1/2-Prevention of Relapse & Recurrence of Bipolar Depression

描述（由申请人提供）：本次资助的对象，双相I型（BP I）重度抑郁发作（MDE）复发，现在被认为是一种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，其治疗对临床医生来说仍然是一个挑战。迄今为止，BP I MDE的初始和长期治疗都是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使用AD。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方面优于MS + AD联合治疗。也没有证据表明长期多发性硬化症加阿尔茨海默病治疗会导致更多的躁狂转换发作。我们提供的证据表明，在长期治疗BP I MDE期间，AD诱发的躁狂被高估了，并且长期使用MS加AD治疗可能比单独使用MS治疗在预防复发性BP I MDE方面更好。在本申请中，我们将问：“锂+氟西汀联合继续治疗是否比锂单药治疗导致更少的MDE复发和复发？”为了回答这个问题，BP I型MDE患者将接受锂+氟西汀联合治疗8周。在4周的巩固治疗中保持良好的应答者将被随机分配到(i)锂+氟西汀联合治疗或（ii）锂单独治疗（在氟西汀逐渐减少和停药后）的双盲继续治疗中，再进行50周。我们假设长期锂离子加氟西汀治疗与锂离子单药治疗相比会导致更少的MDE复发和复发。我们还会问：“在锂+氟西汀联合治疗与锂单药治疗继续治疗期间，综合征和亚综合征型躁狂、轻躁狂和混合状态转换的相对安全性、耐受性和频率是什么？”为了回答这个问题，我们将测量：症状型和亚症状型躁狂、轻躁狂和混合状态转换的频率、严重程度和持续时间；治疗中出现的不良事件的频率、严重程度和持续时间；停止治疗的频率；第一证和亚证转换事件发生的时间；各证候及亚证转换事件至首次治疗干预的时间；自杀意念事件发生的时间也在增加。我们假设锂+氟西汀治疗将导致相似频率的综合征和亚综合征转换事件，以及相似频率的治疗-紧急不良事件。我们进一步假设，与锂单药治疗相比，锂加氟西汀治疗将导致更少的自杀意念事件和更少的研究中断。我们认为，该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。

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.