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Randomized Controlled Trial
, 9, 947-61
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Add-on Prolonged-Release Melatonin for Cognitive Function and Sleep in Mild to Moderate Alzheimer's Disease: A 6-month, Randomized, Placebo-Controlled, Multicenter Trial

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Randomized Controlled Trial

Add-on Prolonged-Release Melatonin for Cognitive Function and Sleep in Mild to Moderate Alzheimer's Disease: A 6-month, Randomized, Placebo-Controlled, Multicenter Trial

Alan G Wade et al. Clin Interv Aging.

Abstract

Purpose: A link between poor sleep quality and Alzheimer's disease (AD) has recently been suggested. Since endogenous melatonin levels are already reduced at preclinical AD stages, it is important to ask whether replenishing the missing hormone would be beneficial in AD and whether any such effects would be related to the presence of sleep disorder in patients.

Patients and methods: The effects of add-on prolonged-release melatonin (PRM) (2 mg) to standard therapy on cognitive functioning and sleep were investigated in 80 patients (men [50.7%], women [49.3%], average age 75.3 years [range, 52-85 years]) diagnosed with mild to moderate AD, with and without insomnia comorbidity, and receiving standard therapy (acetylcholinesterase inhibitors with or without memantine). In this randomized, double-blind, parallel-group study, patients were treated for 2 weeks with placebo and then randomized (1:1) to receive 2 mg of PRM 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.

Results: Patients treated with PRM (24 weeks) had significantly better cognitive performance than those treated with placebo, as measured by the IADL (P=0.004) and MMSE (P=0.044). Mean ADAS-Cog did not differ between the groups. Sleep efficiency, as measured by the PSQI, component 4, was also better with PRM (P=0.017). In the comorbid insomnia (PSQI ≥6) subgroup, PRM treatment resulted in significant and clinically meaningful effects versus the placebo, in mean IADL (P=0.032), MMSE score (+1.5 versus -3 points) (P=0.0177), and sleep efficiency (P=0.04). Median ADAS-Cog values (-3.5 versus +3 points) (P=0.045) were significantly better with PRM. Differences were more significant at longer treatment duration. PRM was well tolerated, with an adverse event profile similar to that of placebo.

Conclusion: Add-on PRM has positive effects on cognitive functioning and sleep maintenance in AD patients compared with placebo, particularly in those with insomnia comorbidity. The results suggest a possible causal link between poor sleep and cognitive decline.

Keywords: acetylcholinesterase inhibitors; insomnia; memantine.

Figures

Figure 1
Figure 1
Overall study design. Notes: The study was comprised of a 2-week, single-blind, placebo run-in period, followed by randomization (1:1) to add-on PRM 2 mg or placebo for 24 weeks. Once the treatment period was over, the patients underwent a 2-week placebo run-out period. Abbreviation: PRM, prolonged-release melatonin.
Figure 2
Figure 2
Overall study patient disposition. Abbreviations: AE, adverse event; FAS, full analysis set; PRM, prolonged-release melatonin; SAE, serious adverse event.
Figure 3
Figure 3
Cognitive assessments. Notes: (A) The change in median ADAS-Cog between baseline and 24 weeks, by treatment FAS and insomnia subpopulation (PSQI ≥6 at baseline). P-value indicates significant for changes from baseline between the two study groups (median test). (B) The change in mean MMSE (± SEM) between baseline and 24 weeks of treatment in the FAS and in the insomnia subpopulation (PSQI ≥6 at baseline). P-value indicates significant for changes from baseline between the two study groups, with adjustment for baseline assessment (ANCOVA model). (C) The change in mean IADL (± SEM) between baseline and 24 weeks, by treatment in the FAS and insomnia subpopulation (PSQI ≥6 at baseline). P-value indicates significant for changes from baseline between the two study groups, with adjustment for baseline assessment (ANCOVA model). (D) Global treatment effect of PRM on mean IADL (± SEM) change from baseline, over the 24-week period (MMRM), in the FAS. Abbreviations: AD, Alzheimer’s disease; ADAS-Cog, AD Assessment Scale–Cognition; ANCOVA, analysis of covariance; FAS, full analysis set; IADL, Instrumental Activities of Daily Living; MMRM, mixed-effects model for repeated measures; MMSE, Mini–Mental State Examination; PRM, prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index; SEM, standard error of the mean.
Figure 4
Figure 4
Sleep assessments. Notes: (A) The improvement from baseline (absolute value) in mean sleep efficiency over time (sleep efficiency PSQI component 4) – FAS. (B) The improvement from baseline (absolute value) in mean sleep efficiency (sleep efficiency PSQI component 4) in the insomnia subpopulation (PSQI ≥6 at baseline). P-value indicates significant changes from baseline between the two study groups, with adjustment for baseline assessment (ANCOVA model). Abbreviations: ANCOVA, analysis of covariance; C4, component 4; FAS, full analysis set; PRM, prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index.

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