Effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimer's disease and sleep disorder: A randomized controlled trial

Abstract Objective To investigate the effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimer's disease (AD) and sleep disorders. Methods This study was a prospective study of 96 elderly patients with AD and sleep disturbance treated in our hospital from April 2019 to December 2020. All patients were divided into a control group (48 patients, given alprazolam tablets) and a study group (48 patients, given eszopiclone) according to the random number table method. Results After treatment, compared with the control group, the study group had lower sleep latency, daytime function, sleep disturbance, sleep efficiency, sleep quality, sleeping time, and hypnotic medication scores (p < .05). After treatment, sleep progression and sleep architecture improvement were more obvious in the study group compared with the control group (p < .05). After treatment, compared with the control group, the rhythm disturbance, psychotic disorder, hallucination, phobic anxiety, and disorder in the study group improved more significantly (p < .05). After treatment, compared with the control group, the scores of orientation, attention, memory, calculation, recall, and language ability in the study group improved more significantly (p < .05). After treatment, the scores of the physical life self‐care scale and instrumental activities of daily living scale in the study group were improved more obviously compared with the control group, with significant differences (p < .05). Conclusion Eszopiclone can effectively improve the quality of sleep and cognitive function in elderly patients with AD and sleep disorder.

had other severe multi-organ diseases; had other psychiatric diseases; the patient's family members were blinded to the study; had poor adherence; and were allergic to the study's drugs.

Therapeutic method
The patients in the control group were treated with alprazolam tablets (manufacturer: Hunan Dongting Pharmaceutical Co., Ltd.; Approval Number: H43020578) at 0.4 mg/day for 4 weeks, and the patients in the study group were treated with eszopiclone (manufacturer: Jiangsu Tianshili Diyi Pharmaceutical Co., Ltd.; Approval Number: H20070069) at 3 mg/day for 4 weeks.

Outcome measures
1. Sleep quality: Quality of sleep was assessed using the Pittsburgh sleep quality index (PSQI) scale before and after treatment (Zhou et al., 2006 was used to assess patients' cognitive function before and after treatment (Gao et al., 2015). The scale consists of five items: orientation, attention, memory and calculation, recall, and language ability. Each item is answered correctly with a score of 1, incorrectly or unknowingly with a score of 0, unsuited with a score of 9, and rejected with a score of 8. When the total score is summed, both 8 and 9 points are scored 0. The maximum score is 30, with higher scores indicating better cognitive function.
5. Living ability: The activities of daily living scale (ADL) was used to assess the living ability of patients before and after treatment (Weng & Huang, 2014

Statistics
The data were analyzed by SPSS 21.0 software. All the data were tested for normality distribution and homogeneity of variance before further analysis. The measurement data such as sleep quality, psychiatric symptoms, and cognitive function were met assumptions for parametric analyses and expressed inx ± s, and the statistical analysis was performed by t-test. The counting data were expressed as a rate (%), and the chi-square test was used. The p < .05 was considered to be statistically significant.

Eszopiclone can better improve the sleep quality of patients
We first investigated the effect of eszopiclone on the quality of patients' sleep. Before treatment, there were no significant differences in sleep latency, daytime function, sleep disturbance, sleep efficiency, sleep quality, sleeping time, or hypnotic medication scores between the two groups (p > .05). After treatment, the two groups' sleep latency, daytime function, sleep disturbance, sleep efficiency, sleep quality, sleeping time, and hypnotic medication scores decreased compared with those before treatment (p < .05). Compared with the control group, the study group had lower sleep latency, daytime function, sleep disturbance, sleep efficiency, sleep quality, sleeping time, and hypnotic medication scores (p < .05) ( Table 1). This illustrates that both alprazolam and eszopiclone improve the quality of patients' sleep, but the effect of eszopiclone is more obvious.

Eszopiclone resulted in more significant alleviation of the patient's sleep disturbance
We also studied the condition of sleep disturbance in our patients.
Before treatment, there were no significant differences in sleep progression or sleep architecture between the two groups (p > .05). After treatment, sleep progression and sleep architecture in the two groups improved compared with those before treatment (p < .05). And sleep progression and sleep architecture improvement were more obvious in the study group compared with the control group (p < .05) ( Table 2).
This illustrates that both alprazolam and eszopiclone can relieve the patient's sleep disturbance, but the eszopiclone effect is more obvious.

4.3
After eszopiclone treatment, the patient's mental symptoms were significantly relieved Psychiatric symptoms such as fear and anxiety are frequent in AD patients with sleep disorders, so we assessed the remission of psychiatric symptoms in our patients. Before treatment, there were no differences in rhythm disturbances, psychotic disorders, hallucinations, phobic anxiety, or disorders between the two groups (p > .05).
After treatment, the rhythm disturbance, psychotic disorder, hallucination, phobic anxiety, and disorder in the two groups were improved compared with those before treatment (p < .05). Compared with the control group, the rhythm disturbance, psychotic disorder, hallucination, phobic anxiety, and disorder in the study group improved more significantly (p < .05) ( Table 3). This confirms the remarkable efficacy of eszopiclone in alleviating psychiatric symptoms in such patients.

Eszopiclone can significantly improve the cognitive function of patients
In terms of cognitive function, before treatment, there were no differences in the scores of orientation, attention, memory and calculation, recall, and language ability between the two groups (p > .05). After treatment, the scores of orientation, attention, memory, calculation, recall, and language ability of the two groups were improved compared with those before treatment (p < .05). Compared with the control group, the scores of orientation, attention, memory, calculation, recall, and language ability in the study group improved more significantly (p < .05) (Table 4). This proves that eszopiclone has a better effect on improving cognitive function in such patients than alprazolam.

The patient's living ability significantly improved after eszopiclone treatment
The self-care ability of such patients in life directly affects their quality of life, so we also evaluated the effect of eszopiclone on their viability.
Before treatment, there were no differences in the scores of the physical life self-care scale and instrumental ADL between the two groups (p > .05). After treatment, the scores of the physical life self-care scale and instrumental ADL in the two groups were improved, compared with those before treatment (p < .05), and the scores of the physical life self-care scale and instrumental ADL in the study group were improved more obviously compared with the control group, with significant differences (p < .05) ( Table 5).

4.6
The incidence of adverse reactions in the two groups The incidence of adverse reactions in the observation group was lower than that in the control group (p < .05) ( Table 6).

DISCUSSION
AD can be caused by various factors, such as cardiovascular disease, endocrine disorders, genetics, and viral infections, and as the integration of brain upper and lower motor neurons with extrapyramidal and cerebellar systems becomes dysfunctional, patients can experience cognitive dysfunction, which can affect sleep quality (Naseri et al., 2019). Poor sleep quality has a large adverse effect on the improvement of AD prognostic status, and behavioral abnormalities in aspects such as emotional cognition due to AD can worsen sleep quality and induce sleep disorders. About 44% of AD patients have sleep disorders.
Moreover, sleep disorders can aggravate cognitive dysfunction and behavioral abilities, aggravate psychiatric symptoms, and accelerate the course of brain functional decline in AD patients (Villain & Dubois, 2019). Patients with AD have a variety of dysfunctions such as memory, language, and cognition. Therefore, it is clinically important to intensify the aggressive treatment of sleep disorders while treating AD, to be able to improve its clinical symptoms and the level of prognosis.
In this study, both groups of patients were routinely treated with donepezil hydrochloride, which is a second-generation cholinesterase inhibitor that can selectively inhibit the hydrolysis of acetylcholine in the central nervous system, increase the concentration of acetylcholine, and improve the function of the brain choline system and TA B L E 3 Comparison of psychiatric symptoms between the two groups (score,x ± s) cognitive function of patients, and is a long-acting symptomatic treatment drug for AD (Dubois et al., 2012;Zhang et al., 2018). Currently, sedative hypnotic drugs, such as clonazepam and estazolam, are often used in the clinic to treat sleep disorders in AD patients, and this class of drugs has anti-anxiety and depression effects, which can effectively improve the quality of sleep in patients, but such drugs may cause over sedation, affect the cognitive function of patients, and easily produce drug dependency, etc., which is not conducive to clinical promotion (Zhang et al., 2021). Alprazolam is a benzodiazepine drug, the mechanism of which is to bind to the benzodiazepine receptor coupled gamma-aminobutyric acid (GABA) complex, which helps the patients to calm down through a mechanism that affects the function of the limbic system, that produces a hypnotic effect (Du et al., 2019).
However, studies have pointed out that alprazolam may have a hangover effect and have certain effects on cognition, memory, and motor functions. Therefore, new and independent non-benzodiazepine drugs for improving sleep have attracted more and more clinical attention.
Eszopiclone belongs to a non-benzodiazepine class of drugs. It is a commonly used clinical medicine for the treatment of sleep disorders, and it has achieved good results in patients with mental illness sleep disorders. (Huang, 2021;Wang et al., 2015). Eszopiclone was approved by This was the reason why eszopiclone was chosen for this study to treat elderly patients with dementia and sleep disorders. Among various drugs to treat sleep disorders, eszopiclone has more advantages. It has a rapid onset and duration of action of 5 to 6 h, and the patients' hangover manifestations and drug residual effects after drug administration are all milder, with significantly fewer nocturnal awakenings, no obvious drug resistance after long-term administration, and fewer toxic effects (Trauer et al., 2015). In addition, eszopiclone is a new type of anti-sleep disorder drug, which belongs to the class of cyclopyrrolones.
Previous studies have confirmed that eszopiclone has a shorter time to peak than zopiclone, and its active ingredient half-life is shorter   (Trauer et al., 2015), which is consistent with the findings of this study. In this study, we further analyzed the pathological behaviors of elderly patients with AD and sleep disorder, and the results showed that the improvement of rhythm disturbances, psychotic disorders, hallucinations, phobic anxiety, and disorders was more obvious in the study group compared with the control group, suggesting that eszopiclone could effectively relieve the pathological behaviors of patients with AD and sleep disorder. This may be due to the ability of eszopiclone to improve the quality of sleep in these patients, and the specific mechanism needs to be confirmed by further research.
The MMSE has been widely used to screen and aid in the diagnosis of AD by using convenient and multiple measurement items, simple scoring, and high sensitivity (Jian et al., 2014). Research by Zou, 2019 and others pointed out that eszopiclone and alprazolam are equivalent in improving AD with sleep disorders, but the incidence of adverse reactions of eszopiclone is lower, and it also helps to improve patients' cognitive function and activity ability. The results of this study showed that during the treatment process, the two groups of patients had adverse reactions such as fatigue, bitter mouth, and dizziness. The incidence of adverse reactions in the observation group was lower than that in the control group (p < .05). The degree of adverse reactions in both groups was mild, and the symptoms disappeared spontaneously without any intervention. The results of this study showed that, after treatment, scores for orientation, attention, memory and calculation, recall, and language were improved more significantly in the study group compared with the control group, indicating that eszopiclone is effective in improving cognitive function in patients with AD and sleep disorders.
Moreover, eszopiclone was also effective in improving the living ability of these patients.

Limitations
This study has several limitations. First, the sample size of the control group and the study group is relatively small. Studies with a larger sample size should be conducted to further confirm the conclusions in this study. Second, the data in this study is collected from a single center, which may be only representative of patients in the central region of China. More studies with multiple centers should be performed in the future. Third, the mechanisms of eszopiclone on sleep quality and cognitive function has not been clarified in this study, which is the next research plan of our group.

CONCLUSION
In summary, it is suggested that dexzopiclone can effectively improve the sleep quality of patients with Alzheimer's and sleep disorders, help improve the degree of sleep disorders, and restore the patients' mental symptoms and cognitive functions, improve living ability, and have higher safety. It is worthy of clinical application.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.2488