In recent years, with the increasing competition and the quickening pace of modern life, the incidence rate of insomnia has been drastically increasing, which seriously affects people’s overall health. Insomnia is presented in around 10–30% of the global population, and about 50% of which suffer from chronic insomnia (Bhaskar et al., 2016). It is reported that in healthy subjects, sleep disorders increase levels of beta-amyloid (Aβ) in the cerebrospinal fluid (CSF), leading to the gradual progression toward neurodegeneration and the emergence of mild cognitive impairment (MCI) (Livingston et al., 2017; Atkin et al., 2018; Burke et al., 2018). Animal studies have shown that sleep restriction increases the susceptibility to aβ aggregation-induced memory impairment in mice, accompanied by the increase of plasma corticosterone and pro-inflammatory cytokines in the brain, resulting in memory impairment and synaptic damage (Kincheski et al., 2017). Therefore, sleep disorders have become the major risk factor for the development of Alzheimer’s disease (AD) (Hennawy et al., 2019). Treatment of sleep disorders may reduce the risk of probable future AD (Burke et al., 2019).

The treatment of chronic insomnia mainly includes cognitive behavioral therapy (CBT), light therapy, complementary and alternative drug therapy. Although CBT is the recommended first-line treatment (Riemann et al., 2017), there are several limitations in its clinical implementation. Therefore, benzodiazepines (BZDs) and their receptor agonist Z drugs are commonly used for insomnia. However, long-term use of BZDs in the elderly causes serious side effects, which not only lead to drug dependence and tolerance but also increase the risks of fall and fractures (Dyer et al., 2020). Moreover, the effects of BZDs on cognition in the elderly are highly debated. Some studies have reported that long-term use may even increase the risk of permanent cognitive impairment (Billioti et al., 2014; Shash et al., 2016; Chan et al., 2017), while others have shown the contrary results (Imfeld et al., 2015; Bietry et al., 2017; Desmidt et al., 2019; Grossi et al., 2019; Dyer et al., 2020). Although the exact pharmacological association between BZDs and cognitive decline remains uncertain, it was determined that the use of BZDs in the elderly should be avoided or limited to short-term therapy.

Z drugs as an agonist of the BZD receptor component of the GABA_A receptor complex are commonly used for insomnia. Z drugs usually include Zolpidem, Zopiclone, Eszopiclone, and Zaleplon. There are limited clinical studies on the association between Z drugs and cognitive impairment. Cheng et al. (2017) have reported that the use of a high cumulative dose of zolpidem increases the risk of AD among the elderly living in Taiwan. Shih et al. (2015) have suggested that the effect of zolpidem on cognition in patients with AD remains uncertain. Furthermore, the association between the Z drugs’ use and the risk of developing cognitive impairment in middle-aged and older patients with chronic insomnia is unknown. The aim of this study was to evaluate the effect of Z drugs on cognition among middle-aged and older patients with chronic insomnia.

As far as we know, this was the first study to evaluate the effect of Z drugs on cognitive function in middle-aged and older patients with chronic insomnia. In all patients with chronic insomnia, we found that severity of insomnia, income level, and age were independent factors associated with global cognitive function (MoCA). Patients with higher PSQI scores and/or lower income levels were likely to have the worse global cognitive function. Among the sedative-hypnotics users, we observed BZD exposure density and PSQI score, income level, and age were independently associated with global cognitive function. It suggested that patients with normal cognition would have lower BZD exposure density, lower PSQI score, higher income level, and younger age. We found that neither Z drug use nor Z drug exposure density correlated with the global cognitive function. The use of BZDs might hurt attention, while the use of Z drugs might protect the verbal function at the same time.

The correlation of Z drugs and cognition in this study was not aligned with that of previous studies. Cheng et al. (2017) and Lee et al. (2018) have reported that the use of zolpidem is associated with an increased risk of AD among older people, especially a high cumulative dose, while Shih et al. (2015) has found that the effect of zolpidem on cognition in patients with AD remains uncertain. Our findings on BZD use were consistent with several previous studies that reported long-term use of BZDs increases the risk of cognitive decline (Billioti et al., 2014; Shash et al., 2016; Chan et al., 2017), though there are also some studies reporting no association between BZD use and cognitive impairment (Imfeld et al., 2015; Bietry et al., 2017; Desmidt et al., 2019; Grossi et al., 2019; Dyer et al., 2020). For retrospective studies, lacking well-controlling confounders, such as education level, marital status, depression, stroke, diabetes, hypertension, coronary heart disease, physical activity, smoking, medicines affected cognition, especially insomnia, might be the possible cause of these inconsistent findings. As known, insomnia increases the risk of developing AD. If we do not adjust the confounder of insomnia, the correlation between sedative-hypnotics and cognitive decline may not be reliable.

The mechanism of how sedative-hypnotics could increase the risk of cognitive decline is still unclear. There is a hypothesis that the cognitive reserve capacity of the elderly is limited after taking BZD for a long time. Because BZDs and Z drugs are positive regulators of the GABA_A receptor, they will reduce brain activation, decrease synaptic plasticity, and affect the ability of patients to create new memories (Stern, 2012). Secondly, the binding of BZDs to α5GABA_A subunit, which is mainly expressed in the hippocampus, impairs context memory information in monkey models. However, zolpidem does not impair the performance of visual cue-based tasks due to the affinity for α1GABA_A rather than α5GABA_A (Mohamad and Has, 2019). These results suggest that α5GABA_A receptor plays a special role in BZD-related cognitive impairment. It is thus speculated that BZD can increase the risk of cognitive impairment through α5GABA_A in the hippocampus, while Z drugs, which bind to α1GABA_A have a lower risk. However, another study has shown that the activation of α1GABA_A receptor can influence the spatial learning ability of rodents (Joksimovic et al., 2013). Our current study found no association between Z drugs and cognitive impairment, which could partly be explained by its affinity for α1GABA_A subunit rather than α5GABA_A.

Another reason for this association might be related to the increase of slow-wave sleep. Insomnia increases neuronal activity, decreases the clearance of β-amyloid protein (A β) and tau, and increases the accumulation of Aβ plaque and tau protein by reducing slow-wave sleep, which leads to neurodegeneration and AD. Slow-wave sleep plays an important role in sleep-dependent declarative memory consolidation (Xie et al., 2013; Rasmussen et al., 2018). Insomnia patients with less slow-wave sleep show a decrease in declarative memory consolidation the next day (Lu and Goder, 2012). The Z drugs used in this study were zolpidem and zopiclone, which could maintain sleep stages and promote slow-wave sleep, which might be part of the reason why Z drugs did not lead to cognitive decline in this study. This might also be part of the reason why BZDs, which reduced slow-wave sleep impaired cognition. The molecular mechanisms of cognitive impairment caused by BZD and Z drug need a further prospective study to confirm.

In this study, the uses of BZDs and Z drugs in patients aged 50–80 years old with chronic insomnia were up to 53.33%. The high prevalence of drugs might vary due to doctors’ and patients’ ignorance of the risk of drug-induced falls, fractures, and cognitive decline, as well as the lack of attention to cognitive behavioral therapy. Besides, the exclusion of patients without sedative-hypnotics who had not visited the outpatient department might partly contribute to the high prevalence of drugs. Due to age-related pharmacokinetic and pharmacodynamic changes, the elderly were more sensitive to the effects of BZDs on the central nervous system (Trifiro and Spina, 2011). Therefore, the use of BZDs in this population might lead to daytime sedation and decreased alertness (Dell’Osso, 2013). Our study found that BZD exposure density was an independent factor of cognitive impairment in patients with chronic insomnia. This evidence indicated that the high dose use of BZDs should be avoided in middle-aged and elderly subjects. Like BZDs, Z drug may be problematic in those predisposed toward substance abuse (Krystal et al., 2019), this can induce addiction and tolerance. Furthermore, some Z drugs also have rebound insomnia and withdrawal effects. Therefore, Z drugs should also be prescribed with great caution and avoid abrupt cessation.

This study had several strengths. First, this study recorded the patients’ education and income level, marital status, smoking, physical activity, concomitant illness, laboratory examination, and sleep assessment so that well-controlled the confounders of cognition. Second, anxiety and depression are closely related to chronic insomnia and affect cognition. This study evaluated the degree of anxiety and depression of patients through HAMA and HAMD scales to avoid the interference of emotional disorders on cognition. Third, the medication of each patient was recorded in detail, including drug type, dose, medication time, and frequency, and provided data for clarifying the possible dose-effect relationship and the correlation between duration of exposure and cognitive decline. This study improved our understanding of the cognitive progression and emphasized the medication selection among patients with a high risk of developing dementia. Notably, the study design excluded patients taking antipsychotics and antidepressants, potentially avoiding the impact of the above drugs on cognition. Finally, this study assessed the cognitive status of patients in detail, including global cognitive function and memory, executive function, visuospatial ability, verbal function, and attention, to better evaluate the effect of BZDs and Z drugs on cognition. We were confident to the reliability of the conclusion of the correlation between hypnotics and cognition.

This study also has certain limitations. Insomnia is considered to be a prodromal symptom of dementia. The use of BZDs may not be a cause of dementia, but indeed insomnia is a clinical manifestation at an early stage of dementia. Our study did not completely exclude the possibility of reverse causation. The investigation was designed/performed as a single-center study with a limited sample size. We are recruiting the patients from multiple centers, where we can focus on increasing the enrollment for male gender. The electrophysiology data such as polysomnography (PSG), has been also included in our recent research. Since it is common in older adults, females, and people with medical and mental ill health to suffer from chronic insomnia (Taylor et al., 2007; Schutte-Rodin et al., 2008), male patients accounted for 38.30% in this study. A larger sample prospective study is being proposed to confirm the findings and extend our research.

We found that BZD exposure density was an independent risk factor of cognitive impairment in middle-aged and older patients with chronic insomnia, but no correlation was found between Z drug use and cognitive impairment. Moreover, our study showed that Z drug use might protect attention compared with non-Z drug use. Additionally, income level, the severity of insomnia, and age were also independent factors of global cognitive function. Our findings suggested that the cognitive status should be extensively evaluated and monitored in middle-aged and older patients with sedative-hypnotics; the prescription of BZDs should be avoided or limited in low doses. Although there is no evidence of cognitive decline in this study, the occurrence of side effects and death of Z drug may be similar to that of BZDs (Gunja, 2013). Z drugs should also be prescribed with great caution in middle-aged and elderly.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Review Committee of Beijing Friendship Hospital Affiliated to Capital Medical University (2019-P2-051-01). The patients/participants provided their written informed consent to participate in the study.

LY and WZ participated in data collection. FG participated in data analysis, prepared and revised the manuscript, and created tables. Y-BZ oversaw data analysis, manuscript revision, and financial support. All authors read and approved the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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