Table 2.

Clinical studies on melatonin efficacy in MCI.

Design	Subjects (M, F)	Treatment	Study's duration	Measured	Results	Reference(s)
Double-blind, placebo-controlled, crossover study	10 (4, 6) patients with mild cognitive impairment (MCI)	6 mg melatonin p.o./daily at bed time	10 days	Actigraphy. Neuropsychological assessment.	Enhanced the rest-activity rhythm and improved sleep quality (reduced sleep onset latency and in the number of transitions from sleep to wakefulness Total sleep time unaffected. The ability to remember previously learned items improved along with a significant reduction in depressed mood.	[131]
Double-blind, placebo-controlled pilot study	26 individuals with age-related MCI	1 mg melatonin p.o. or placebo at bed time	4 weeks	Sleep questionnaire and a battery of cognitive tests at baseline and at 4 weeks	Melatonin administration improved reported morning “restedness” and sleep latency after nocturnal awakening and also improved scores on the California Verbal Learning Test-interference subtest.	[132]
Open-label, retrospective study	50 (13, 37) MCI outpatients	25 had received daily 3–9 mg of a fast-release melatonin preparation p.o. at bedtime. Melatonin was given in addition to the standard medication	9–18 months	Daily logs of sleep and wake quality. Initial and final neuropsychological assessment.	Patients treated with melatonin showed significantly better performance in neuropsychological assessment. Abnormally high. Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with an improvement in wakefulness and sleep quality.	[133]
Randomized, double blind, placebo-controlled study	354 individuals with age-related cognitive decay	prolonged release melatonin (Circadin, 2 mg) or placebo, 2 h before bedtime	3 weeks	Leeds Sleep Evaluation and Pittsburgh Sleep Questionnaires, Clinical Global Improvement scale score and quality of life.	PR-melatonin resulted in significant and clinically meaningful improvements in sleep quality, morning alertness, sleep onset latency, and quality of life	[134]
Long-term, double-blind, placebo-controlled, 2 × 2 factorial randomized study	189 (19, 170) individuals with age-related cognitive decay	Long-term daily treatment with whole-day bright (1000 lux) or dim (300 lux) light. Evening melatonin (2.5 mg) or placebo administration	1 to 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 and also ameliorated depressive symptoms. Melatonin shortened sleep onset latency and increased sleep duration but adversely affected scores for depression. The combined treatment of bright light plus melatonin showed the best effects.	[105]
Prospective, randomized, double-blind, placebo-controlled, study	22 (15, 7) individuals with age-related cognitive decay	Participants received 2 months of melatonin (5 mg o.o./day) and 2 months of placebo	2 months	Sleep disorders were evaluated with the Northside Hospital Sleep Medicine Institute (NHSMI) test. Behavioral disorders were evaluated with the Yesavage Geriatric Depression Scale and Goldberg Anxiety Scale.	Melatonin treatment significantly improved sleep quality scores. Depression also improved significantly after melatonin administration.	[135]