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。它会严重影响生活质量和日常功能。目前，大多数治疗失眠的药物都使用镇静催眠药物，长期使用后可能导致依赖性、戒断副作用和疗效降低。越来越多的研究表明，褪黑素可能在失眠中起作用。褪黑素是松果体产生的一种神经激素，受视交叉上核（主要的昼夜节律起搏器）的调节。宾夕法尼亚大学（University of Pennsylvania）正在对180名老年失眠症患者进行的研究发现，有统计学意义的显著证据表明，褪黑素水平低的失眠症患者睡眠效率下降。因此，在老年失眠患者的亚组中，褪黑激素的产生受损，这可能是导致他们失眠的原因。然而，褪黑素治疗老年失眠症的试验一直模棱两可。这些研究存在严重的方法学局限性，包括样本量不足（II型误差），缺乏对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，比如褪黑激素缺乏是失眠的标志还是一个促成因素，以及是否需要增加剂量来重现脑脊液室中较高的水平。此外，褪黑激素被广泛用作非处方助眠剂，其有效性/安全性值得深入研究，尤其是在老年人中。为了验证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，首席研究员建议在一组明确定义的褪黑激素水平低的老年失眠症患者（共189名受试者）中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。具体目的是1)评估褪黑激素的有效性，2)评估褪黑激素治疗在这一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白天功能的客观和主观参数的影响。通过严格测试靶向褪黑激素替代疗法作为老年人失眠有效治疗的作用，以及通过评估褪黑激素的安全性，特别是白天功能，该协议将远远超出迄今为止所做的研究。

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.