Pharmacological interventions to improve sleep in people with Alzheimer’s disease: a meta-analysis of randomized controlled trials

Figures & data

Figure 1. Study selection process – PRISMA.

Table 1. Study characteristics of the 14 RCTs included in our review.

Study Characteristics					Assessment		Intervention – outcome
Author	Study design	Mean age	Females/N	Common comorbid conditions	Diagnosis and severity of disease	Sleep assessment	Intervention group and number of participants who completed
Serfaty et al. (UK − 2002) [22]	2-week randomized double-blind, placebo-controlled two period crossover design	84.2	9/25	N/A	AD, Vascular dementia, Mixed Alzheimer’s, Vascular Lewy body dementia	Actigraphy	Group 1 – Melatonin 6 mg SR/Placebo n = 23 Group 2 – Placebo/Melatonin 6 mg SR n = 21
Asayama et al. (Japan − 2003) [23]	4-week randomized double-blind, placebo-controlled trial	79.2	17/20	N/A	Alzheimer’s type dementia	Actigraphy	Group 1 – Placebo n = 9 Group 2 – Melatonin 3 mg n = 11
Markowitz et al.. (Global − 2003) [24]	3-month randomized, double-blind flexible dose trial	75	157/261	N/A	Mild to moderate AD	PSQI score	Group 1 – Placebo n = 125 Group 2 – Galantamine 24 mg n = 136
Singer et al. (U.S.A. − 2003) [25]	8-week, randomized, double – blind placebo-controlled trial	77.4	88/157	Depression	Probable AD, moderate dementia	Actigraphy, polysomnography and daily sleep diary	Group 1 – Placebo n = 52 Group 2 – Melatonin SR 2.5 mg n = 54 Group 3 – Melatonin IR 10 mg n = 51
Dowling et al. (U.S.A. − 2008) [26]	10-week randomized, placebo – controlled trial	86	43/50	N/A	Probable AD	Actigraphy	Group 1 – Placebo and lux light (2500) exposure for one hour with intervention given at night n = 17 Group 2 – Melatonin 5 mg and lux light (2500) exposure for one hour with intervention given at night n = 16 Group 3 - Control involved exposure to indoor light (15–200 lux) for one hour n = 17
Moraes et al. (Brazil − 2008) [27]	3-month randomized, double blind, placebo-controlled trial	74.7	15/23	Obstructive sleep apnea	Mild to moderate AD	Polysomnography	Group 1 – Placebo n = 12 Group 2 – Donepezil 5 mg n = 11
Gehrman et al. (U.S.A. − 2009) [28]	10-day randomized double-blind, placebo-controlled trial	82.9	28/41	N/A	Severe AD	Actigraphy	Group 1 – Placebo n = 17 Group 2 – Melatonin 8.5 mg IR and 1.5 mg SR n = 24
Camargos et al.. (Brazil − 2014) [29]	2-week randomized, double-blind, placebo-controlled trial	81.0	20/30	Depression	Probable AD	Actigraphy	Group 1 – Placebo n = 15 Group 2 – Trazodone 50 mg n = 15
Wade et al. (Global − 2014) [30]	24-week randomized, placebo-controlled double-blind, parallel-group trial	75.3	39/80	N/A	Mild to moderate AD	PSQI score, sleep diary	Group 1 – Placebo n = 34 Group 2 – Melatonin PR 2 mg n = 39
Grippe et al. (Brazil − 2015) [31]	2-week randomized, double-blind, placebo-controlled trial	81.0	20/30	Depression	Probable AD	Actigraphy	Group 1 – Placebo n = 15 Group 2 – Trazodone 50 mg n = 15
Herring et al. (Global − 2020) [32]	4-week randomized, double-blind, placebo-controlled trial	69.35	186/285	Depression	Mild to moderate dementia and probable AD	Polysomnography	Group 1 – Placebo n = 143 Group 2 – Suvorexant 10 mg (dose increase to 20 mg for some participants) n = 142
Moline et al. (Global − 2021) [33]	4-week randomized, double-blind placebo-controlled, parallel group trial	74.48	37/62	N/A	Mild to moderate AD	Actigraphy	Group 1 – Placebo n = 12 Group 2 – Lemborexant 2.5 mg n = 12 Group 3 – Lemborexant 5 mg n = 13 Group 4 – Lemborexant 10 mg n = 13 Group 5 – Lemborexant 15 mg n = 12
Huo et al. (China − 2022) [34]	4-week randomized control trials-prospective study	67.35	57/96	N/A	Mild to severe dementia	PSQI score & electroencephalogram	Group 1 – Alprazolam n = 48 Group 2 – Eszopiclone n = 48
Louzada et al. (Brazil − 2022) [35]	2-week randomized controlled trial, triple-blind placebo-controlled trial	80.5	36/59	Depression	Major Neurocognitive disorder and probable late onset AD	Actigraphy	Group 1 – Placebo n = 20 Group 2 – Zolpidem 10 mg n = 21 Group 3 – Zopiclone 7.5 mg n = 18

AD: Alzheimer’s disease, MMSE: Mini mental state examination, PSQI: Pittsburgh Sleep Quality Index, PR: Prolonged release, SR: Sustained release, IR: Immediate release, N: Number of patients.

Figure 2. Risk of bias (RoB 2): review authors’ judgments about each risk of bias item presented as percentages across included RCTs.

Figure 3. Bar chart showing the outcomes included in 14 final studies.

Figure 4. Pharmacological Interventions versus placebo: sleep efficiency, using standardized mean difference.

Figure 5. Pharmacological Interventions versus placebo: wakefulness after sleep onset (WASO), using weighted mean difference.

Figure 6. Melatonin, Orexin antagonist, and hypnotics versus placebo: nocturnal total sleep time (minutes), using weighted mean difference (WMD).

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