Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease.
Previously, we reported that morning bright light therapy improved sleep time and cognitive function in Alzheimer type of dementia. We conducted a double blind study to examine the effects of melatonin on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type of dementia. The subjects were 9 persons given a placebo (PLA), and 11 given melatonin ( 3 mg)(MLT). The mean age was 79.2+/-6.4 (17 females and 3 males). The drugs were given at 20: 30 each day for 4 weeks. We checked sleep time and activity by Actigraph through one week before and the 4th week after drug administration. Cognitive and non-cognitive functions were evaluated with the clinical dementia rating scale (CDR), and Mini Mental State Examination (MMSE), and the Alzheimer's Disease Assessment Scale (ADAS). We successfully recorded Actigraph data from 18 patients (PLA8, MLT10). The mean sleep time change ratio and SD of the administration of PLA in the night was-0.2+/-13.7%, and MLT was 33.2+/-37.6%. The mean activity counts and SD of the administration of PLA in the night was 29.8+/-77.0%; in MLT it was-44.9+/-21.9%. Melatonin significantly prolonged the sleep time (p=0.017) and decreased activity (p=0.014) in the night (21: 00-6: 00) in the MLT group, although no significant difference in sleep time or activity in the daytime (6: 00-21: 00) was recognized between the two groups. In comparison with ADAS cognition score changes, the mean change and SD in the PLA was 0.3+/-3.7; in MLT it was-4.3+/-3.6 points. In comparison with ADAS non-cognition score, the mean change and SD in the PLA group was-0.8+/-1.0, in the MLT group it was-4.1+/-2.2 points. There were also significant differences between the PLA and the MLT groups in the comparison with the score improvement of ADAS cognition (p=0.017) and non-cognition (p=0.002), otherwise there was no significant difference in improvement of MMSE between both groups. Melatonin administration had effect to improve sleep time and night activity, but no significant effect to improve daytime naps and activity. Although melatonin administration might has less strong effect on circadian rhythm than morning bright light therapy we previously reported, cognitive and non-cognitive functions were improved. Melatonin seemed to be useful for care of the Alzheimer type of dementia patients. Patients with Alzheimer dementia often display both agitated behavior and poor sleep. Given that the disease is often associated with low endogenous levels of melatonin, exogenous melatonin administration may lead to improvements in sleep and agitation.
                Randomized, placebo-controlled study.
                Nursing homes in San Diego, CA, metropolitan area.
                Subjects were patients with probable Alzheimer disease.
                Melatonin (8.5 mg immediate release and 1.5 mg sustained release) (N = 24) or placebo (N = 17) administered at 10:00 P.M. for 10 consecutive nights. The protocol consisted of baseline (3 days), treatment (10 days), and posttreatment (5 days) phases.
                Sleep was measured continuously using actigraphy. Agitation was rated using both the Agitated Behavior Rating Scale and the Cohen-Mansfield Agitation Inventory. Treatment effects were examined both across the 24-hr day and separately by nursing shift.
                There were no significant effects of melatonin, compared with placebo, on sleep, circadian rhythms, or agitation.
                : This study failed to find a beneficial effect of exogenous melatonin, consistent with a number of other studies. The lack of efficacy may be related to the absence of a true treatment effect or to the superphysiologic dose of melatonin used. Disturbance of sleep is common in individuals with dementia where there may be reversal of the sleep-wake cycle. People with dementia of the Alzheimer's type have melatonin secretion rhythm disorders. There is some evidence that treatment with exogenous melatonin is an effective treatment for sleep disturbance associated with dementia. A randomised double blind placebo controlled cross over trial was undertaken to test the hypothesis that slow release exogenous melatonin 6 mg improves sleep for people with dementia.
                Forty-four participants with DSM-IV diagnoses of dementia with sleep disturbance were selected for a seven week randomised double blind cross over trial of slow release melatonin 6 mg versus placebo. Sleep parameters were objectively measured using wrist actigraphy.
                Twenty-five out of 44 completed the trial. Sleep was significantly disturbed in the sample population. Melatonin had no effect on median total time asleep (n=25, z=1.35, p=0.18), number of awakenings (n=25, z=0.32, p=0.75) or sleep efficiency (n=25, z=0.17, p=0.24). Nor were there any carry over effects from melatonin.
                Contrary to previous findings, we found no evidence that two weeks of exogenous melatonin is effective in improving sleep in people with dementia, although possible benefits of melatonin following longer periods of administration cannot be discounted.
                Copyright 2002 John Wiley & Sons, Ltd. Cognitive decline, mood, behavioral and sleep disturbances, and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers. Circadian rhythm disturbances have been associated with these symptoms.
                To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: bright light and melatonin.
                A long-term, double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands; mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia.
                Random assignment by facility to long-term daily treatment with whole-day bright (+/- 1000 lux) or dim (+/- 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years).
                Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months.
                Light attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (-0.5 points; 95% CI, -0.10 to -1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or 9% (treatment x time effect).
                Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia. To counteract the adverse effect of melatonin on mood, it is recommended only in combination with light.
                controlled-trials.com/isrctn Identifier: ISRCTN93133646. To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer's disease.
                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.
                Private homes and long-term care facilities.
                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.
                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.
                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.
                Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer's disease.
The analyses did not support the use of melatonin for treatment of cognitive impairment associated with dementia. Meta-analysis of psychopathologic behavior scale scores suggested that melatonin may be effective in treating these dementia-related disturbances.