Table 3.

Studies including treatment of MCI patients with melatonin.

Subjects	Design	Study's duration	Treatment	Measured	Results	References
10 patients with MCI	Double-blind, placebo-controlled, crossover study	10 days	6 mg melatonin p.o./daily at bed time	Actigraphy. Neuropsychological assessment	Melatonin enhanced the rest-activity rhythm and improved sleep quality. Total sleep time unaffected. The ability to remember previously learned items improved along with a significant reduction in depressed mood	(132)
26 individuals with age-related MCI	Double-blind, placebo-controlled pilot study	4 weeks	1 mg melatonin p.o. or placebo at bed time	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. It also improved scores on the California Verbal Learning Test-interference subtest	(133)
354 individuals with age-related MCI	Randomized, double blind, placebo-controlled study	3 weeks	Prolonged release melatonin (Circadin, 2 mg) or placebo, 2 h before bedtime	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)
60 MCI outpatients	Open-label, retrospective study	9–24 months	35 patients received daily 3–9 mg of a fast-release melatonin preparation p.o. at bedtime. Melatonin was given in addition to the standard medication	Daily logs of sleep and wake quality. Initial and final neuropsychological assessment	Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with an improvement in wakefulness and sleep quality. Patients treated with melatonin showed significantly better performance in neuropsychological assessment	(135)
189 individuals with age-related cognitive decay	Long-term, double-blind, placebo-controlled, 2 × 2 factorial randomized study	1–3.5 years	Long-term daily treatment with whole-day bright (1,000 lux) or dim (300 lux) light. Evening melatonin (2.5 mg) or placebo administration	Standardized scales for cognitive and non-cognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months	Light attenuated cognitive deterioration and 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	(108)
22 individuals with age-related cognitive decay	Prospective, randomized, double-blind, placebo-controlled, study	2 months	Participants received 2 months of melatonin (5 mg p.o. /day) and 2 months of placebo	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	(136)
25 MCI outpatients	Randomized, double-blind, placebo-controlled study	12 weeks	11 patients received an oily emulsion of docosahexaenoic acid-phospholipids containing melatonin (10 mg) and tryptophan (190 mg)	Initial and final neuropsychological assessment of orientation and cognitive functions, short-term and long-term memory, attentional abilities, executive functions, visuo-constructional and visuo-spatial abilities, language, and mood	Older adults with MCI had significant improvements in several measures of cognitive function when supplemented with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan for 12 weeks, compared with the placebo. The antioxidant capacity of erythrocytes and membrane lipid composition improved after treatment	(137, 138)
96 MCI outpatients	Open-label, retrospective study	15–60 months	61 patients received daily 3–24 mg of a fast-release melatonin preparation p.o. at bedtime. Melatonin was given in addition to the standard medication	Daily logs of sleep and wake quality. Initial and final neuropsychological assessment	Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with an improvement in wakefulness and sleep quality. Patients treated with melatonin showed significantly better performance in neuropsychological assessment. Only 6 out of 61 patients treated with melatonin needed concomitant benzodiazepine treatment vs. 22 out of 35 MCI patients not receiving melatonin	(139)
80 patients diagnosed with mild to moderate AD, with and without insomnia comorbidity, and receiving standard therapy (acetylcholinesterase inhibitors with or without memantine)	Randomized, double-blind, parallel-group study	28 weeks	Patients were treated for 2 weeks with placebo and then randomized (1:1) to receive 2 mg of prolonged release melatonin or placebo nightly for 24 weeks, followed by 2 weeks placebo	The AD Assessment Scale-Cognition (ADAS-Cog), Instrumental Activities of Daily Living (IADL), Mini-Mental State Examination (MMSE), sleep, as assessed by the Pittsburgh Sleep Quality Index (PSQI) and a daily sleep diary, and safety parameters were measured	Patients treated with melatonin had significantly better cognitive performance than those treated with placebo. Sleep efficiency, as measured by the PSQI, component 4, was also better. Differences were more significant at longer treatment duration	(140)
142 patients meeting DSM-IV-TR criteria for major depression disorder were enrolled	Double-blind, placebo-controlled, randomized trial	6 weeks	Combination treatment: (buspirone 15 mg with melatonin- 3 mg) vs. buspirone 15 mgmonotherapy, vs. placebo	Clinical global impression of severity (CGI-S) and improvement (CGI-I), the QIDS-SR16, and the Hamilton rating scale for anxiety (Ham-A) at the baseline, week 2, week 4, and week 6 endpoint	Treatment responders improved significantly more on the total CPFQ than non-responders regardless of treatment assignment. The cognitive dimension of the CPFQ score favored the combination treatment over the other two groups	(141)
139 patients older than 65 year. of age scheduled for hip arthroplasty	Prospective cohort study	7 days	Patients were randomized to receive 1 mg oral melatonin or placebo daily 1 h before bedtime 1 day before surgery and for another 5 consecutive days post-operatively	Subject assessment, including Mini-Mental State Examination (MMSE) score, subjective sleep quality, general well-being, post-operative fatigue, and visual analog scale for pain were evaluated pre-operatively and at days 1, 3, 5, and 7 after surgery	The MMSE score in the control group decreased significantly after surgery. The MMSE score in the melatonin group remained unchanged during the 7 days of monitoring. In addition, significant post-operative impairments of subjective sleep quality, general well-being, and fatigue were found in the control group when compared with the melatonin group	(142)