BackgroundAbout 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.ObjectiveThe 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.MethodsFrom 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.ResultsFinally, 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.ConclusionWe 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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Orexin is a neuropeptide produced by the lateral hypothalamus that plays an important role in regulating the sleep-wake cycle. The overexpression of the orexinergic system may be related to the pathology of sleep/wakefulness disorders in Alzheimer's disease (AD). In AD patients, the increase in cerebrospinal fluid orexin levels is associated with parallel sleep deterioration. Dual orexin receptor antagonist (DORA) can not only treat the sleep-wakefulness disorder of AD but also improve the performance of patients with cognitive behavior disorder. It is critical to clarify the role of the orexin system in AD, study its relationship with cognitive decline in AD, and evaluate the safety and efficacy of DORA.