Abstract: We found six RCTs eligible for inclusion for three drugs: melatonin (222 participants, four studies, but only two yielded data on our primary sleep outcomes suitable for meta-analysis), trazodone (30 participants, one study), and ramelteon (74 participants, one study, no peer-reviewed publication, limited information available). The participants in the trazodone study and almost all participants in the melatonin studies had moderate-to-severe dementia due to Alzheimer's disease (AD); those in the ramelteon study had mild-to-moderate AD. Participants had a variety of common sleep problems at baseline. All primary sleep outcomes were measured using actigraphy. In one study of melatonin, drug treatment was combined with morning bright light therapy. Only two studies made a systematic assessment of adverse effects. Overall, the evidence was at low risk of bias, although there were areas of incomplete reporting, some problems with participant attrition, related largely to poor tolerance of actigraphy and technical difficulties, and a high risk of selective reporting in one trial that contributed very few participants. The risk of bias in the ramelteon study was unclear due to incomplete reporting. We found no evidence that melatonin, at doses up to 10 mg, improved any major sleep outcome over 8 to 10 weeks in patients with AD who were identified as having a sleep disturbance. We were able to synthesize data for two of our primary sleep outcomes: total nocturnal sleep time (mean difference (MD) 10.68 minutes, 95% CI -16.22 to 37.59; N = 184; two studies), and the ratio of daytime sleep to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03; N = 184; two studies). From single studies, we found no difference between melatonin and placebo groups for sleep efficiency, time awake after sleep onset, or number of night-time awakenings. From two studies, we found no effect of melatonin on cognition or performance of activities of daily living (ADL). No serious adverse effects of melatonin were reported in the included studies. We considered this evidence to be of low quality. There was low-quality evidence that trazodone 50 mg given at night for two weeks improved total nocturnal sleep time (MD 42.46 minutes, 95% CI 0.9 to 84.0; N = 30; one study), and sleep efficiency (MD 8.53%, 95% CI 1.9 to 15.1; N = 30; one study) in patients with moderate-to-severe AD, but it did not affect the amount of time spent awake after sleep onset (MD -20.41, 95% CI -60.4 to 19.6; N = 30; one study), or the number of nocturnal awakenings (MD -3.71, 95% CI -8.2 to 0.8; N = 30; one study). No effect was seen on daytime sleep, cognition, or ADL. No serious adverse effects of trazodone were reported. Results from a phase 2 trial investigating ramelteon 8 mg administered at night were available in summary form in a sponsor's synopsis. Because the data were from a single, small study and reporting was incomplete, we considered this evidence to be of low quality in general terms. Ramelteon had no effect on total nocturnal sleep time at one week (primary outcome) or eight weeks (end of treatment) in patients with mild-to-moderate AD. The synopsis reported few significant differences from placebo for any sleep, behavioural, or cognitive outcomes; none were likely to be of clinical significance. There were no serious adverse effects from ramelteon. We discovered a distinct lack of evidence to help guide drug treatment of sleep problems in dementia. In particular, we found no RCTs of many drugs that are widely prescribed for sleep problems in dementia, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks associated with these common treatments. From the studies we identified for this review, we found no evidence that melatonin (up to 10mg) helped sleep problems in patients with moderate to severe dementia due to AD. There was some evidence to support the use of a low dose (50 mg) of trazodone, although a larger trial is needed to allow a more definitive conclusion to be reached on the balance of risks and benefits. There was no evidence of any effect of ramelteon on sleep in patients with mild to moderate dementia due to AD. This is an area with a high need for pragmatic trials, particularly of those drugs that are in common clinical use for sleep problems in dementia. Systematic assessment of adverse effects is essential.

Plain-language summary: We searched the medical literature up to March 2016 for all randomised trials that compared any medicine used for treating sleep problems in people with dementia with a fake medicine (placebo). We found six trials (326 participants) that investigated three medicines: melatonin (four trials), trazodone (one trial), and ramelteon (one trial). The ramelteon trial and one melatonin trial were commercially funded; the other trials had non-commercial funding sources. Limited information was available for the ramelteon trial, and it came from the trial's sponsor. Overall, the evidence was of low quality, meaning that further research is very likely to affect the results. Participants in the melatonin and trazodone trials almost all had moderate to severe dementia, while those in the ramelteon trial had mild to moderate dementia. The four melatonin trials had a total of 222 participants. From the evidence we found, we could be moderately confident that melatonin did not improve sleep in patients with dementia due to Alzheimer's disease. No serious harms were reported. The trazodone trial had 30 participants. Because it was so small, we could only have limited confidence in its results. It showed that a low dose of the sedative anti-depressant trazodone, 50 mg, given at night for two weeks, increased the total time spent asleep each night by an average of 43 minutes. This medicine improved sleep efficiency (the percentage of time in bed spent sleeping), but had no effect on the time spent awake after falling asleep, or on the number of times the participants woke up at night. No serious harms were reported. The ramelteon trial had 74 participants. The limited information available did not provide any evidence that ramelteon was better than placebo. There were no serious harms caused by ramelteon. The trials did not report on some of the outcomes which interested us, including quality of life and the impact on carers. Although we searched for them, we were unable to find any trials of other sleeping medications that are commonly prescribed to people with dementia. All of the participants had dementia due to Alzheimer's disease, although sleep problems are also common in other forms of dementia. We concluded that there is very little evidence to guide decisions about medicines for sleeping problems in dementia. Any medicine used should be used cautiously, with a careful assessment of how well it works, and its side effects in individual patients. More trials are needed to inform medical practice, with a particular need for trials investigating medicines that are commonly used for sleep problems in dementia. It is essential that trials include careful assessment of side effects.