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The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer’s disease: a randomized, triple-blind, placebo-controlled trial

Abstract

No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer’s dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): −0.8, 163.2), a 26 min reduction in WASO (95% CI: −56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: −4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: −52.5, 8.3) and a reduction of 1 awakening each night (95% CI: −3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: −4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: −21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.

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Funding

This research was funded by the Foundation for Research Support of the Brazilian Federal District (grant # 193.000.659-2015), by the National Council for Scientific and Technological Development—Brazil (grant # 400927-2016-0), and by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—FinanceCode 001. OTN is recipient of a fellowship for productivity in research from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant # 303540/2019-2). The authors report no conflicts with any product mentioned or concept discussed in this paper. This study was not supported by any manufacturer.

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All authors contributed to the conception and design of the study, interpretation of data, drafting and writing the paper. LLL and FVM participated in the acquisition of the data collection and BSBG in the analysis of the data for the work. OTN and EFC had substantial contribution in editing and revising critically the paper for important intellectual content. All authors approved the final version to be published and agreed to be accountable for all aspects of the work.

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Correspondence to Luciana L. Louzada.

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Louzada, L.L., Machado, F.V., Quintas, J.L. et al. The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer’s disease: a randomized, triple-blind, placebo-controlled trial. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01191-3

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