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.

Conflict of interest statement

Disclosure Statement

No significant financial interest/other relationship to disclose.

Figures

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.