The association of physical activity and sleep duration with incident anxiety symptoms: A cohort study of 134,957 Korean adults

Journal of Affective Disorders 265 (2020) 305–313

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Research paper

The association of physical activity and sleep duration with incident anxiety symptoms: A cohort study of 134,957 Korean adults

T

Sun-Young Kima, Kang-Seob Ohb, Dong-Won Shinb, Weon-Jeong Lima, Sang-Won Jeonb,c, ⁎ Eun-Jin Kimb,c, Sung Joon Chob,c, Young-Chul Shinb,c, a

Department of Psychiatry, Ewha Woman's University Seoul Hospital, Ewha Woman's University College of Medicine, 29 Saemunan-ro, Seoul, Republic of Korea Department of Psychiatry, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea c Workplace Mental Health Institute, Kangbuk Samsung Hospital, Seoul, Republic of Korea b

ARTICLE INFO

ABSTRACT

Keywords: Anxiety Prevention Physical activity Sleep duration

Background: Maintaining adequate levels of sleep and physical activity (PA) as self-help for the prevention of new-onset anxiety symptoms is becoming more important. Methods: A cohort study was performed with 134,957 adults, free of anxiety symptoms at baseline who underwent at least two comprehensive health screening examinations between 2012 and 2017. At baseline, the amount of PA was measured using the International Physical Activity Questionnaire-Short Form and sleep duration per day was assessed using a self-report questionnaire. The study's end point was new-onset anxiety symptoms, defined as a Beck Anxiety Inventory score of ≥19. Results: During 361,969 person-years of follow-up, 5086 participants developed case-level anxiety. Compared with a reference (0–600 METs-min/wk), a U-shaped relationship was observed between PA and case-level anxiety. The most beneficial levels of PA for reducing incident anxiety symptoms were higher in men than women (men: 1800–3000 METs-min/wk HR, 0.88 [95% CI, 0.78–0.81], 3000–6000 METs-min/wk HR, 0.81 [95% CI, 0.70–0.93]; women: 600–1,200 METs-min/wk HR, 0.86 [95% CI, 0.76–0.98]). In comparison with a reference (<6 h), the relationship between sleep duration and case-level anxiety also had a U-shaped pattern. The optimal sleep duration for decreasing the onset of case-level anxiety was 7–8 h, regardless of sex (men: HR, 0.75 [95% CI, 0.63–0.90]; women; HR, 0.61 [95% CI, 0.54–0.70]). Limitations: PA, sleep duration, and anxiety symptoms were measured using self-report questionnaires. Conclusions: The results of this study revealed the appropriate levels of PA and total sleep time for reducing incident anxiety symptoms.

1. Introduction Anxiety disorders are widespread and burdensome psychiatric conditions. The global prevalence of anxiety disorders ranges from 2.4 to 44% (Baxter et al., 2013; Kessler et al., 2005). In addition, anxiety disorders are the sixth leading cause of disability, accounting for 390 disability-adjusted life years per 100,000 persons in Baxter et al. (2014). Anxiety disorders have negative effects on individuals’ quality of life and functioning, and also cause societal and financial problems (Chisholm et al., 2016; Olantunji et al., 2007). According to various guidelines, the first-line treatments for anxiety disorders are antidepressants, such as selective serotonin reuptake inhibitors, and cognitive behavioral therapy (Bandelow et al., 2015; Katzman et al., 2014; NICE 2014). However, 40–60% of patients are treatment-resistant and

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continue to have residual symptoms (Bandelow et al., 2008). In addition, in terms of cost-effectiveness, previous studies reported that treatment alone is not sufficient to reduce the disease burden related to anxiety disorders (Andrews et al., 2004). Therefore, the public health priority has changed from treating anxiety symptoms to preventing the onset of anxiety disorders. A recent meta-analysis study concluded that psychological and educational interventions had a positive effect on preventing anxiety, with a small effect size (Moreno-Peral et al., 2017). However, it is not easy to identify oneself as being at high risk of developing an anxiety disorder and seek anxiety prevention programs voluntarily, because anxiety itself is a normal emotion (Hudson, 2017). Therefore, although evidence-based intervention programs for the prevention of anxiety exist, there is an enormous gap between the scientific evidence and

Corresponding author at: Department of Psychiatry, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. E-mail address: [email protected] (Y.-C. Shin).

https://doi.org/10.1016/j.jad.2020.01.072 Received 17 June 2019; Received in revised form 14 January 2020; Accepted 17 January 2020 Available online 20 January 2020 0165-0327/ © 2020 Elsevier B.V. All rights reserved.

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what is delivered in practice. Given the aforementioned facts, maintaining adequate levels of sleep and physical activity (PA) as self-help for the prevention of newonset anxiety symptoms is becoming more important. However, in terms of PA, although there is much evidence that PA can be used to treat symptoms of anxiety (Bartley et al., 2013; Jayakody et al., 2014; Kandola et al., 2018; Rebar et al., 2015; Stubbs et al., 2017; Wipfli et al., 2008), meta-analyses or systematic review studies about the prevention of anxiety symptoms are virtually non-existent. To date, two prospective studies have been conducted to find evidence that PA prevents new-onset anxiety, using large population-based cohorts (Brunes et al., 2015; Harvey et al., 2018). However, the results of these studies were inconsistent; Brunes et al. (2015) reported that weekly hours of physical activity with moderate-high intensity was associated with less likelihood of developing anxiety symptoms in healthy adults, while Harvey et al. (2018) reported that level of exercise was not associated with incident case-level anxiety symptoms. With regard to sleep duration, although the American Academy of Sleep Medicine and the Sleep Research Society support the general recommendation that 7 or more hours of sleep per night on a regular basis are needed to promote optimal health among adults aged 18 to 60, they have not published recommendations on the upper limit of an appropriate sleep duration (Watson et al., 2015). Many studies have reported that there exists a U-shaped relationship between sleep duration and multiple health outcomes such as mortality, diabetes, cardiovascular disease, coronary heart disease, and obesity (Itani et al., 2017; Jike et al., 2018). However, no study has conducted a dose-relationship analysis between sleep duration and anxiety symptoms. Therefore, the aim of this study was to use a large cohort to address three questions. First, are PA and sleep duration associated with protection against new-onset anxiety symptoms? Second, if so, what is the optimal amount of PA and sleep duration to prevent the onset of anxiety? Third, is there a sex difference in the level of PA and sleep duration for reducing incident anxiety symptoms?

Such diagnoses were as follows: cardiopulmonary diseases (angina, myocardial infarction, hypertrophic myocardiopathy, heart failure, heart valve disease, atrial fibrillation, emphysema, chronic bronchitis, and asthma), orthopedic problems (degenerative arthritis and rheumatoid arthritis), or neurologic illness (stroke, brain hemorrhage, Alzheimer's disease, and Parkinson's disease) (Broen et al., 2016; Cohen et al., 2015; Fiest et al., 2017; Rafsten et al., 2018; Stubbs et al., 2016; Yohannes et al., 2017; Zhao et al., 2016). After excluding several individuals who met more than one exclusion criterion, the total number of eligible participants was 134,957 (Appendix 1). 2.2. Study variables and measurements 2.2.1. Assessment of the levels of total PA at baseline Levels of total PA at baseline were measured using the International Physical Activity Questionnaire-Short Form (IPAQ-SF) (The IPAQ group, 2011). The reliability of the Korean version of the IPAQ-SF was validated; the Spearman Rho coefficients and kappa values of the testretest reliability were 0.43–0.65 and 0.37–0.62, respectively (Oh et al., 2007). This study used total PA including leisure time PA and nonleisure time PA, and then PA energy expenditure was estimated using the metabolic equivalent task (MET). An absolute MET value was assigned for walking, moderate, and vigorous intensity (3.3, 4.0, and 8.0 METs, respectively). The amount of weekly PA at each intensity level was calculated by multiplying the minutes spent on specific intensity per week by absolute MET values assigned to each category of PA intensity. Energy expended per week at all three PA intensity levels was summed up to calculate the total energy expended. The process for calculating total weekly PA was described in detail in our previous study (Kim et al., 2018). According to Pate et al., 600METs-min/wk was regarded as the minimum recommended total PA per week; therefore, those engaging in less than 600METs-min/wk were defined as sedentary (Pate et al., 1995). Total energy expended per week was categorized into six categories by multiples of 600METs-min/wk: 0≤ to <600, 600≤ to <1200, 1200≤ to <1800, 1800≤ to <3000, 3000≤ to <6000, and ≥6000 METs-min/wk. This procedure was also used in previous studies (Arem et al., 2015; Pate et al., 1995).

2. Methods 2.1. Participants

2.2.2. Assessment of the amount of total sleep time at baseline Total sleep time was assessed using a self-report questionnaire that asked “During the past month, how many hours of actual asleep did you get at night?” Based on a previous study that examined the relationship between sleep duration and self-rated health (Frange et al., 2014), participants were categorized into six groups: <6, 6≤ to <7, 7≤ to <8, 8≤ to <9, 9≤ to <10, and more than 10 h per day.

Our study was part of the Kangbuk Samsung Health Study, which is a cohort study including South Korean adults aged 18 and older who had undergone an annual or biennial health screening examination at the health promotion centers of Kangbuk Samsung Hospital in Seoul and Suwon. Employees of various companies and their family members accounted for over 80% of this study's participants. In South Korea, the Industrial Safety and Health Law guarantees all workers annual or biennial health examinations free of charge. The remaining participants (under 20%) were individuals voluntarily taking health screening examinations. The Kangbuk Samsung Health Study has already been described in previous studies (Chang et al., 2016; Ryu et al., 2015). This study's protocol was approved by the Institutional Review Board of Kangbuk Samsung Hospital. The informed consent requirement was waived because only de-identified data routinely collected during health screening visits were used.

2.2.2. Assessment of anxiety symptoms The levels of anxiety symptoms were measured using the BAI. The internal consistency and test-retest reliability of the Korean BAI have been reported as 0.91–0.93 and r #x003D; 0.84, respectively (Han et al., 2003; Lee et al., 2016; Yook et al., 1997). BAI scores of 19 and above were defined as a clinically anxious state and caseness (Julian, 2011; Yook et al., 1997).

2.1.1. Selection of a “healthy” sample at baseline This study included 149,054 Korean employees aged 18–64 who underwent at least two health screening examinations at the health promotion centers of Kangbuk Samsung Hospital in Seoul and Suwon from January 2012 to December 2017. To confirm the improved confidence of the direction of any associations found, those who reported any of the following exclusion criteria were excluded at the baseline: scored 19 or greater on the Beck Anxiety Inventory (BAI), had any psychiatric disorders, or took any psychiatric medications. Individuals who had been diagnosed with a serious medical illness that could have negative effects on anxiety symptoms, PA, or sleep were also excluded.

2.2.3. Other variables Information on the participants’ age, sex, center (Seoul and Suwon), marital status, education, employment, income, alcohol consumption, smoking status, medical history, medication use, and depressive symptoms was collected through standardized, self-report questionnaires. The Alcohol Use Disorders Identification Test (AUDIT) was used to detect harmful patterns of alcohol consumption (Lee et al., 2000). Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (CES-D) validated by Cho and Kim (1998). Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. 306

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2.3. Statistical analysis

illnesses). Third, we included the time of the follow-up as an additional covariate in our final model. In all sensitivity analyses, the results were virtually unchanged and the conclusions were the same. The statistical analyses were performed using STATA version 14.0 (StataCorp LLC, College Station, TX, USA). All p-values were two-tailed. P-values of < 0.05 were considered statistically significant.

Baseline characteristics were displayed as mean ± standard deviation and numbers with percentages. T-tests were performed to determine the differences between anxious and non-anxious groups for continuous variables such as age, AUDIT score, BMI, and CESD score. The Chi-square test was used to evaluate the differences between participants with and without case-level anxiety symptoms in frequencies and proportions of categorical variables such as sex, center (Seoul or Suwon), marital status, education, employment, income, and smoking status. The primary endpoint was the development of case-level anxiety symptoms (a BAI score of 19 or above). We recorded the study participants’ follow-up time from their baseline visit until the development of case-level anxiety symptoms or until the last health examination conducted prior to December 31, 2017. The incidence rate was calculated by dividing the number of incident cases by the total number of person-years of follow-up. To provide detailed dose-response analyses, the amounts of total PA and sleep duration were categorized into six groups (Arem et al., 2015; Frange et al., 2014; Kim et al., 2018). Cox proportional hazard models were used to estimate the hazard ratios for case-level anxiety symptoms by levels of total PA or sleep duration. All statistical models were adjusted for age, sex, center (Seoul or Suwon), marital status, education, employment, income, alcohol consumption, smoking status, BMI, and total CESD score. To examine sex differences, we performed separate sex-stratified analyses. We also performed sensitivity analyses. First, considering the possibility that there was recurrent anxiety symptoms, we repeated all analyses using time-varying anxious status from each health examination. Second, considering medical comorbidities that can change over time, we repeated all analyses using time-varying medical illnesses (cardiopulmonary diseases, orthopedic problems, and neurologic

3. Results During 361,969 person-years of follow-up, 5086 participants developed case-level anxiety (1.4% incident rate). The average follow-up period was 2.7 years (SD = 1.04). The minimum and maximum of the time of follow-up were 1 and 4 years, respectively. The baseline characteristics of the participants according to anxiety symptoms are presented in Table 1. The group with case-level anxiety symptoms was more likely to be female and currently smoking. They also had a lower level of education and income and higher AUDIT and CESD scores. In terms of the relationship between the total amount of PA undertaken at baseline and the risk of future case-level anxiety symptoms, compared with the sedentary group (0–600 METs-min/wk), those performing 2 to 10 times the minimum recommended amount of PA (1200–6000METs-min/wk) were associated with a significantly lower risk of incident anxiety symptoms with a U- or J-shaped relationship. We found a function of the relationship between the levels of PA and incident anxiety symptoms using the trend line (y #x003D; 1E-08×2 7E-05x + 0.9841, Fig. 1(a)). Specifically, a 10% lower risk of incident anxiety symptoms (HR, 0.90 [95% CI, 0.82–0.99]) was observed among individuals performing

Table 1 Sociodemographic characteristics of sample (134,957 Korean adults).

Age (years), mean ± sd Sex, n (%) Male Female Center, n (%) Seoul Suwon Marital status, n (%) Never married Married Others Education, n (%) Less than middle school degree High school degree College degree or higher Employment, n (%) Yes No Income, n (%) >$4000/month <$4000/month Others AUDIT, mean ± sd Smoking status, n (%) Never smoked Former smoker Current smoker BMI, mean ± sd CESD, mean ± sd

Without caselevel anxiety symptoms (n = 129,871)

With case-level anxiety symptoms (n = 5,086)

P

37.72 ± 6.65

37.47 ± 6.23

0.005

85,050 (65.49) 44,821 (34.51)

3084 (60.64) 2002 (39.36)

<0.001

76,173 (58.65) 53,698 (41.35)

2946 (57.92) 2140 (42.08)

0.300

21,114 (16.26) 107,432 (82.72) 1325 (1.02)

875 (17.20) 4149 (81.58) 62 (1.22)

0.069

285 (0.22) 16,583 (12.77) 113,003 (87.01)

9 (0.18) 749 (14.73) 4328 (85.10)

<0.001

104,358 (80.36) 25,513 (19.64)

4074 (80.10) 1012 (19.90)

81,917 (63.08) 30,831 (23.74) 17,123 (13.18) 6.98 ± 5.21

3006 (59.10) 1365 (26.84) 715 (14.06) 8.08 ± 6.11

71,573 (55.11) 27,158 (20.91) 31,140 (23.98) 23.48 ± 3.28 9.62 ± 4.91

2629 1032 1425 23.42 13.92

(51.69) (20.29) (28.02) ± 3.43 ± 6.74

0.656

<0.001 <0.001 <0.001 0.265 <0.001

Fig. 1. (a) The relationship between levels of physical activity (PA) and incident anxiety symptoms. (b) The relationship between sleep duration and incident anxiety symptoms.

AUDIT: Alcohol Use Disorders Identification Test, BMI: Body Mass Index, CESD: Center for Epidemiologic Studies Depression Scale. 307

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Table 2 Development of anxiety symptoms according to total physical activity in sample. Total physical activity (METs-min/wk)

Person-years

Incident case

Incidence density (per 100 person-years)

Crude HR (95% CI)

Multivariable-adjusted HR (95% CI)

0 to <600 600 to <1200 1200 to <1800 1800 to <3000 3000 to <6000 ≥6000

165613.6 71271.9 44757.2 42743.1 27661.3 9921.7

2513 955 576 542 356 144

1.52 1.34 1.29 1.27 1.29 1.45

1 (reference) 0.86 (0.80–0.93)⁎⁎ 0.83 (0.76–0.91)⁎⁎ 0.81 (0.74–0.89)⁎⁎ 0.83 (0.74–0.93)⁎⁎ 0.95 (0.81–1.13)

1 (reference) 0.93 (0.86–1.00) 0.90 (0.82–0.99)* 0.89 (0.81–0.98)* 0.87 (0.77–0.97)* 0.91 (0.77–1.07)

METs: metabolic equivalents, CI: confidence interval, HR: hazard ratio. Adjustment for age, sex, center, marital status, education, employment, income, total AUDIT score, smoking status, total BMI score, and total CESD score at baseline. ⁎ <0.05. ⁎⁎ <0.01.

2 to 3 times the minimum recommended level of PA (1200–1800 METsmin/wk). This inverse association grew stronger among those performing 3 to 5 times the minimum recommended amount of PA (1800–3000 METs-min/wk: HR, 0.89 [95% CI, 0.81–0.98]) but appeared to reach a threshold of a 13% lower risk of incident anxiety symptoms among those performing 5 to 10 times the minimum recommended amount (3000–6000 METs-min/wk: HR, 0.87 [95% CI, 0.77–0.97]). Performing above 10 times the minimum recommended amount had no significant association with the lower risk of incident anxiety symptoms (Table 2). With regard to the relationship between total sleep time taken at baseline and the risk of future case-level anxiety symptoms, when defining individuals taking less than six hours as the reference category, those taking six to nine hours were associated with a significantly lower risk of incident anxiety symptoms with a U- or J- shaped relationship. We found a function of the relationship between sleep duration and anxiety symptoms using the trend line (y #x003D; 0.0099×2 0.1087x + 1.0052, Fig. 1(b)). In detail, a 23% lower risk of incident anxiety symptoms (HR, 0.77 [95% CI, 0.72–0.82]) was observed among those taking 6 to 7 h and this inverse relationship grew stronger among individuals taking 7 to 8 h (HR, 0.70 [95% CI, 0.64–0.75]). We observed a still reduced, but not as strong, a 26% lower risk of incident anxiety symptoms for those taking 8 to 9 h (HR, 0.74 [95% CI, 0.66–0.83]). Sleeping for over nine hours did not have a significant association among the lower risks of incident anxiety symptoms (Table 3). To examine sex difference, our data were stratified by sex. In terms of the relationship between the total amount of PA at baseline and the risk of future case-level anxiety, 1800–6000 METs-min/wk were associated with a lower risk of incident anxiety symptoms for men (1800–3000 METs-min/wk: HR, 0.88 [95% CI, 0.78–0.81]; 3000–6000 METs-min/wk: HR, 0.81 [95% CI, 0.70–0.93]), and 600–1200 METsmin/wk were related to a lower development of anxiety symptoms (HR, 0.86 [95% CI, 0.76–0.98]) (Table 4). With regard to the association between total sleep time at baseline and the risk of future case-level

anxiety, a U- or J-shaped relationship was observed for both sexes. Additionally, the optimal level of sleep duration for a lower risk of incident anxiety symptoms was 7 to 8 h regardless of sex (men: HR, 0.75 [95% CI, 0.63–0.90]; women; HR, 0.61 [95% CI, 0.54–0.70]). Compared with individuals who slept less than 6 h, the upper limits of the sleep duration associated with reducing anxiety symptoms were 9 h for men and 10 h for women (Table 5). 4. Discussion This study showed that the total amount of PA undertaken at baseline had a U- or J-shaped relationship with incident case-level anxiety. The optimal levels of PA for reducing the risk of future caselevel anxiety were higher for men than for women. In terms of the dose-response anxiolytic effect of PA, the metaanalysis study of randomized trials by Wipfli et al. (2008) reported that the relationship between exercise dose and effect size has a quadraticshaped curve: the effect size magnitude increases as exercise approaches a dose of 12.5 kcal•kg−1•week−1 (750 METs-min/wk), and then begins to decrease as the exercise dose increases. Generally, a U- or J-shaped relationship between the amount of PA and anxiety is consistent with the results of our study; however, when it comes to the most efficacious level of PA for reducing anxiety symptoms, the range of PA presented by this study was lower than that found in the present study. There are several reasons for this difference. First, our study defined PA as the total amount of PA including non-leisure time PA associated with one's regular occupation, household, or transportation as well as leisure time PA. Wipfli et al. (2008) included randomized control studies using only fitness interventions as a PA variable for their dose-response analysis. Second, Wipfli et al. (2008) examined the anxiolytic effects of PA; however, our study analyzed the total amount of PA required to prevent anxiety. Third, regarding the methodological aspects, since sufficient information was required to calculate the exercise dose, only a few studies could be included, so the sample size for Wipfli et al. (2008)’s study was relatively small. Lastly, nearly half of

Table 3 Development of anxiety symptoms according to total sleep time in sample. Total sleep time (hours/day)

Person-years

Incident case

Incidence density (per 100 person-years)

Crude HR (95% CI)

Multivariable-adjusted HR (95% CI)

<6 >=6 to <7 >=7 to <8 >=8 to <9 >=9 to <10 ≥10

76,001.1 149496.8 97884.0 31193.7 4049.9 3343.4

1404 1997 1160 403 61 61

1.8 1.3 1.2 1.3 1.5 1.8

1 (reference) 0.72 (0.69–0.77)⁎⁎ 0.64 (0.59–0.69)⁎⁎ 0.70 (0.63–0.79)⁎⁎ 0.83 (0.64–1.07) 1.00 (0.77–1.29)

1 (reference) 0.77 (0.72–0.82)⁎⁎ 0.70 (0.64–0.75)⁎⁎ 0.74 (0.66–0.83)⁎⁎ 0.80 (0.61–1.03) 0.95 (0.73–1.23)

Adjustment for age, sex, center, marital status, education, employment, income, total AUDIT score, smoking status, total BMI score, total CESD score at baseline. ⁎ <0.05 ⁎⁎ <0.01

308

99273.1 51054.6 33293.3 31946.1 20097.1 6501.4

Person-years

1356 651 403 373 225 76

Incident case 1.37 1.28 1.21 1.17 1.12 1.17

Incidence density (per 100 person-years) 1 (reference) 0.92 (0.84–1.01) 0.88 (0.78–0.98)* 0.84 (0.75–0.94)⁎⁎ 0.81 (0.70–0.93)⁎⁎ 0.87 (0.69–1.09)

Crude HR (95% CI)

Men (n = 88,134)

1 (reference) 0.95(0.87–1.05) 0.92(0.82–1.03) 0.88(0.78–0.81)⁎⁎ 0.81(0.70–0.93)⁎⁎ 0.79(0.63–1.00)

Multivariable-adjusted HR (95% CI) 66340.6 20217.3 11464.0 10797.0 7564.2 3420.4

Person-years 1157 304 173 169 131 68

Incident case

309

56641.1 110460.8 60479.0 12497.5 831.8 1255.3

908 1336 664 145 13 18

Person-years Incident case 1.6 1.2 1.1 1.2 1.6 1.4

Incidence density (per 100 person-years) 1 (reference) 0.75 (0.69–0.81)⁎⁎ 0.68 (0.61–0.75)⁎⁎ 0.72 (0.61–0.86)⁎⁎ 0.98 (0.57–1.69) 0.91 (0.57–1.45)

Crude HR (95% CI)

Men (n = 88,134)

1 (reference) 0.79(0.72–0.86)⁎⁎ 0.73(0.66–0.81)⁎⁎ 0.75(0.63–0.90)⁎⁎ 0.90(0.52–1.55) 0.92(0.58–1.47)

Multivariable-adjusted HR (95% CI)

19360.0 39036.1 37405.0 18696.1 3218.1 2088.2

496 661 496 258 48 43

Person-years Incident case

1 (reference) 0.84 (0.74–0.95)⁎⁎ 0.84 (0.72–0.99)* 0.86 (0.74–1.02) 0.95 (0.79–1.14) 1.11 (0.87–1.41)

2.6 1.7 1.3 1.4 1.5 2.1

Incidence density (per 100 person-years)

1 (reference) 0.66 (0.58–0.74)⁎⁎ 0.51 (0.45–0.58)⁎⁎ 0.53 (0.46–0.62)⁎⁎ 0.58 (0.43–0.78)⁎⁎ 0.79 (0.58–1.08)

Crude HR (95% CI)

Women (n = 46,823)

Adjustment for age, center, marital status, education, employment, income, total AUDIT score, smoking status, total BMI score, total CESD score at baseline. ⁎ <0.05. ⁎⁎ <0.01.

<6 >=6 to <7 >=7 to <8 >=8 to <9 >=9 to <10 ≥10

Total sleep time (hours/day)

Table 5 Sex differences in the relationship between total sleep time at baseline and future case-level anxiety in male and female adults.

1.74 1.50 1.51 1.57 1.73 1.99

Crude HR (95% CI)

Women (n = 46,823) Incidence density (per 100 person-years)

Adjustment for age, center, marital status, education, employment, income, total AUDIT score, smoking status, total BMI score, total CESD score at baseline. ⁎ <0.05. ⁎⁎ <0.01.

0 to <600 600 to <1200 1200 to <1800 1800 to <3000 3000 to <6000 ≥6000

Physical activity (METs-min/wk)

Table 4 Sex differences in the relationship between total amount of physical activity undertaken at baseline and future case-level anxiety in male and female adults.

1 (reference) 0.75(0.66–0.84)⁎⁎ 0.61(0.54–0.70)⁎⁎ 0.64(0.54–0.74)⁎⁎ 0.66(0.49–0.89)⁎⁎ 0.83(0.61–1.14)

Multivariable-adjusted HR (95% CI)

1 (reference) 0.86 (0.76–0.98)* 0.88 (0.75–1.03) 0.93 (0.79–1.09) 1.00 (0.83–1.20) 1.11 (0.87–1.42)

Multivariable-adjusted HR (95% CI)

S.-Y. Kim, et al.

Journal of Affective Disorders 265 (2020) 305–313

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the effect sizes in the meta-analysis were derived from studies that did not report the intensity of the exercise used. With regard to the upper limits of PA that had no significant associations with reducing the risk of future case-level anxiety in the present study, previous studies have reported that overreaching and overtraining are part of overtraining syndrome (OTS) (Halson and Jeukendrup, 2004). OTS is defined as the accumulation of stress primarily through intense training and inadequate recovery periods, which result in long-term performance decrements. Although no successful explanations of the mechanism behind OTS exist, numerous hypotheses have been suggested, such as the cytokine, hypothalamic, and glycogen hypotheses (Carfagno and Hendrix, 2014). Muscle contractions and joint movements result in acute inflammation through tissue microtrauma. Prolonged activation of muscles and joints can amplify cytokines such as IL-1β, IL-6, and TNF-α, pervasively. These cytokines can account for appetite suppression, sleep disturbances, and depression due to their activity in the brain, and these are crucial risk factors for developing anxiety symptoms (Smith, 2000). In addition, intense exercise gives rise to autonomic imbalances and reduced responsiveness to ACTH, which is implicated in the broad family of fatigue and anxiety symptoms (Brooks and Carter, 2013). Also, glycogen deprivation resulting from high levels of PA can cause increased oxidation and decreased levels of branched-chain amino acid, which are related to central neurotransmitter synthesis and thereby develop anxiety (Meeusen et al., 2013). The cognitive component of exercise addiction is perfectionism characterized as struggling to avoid disapproval that comes from not meeting expectations of others (Slade and Owens, 1998). In terms of the behavioral component of exercise addiction, there is an obsessive-compulsive drive that makes excessive exercise a habitual behavior (Davis et al., 1995; Gulker et al., 2001). The hedonic component of exercise addiction is its reduction of negative affect. Vulnerable people who have a pervasive negative affect, tend to be obsessive with engagement in a large amount of exercise to decrease it (Macfarlane et al., 2016). These psychological components of exercise addiction such as negative perfectionism, obsessive-compulsive drive, and negative affectivity are risk factors for the development of anxiety symptoms. To put the risk-to-benefit ratio of extreme PA into perspective, a high level of PA could not have positive effects on reducing the onset of future anxiety. The results of this study showed sex differences in the optimal levels of PA for reducing the risk of future case-level anxiety. Inherent functional and anatomical differences exist between the sexes in lung size and volume, airway diameter, diffusion surface, and maximal expiratory flow rates that affect exercise capacity across one's lifespan, with females at a disadvantage (Harms and Rosenkranz, 2008; Sheel et al., 2004). Therefore, the physical load derived from large amounts of PA could be burdensome enough to offset anxiolytic effects for women. Additionally, according to recent systematic review and meta-analysis studies, intense exercise can result in a significant decrease in both total estradiol and free estradiol, independent of menopausal state or weight loss (Ennour-Idrissi et al., 2015; Li and Graham, 2017). Since estradiol contributes to increasing endogenous anxiolytics such as serotonin, allopregnanolone, and brain-derived neurotrophic factor, the beneficial levels of PA for reducing anxiety were lower for women than men (Barha and Liu-Ambrose, 2018; Li and Graham, 2017). Similar to the association between PA and anxiety, total sleep time taken at baseline had a U-or J-shaped relationship with incident caselevel anxiety, suggesting that the most beneficial sleep duration for decreasing new-onset case-level anxiety is 7≤ to <8 h per day for both sexes. Additionally, compared with the most beneficial sleep duration (7≤ to <8 h), both shorter and longer sleep durations were not efficacious in reducing the onset of case-level anxiety symptoms. A recent

cohort study examining the predictive role of sleep duration on the course of anxiety disorders reported that compared with 7–9 h of sleep, both short (≤6 h) and long (≥10 h) sleep durations were associated with a significant increase in stated anxiety levels, which is consistent with the results of our study (van Mill et al., 2014). In terms of the relationship between a short sleep duration and anxiety-related disorders, a recent systematic review suggested that sleep loss results in dysregulated cortisol and impaired neurocognitive functioning, which lead to allostatic overload that can contribute to the development of an anxiety-related disorder (Cox and Olatunji, 2016). However, few studies have identified the anxiogenic effect of a long sleep duration. Prather et al. revealed that long sleepers showed elevated levels of interleukin-6 and CRP and suggested that increased inflammatory cytokines were the mechanism linking long sleepers and various diseases (Prather et al., 2015). However, although there is evidence of the impact of inflammatory stimuli on the brain and behaviors related to anxiety disorders (Felger, 2018), additional analyses of the development of anxiety symptoms according to sleep duration are necessary. 5. Limitations The results of this study should be interpreted with caution due to its various limitations. First, Kangbuk Samsung Health Study included mainly young and middle-age Korean adults attending health screening visits, which may limit the generalizability of our results to older adults. Future studies are warranted to confirm the relationship between physical activity and anxiety symptoms in older adults. Second, since PA, sleep duration, and anxiety symptoms were measured using selfreport questionnaires, the results could have been affected by response bias. Third, since this study was a naturalistic one and the amount of PA and sleep duration were not manipulated, no statements can be made regarding causality. Fourth, caseness was defined as a BAI score of 19 and above and was not based on an exact clinical diagnosis. Finally, since this study was conducted with a Korean population, the generalizability of the study at the national level is hard to gauge. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. CRediT authorship contribution statement Sun-Young Kim: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing original draft, Writing - review & editing. Kang-Seob Oh: Supervision. Dong-Won Shin: Supervision. Weon-Jeong Lim: Project administration, Resources, Supervision. Sang-Won Jeon: Project administration, Software, Supervision. Eun-Jin Kim: Supervision. Sung Joon Cho: Supervision. Young-Chul Shin: Investigation, Project administration, Resources, Software, Supervision, Writing - review & editing. Declaration of Competing Interest The authors report no conflicts of interest. Acknowledgments We dedicate this paper to the spirit of the departed Professor SeWon Lim.

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Appendix 1. Overview of the participants

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