Melatonin Randomized Trial in Insomnia in the Elderly

描述（由申请人提供）：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，大多数失眠症的药物治疗涉及镇静催眠剂，这可能导致依赖性，戒断副作用和长期使用后疗效降低。越来越多的研究表明，褪黑激素是一种由松果体产生的神经激素，受视交叉上核（主要的昼夜节律起搏器）的调节，可能在调节失眠中发挥作用。宾夕法尼亚大学对180名老年失眠症患者进行的研究发现，低褪黑激素失眠症患者的睡眠效率降低具有统计学意义。因此，褪黑激素的产生受损的老年失眠患者的亚组，这可能有助于他们的失眠。 然而，褪黑激素治疗老年失眠症的试验一直模棱两可。这些研究有严重的方法学局限性，包括样本量不足（II型错误），缺乏睡眠或日间功能的客观测量，没有安慰剂对照组，这提出了许多问题，如褪黑激素缺乏是否是失眠的标志物，或者相反，一个促成因素，以及是否需要增加剂量来重现脑脊液室中的较高水平。此外，褪黑激素被广泛用作非处方睡眠辅助剂，特别是在老年人中，其有效性/安全性得到了真正的了解。 为了解决褪黑激素可以治疗褪黑激素缺乏的老年人失眠的主要假设，主要研究者建议进行一项大型随机双盲临床试验，比较低剂量褪黑激素（0.4 mg），高剂量褪黑激素（4.0 mg）和安慰剂在一组明确定义的低褪黑激素水平的老年失眠症患者（共189名受试者）。具体目的是1）评价褪黑激素的有效性和2）评估褪黑激素治疗在该人群中的日间后果和安全性。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对睡眠和日间功能的客观和主观参数的影响。该方案将远远超出迄今为止所做的研究，通过严格测试靶向褪黑激素替代疗法作为老年人失眠的有效治疗方法的作用，并通过评估褪黑激素的安全性，特别关注白天功能。

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.