摘要

BACKGROUND:Delayed Sleep-Wake Phase Disorder (DSWPD) is characterised by sleep initiation insomnia when attempting sleep at conventional times and difficulty waking at the required time for daytime commitments. Although there are published therapeutic guidelines for the administration of melatonin for DSWPD, to our knowledge, randomised controlled trials are lacking. This trial tested the efficacy of 0.5 mg melatonin, combined with behavioural sleep-wake scheduling, for improving sleep initiation in clinically diagnosed DSWPD patients with a delayed endogenous melatonin rhythm relative to patient-desired (or -required) bedtime (DBT). METHODS:This randomised, placebo-controlled, double-blind clinical trial was conducted in an Australian outpatient DSWPD population. Following 1-wk baseline, clinically diagnosed DSWPD patients with delayed melatonin rhythm relative to DBT (salivary dim light melatonin onset [DLMO] after or within 30 min before DBT) were randomised to 4-wk treatment with 0.5 mg fast-release melatonin or placebo 1 h before DBT for at least 5 consecutive nights per week. All patients received behavioural sleep-wake scheduling, consisting of bedtime scheduled at DBT. The primary outcome was actigraphic sleep onset time. Secondary outcomes were sleep efficiency in the first third of time in bed (SE T1) on treatment nights, subjective sleep-related daytime impairment (Patient Reported Outcomes Measurement Information System [PROMIS]), PROMIS sleep disturbance, measures of daytime sleepiness, clinician-rated change in illness severity, and DLMO time. FINDINGS:Between September 13, 2012 and September 1, 2014, 307 participants were registered; 116 were randomised to treatment (intention-to-treat n = 116; n = 62 males; mean age, 29.0 y). Relative to baseline and compared to placebo, sleep onset occurred 34 min earlier (95% confidence interval [CI] -60 to -8) in the melatonin group. SE T1 increased; PROMIS sleep-related impairment, PROMIS sleep disturbance, insomnia severity, and functional disability decreased; and a greater proportion of patients showed more than minimal clinician-rated improvement following melatonin treatment (52.8%) compared to placebo (24.0%) (P < 0.05). The groups did not differ in the number of nights treatment was taken per protocol. Post-treatment DLMO assessed in a subset of patients (n = 43) was not significantly different between groups. Adverse events included light-headedness, daytime sleepiness, and decreased libido, although rates were similar between treatment groups. The clinical benefits or safety of melatonin with long-term treatment were not assessed, and it remains unknown whether the same treatment regime would benefit patients experiencing DSWPD sleep symptomology without a delay in the endogenous melatonin rhythm. CONCLUSIONS:In this study, melatonin treatment 1 h prior to DBT combined with behavioural sleep-wake scheduling was efficacious for improving objective and subjective measures of sleep disturbances and sleep-related impairments in DSWPD patients with delayed circadian phase relative to DBT. Improvements were achieved largely through the sleep-promoting effects of melatonin, combined with behavioural sleep-wake scheduling. TRIAL REGISTRATION:This trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000425897.

译文

背景: 延迟睡眠-觉醒期障碍 (DSWPD) 的特征是在常规时间尝试睡眠时的睡眠起始失眠和在白天工作所需的时间醒来困难。尽管有发表的褪黑素治疗 DSWPD 的治疗指南，但据我们所知，缺乏随机对照试验。该试验测试了 0.5 毫克褪黑激素与行为睡眠-觉醒计划相结合的功效, 用于改善临床诊断为内源性褪黑激素节律相对于患者期望 (或要求) 就寝时间 (DBT) 延迟的 DSWPD 患者的睡眠起始。方法: 这项随机、安慰剂对照、双盲临床试验在澳大利亚门诊 DSWPD 人群中进行。遵循 1-wk 基线，临床诊断为与 DBT 相关的褪黑素节律延迟的 DSWPD 患者 (在 DBT 后或 DBT 前 30 分钟内唾液昏暗光褪黑素发作 [DLMO]) 在 DBT 前 1 小时随机使用 0.5 毫克快速释放褪黑激素或安慰剂进行 4-wk 治疗，每周至少连续 5 晚。所有患者都接受行为睡眠-觉醒计划，包括 DBT 计划的就寝时间。主要结果是活动睡眠开始时间。次要结果是治疗晚上在床上前的睡眠效率 (SE T1)，主观睡眠相关的日间损伤 (患者报告结果测量信息系统 [PROMIS]), PROMIS 睡眠障碍，白天嗜睡的测量，临床医生评估的疾病严重程度的变化和 DLMO 时间。调查结果: 2012年9月13日至 2014年9月1日间，登记了 307 名参与者; 116 名被随机分配到治疗 (意向治疗 n = 116; n = 62 名男性; 平均年龄，29.0 岁)。与基线相比，与安慰剂相比，褪黑激素组的睡眠开始时间提前 34 分钟 (95% 置信区间 [CI]-60 至-8)。SE T1 增加; PROMIS 睡眠相关障碍、 PROMIS 睡眠障碍、失眠严重程度和功能障碍减少; 与安慰剂 (52.8%) 相比，更大比例的患者在褪黑激素治疗后表现出超过最低临床医生评价的改善 (24.0%) (P <0.05)。两组在根据协议接受治疗的夜晚数量上没有差异。在一组患者 (n = 43) 中评估的治疗后 DLMO 在组间没有显著差异。不良事件包括头晕、白天嗜睡和性欲下降，尽管治疗组之间的发生率相似。没有评估褪黑激素长期治疗的临床益处或安全性，同样的治疗方案是否有益于经历 DSWPD 睡眠症状的患者，而不会延迟内源性褪黑激素节律，这仍然是未知的。结论: 在本研究中, 在 DBT 前 1 小时进行褪黑激素治疗，结合行为睡眠-觉醒计划，对于改善与 DBT 相关的昼夜相位延迟的 DSWPD 患者的睡眠障碍和睡眠相关损伤的客观和主观测量是有效的。改善主要是通过褪黑激素的睡眠促进作用，结合行为睡眠-觉醒计划实现的。试验注册: 该试验在澳大利亚新西兰临床试验注册处注册，actrn12612000425897。