Melatonin and Its Agonist Ramelteon in Alzheimer's Disease: Possible Therapeutic Value

Table 1

Clinical studies on melatonin efficacy in AD.

Design	Subjects (M,F)	Treatment	Study’s duration	Measured	Results	Reference
Open-label study	10 (6, 4) demented patients	3 mg melatonin p.o./daily at bed time	3 weeks	Daily logs of sleep and wake quality completed by caretakers	Seven out of ten dementia patients having sleep disorders treated with melatonin showed a significant decrease in sundowning and reduced variability of sleep onset time	[116]
Open-label study	14 (8, 14) AD patients	9 mg melatonin p.o./daily at bed time	22 to 35 months	Daily logs of sleep and wake quality completed by caretakers. Neuropsychological assessment.	At the time of assessment, a significant improvement of sleep quality was found. Sundowning was not longer detectable in 12 patients and persisted, although attenuated in 2 patients. Clinically, the patients exhibited lack of progression of the cognitive and behavioral signs of the disease during the time they received melatonin.	[111]
Case report	Monozygotic twins with AD of 8 years duration	One of the patients was treated with melatonin 9 mg p.o./daily at bed time.	36 months	Neuropsychological assessment.; Neuroimaging.	Sleep and cognitive function severely impaired in the twin not receiving melatonin as compared to the melatonin-treated twin.	[112]
Open-label, placebo-controlled trial	14 AD patients	6 mg melatonin p.o./daily at bed time or placebo	4 weeks	Daily logs of sleep and wake quality completed by caretakers. Actigraphy	The 7 AD patients receiving melatonin showed a significantly reduced percentage of nighttime activity compared to a placebo group	[113]
Open-label study	11 (3, 8) AD patients	3 mg melatonin p.o./daily at bed time	3 weeks	Daily logs of sleep and wake quality completed by the nurses.	Analysis revealed a significant decrease in agitated behaviors in all three shifts and a significant decrease in daytime sleepiness.	[117]
Open-label study	45 (19, 26) AD patients	6–9 mg melatonin p.o./daily at bed time	4 months	Daily logs of sleep and wake quality completed by caretakers. Neuropsychological assessment.	Melatonin improved sleep and suppressed sundowning, an effect seen regardless of the concomitant medication employed to treat cognitive or behavioral signs of AD.	[115]
Randomized double blind placebo controlled cross over study	25 AD patients	6 mg of slow release melatonin p.o. or placebo at bed time	7 weeks	Actigraphy	Melatonin had no effect on median total time asleep, number of awakenings, or sleep efficiency.	[118]
Double-blind, placebo-controlled study	20 (3, 17) AD patients	Placebo or 3 mg melatonin p.o./daily at bed time	4 weeks	Actigraphy. Neuropsychological assessment.	Melatonin significantly prolonged the sleep time and decreased activity in the night. Cognitive function was improved by melatonin.	[119]
Randomized, placebo-controlled clinical trial	157 (70, 87) AD patients	2.5 mg slow-release melatonin, or 10 mg melatonin or placebo at bed time	2 months	Actigraphy. Caregiver ratings of sleep quality	Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5 mg sustained-release melatonin group relative to placebo.	[120]
Open-label study	7 (4, 3) AD patients	3 mg melatonin p.o./daily at bed time	3 weeks	Actigraphy. Neuropsychological assessment.	Complete remission of daynight rhythm disturbances or sundowning was seen in 4 patients, with partial remission in other 2.	[114]
Randomized, placebo-controlled study	17 AD patients	3 mg melatonin p.o./daily at bed time (7 patients). Placebo (10 patients)	2 weeks	Actigraphy. Neuropsychological assessment.	In melatonin-treated group, actigraphic nocturnal activity and agitation showed significant reductions compared to baseline.	[121]
Randomized, placebo-controlled study	50 AD patients	Morning light exposure (2,500 lux, 1 h) and 5 mg melatonin (𝑛=16) or placebo (𝑛=17) in the evening. Control subjects (𝑛=17) received usual indoor light (150–200 lux).	10 weeks	Night time sleep variables, day sleep time, day activity, day : night sleep ratio, and rest-activity parameters were determined using actigraphy.	Light treatment alone did not improve night time sleep, daytime wake, or rest-activity rhythm. Light treatment plus melatonin increased daytime wake time and activity levels and strengthened the rest-activity rhythm.	[122]
Case report	68-year-old man with AD who developed rapid eye movement (REM) sleep behavior disorder	5–10 mg melatonin p.o./daily at bed time.	20 months	Polysomnography	Melatonin was effective to suppress REM sleep behavior disorder	[123]
Randomized, placebo-controlled study	41 (13, 28) AD patients	Melatonin (8.5 mg immediate release and 1.5 mg sustained release) (𝑁=24) or placebo (𝑁=17) administered at 10 : 00 P.M.	10 days	Actigraphy.	There were no significant effects of melatonin, compared with placebo, on sleep, circadian rhythms, or agitation.	[124]