1/2 Cognitive Behavioral Therapy and Trazodone Effects on Sleep and Blood Pressure in Insomnia Phenotypes Based on Objective Sleep Duration: A Sequential Cohort/Randomized Controlled Trial

项目总结 失眠是一种普遍的健康问题，与不利的心血管、代谢和心理健康有关。 结果。以前提出的亚型，基于传统的临床方法，可靠性和效度较差。 并没有被证明对指导失眠治疗决策有用。基于大量的初步数据 从不同的领域和几个研究小组，我们已经确定了一种特殊的表型，失眠与 睡眠时间短(ISS)，这与不良健康后果的风险增加相关， 由下丘脑-垂体-肾上腺(HPA)轴激活所表明的生理性高觉醒，甚至更糟 对失眠认知行为疗法(CBT-I)的反应。拟议的研究代表了下一步 我们先前观察的合乎逻辑的延伸：确定CBT-I对患有 在血压升高的成年人中，ISS与睡眠时间正常(INS)的失眠症，以及 研究曲唑酮在CBT-I未缓解患者中的疗效。建议将CBT-I作为一线 曲唑酮是一种被广泛开出的治疗失眠的药物，但对它的研究还很少。 此外，我们的试验数据显示了CBT-I和曲唑酮在ISS和INS中的不同疗效：曲唑酮， 但不是CBT-I，增加了客观总睡眠时间(TST)，并降低了国际空间站的血压和夜间皮质醇。我们会 对600名患有失眠的成年人(≥18岁)进行4个部位的队列研究，然后进行安慰剂对照随机对照试验。这个 队列研究将检验CBT-L在ISS和INS表型(n=300)个体中的疗效。 由多导睡眠图(PSG)TST定义。随后的RCT将比较曲唑酮和曲唑酮的疗效。 CBT-I非汇款患者中的安慰剂。4个研究地点(好时、丹佛、匹兹堡和魁北克)的调查人员 有很长的合作历史并成功完成了NIH资助的机械学和临床试验 学习。我们的主要结果将是8周后失眠缓解，定义为失眠严重程度指数 (ISI)&lt；8；ISI是失眠症状自我报告的黄金标准。次要结果将包括 (在CBT-I队列研究中)睡眠效率的ISI(连续的)、客观的(即PSG和动作图)测量 以及TST、HBP和夜间皮质醇(曲唑酮-安慰剂RCT)。在探索性分析中，我们将测试 夜间皮质醇的变化是否介导曲唑酮对目标TST和HBP的影响。结果将会 在治疗结束后8周和6个月进行评估，以评估治疗的持久性 效果。证明CBT-I作为失眠表型的功能的不同疗效将有助于实现这些目标 精准医学，它根据临床表型和生理以及 遗传学。尽管CBT-I被推荐为所有患有失眠的成年人的一线治疗，但发现更糟糕的是 ISS表型的反应将导致重新考虑这一当前指南，而不是匹配的患者的指南 要治疗的表型。在CBT-I非汇款患者中展示曲唑酮的有效性将填补一个明显的 而L在治疗失眠方面的重要知识缺口，因为它属于目前广泛使用的标签外。

PROJECT SUMMARY Insomnia is a prevalent health problem associated with adverse cardiovascular, metabolic, and mental health outcomes. Previously proposed subtypes, based on traditional clinical measures, have poor reliability and validity and have not proven useful for guiding insomnia treatment decisions. Based on a large base of preliminary data from various domains and several investigative groups, we have identified a particular phenotype, insomnia with short sleep duration (ISS), that is associated with increased risk for adverse health outcomes, greater physiological hyperarousal as indicated by hypothalamic-pituitary-adrenal (HPA) axis activation, and worse response to Cognitive-Behavioral Treatment for Insomnia (CBT-I). The proposed study represents the next logical extension of our previous observations: To determine the efficacy of CBT-I in individuals with ISS vs. Insomnia with normal sleep duration (INS) among adults with elevated blood pressure (BP), and to examine the efficacy of trazodone among non-remitters to CBT-I. CBT-I is recommended as first-line treatment for insomnia, and trazodone is a widely-prescribed but grossly understudied medication for insomnia. In addition, our pilot data demonstrate differential efficacy of CBT-I and trazodone in ISS and INS: trazodone, but not CBT-I, increases objective total sleep time (TST), and lowers BP and evening cortisol in ISS. We will conduct a 4-site cohort study followed by a placebo-controlled RCT in 600 adults (≥18y) with insomnia. The cohort study will examine the efficacy of CBT-l among individuals with ISS vs. INS phenotypes (n=300 each), defined by polysomnographic (PSG) TST. The subsequent RCT will compare the efficacy of trazodone vs. placebo among CBT-I non-remitters. Investigators at the 4 study sites (Hershey, Denver, Pittsburg, and Quebec) have a long history of collaboration and successful completion of NIH-funded mechanistic and clinical trial studies. Our primary outcome will be the insomnia remission at 8 weeks, defined as Insomnia Severity Index (ISI) <8; ISI is the gold-standard self-report measure of insomnia symptoms. Secondary outcomes will include ISI (continuous), objective (i.e., PSG and actigraphy) measures of sleep efficiency (in the CBT-I cohort study) and TST, HBP, and evening cortisol (in the trazodone-placebo RCT). In exploratory analyses, we will test whether changes in evening cortisol mediate the effect of trazodone on objective TST and HBP. Outcomes will be assessed at 8 weeks and 6 months following the end of treatment to evaluate the durability of treatment effects. Demonstrating a differential efficacy of CBT-I as a function of insomnia phenotype would aid the goals of precision medicine, which directs therapy on the basis of clinical phenotypes and physiology as well as genetics. Although CBT-I is recommended as first-line treatment for all adults with insomnia, finding a worse response in the ISS phenotype will lead to reconsidering this current guideline in lieu of matching patients’ phenotype to treatment. Demonstrating the efficacy of trazodone among CBT-I non-remitters will fill an obvious and important knowledge gap in insomnia treatment l as it pertains to its current wide-spread off-label use.