Introduction

Stroke is the leading cause of death in China^1-3 and many stroke survivors experience neurological impairments and mood disorders that affect their daily functioning and work capacity.⁴ Among the mood disorders, post-stroke depression (PSD) is the most common complication of acute ischemic stroke (AIS), with a prevalence of 24%–31%.^5,6 PSD after stroke significantly reduces patient quality of life and increases the risk of mortality,^7–9 where a meta-analysis showed a 1.59-fold increased risk of mortality in PSD patients.¹⁰

Sleep disorders are reported to be associated with a worsening functional outcome and increased risk of depression after stroke. Previous studies have indicated that up to 90% of patients with depression have sleep complaints¹¹ and that sleep disorders were secondary manifestations of depression, suggesting that impaired sleep is a major risk factor.¹² Studies have also demonstrated a U-shaped relationship between sleep duration and depression.¹³ Longitudinal studies showed that self-reported sleep issues represent a greater risk of developing depression.¹⁴ Sleep duration of <7 hours has been shown to be closely related to the development of depression and stroke.¹⁵ Sleep duration of shorter than 6 hours is, however, predictive of depression after ischemic stroke at 3 months.¹⁶ According to the American Heart Association, nightly sleep duration is one of the eight essential components for optimal cardiovascular health¹⁷ and it recommends, an appropriate nightly sleep duration for adults of 7 to 9 hours.¹⁵ Adequate sleep duration plays a vital role in maintaining physical and psychological health. Excessively long (>9 hours) or short sleep duration (<7 hours) has been identified as risk of adverse outcomes.¹⁸ A prior study showed that prolonged sleep was associated with lower scores of stroke-related quality of life (QOL).¹⁹ And some studies have reported that shorter or longer sleep duration was associated with increased mortality compared with participants with a sleep duration of 7–8 hours/night.^20,21 Several studies have established an association between both self-reported short and long sleep duration and increased stroke risk^22,23 and also found that both short and long sleep durations could be predictive of mortality risk.^20,24 Previous studies on the relationship between sleep duration and PSD, quality of life, and stroke outcome were mostly conducted at one time point and lacked the metric of alterations in sleep duration. Whether the alterations in sleep duration, such as transitioning from normal to shorter or excessive sleep, affect PSD, quality of life, and adverse outcomes after stroke remains uncertain.

In this study, we seek to investigate the associations between changes in sleep duration after stroke, with depression, functional disability, and quality of life at 1-year post-stroke in patients from a Chinese national registry.

Materials and Methods

Subjects

Patients were enrolled from the Impairment of Cognition and Sleep after AIS or transient ischemic attack (TIA) in Chinese patients (ICONS) study. The ICONS study is one subgroup of the Chinese National Stroke Registry-III (CNSR-III), which is a multicenter prospective registry for patients presented to hospitals with AIS or TIA (within 7 days of onset) between August 2015 and March 2018, from 201 hospitals.²⁵ Patients were eligible if they met all the following criteria: age over 18 years; completed the baseline and follow-up tests.

The exclusion criteria were as follows: (1) stroke mimics (ie, seizures, migraine); (2) illiteracy; (3) prior diagnosis of dementia (as diagnosed by physicians), or any major mental conditions; (4) neurological disorders that could not cooperate to evaluate cognition or sleep questionnaire, for example, aphasia, hemispatial neglect, disturbance of consciousness, or limb dyskinesia.

A total of 2625 patients enrolled in the ICONS subgroup. We excluded 281 patients with missing data for bedtime or waketime at 2 weeks or 3 months, and 894 patients without Health Questionnaire-9 (PHQ-9), General Anxiety Disorder-7 (GAD-7), or Modified Rankin Scale (mRS) data at 1-year. Finally, 1450 patients with TIA/minor stroke were enrolled in this study (Figure 1).

Figure 1 Flowchart of study participants.

The data collection was approved by the ethics committee of Beijing Tiantan Hospital (KY2015-001-01). The study protocol has been conducted in accordance with the Declaration of Helsinki. Prior to data collection, all participants signed written informed consents.

Data Collection

The baseline demographic information and characteristics for all participants were noted, including age, gender, body mass index (BMI) [weight (kg)/height² (m²)], current smoking habits, current drinking habits, systolic blood pressure (SBP), diastolic blood pressure (DBP), monthly income, marital status, medical history, and medication history. The medical history included previous stroke, hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, heart failure, coronary heart disease, and peripheral vascular disease. The medication history contains antiplatelet or anticoagulant therapy, antihypertensive therapy, lipid-lowering therapy, and hypoglycemic therapy. Etiologic subtypes of ischemic stroke were classified by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification criteria.²⁶ The National Institutes of Health Stroke Scale (NIHSS) was used to evaluate stroke severity.²⁷ Functional outcomes were evaluated using mRS and the quality of life was evaluated using the Stroke Impact Scale (SIS)-16 questionnaire.²⁸ The SIS-16 measures 8 domains – strength, memory, emotion, communication, activities of daily living, mobility, hand function, and social participation. It has been widely used to assess the impact of stroke on quality of life in stroke patients.²⁹

Sleep Duration

Sleep duration was defined as the time interval between bedtime and wake-up in the Pittsburgh Sleep Quality Index (PSQI).³⁰ Sleep duration was classified as short sleep (<7 hours), normal sleep (≥7 and <9 hours) and long sleep (≥9 hours). Because of changes in sleep duration from 2 weeks to 3 months, we divided patients into four groups as mentioned above: group A (persisting normal); group B (Change from long or short to normal); group C (Change from normal into long or short); group D (persisting long or short). We also performed a secondary evaluation for the changes of sleep duration as follows: 1) >-1 hour (decrease in sleep duration of >1 hour); 2) −1 hour (decrease in sleep duration of 0.1 to 1 hour); 3) 0 (stable sleep duration, reference); 4) >1 hour (increase in sleep duration of ≥1 hour). The Epworth Sleeping Scale (ESS) was used to evaluated excessive daytime sleepiness.³¹

Outcome Assessment

Patients were asked standardized follow-up questions at 3 months and 1-year after stroke onset and outcome data included 1-year PSD, functional outcome, and quality of life after stroke. Evaluation of PSD was collected by face-to-face interviews at 2 weeks or discharge, 3 months, and 1-year. PHQ-9 was used to evaluate depression with a total score of 27 points. PSD was defined as a PHQ-9 score of ≥5, and moderate and severe PSD was defined as ≥10.³² GAD-7 was used to assess the severity of anxiety, with a total score of 21 points (whereby ≤4 represents no anxiety and 5–9, 10–14, and 15–21 represent mild, moderate, and severe anxiety).³³ A poor functional outcome was defined as a score of 3 to 6 on the mRS.³⁴ Poor quality of life was defined as a percentage of SIS-16<25%.^35,36

Statistical Analyses

All statistical analyses were conducted with SAS 9.4 software (SAS Institute Inc, Cary, NC). The differences in baseline demographic and clinical features among the four groups were tested for continuous variables with normal distribution using ANOVA test and with skewed distribution using a nonparametric test. The χ² or Fisher exact test was used for categorical variables.

Continuous variables were expressed as mean ± standard deviation (SD) or median with interquartile ranges (IQRs) and analyzed using the Kruskal–Wallis test. Categorical variables were described as frequencies (percentages) and tested with the χ² or Fisher’s exact probability test.

We analyzed the associations between clinical outcomes including PSD, quality of life, and functional outcomes. For PSD, quality of life, poor functional outcome, and odds ratios (ORs) with 95% CIs were estimated by logistic regression models and fitted three adjusted models. Model 1 was adjusted for age and gender. Model 2 was further adjusted for PHQ-9, GAD-7, NIHSS, and mRS scores at admission, hypertension, diabetes, coronary heart disease, and stroke recurrence at 3 months, antiplatelets, antihypertensive therapy, lipid-lowering therapy and hypoglycemic therapy. Model 3 was additionally adjusted for history of sleep apnea, antiplatelets, antihypertensive therapy, lipid-lowering therapy, hypoglycemic therapy, sleep medicine usage(≥3 time a week). We determined that a two-tailed p values less than 0.05 was statistically significant.

Results

Baseline Characteristics of TIA/AIS Patients Categorized by Different Alterations of Sleep Duration

Among 2625 patients with ischemic stroke or TIA enrolled in the ICONS subgroup (CNSR-III study), 1175 patients were excluded (Figure 1). Finally, 1450 patients (mean age, 60.73±10.82 years), and 1055 (72.76%) were male. Participants included in the study had general characteristics similar to subjects who were excluded (Supplementary Table S1). Included participants had lower income, higher percentage of history of lipid metabolism disorders, antiplatelet or anticoagulant therapy, and lipid-lowering therapy sever anxiety and lower percentage of intravenous thrombolysis than patients excluded. (Supplementary Table S1).

According to their sleep duration, patients were divided into four groups: group A (persisting normal), group B (changed from long or short to normal), group C (changed from normal to long or short), and group D (persisting long or short). The baseline characteristics of the four groups are summarized in Table 1. In group D (persisting long or short), the proportion of patients that smoked was significantly lower and the average age, NIHSS score and GAD-7 scores were significantly higher when compared to those in group A (persisting normal). No significant differences were detected for sex, income, marital status, BMI, SBP, DBP, TOAST subtype, mRS score at admission, medication history, subjective sleep quality, the proportions of patients currently drinking, previous stroke, hypertension, diabetes, lipid metabolism disorders, atrial fibrillation, heart failure, coronary heart disease, sleep apnea or peripheral vascular disease. As for the use of sleep medication, 1358(94.17%) patients did not use any sleep medication, while 36(2.5%),17(1.18%) and 31 (2.15%) patients used sleep medicine once, twice and three or more times a week for the whole population. And there were no significant differences in the use of sleep medication among the 4 groups.

Table 1 Baseline Characteristics of Study Participants by Sleep Duration Change Category

At the 3-month assessment, 484 (33.38%) patients had persisting normal sleep duration, 260 (17.93%) patients had altered sleep duration transitioning from normal to long or short, 202 (13.93%) patients had altered sleep duration transitioning from long or short to normal, and 504 (34.76%) patients had persisting short or long sleep duration.

Association Between Different Sleep Duration Changes and 1-year Depression, Quality of life, and Functional Outcomes After Stroke

During the 1-year follow-ups, 252 (17.4%) of patients had PSD and 87 (6.0%) had moderate and severe PSD (Table 2). Patients with persisting long or short sleep duration (group D) had a higher risk of PSD (22.02% vs 12.6%, p<0.05), functional outcome (6.94% vs 3.10%, p<0.05), and quality of life (36.71% vs 24.59%, p<0.05) when compared to those with persisting normal sleep duration. Patients with persisting long or short sleep duration (group D) and patients with newly developed long or short sleep duration (group C) had higher risks of poorer functional outcome (6.94% vs 3.10%,7.31% vs 3.10%, p<0.05) when compared to those with persisting normal sleep duration (group A). The distribution of changes in sleep duration and the functional outcomes of AIS are shown in Figure 2.

Table 2 Associations of Sleep Duration Change Category with Depression, Poor Functional Outcomes, Quality of Life After Stroke at 1 year

Figure 2 (A) Distribution of modified Rankin scale score at 12 months among different groups according to changes in sleep duration as mentioned above: group A (persisting normal); group B (Change from long or short to normal); group C (Change from normal into long or short); group D (persisting long or short); (B) Distribution of modified Rankin scale score at 12 months among different groups according to other changes of sleep duration as mentioned above: 1) >-1 h (decrease in sleep duration of >1 hour); 2) −1 h (decrease in sleep duration of 0.1 to 1 hour); 3) 0 (stable sleep duration, reference); 4) >1 h (increase in sleep duration of ≥1 hour).

The association of sleep duration changes with 1-year PSD, quality of life, and functional outcomes after stroke is shown in Table 2. We found that compared with the patients with persisting normal sleep duration, those with persisting long or short sleep duration had an increased risk of PSD (PHQ-9≥5) (adjusted OR, 1.58; 95% CI, 1.06~2.33; p=0.01) and poorer quality of life (SIS-16<25%) after adjustment (adjusted OR, 1.42; 95% CI, 1.04~1.94; p=0.03), and those with newly developed long or short sleep duration had a poorer functional outcome after adjustment (adjusted OR, 2.82; 95% CI, 1.33~5.96; p=0.01), and those with persisting long or short sleep duration had a trend towards poor functional outcomes after adjustment (adjusted OR, 1.80; 95% CI, 0.92~3.52; p=0.09) (Table 2). A decrease in sleep duration of >1 hour was more likely to be associated with an increased risk of moderate and severe PSD (adjusted OR, 2.26; 95% CI, 1.13~4.53; p=0.02) (Table 3). The prolonged sleep duration of >1 hour trended towards a high risk for moderate and severe PSD (adjusted OR, 2.05; 95% CI, 1.04~4.04; p=0.04) (Table 3).

Table 3 Associations of Sleep Duration Changes with Depression, Poor Functional Outcomes, Quality of Life After Stroke at 1 year

Discussion

In this prospective cohort study, we investigated the effects of altered sleep duration on PSD, quality of life, and functional outcome after AIS/TIA at 1-year. Our findings revealed that patients with persisting short or long sleep duration were associated with 1-year PSD and poor quality of life after stroke. Especially, decreased sleep duration of >1 hour was associated with moderate to severe PSD. Altered sleep duration transitioning from normal to short or long was associated with an increased risk of 1-year poor functional outcome after AIS/TIA, even after adjusting for age, gender, medical histories, and sleep medicine usage. No significant associations were found between changes of sleep duration and others factors, including heart failure, sleep apnea and usage of sleep medicine. While other studies showed that heart failure, sleep apnea³⁷ and usage of sleep medicine have impacts on sleep duration.³⁸

According to the dynamic changes of sleep duration, we classified them into 4 groups. Both short and long sleep durations are reported to be related to adverse health outcomes. A meta-analysis containing seven prospective studies concluded that both short and long sleep durations are risk factors for depression.³⁹ However, most studies were cross-sectional, and few longitudinal studies have investigated the effects of changed sleep duration on depression.⁴⁰ Little is known about the impact of changes in sleep duration over time on the risk of PSD. Our study expands previous work in stroke patients by providing data on the role of altered sleep duration on the development of 1-year PSD. In this study, during 1-year follow-ups, the risk of PSD was significantly higher in those with persisting long or short sleep duration than in stroke survivors with persistently normal sleep duration (Table 2). Our findings are similar to existing evidence from the UK Household Longitudinal Study where reduced sleep duration was associated with depression.¹⁸ Furthermore, we found that a reduction in sleep duration >1 hour or prolonged sleep duration >1 hour had a higher risk of moderate to severe PSD than patients with no changed sleep duration, especially for patients with reduced sleep duration>1 hour. A prior study suggested that acute reduction in sleep duration was associated with various adverse health effects.⁴¹ Evidence suggests that >1 hour reduction in sleep duration for only a short period (approximately four days) could result in poorer emotional functioning⁴² and a decreased sleep duration of more than one hour might be a sensitive indicator of moderate to severe PSD. In a different study with young adults, results revealed that short sleep duration was associated with the incidence of depression.⁴⁰ Reduced sleep duration might be associated with increased daytime sleepiness and fatigue, likely resulting in decreased social activity and increased social withdrawal and loneliness,⁴³ both of which are risk factors for depression.⁴⁰ Sleep deficiency results in endothelial dysfunction and an increase in inflammatory cytokine levels, such as interleukin-6 and tumor necrosis factor,¹² and these inflammatory markers may contribute to the onset of depression. The increased inflammatory response can activate the kynurenine pathway, decrease serotonin synthesis, and affect other factors involved in the pathophysiology of neuropsychiatric conditions. Persisting long or short sleep duration might lead to alterations in sleep patterns, circadian rhythms, sleep self-balancing mechanisms, as well as levels and patterns of sleep-related hormone secretion.⁴⁴ Sleep and depression are both associated with the activation of the hypothalamic-pituitary-adrenal axis. Moreover, sleep disorders and depression can change the gut microbiota and alter the microbiota-gut-brain axis.⁴⁵ These mechanisms may partly explain the correlation between short or long sleep duration and depression.

Another study proposed a U-shaped association between sleep duration and the incidence of depression.⁴⁶ An increased sleep duration (>9 hours) is associated with depression^46,47 and prolonged sleep may lead to reduced physical activity, possibly decreasing the production of key hormones that regulate mood, such as serotonin or dopamine, or weakening self-efficacy and sense of well-being.⁴⁸ Alternatively, excessive sleep has been suggested to be associated with poor socioeconomic status and increased social isolation, such as living alone, unemployment, or an unhealthy lifestyle, which can have a negative influence on psychological health, leading to depression.^46,48 Persisting long or short sleep duration serves as a consequential predictor for PSD. There was a negative bidirectional relationship between sleep duration and psychological resilience.⁴⁹ Good-quality sleep may enhance resilience and reduce symptoms of depressive symptom, thereby enhancing mental health.⁴⁹

In this study, we also found that persisting short or long sleep duration was associated with a higher risk of poor quality of life at 1-year after stroke. In general, individuals with a sleep duration of 7~8 hours have lower morbidity risks and better quality of life than those without.⁵⁰ Changes in sleep patterns resulted in the dysfunction of sleep-related hormone secretion, substantial changes in the brain, and were related to poor quality of life.⁴⁴ A prior study assessing the quality of life(SIS-16) showed that the most impacted domains were strength, hand function, participation, and overall recovery.⁵¹

A prolonged sleep duration (>9 hours) was significantly associated with less time standing and a lower number of sit-to-stand transitions and steps, which might hinder stroke rehabilitation, and eventually result in a poor quality of life.⁵¹ Another study revealed that stroke patients without optimal sleep duration were associated with emotional instability and a lower score of health-related quality of life⁵² and this is inconsistent with our findings. Similarly, one cross-sectional study showed that most stroke survivors had emotional disorders, which are associated with a decline in life quality. Furthermore, sleep duration was reported to partially mediate the association between emotional disorders and quality of life.⁵² Stroke patients should be educated and supported to reach their optimal sleep duration, which is an important determinant of health.

Furthermore, we found that the changes in sleep duration from normal to long or short were associated with poor functional outcomes at 1-year after stroke and patients with persistent long or short sleep duration were also at a higher risk of 1-year poor functional outcomes, but this association weakened and did not reach statistical significance after adjustment for covariance, which may be related to its small sample size. Accumulating evidence suggests that sleep duration is related to stroke risk. Some have reported a J-shape relationship between long or short sleep duration and stroke,^53,54 while other studies reported a U-shape relationship.^55,56 One longitudinal study showed that individuals with a short-stable sleep duration (<7 hours) were significantly associated with a higher risk of stroke.⁵⁷ Conversely, there is evidence showing that older adults who sleep for 9 or more hours have a higher prevalence of stroke⁵⁵ and a prolonged sleep duration is associated with cardiovascular morbidity and mortality. One study reported that long sleep was associated with greater odds of the presence of carotid plaques relative to plaque absence and larger total plaque area after adjustment for covariance.⁵⁸ The association between long sleep and subclinical carotid atherosclerosis may partially explain the associations between long sleep and stroke. Long sleep is also reported to be associated with inflammatory markers and white matter hyperintensity, which might be associated with adverse outcomes. Prolonged sleep duration may be an epiphenomenon of comorbidity,⁵⁹ which is usually associated with adverse outcomes. Relative to prior studies that defined short sleep as <5 hours, our study’s categorization of sleep duration as short (<7 hours), intermediate (≥7 and <9 hours), and long (≥9 hours) are more consistent with consensus recommendations.

Sleep duration, mood, and stroke interact with each other, and sleep disorders and depression are not only considered risk factors for stroke but also predict adverse outcomes. Abnormal sleep duration, while increasing the risk of depression after stroke, together with psychosocial factors, will affect the quality of life and functional prognosis in AIS/TIA patients. Therefore, the results of this study have highlighted that AIS/TIA patients with persisting short or long sleep duration or with transitioning from normal to long or short should be given prioritized attention, and, if necessary, early intervention. As sleep duration is modifiable, it may serve as a target for interventions that could mitigate depression, quality of life and poor functional outcomes after stroke.

To the best of our knowledge, this study is the first to investigate the effects of altered sleep duration on PSD, quality of life, and functional outcomes after stroke. However, our study has some limitations. Firstly, sleep duration was assessed using a self-reported questionnaire. This study did not obtain polysomnography, which objectively measures sleep activity. Although previous studies suggested that self-reported sleep assessment correlates well with actigraphy,^60,61 the self-reported sleep status may not reflect what it was in reality. Further study needs partial polysomnography recordings and validates the self-reported sleep duration. Although we record and adjust the history of sleep apnea in the regression model, it maybe more accuracy to use the polysomnography to record the sleep-disordered breathing and clarify whether the association between long sleep and functional outcomes was independent of sleep-disordered breathing. Thirdly, because of this study design, the causal relationships could not be established.

Conclusions

This study showed that AIS/TIA patients with persisting long or short sleep duration are associated with a higher risk of 1-year depression, as well as poor quality of life. Patients transitioning from normal to long or short sleep duration had a higher risk of poor functional outcome at 1-year follow-ups. Our findings highlight the importance of improving sleep duration and establishing healthy sleep habits to prevent emotional symptoms and poor functional outcomes. Thus, stroke education should offer sleep health education to stroke survivors, thereby increasing their awareness regarding healthy sleep. Targeted interventions are needed to address those with persistently long or short sleep duration or with transitioning from normal to short or long sleep duration in this population.