Pharmacological and non-pharmacological treatment options for sleep disturbances in Alzheimer’s disease

Figures & data

Table 1. Drugs used for the treatment of AD.

Drug class	Drug name	Indication	Side effects	MoA
Reversible non-competitive cholinesterase inhibitor	Donepezil Hydrochloride Rivastigmine	Mild to moderate dementia in AD	Gastrointestinal discomfort Aggression Headache Hypertension	By irreversibly inhibiting cholinesterase, they prevent the breakdown of ACh, leading to an increased concentration of ACh in the synaptic cleft. This prolonged presence of ACh enhances cholinergic neurotransmission, resulting in prolonged stimulation of cholinergic receptors, including nicotinic and muscarinic receptors.
Reversible cholinesterase inhibitor	Galantamine	Mild to moderately severe dementia in AD	Arrhythmias Diarrhoea Hypertension	It works by inhibiting the breakdown of ACh, leading to enhanced cholinergic neurotransmission. It also acts as a positive allosteric modulator of nicotinic receptors, which can enhance the sensitivity and response of these receptors to acetylcholine.
N-methyl-D-aspartate (NMDA) receptor antagonists	Memantine	Moderate to severe dementia in AD	Constipation Drowsiness Hypertension	By binding to and blocking NMDA receptors, it helps regulate glutamate neurotransmission, protect against excitotoxicity, and modulate synaptic plasticity.
Monoclonal antibody	Aducanumab	Mild dementia in AD	Headache Nausea Confusion	It binds to aggregated forms of beta-amyloid and helps facilitate their clearance from the brain, potentially slowing down the progression of AD.

Table 2. Summary of 42 studies with the effect of the intervention on sleep quality and sleep disturbances.

Author	Sample Size	Intervention	Summary of findings
Randomized controlled trial
Chong et al. [11]	n=39	Sham continuous positive airway pressure(CPAP) for 3 weeks followed by therapeutic CPAP (tCPAP) for 3 weeks or tCPAP for 6 weeks	In tCPAP group, Epworth Sleepiness Scale after 3 weeks went from 8.89 at baseline to 6.56 and after 6 weeks further reduced to 5.53. In sham CPAP group followed by 3 weeks of tCPAP, there was no significant difference after 3 weeks of sham CPAP but a significant decrease of Epworth Sleepiness Scale from 7.68 to 6.47 after 3 weeks of tCPAP.
Cooke et al. [12]	n=52	Placebo CPAP for 3 weeks followed by tCPAP for 3 weeks or 3 weeks of tCPAP	tCPAP for 3 weeks led to Change in wakefulness after sleep onset (WASO) scores from 126.0 ± 79.5 to 92.3 ± 44.6 Change in percentage Stage 1 sleep from 23.5 ± 14.5 to 16.3 ± 10.1 Change in percentage Stage 3 sleep from 1.9 ± 3.1 to 4.0 ± 6.2
Nascimento et al. [13]	n=42	Multimodal exercise program: three 1-h sessions every week for 6 months	Improvement of Mini-Sleep Questionnaire (MSQ) score by 18.7%
Figueiro et al. [14]	n=46	Two 4-week periods of active intervention of 350 lx of 6000 K light or control of 100 lx of 2700 K light.	Mean Pittsburgh Sleep Quality Index (PSQI) scores after active intervention went from a baseline of 10.30 ± 0.40 to 6.67 ± 0.48 and from 9.80 ± 0.44 to 8.41 ± 0.47 after control intervention.
Dowling et al. [15]	n=50	Experimental group received 10-week active intervention with 2500 lx light exposure for 1 hour along with 5 mg melatonin (LM group) or placebo (LP group) in the evening while control group received exposure to usual indoor light	Night sleep time in minutes In LP group went from 493 ± 105 to 521 ± 108 In LM group went from 459 ± 109 to 489 ± 105. In LM group, daytime sleep-in minutes went from 315 ± 129 to 249 ± 103 showing significant improvement in daytime somnolence.
Gfigueiro et al. [16]	n=14	Low-level “bluish-white” lighting was administered at daytime for 4 weeks	Sleep efficiency changed from 80 ± 5% at baseline to 84 ± 4% at the end of the intervention. Total sleep time (in minutes) changed from 431 ± 37 at baseline to 460 ± 25 at the end of the intervention.
McCurry et al. [17]	n=132	Subjects assigned to one of the three active treatments (walking, light, combination treatment) or contact control	Changes in total wake time per night (min) after 2 months for control, walking, light, and combination treatment were 7.4, −25.8, −31.6, and 32.4, respectively
Fontana Gasio et al. [18]	n=13	Dawn–dusk simulation (DDS) light therapy for 3 weeks in which signal was curtailed at 0.001 lux and at 70% of maximum 400 lux or placebo dim red light (>5 lux)	Sleep efficiency (%) for DDS was 77.2 ± 4.4 at baseline, 80.4± 2.1 during treatment, and 76.5 ± 1.0 during follow-up
Burns et al. [19]	n=48	Exposure to bright light therapy (BLT) of 10,000 lx (full spectrum) or standard fluorescent tube light at 100 lx for two hours	Nocturnal sleep (mean duration) went from 8.3 hours at baseline to 8.6 hours at the end of the intervention with no significant difference
Wade et al. [20]	n=80	2 mg of prolonged-release melatonin (PRM) or placebo for 24 weeks	Significant decrease of −5.5 in the PSQI global score in the PRM group but not in the placebo group.
Singer et al. [21]	n=157	Treatment with placebo, 2.5-mg slow-release (SR) melatonin (ML), or 10-mg melatonin.	Nocturnal total sleep time (NTST) increased by 16 ± 54 minutes in the ML 2.5SR group and 13 ± 44 minutes in the ML 10 group compared to 3 ± 39 minutes for placebo, indicating a weak trend for more nighttime sleep in the melatonin groups.
Serfaty et al. [22]	n=44	6 mg PRM for 2 weeks followed by a week of the washout phase Participants in group 1 were administered melatonin in the first treatment period and received a placebo in the second treatment period and vice versa for group 2	Melatonin had no effect on median total time asleep, number of awakenings, and sleep efficiency.
Fisman et al. [23]	n=27	100 mg t.i.d. of 2-dimethylaminoethanol for 2 days which was increased every 2 days till a maximum 1800 mg/day or placebo for 2 months	No significant improvement was observed
Moraes et al. [24]	n=23	5 mg of donepezil or placebo	Percentage REM sleep changed significantly from 7.2 ± 4.3 at baseline to 15.9 ± 11.1 at the end of treatment (p < 0.05)
Moline et al. [25]	n=62	Lemborexant (LEM 2.5 mg, 5 mg, 10 mg or 15 mg) or placebo for 4 weeks	Mean number of sleep bouts during the daytime In placebo group, went from baseline of 4.76 ± 3,12 to 4.44 ± 3.10 at Week 4 In LEM2.5 group, went from baseline of 5.90 ± 3.05 to 6.07 ± 3.60 at Week 4 In LEM5 group, went from baseline of 4.97 ± 2.97 to 4.21 ± 2.58 at Week 4 In LEM10 group went from baseline of 6.24 ± 3.23 to 7.08 ± 4.21 at Week 4 In LEM15 group, went from baseline baseline of 4.75 ± 2.55 to 4.93 ± 2.22 at Week 4
Stahl et al. [26]	n= 1698	Galantamine: 8 mg BID galantamine (GAL16) or 12 mg BID galantamine(GAL24) or placebo	The rates of sleep problems for GAL 24, GAL 16, and placebo arms were 2.6%, 1.1%, and 2.2%, respectively, and for nightmares were 1.1%, 0.4%, and 0.1%, respectively.
Grippe et al. [27]	n=47	Trazodone 50 mg or placebo for 14 days	Relative rhythm amplitude for the trazodone arm went from 0.68 at baseline to 0.75 post-treatment Mean daily activity levels for the trazodone arm at baseline and post-treatment were 171.481 and 211.341, respectively.
Camargos et al. [28]	n=30	50 mg of trazodone or placebo for 2 weeks	Subjects in the trazodone treatment group had 42.5 minutes more sleep at night compared to the placebo group and had their nighttime percent sleep increased by 8.5% points with respect to baseline.
Kouzuki et al. [29]	n=35	Aroma bath salt with concentrations 0.1%, 0.5% or 1% for a duration of ≥10 min for 24 weeks was preceded and succeeded by an observation period for 4 weeks each.	Changes in the PSQI-J scores from pre-intervention at week 4 to post-intervention at week 28: Ffor 0.1% group = −0.2 ±0.5 Ffor 0.5% group = −0.4 ±0.2 Ffor 1% group = 0.1 ±0
Rose et al. [30]	n=38	CES device provided electrical stimulation (CES) at an intensity of 100 μA for 60 minutes/day for 4 weeks or sham CES	A trend toward statistical significance (p =.09) in PSQI scores for daily disturbances was found between the intervention group (2.34) and sham control group (2.65).
Markowitz et al. [31]	n=136	Galantamine 24 mg or placebo	Mean changes in PSQI score for galantamine and placebo were 0.01 and −0.17, respectively.
Scoralick et al. [32]	n=24	15-mg mirtazapine or placebo for 14 days	Mean NTST (min) for the mirtazapine group went from 383.4 at baseline to 414.0 post-treatment.
Meguro et al. [33]	n=34	1 mg of risperidone or placebo for 1 month	Patients treated with risperidone had a decrease of 1.2 hours in the mean daytime sleep while an increase of 3.8 hours in mean nighttime sleep.
Herring et al. [34]	n= 285	Suvorexant 10 mg or placebo for 4 weeks	Total sleep time (mins) in the suvorexant group went from 277.7 ± 76.9 at baseline to 349.4 ± 71.9 at the end of treatment. The model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant group.
Savaskan et al. [35]	n=30	Quetiapine (25–200 mg) or haloperidol (0.5–4 mg)	Subjects administered with quetiapine had shorter wake bouts at the end of intervention as compared to baseline Subjects administered with haloperidol had fewer immobile phases but with increased duration compared with baseline
Ito et al. [36]	n=28	BLT (3000 lx, 0.900–11.00 h) for 8 weeks and for the latter 4 weeks, half were treated with BLT + Vitamin B12 (1.5 mg/day for the fifth-sixth week, 3.0 mg for the seventh-eighth week)	Percentage sleep during the daytime after BLT for 4 weeks was 27.9 ± 13.2, and after BLT for 8 weeks + Vitamin B12 treatment was 25.5 ± 12.5.
Cooke et al [37].	n=76	Donepezil galantamine, rivastigmine, or no AChEI	Significantly lower percentage of stage 1 sleep in the donepezil group than patients in the galantamine group, but there was no significant difference between the donepezil group and the rivastigmine or no AChEI groups Significantly higher percentage of stage 2 sleep in the donepezil group than patients in the no AChEI group, but there was no significant difference between the donepezil group and either the galantamine group or the rivastigmine group
Exploratory study
Cooke et al. [38]	n=10	6-week of CPAP, after which follow-up of 5 patients who continued CPAP (CPAP+), and 5 patients who discontinued CPAP (CPAP-)	CPAP+ group showed a significant clinical and statistical improvement in PSQI
Open clinical trial
Skjerve et al. [39]	n=11	BLT (5000–8000 lx at a distance of 0.3–0.5 m) 45 mins daily for 4 weeks daily	Sleep–wake disturbances in dementia scores before treatment, during treatment, and after treatment were 13.10 ± 2.08, 13.20 ± 2.67, 12.10 ± 3.25, respectively, with no significant difference.
Yamadera et al. [40]	n=27	BLT (3000 lx) 2 h daily for 4 weeks.	Percentage of sleep time at night went from 49.8 ± 15.8 to 55.0 ± 17.9 before and after therapy, respectively. Percentage of nap time during the day went from 30.6 ± 15.7 to 23.8 ± 13.2 before and after therapy, respectively.
Mizuno et al. [41]	n=12	Donepezil 3 mg daily for 7 days, followed by 5 mg daily for 6 weeks.	Total sleep time in minutes changed from 332.0 ± 118.2 at baseline to 398.6 ± 98.5 after 6 weeks.
Case control study
Mishima et al. [42]	n=14	BLT (3000–5000 lx) 2 h daily for 4 weeks.	Total sleep time and nocturnal sleep time before the light therapy were 7.1 ± 1.5 h and 5.7 ± 1.3 h, respectively, and during the light therapy were 7.6 ± 1.1 h and 6.7 ± 1.2 h, respectively.
Sekiguchi et al. [43]	n=17	BLT (5000 lx) 1 h daily for 2 weeks.	Improvement in sleep quality in four out of seventeen AD patients.
Retrospective study
La et al.[44]	n=25	Trazodone with a median dosage of 50 mg per day (25th percentile 50 mg; 75th percentile 100–125 mg)	Participants treated with trazodone with concomitant baseline sleep complaints, especially those who reported improvement in sleep quality over time, had delayed cognitive decline, compared to patients with sleep disruption that were not on trazodone.
Brusco et al. [45]	n=14	Melatonin 9 mg at bedtime daily for variable periods, ranging from 22 to 35 months	Coefficient of variation of bed time values (indirect estimation of agitated behavior at the beginning of the night) for days 0–2 and days 19–21 for patients with sleep disturbances alone were 32.6 ± 14.9 and 31.5 ± 10.8, respectively, while for patients with sleep disturbances and depression were 27.1 ± 14.1 and 24.5 ± 13.5, respectively, and for patients with sleep disturbances and dementia were 58.0 ± 24.7 and 41.5 ± 20.9, respectively.
Bromundt et al. [46]	n=20	Individually timed DDS over the subjects’ beds for 7–8 weeks.	The sleep efficiency [%] for the participants undergoing DDS went from 79.23 ± 11.21 to 82.64 ± 10.84.
Katsunuma et al. [47]	n=9	Zopiclone 7.5 mg/day for 20 days with concomitant administration of aniracetam	In 7/9 cases (78%), there was a 50% prolongation of sleeping time, while in the remaining two cases (22%), there was no significant improvement.
Cross-sectional study
Shih et al. [48]	n=184	Observation of patients who were able to walk with or without a walking aid (e.g. walker or cane) as well as participation in a regular program of physical activity	Significant improvement in sleep quality by having an accompanying walker Improvement in sleep was also seen in those doing weekly walking
Case report
Niitsu et al. [49]	-	Donepezil 5 mg/day with concomitant tiapride (50 mg daily) and yokukansan (7.5 g per day) which was later switched to keishi-ka-ryukotsu-borei-to (KRBT) at 7.5 g per day	Improvement in Neuropsychiatric Inventory (NPI) total score from 76 to 35.
Anderson et al. [50]	-	Melatonin 5 mg nocte followed by 10 mg nocte after 1 month.	At 5 mg dose, there was partial mitigation of the symptoms of REM sleep behavior disorder, while 10 mg dose led to a complete resolution of these symptoms. Every 2–3 days, nocturnal jerks were observed initially, but after melatonin treatment, there were no such episodes observed.
Prospective study
Simoncini et al. [51]	n= 129	Device H7 Insomnia Control was used to apply manual acupressure locally all night (from 7 pm to 7 am) for 2 months.	Change in PSQI scores from 12.59 ± 8.56 at baseline to 8.56 ± 3.27 after 2 months and to 9.2 ± 3.6 after 4 months.

Figure 1. Link between aggregation of toxic metabolites of AD with sleep dysfunction.

Figure 2. A proposed stepwise algorithm for the management of sleep disturbances in AD.

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