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Alzheimer’s disease is the most common cause of dementia, affecting an estimated 5.3 million Americans, and is the sixth leading cause of death in the United States. The direct costs of caring for institutionalized patients and indirect costs of lost productivity are high. These costs are estimated at over 148 billion U.S. dollars annually (1).
Dementia is a clinical syndrome characterized by cognitive, neuropsychiatric, and functional impairments. Cognitive impairments include disturbances with memory, language, visuospatial function, perception, recognition, praxis, and the executive. Neuropsychiatric symptoms that occur in almost all dementia patients over the course of illness include disturbances in the domains of affect, perception, behavior, motivation, personality and sleep. Functional impairments include …
Sleep disturbance is a common occurrence in dementia associated with Alzhiemer’s disease (AD) affecting up to 44% of patients in clinic and community-based samples(2)(3). Impairments in sleep present a background for unsupervised and potentially unsafe behaviors such as wandering and pacing, and place patients and others at risk of harm. In addition, disruption of the normal sleep process in dementia is associated with significant caregiver distress and often precipitates institutionalization into hospitals, assisted living or nursing homes contributing to the rising costs associated with dementia (4).
Significant strides in the study of sleep problems with advancing age have provided greater insights and understanding into the causes and patterns of sleep disturbance in the elderly in general and in patients with dementia specifically. The evidence for effective treatments of sleep impairments in dementia is, however, less encouraging. The aim of this systematic review was to define the current evidence-based behind treatment options for sleep disturbance in dementia.
We conducted a comprehensive search of the scientific literature in MEDLINE and the Cochrane Central Register using Alzheimer’s, dementia, and sleep disturbance as keywords. We limited the search to clinical trials, randomized controlled trials, case reports, comparative studies, controlled clinical trials and meta-analyses in humans. Our goal was to identify intervention studies which employed one or more approaches targeting sleep disturbances in dementia as either a primary or secondary measure. Studies with interventions targeting other aspects of the neuropsychiatric symptoms of dementia, but which reported an effect on sleep as an outcome in their objective data were also included in our review.
We initially grouped studies based on their intervention strategies. Within each intervention group, we separated different types of samples from where the participants were randomized or studied i.e. community based population, nursing home, inpatient etc. We also reviewed the types of sleep disturbances reported in the patients with dementia. We compared study designs and outcome measures within each intervention group and finally examined the reported effects of the intervention strategies employed on sleep disturbance.
Following our review, we found extensive literature available on the features of sleep disturbance and other neuropsychiatric symptoms associated with AD. We however found a limited number of well designed randomized controlled trials of treatment options aimed at improving sleep symptoms in AD. Several studies employed both pharmacological and non-pharmacological treatments of the neuropsychiatric symptoms of AD including sleep, but the majority did not include objective sleep assessments including PSG or actigraphy in their outcome measures. Some assessed for sleep using caregiver reports, sleep logs, rating scales and other neuropsychological instruments including the Neuropsychiatric Inventory. There were mixed results on the efficacy of treatments for insomnia in AD.
Non pharmacological interventions involving behavioral modification, stimulus control, and bright light therapy have shown a significant improvement in sleep symptoms (See Tables 6–7). Pharmacological agents have shown variability in their efficacy and safety based on the specific agents used including second generation antipsychotics, sedative-hypnotics, mood stabilizing anticonvulsants, circadian rhythm modulators, acetylcholinesterase inhibitors and alternative medicines (See Tables 1–5). Most of these agents were used to target primarily other behavioral symptoms associated with AD and for the most part, produce an effect based on their sedative properties. Although acetylcholinesterase inhibitors appear to alter sleep architecture by increasing REM sleep duration.
Key features of disturbed sleep in dementia are sleep fragmentation with frequent nocturnal awakenings, and daytime somnolence and napping. There may be impairment with the sleep architecture in dementia including increased sleep latency, increased REM latency, less sleep efficiency, increased stage 1 NREM and decreased REM sleep (5) (6) (7) (8) (9). Other sleep disorders may be co-morbid with dementia including sleep related breathing disorders, sleep related movement disorders and essentially the spectrum of primary sleep disorders. These disorders should be treated based on recommended standards of care and appropriateness given the challenges of treating those with cognitive impairment. With regards to insomnia associated with AD, the interventions used include both pharmacological and non-pharmacological.
The non-pharmacological approaches involved decreasing the time spent in bed during the day, increased daily sunlight exposure, increased physical activity, structured bedtime routine, and decreased nighttime noise and light. In four studies, these measures showed a reduction in daytime sleepiness, a decrease in average duration and frequency of nocturnal awakenings, although one study found no significant change (10). The effects of bright light therapy (BLT) have been well studied. BLT applied at an intensity of greater than 2500 Lux for half an hour or greater in the morning or all day shows a trend towards improved quality and duration of nocturnal sleep and reduced daytime sleepiness (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). These interventions may be a good first line treatment strategy due to the relatively low risk involved with employing these interventions, in addition to the evidence in support of efficacy.
There have been several medication trials of effectiveness in sleep disturbance associated with AD. The use of melatonin, a circadian rhythm modulator has shown mixed results. Other than a few individual studies reporting improved sleep duration (21) (22), melatonin has demonstrated no statistically significant differences between treatment groups or placebo. There is stronger evidence for efficacy of BLT in combination with melatonin when compared with use of melatonin alone, and in one study melatonin produced an adverse effect on mood unless combined with BLT (23). Ramelteon, acts on melatonin receptors and appears similar to melatonin in its mode of action. It is FDA approved for the treatment of insomnia in the general population and it promotes increased total sleep time in addition to shortening sleep latency. It is well tolerated and appears to lack significant adverse effects including excessive sedation and cognitive impairment that is often associated with other sedative agents (24). There is however limited data on its use in patients with AD.
On account of the importance of the effects of acetylcholine of sleep, it is pertinent to explore the possible efficacy of acetylcholinesterase inhibitors on both cognitive impairment and sleep disturbance. Although there appears to be an effect on sleep architecture, with increased REM duration using donepezil and rivastigmine (25), the overall impact of acetylcholinesterase inhibitors on sleep seems limited.
The evidence for sedative-hypnotics and second generation antipsychotics on sleep disturbance in dementia appears to be associated with sedation and attenuating the behavioral and other neuropsychiatric manifestations of dementia rather than a primary effect on sleep. However the rationale for using these agents long-term for sleep is limited given the associated risks and their adverse effect profiles including propensity for metabolic abnormalities. Sedative-hypnotic agents including benzodiazepines and non-benzodiazepines are used extensively. These agents promote sedation and also alter sleep architecture by increasing N2 Non-REM sleep. Although randomized controlled trials of their efficacy in treating insomnia in AD is limited, the non-benzodiazepines including zolpidem, zaleplon and eszoplicone appear to have a better safety profile than traditional benzodiazepines and cause less disorientation, memory loss and excess sedation with the associated risk of falls. Second generation antipsychotics are not indicated for use in patients with AD, given the risk of cardiovascular adverse events and sudden death.
There is limited evidence on the efficacy and safety of sedating antidepressants in the treatment of insomnia in AD. However, their antidepressant effects may be beneficial in cases of co-morbid affective and cognitive disturbance as insomnia may be a manifestation of either or both.
There are limits to the efficacy and safety of the current treatment strategies aimed at ameliorating insomnia in patients with AD. Nevertheless, several interventions have shown some modicum of efficacy and the non-pharmacological treatments expose patients to the least amount of risk in comparison to medication therapies. Further investigation and research is needed to improve the available armamentarium and subsequently improve treatment outcomes, decrease distress experienced by both patients and care providers and increase overall level of function.