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

基于客观睡眠持续时间的 1/2 认知行为疗法和曲唑酮对失眠表型睡眠和血压的影响：序贯队列/随机对照试验

• 批准号: 10590135
• 负责人: Daniel J. Buysse
• 金额: $ 185.17万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590135
• 关键词: Adult; Age; Blood Pressure; Cardiovascular system; Characteristics; Classification; Clinical; Clinical Trials; Cognitive Therapy; Cohort Studies; Collaborations; Data; Decision Making; Disease; Disease remission; Double-Blind Method; Down-Regulation; Drug Prescriptions; Evidence based treatment; Functional disorder; Funding; Genetic; Goals; Guidelines; Health; Health Care Costs; Home Blood Pressure Monitoring; Hydrocortisone; Impairment; Individual; Knowledge; Measures; Mediating; Mental Health; Metabolic; Occupational Health; Outcome; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Placebo Control; Placebos; Polysomnography; Quebec; Randomized; Randomized, Controlled Trials; Recommendation; Recording of previous events; Research Personnel; Risk; Salivary; Sampling; Severities; Side; Site; Sleep; Sleeplessness; Symptoms; Testing; Time; Trazodone; United States National Institutes of Health; Validity and Reliability; actigraphy; base; blind; blood pressure elevation; blood pressure reduction; cardiovascular disorder risk; clinical phenotype; clinical practice; cohort; comparative efficacy; diaries; efficacy evaluation; hypothalamic-pituitary-adrenal axis; improved; indexing; off-label use; precision medicine; predicting response; primary outcome; randomized placebo controlled trial; response; secondary outcome; sex; side effect; treatment effect; treatment guidelines; treatment response; trial design

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.

项目概要 失眠是一种普遍存在的健康问题，与心血管、代谢和心理健康不良相关 结果。先前提出的亚型基于传统的临床测量，信度和效度较差 尚未证明对指导失眠治疗决策有用。基于大量初步数据 从各个领域和几个研究小组中，我们发现了一种特殊的表型，即失眠症 睡眠时间短（ISS），这与不良健康结果的风险增加有关， 下丘脑-垂体-肾上腺 (HPA) 轴激活表明生理性过度兴奋，甚至更糟 对失眠认知行为治疗（CBT-I）的反应。拟议的研究代表了下一步 我们之前观察的逻辑延伸：确定 CBT-I 对患有以下疾病的个体的功效 血压升高 (BP) 的成年人中 ISS 与正常睡眠时间 (INS) 的失眠，以及 检查曲唑酮对 CBT-I 非缓解者的疗效。 CBT-I 被推荐作为一线药物 曲唑酮是一种广泛使用但研究严重不足的失眠药物。 此外，我们的试验数据证明了 CBT-I 和曲唑酮在 ISS 和 INS 中的不同功效：曲唑酮、 但 CBT-I 则不然，它会增加客观总睡眠时间 (TST)，并降低 ISS 中的血压和夜间皮质醇。我们将 对 600 名患有失眠症的成年人（≥18 岁）进行了 4 中心队列研究，随后进行了安慰剂对照随机对照试验。这 队列研究将检验 CBT-1 在 ISS 与 INS 表型个体中的疗效（各 n=300）， 由多导睡眠图 (PSG) TST 定义。随后的随机对照试验将比较曲唑酮与曲唑酮的疗效。 CBT-I 非缓解者中的安慰剂。 4 个研究地点（好时、丹佛、匹兹堡和魁北克）的研究人员 有着悠久的合作历史，并成功完成了 NIH 资助的机械和临床试验 研究。我们的主要结果是 8 周时失眠缓解，定义为失眠严重程度指数 （ISI）<8； ISI 是失眠症状自我报告测量的黄金标准。次要成果将包括 ISI（连续）、客观（即 PSG 和体动记录仪）睡眠效率测量（在 CBT-I 队列研究中） 以及 TST、HBP 和夜间皮质醇（在曲唑酮-安慰剂 RCT 中）。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客观 TST 和 HBP 的影响。结果将 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 影响。证明 CBT-I 作为失眠表型函数的差异功效将有助于实现目标 精准医学，根据临床表型和生理学以及 遗传学。尽管 CBT-I 被推荐作为所有患有失眠症的成年人的一线治疗方法，但发现更糟糕的治疗方法 ISS 表型的反应将导致重新考虑当前的指南，以代替匹配患者的 表型到治疗。证明曲唑酮在 CBT-I 非缓解者中的疗效将填补明显的空白 失眠治疗方面存在重要的知识差距，因为它涉及目前广泛的标签外使用。