Melatonin is recommended as a first-line treatment in isolated REM sleep behavior disorder (iRBD), although no large patient group has been reported. To assess effects, time course and confounding factors in the treatment of patients with iRBD using melatonin, 209 consecutive patients were included in this single-center, observational cohort study. A total of 171 patients had taken melatonin according to our chronobiotic protocol (2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype), 13 had applied melatonin for about 1-3 months, and 25 underwent mixed treatments. In total, 1529 clinical evaluations were performed, including Clinical Global Impression (CGI) and a newly developed RBD symptom severity scale (Ikelos-RS), analyzed using linear mixed models. Validation of Ikelos-RS showed excellent inter-rater reliability (ρ = 0.9, P < .001), test-retest reliability (ρ = 0.9, P < .001) and convergent validity (ρ = 0.9, P < .001). With melatonin, RBD symptom severity gradually improved over the first 4 weeks of treatment (Ikelos-RS: 6.1 vs. 2.5; CGI Severity: 5.7 vs. 3.2) and remained stably improved (mean follow-up 4.2 ± 3.1years; range: 0.6-21.7years). Initial response was slowed to up to 3 months with melatonin-suppressing (betablockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, symptoms remained stably improved (mean follow-up after discontinuation of 4.9 ± 2.5years; range: 0.6-9.2). When administered only 1-3 months, RBD symptoms gradually returned. Without any melatonin, RBD symptoms persisted and did not wear off over time. Clock-timed, low-dose, long-term melatonin treatment in patients with iRBD appears to be associated with the improvement of symptoms. The outlasting improvement over years questions a pure symptomatic effect. Clock-time dependency challenges existing prescription guidelines for melatonin.

中文翻译：

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使用褪黑激素作为时间生物治疗孤立的快速眼动睡眠行为障碍

褪黑激素被推荐作为孤立性 REM 睡眠行为障碍 (iRBD) 的一线治疗，尽管尚未报告大型患者群体。为了评估使用褪黑激素治疗 iRBD 患者的效果、时间过程和混杂因素，这项单中心观察性队列研究连续纳入了 209 名患者。共有 171 名患者根据我们的 chronobiotic 方案服用了褪黑激素（2 毫克，≥6 个月，始终在同一时间，晚上 10 点到 11 点，根据时间表进行校正），13 人使用褪黑激素约 1-3 个月，25 人接受混合治疗。总共进行了 1529 项临床评估，包括临床总体印象 (CGI) 和新开发的 RBD 症状严重程度量表 (Ikelos-RS)，使用线性混合模型进行分析。Ikelos-RS 的验证显示出色的评分者间信度 (ρ = 0.9, P  < .001)、重测信度 (ρ = 0.9, P  < .001) 和收敛效度 (ρ = 0.9, P < .001)。使用褪黑激素后，RBD 症状严重程度在治疗的前 4 周内逐渐改善（Ikelos-RS：6.1 对 2.5；CGI 严重程度：5.7 对 3.2）并保持稳定改善（平均随访 4.2 ± 3.1 年；范围：0.6 -21.7 年）。使用抑制褪黑激素（β受体阻滞剂）或破坏快速眼动睡眠的联合药物（抗抑郁药）可使初始反应减慢至长达 3 个月，并且因褪黑激素摄入时间不足而失败。当褪黑激素在 6 个月后停药时，症状保持稳定改善（停药后的平均随访时间为 4.9 ± 2.5 年；范围：0.6-9.2）。仅施用 1-3 个月时，RBD 症状逐渐恢复。在没有任何褪黑激素的情况下，RBD 症状持续存在，并且不会随着时间的推移而消失。时钟定时，低剂量，iRBD 患者的长期褪黑激素治疗似乎与症状的改善有关。多年来的持久改善质疑纯粹的症状效应。时钟时间依赖性挑战了现有的褪黑激素处方指南。