Melatonin Randomized Trial in Insomnia in the Elderly

描述(申请人提供)：慢性失眠影响高达35%的老年人。它会严重损害生活质量和日间功能。目前，大多数失眠的药物治疗都涉及镇静催眠药，这些药物可能会导致依赖、停药副作用和长时间使用后疗效降低。越来越多的研究表明，褪黑激素可能在调节失眠方面发挥作用。褪黑素是一种神经激素，由松果体产生，受视交叉上核(主要的昼夜节律起搏器)调节。宾夕法尼亚大学正在对180名老年失眠症患者进行的研究发现，有统计学意义的证据表明，低褪黑激素失眠症患者的睡眠效率下降。因此，在老年失眠患者中，褪黑素的产生受到损害，这可能是导致他们失眠的原因之一。然而，褪黑素治疗老年失眠症的试验一直不明确。这些研究具有严重的方法学局限性，包括样本量不足(II型错误)，缺乏睡眠或白天功能的客观测量，以及没有安慰剂对照组。这引发了许多问题，比如褪黑素缺乏是否是失眠的标志，或者相反，是一个促成因素，以及是否需要增加剂量来重现脑脊液隔室中的较高水平。此外，褪黑素被广泛用作非处方药的助眠药物，可以真正了解其有效性/安全性，尤其是在老年人中。为了解决褪黑素可以治疗褪黑素缺乏的老年人失眠的基本假设，首席研究人员建议进行一项大型随机双盲临床试验，比较低褪黑素水平的老年失眠症患者(189名受试者)中的低剂量褪黑素(0.4毫克)、高剂量褪黑素(4.0毫克)和安慰剂。其具体目的是：1)评估褪黑素的有效性；2)评估褪黑素治疗在这一人群中的白天后果和安全性。意向治疗分析将比较低剂量褪黑素、高剂量褪黑素和安慰剂在睡眠和白天功能的客观和主观参数上的差异。该方案将远远超出迄今所做的研究，通过严格测试有针对性的褪黑素替代疗法作为老年人失眠有效治疗的作用，并通过评估褪黑素的安全性，特别是对白天功能的评估。

DESCRIPTION (provided by applicant): Chronic insomnia affects up to 35% of the elderly. It can significantly impair quality of life and daytime functioning. Currently, most medical therapy for insomnia involves sedative-hypnotic agents that may lead to dependence, withdrawal side effects and reduced efficacy after extended periods of use. A growing body of work has suggested that melatonin, a neurohormone produced by the pineal gland and regulated by the suprachiasmatic nucleus, the primary circadian pacemaker, may play a role in mediating insomnia. Ongoing research at the University of Pennsylvania in 180 elderly insomnia patients has found statistically significant evidence of a decreased sleep efficiency in low melatonin insomniacs. Thus, melatonin production is impaired in a subgroup of elderly insomnia patients and this may contribute to their insomnia. However, melatonin treatment trials in elderly insomniacs have been equivocal. These studies have had serious methodologic limitations including inadequate sample size (Type II error), lack of objective measures of sleep or daytime functioning, and no placebo control arm. This has raised many questions such as whether melatonin deficiency is a marker of insomnia or, instead, a contributing factor and whether increased doses are needed to recreate the higher levels seen in the cerebrospinal fluid compartment. In addition, melatonin is widely used as an over-the-counter sleeping aid with litre true insight into its effectiveness/safety, especially in older adults. To address the primary hypothesis that melatonin can treat insomnia in melatonin-deficient elderly, the principal investigator proposes conducting a large randomized, double-blind clinical trial comparing low dose melatonin (0.4 mg), high dose melatonin (4.0 mg) and placebo in a well-defined group of elderly insomniacs with low melatonin levels (189 total subjects). The specific aims are to 1) evaluate the effectiveness of melatonin and 2) assess the daytime consequences and safety of melatonin treatment in this population. Intention-to-treat analysis will compare low dose melatonin, high dose melatonin, and placebo on objective and subjective parameters of sleep and daytime function. This protocol will extend well beyond the research done to date by rigorously testing the role of targeted melatonin replacement therapy as an effective treatment for insomnia in the elderly and by evaluating the safety profile of melatonin with a particular focus on daytime functioning.