Use of Melatonin for Cognitive Function and Sleep in Mild to Moderate Alzheimer’s Disease

The process of Alzheimer’s development and progression is often accompanied by neurobehavioral changes including disrupted sleep, especially night time awakenings.1 Importantly, sleep plays a significant role in learning and memory. Specifically, memory consolidation occurs during sleep via the strengthening of the neural connections that form memories.2 Hence, the combination of Alzheimer’s disease resulting in disrupted sleep and the potential of memory consolidation being further impacted due to disrupted sleep could possibly create a loop with each symptom successively further impacting the other. However, researchers need to evaluate whether improving sleep can reverse this loop by improving outcomes for Alzheimer’s patients.

Patients with mild to moderate Alzheimer’s disease given melatonin for 24-weeks had better cognitive performance and sleep efficiency than those taking a placebo.3 A sub-group of patients also suffering from insomnia were evaluated. Those that took the melatonin had improvements in activities of daily living, mini-mental state exam scores, and sleep efficiency.

This study involved outpatients recruited from five centers in the UK (n=35) and four in the United States (n=45).3 The 80 male and female participants were between age 50 and 85 and were diagnosed with mild to moderate Alzheimer’s disease and had a Mini-Mental State Examination (MMSE) score of >15. Computed tomography (CT), positron emission tomography (PET), or magnetic resonance imaging (MRI) were conducted to ensure the patients had no evidence of focal disease. After their initial diagnosis, all participants underwent a 2-week single-blind run-in period.  Then, they were randomized into groups for treatment with prolonged release melatonin (PRM: Circadin® 2 mg) or placebo for 24 weeks, using double-blind randomization.  The 24-week treatment period was followed with a 2-week placebo run-out period. The placebo tablets were identical to the PRM treatment tablets in appearance, taste, and odor. The PRM study medication or placebo was given approximately 1 to 2 hours before bed, with one tablet taken orally each day. Also, all participants were instructed to spend 2 hours outdoors in sunlight each day.

The researchers measured change from baseline to 12 and 24 weeks during the double-blind treatment period on cognitive parameters using the Alzheimer’s disease Assessment Scale-Cognition (ADAS-Cog), Instrumental Activities of Daily Living (IADL), and MMSE scores (only measured at baseline and 24 weeks). Sleep was assessed after 3, 12 and 24 weeks, using the Pittsburgh Sleep Quality Index (PSQI) and a sleep diary that documented duration and number of midsleep awakenings. The PSQI was administered with the patient and caregiver, and if there was a discrepancy between their reports, the response of the caregiver was used.  Researchers also assessed the caregiver’s sleep using the Sleep Disorders Inventory (SDI).

The study recruitment included 80 individuals, but seven were excluded prior to randomization, so 73 were randomized into PRM (n=39) and placebo (n=34) cohorts. Ultimately, 60 patients completed the study (n=31 PRM and n= 29 placebo). There were no statistically significant differences in demographics or baseline characteristics between the PRM and placebo cohorts. Treatment compliance remained above 90% in both the PRM and placebo treatment groups.

The subpopulation of patients suffering from insomnia experienced an improvement (3.5 point decrease) in the median ADAS-Cog score in the PRM treatment group. However, the placebo group experienced deterioration (increase of 3 points) in ADAS-Cog score, with the difference in treatment effect between the PRM and placebo groups being statistically significant. When evaluated for the mid-way treatment period (12-weeks), the median ADAS-Cog score improved (2 point decrease) in the PRM group and deteriorated (1 point increase) in the placebo group, but the difference between the groups was not statistically significant at this shorter treatment period.

At the end of the 24-week treatment period, the decline in the MMSE in the full population was significantly less in the PRM treatment group as compared to the placebo group. The mean decline in the MMSE score of the placebo group was significantly reduced over the 24-week period, but did not change in the PRM group. In the subpopulation of patients suffering from comorbid insomnia, MMSE scores significantly improved after 24 weeks for the PRM treatment group (increase of 1.5 points) when compared to the placebo group (decrease of 2.8 points). The PRM treatment group also demonstrated improvements in self-care and activities of daily living after 24-weeks of double-blind treatment, as assessed by the IADL. These differences remained significant after adjusting for sex and age, AD severity, insomnia severity, and memantine intake.

Greater than 70% of the study population did not have insomnia. Despite the absence of insomnia in most of the study participants’ scores measuring sleep efficiency improved significantly in the PRM treatment group over the placebo group after 2 weeks of treatment. In the small subpopulation with comorbid insomnia, sleep efficiency improved significantly also in the treatment group compared to the placebo group after 24 weeks of treatment. As reported in the sleep diaries, the quality of sleep was significantly increased at week 12 in the PRM treatment group, but did not change significantly in the placebo group.

Overall, the study results show evidence of possible benefit from prolonged release melatonin treatment in mild and moderate Alzheimer’s disease. The associations were especially strong in patients with comorbid insomnia. The sample size in the study was small, so further investigation in a larger study group is warranted.

 

  1. Pollak CP, Perlick D. Sleep problems and institutionalization of the elderly. Journal of Geriatric Psychiatry and Neurology. 1991;4(4):204–210.
  2. Maquet P. The role of sleep in learning and memory. Science. 2001; 294(5544):1048–1052.
  3. Wade AG, Farmer M, Harari G, et al. 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. Clinical Interventions in Aging.2014; 9: 947

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