A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease

Abstract

Objectives: To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer's disease.

Design: A multicenter, randomized, placebo-controlled clinical trial of 2 dose formulations of oral melatonin coordinated by the National Institute of Aging-funded Alzheimer's Disease Cooperative Study. Subjects with Alzheimer's disease and nighttime sleep disturbance were randomly assigned to 1 of 3 treatment groups: placebo, 2.5-mg slow-release melatonin, or 10-mg melatonin.

Setting: Private homes and long-term care facilities.

Participants: 157 individuals were recruited by 36 Alzheimer's disease research centers. Subjects with a diagnosis of Alzheimer's disease were eligible if they averaged less than 7 hours of sleep per night (as documented by wrist actigraphy) and had 2 or more episodes per week of nighttime awakenings reported by the caregiver.

Measurements: Nocturnal total sleep time, sleep efficiency, wake-time after sleep onset, and day-night sleep ratio during 2- to 3-week baseline and 2-month treatment periods. Sleep was defined by an automated algorithmic analysis of wrist actigraph data.

Results: No statistically significant differences in objective sleep measures were seen between baseline and treatment periods for the any of the 3 groups. Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared to placebo, were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups.

Conclusions: Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer's disease.

Figure 1

Design Flow Chart. ML 2.5SR refers to treatment with 2.5 mg sustained-release melatonin; ML 10, treatment with 10 mg melatonin; ITT, intent to treat.

Figure 2

Actigraph-scored and polysomnography-scored sleep in 7 subjects with Alzheimer’s disease. The Mini-Mitter Actiwatch actigraph sleep algorithm showed excellent correlation (r² = 0.92, P <. 01) with polysomnography-scored sleep, although it consistently overestimated sleep relative to electroencephalogram-based sleep scoring. The sleep studies were carried out at the general clinical research center at Oregon Health Sciences University. PSG refers to polysomnography; ACT, actigraphy; AD, Alzheimer’s disease.

Figure 3

Results of blood assays for melatonin on first day of washout, by treatment arm. Subject ID number is shown by the outlier data points. ML refers to melatonin; ML 2.5SR, treatment with 2.5 mg sustained-release melatonin; ML 10, treatment with 10 mg melatonin; PLA, placebo.