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      Orexin dual receptor antagonists, zolpidem, zopiclone, eszopiclone, and cognitive research: A comprehensive dose-response meta-analysis

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          Abstract

          Background

          About one-third of adults have trouble sleeping, ranging from occasional difficulty to chronic insomnia, along with difficulty maintaining sleep. Many studies reported that the long-term use of hypnotics can cause brain dysfunction and damage cognition.

          Objective

          The objective of the study is to evaluate whether low, medium, and high doses of orexin dual receptor antagonists (DORA), zopiclone (ZOP), eszopiclone (ESZ), and zolpidem (ZST) can impair cognition.

          Methods

          From the beginning through September 20, 2022, PubMed, Embase, Scopus, the Cochrane Library, and Google Scholar were searched. Randomized controlled trials (RCTs) assessing the therapeutic effects of DORA, eszopiclone, and zopiclone for sleep and cognitive function were included. The primary outcomes were indices related to the cognitive profile, including memory, alertness, execution and control function, and attention and orientation. The secondary outcomes were indices related to sleep and adverse events. The standard mean difference (SMD) was generated for continuous variables. Certain data were captured from figures by GetData 2.26 and analyzed using RStudio 4.2.

          Results

          Finally, a total of 8,702 subjects were included in 29 studies. Compared with the placebo, the DSST (Digit Symbol Substitution Test) scores of low, medium, and high doses of DORA were SMD = 0.77; 95% CI: 0.33–1.20; SMD = 1.58; 95% CI: 1.11–2.05; and SMD = 0.85; 95% CI: 0.33–1.36, respectively. The DSST scores of zolpidem at low, medium, and high doses were SMD = −0.39; 95% CI: 0.85–0.07; SMD = −0.88, 95% CI: −2.34–0.58; and SMD = −0.12, 95% CI: −0.85–0.60, respectively. Zopiclone's DSST scale score was SMD = −0.18; 95% CI: −0.54–0.18. In addition, the total sleep time (TST) of low, medium, and high doses of DORA was SMD = 0.28, 95% CI: −0.15–0.70; SMD = 1.36, 95% CI: 0.87–1.86; and SMD = 2.59, 95% CI: 1.89–3.30, respectively. The TST of zolpidem with low, medium, and high doses was SMD = 1.01, 95% CI: 0.18–1.83; SMD = 1.94, 95% CI: 0.46–3.43; and SMD = 1.71, 95% CI: 0.86–2.56, respectively. The TST of low, medium, and high doses of eszopiclone was relatively SMD = 2.03, 95% CI: −0.21–4.27; SMD = 2.38, 95% CI: 1.35–3.42; and SMD = 1.71, 95% CI: 0.60–2.82. Zopiclone's TST was SMD = 2.47, 95% CI: 1.36–3.58.

          Conclusion

          We recommend DORA as the best intervention for insomnia because it is highly effective in inducing and maintaining sleep without impairing cognition. Although zolpidem has a more pronounced effect on maintaining sleep, it is best to reduce its use because of its side effects. Eszopiclone and zopiclone improved sleep quality, but their safety in cognition remains to be verified.

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          Most cited references67

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          The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

          The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.
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            Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.

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              Cognitive deficits in obstructive sleep apnea: Insights from a meta-review and comparison with deficits observed in COPD, insomnia, and sleep deprivation.

              Obstructive sleep apnea (OSA) is a nocturnal breathing disorder that is associated with cognitive impairment. The primary determinants of cognitive deficits in OSA are thought to be sleep disruption and blood gas abnormalities. Cognitive impairment is also seen in other disorders that are characterised primarily by sleep disturbance (e.g., sleep restriction/deprivation, insomnia) or hypoxia/hypercarbia (e.g., chronic obstructive pulmonary disease (COPD)). Assessment of the cognitive deficits observed in these other disorders could help better define the mechanisms underlying cognitive deficits in OSA. This study utilised meta-review methodology to examine the findings from systematic reviews and meta-analyses of the effects of untreated OSA, COPD, insomnia, and sleep deprivation on cognitive function in adults, compared with norms or controls. Eighteen papers met inclusion criteria: seven in OSA, two in insomnia, five in COPD, and four in sleep deprivation. OSA and COPD were both accompanied by deficits in attention, memory, executive function, psychomotor function, and language abilities, suggesting that hypoxia/hypercarbia may be an important determinant of deficits in these domains in OSA. Both OSA and sleep deprivation studies were accompanied by deficits in attention and memory, suggesting that short-term sleep disturbance in OSA may contribute to deficits in these domains. Visuospatial deficits were unique to OSA, suggesting the contribution of a mechanism other than sleep disturbance and hypoxia/hypercarbia to this problem. Our findings suggest that the cognitive deficits associated with untreated OSA are multidimensional, with different physiological disturbances responsible for differing cognitive problems.
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                Author and article information

                Contributors
                Journal
                Front Hum Neurosci
                Front Hum Neurosci
                Front. Hum. Neurosci.
                Frontiers in Human Neuroscience
                Frontiers Media S.A.
                1662-5161
                09 January 2023
                2022
                : 16
                : 1029554
                Affiliations
                [1] 1Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital , Jinan, Shandong, China
                [2] 2Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University, Dalian Innovation Institute of Stem Cell and Precision Medicine , Dalian, Liaoning, China
                Author notes

                Edited by: James Timothy McKenna, Harvard Medical School, United States

                Reviewed by: Qingshan Zheng, Shanghai University of Traditional Chinese Medicine, China; Chung-Yao Hsu, Kaohsiung Medical University Hospital, Taiwan

                *Correspondence: Jiyou Tang tangji0920@ 123456126.com

                This article was submitted to Cognitive Neuroscience, a section of the journal Frontiers in Human Neuroscience

                Article
                10.3389/fnhum.2022.1029554
                9869688
                36699960
                1fd0deae-7eca-417e-bfb2-b7aed3705e0d
                Copyright © 2023 Zhou, Tang, Li, Li and Zhao.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 August 2022
                : 31 October 2022
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 67, Pages: 13, Words: 7627
                Categories
                Human Neuroscience
                Review

                Neurosciences
                dora,nbzd,insomnia,cognition,dose-response
                Neurosciences
                dora, nbzd, insomnia, cognition, dose-response

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