。我们假设锂剂加氟西汀治疗将导致相似的综合征和亚综合征转换事件频率，以及相似的治疗后出现的不良事件频率。我们进一步假设，与锂单药治疗相比，锂+氟西汀治疗将导致更少的自杀意念事件和更少的研究中止。我们认为，这项试验的结果可能对目前治疗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：本申请符合PA-07-092的公共卫生目的，旨在“支持精神障碍患者治疗、预防或康复方面的协作干预试验。“这是一个相互联系的合作赠款机制，允许在两个或更多个地点之间使用共同的协议，以增加样本量和加快患者招募。研究中心的主要研究者有一个既定的“跨中心协调、质量控制、数据管理、统计分析和报告机制”。“这项拨款采用最先进的临床治疗和结果措施，以确定最好的长期治疗双相I型（BP I）重度抑郁发作（MDE）。本研究的结果可能为预防BP I MDE的复发和再发提供新的信息，并可能对BP I MDE的现行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的BP I障碍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.