Gender Differences in Risk Factors for Depressive Symptoms in Patients with COPD: The 2014 and 2016 Korea National Health and Nutrition Examination Survey

Background: Although depression is a common comorbidity of chronic obstructive pulmonary disease (COPD), the role of gender remains unexplored. We evaluated gender differences of risk factors of depressive symptoms in adults with COPD. Methods: This was a population-based cross-sectional study using data from the 2014 and 2016 Korea National Health and Nutrition Examination Survey. Spirometry was used to identify patients with COPD, dened as a FEV 1 /FVC ratio <0.7. Presence of depressive symptoms was dened as a total score ≥ 5 on the Patient Health Questionnaire-9. Results: Overall, 17.8% of participants expressed depressive symptoms, with 13.1% being men and 29.6% being women. Multivariable regression analysis revealed that low BMI (adjusted OR, 2.62), female gender (adjusted OR, 3.48), living alone (adjusted OR, 1.75), currently smoking (adjusted OR, 2.52), and GOLD Stage III/IV (adjusted OR, 2.34) were signicant risk factors for depressive symptoms. In a subgroup analysis, low BMI, low income, living alone, and multiple chronic disorders were risk factors of depressive symptoms in men, whereas low educational attainment, urban living, and currently smoking were risk factors in women. Conclusions: As risk factors of depressive symptoms in COPD patients vary according to gender, different approaches are needed to manage depression in men and women with COPD.


Survey Overview
The study data were obtained from the Korea National Health and Nutrition Examination Survey (KNHANES), a nationally representative population-based cross-sectional survey that evaluates the health and nutritional status of the Korean population conducted annually by the Centers for Disease Control and Prevention in Korea. The survey collected detailed information on demographic, socioeconomic, and clinical characteristics, including age, educational attainment, economic activity, household income, marital status, alcohol consumption, smoking habits, and previous and current diseases.
Survey participants were selected from 192 regions in Korea based on a strati ed multistage sampling method. The survey was composed of several components, including a health behavior questionnaire, health interview, health examination, and nutritional survey. Participants aged over 40 years also performed a spirometry test using a spirometer as part of the health examination. The KNHANES 2014 and 2016 surveys included the Patient Health Questionnaire-9 (PHQ-9), which is a self-reported depression screening scale. Therefore, we used survey data from these two years. The KNHANES provides secondary data that is publicly available and a more detailed description of the survey pro le can be found elsewhere [12].

Study Population
This study initially assessed data from 6,329 eligible participants with valid lung function measurements.
After excluding participants who did not meet the COPD criteria, and those with any missing variables, including PHQ-9 score, a total of 877 participants were included in the nal analysis ( Figure 1).

Assessment of Lung Function
Lung function was measured by trained medical technicians according to the manual of the American Thoracic Society/European Respiratory Society Task Force, using dry rolling seal spirometers (Model 2130; Sensor Medics, Yorba Linda, CA, USA) [13]. The forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio were obtained. COPD was de ned as an FEV1/FVC ratio below 0.7 according to 2018 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [14]. The severity of COPD (GOLD Stage) was classi ed based on the percent-predicted FEV1: Stage I (mild; FEV1 ≥80%), Stage II (moderate; FEV1 50 to 79%), Stage III (severe; FEV1 30 to 49%), and Stage IV (very severe; FEV1 <30%).
Depressive symptoms were assessed using the PHQ-9, a nine-item self-reported questionnaire [16]. The questionnaire is based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, which is used to diagnose several speci c types of depressive disorders [17]. Each item on the PHQ-9 is scored on a scale from 0 to 3. The scores are then summed as a total score ranging between 0 and 27. PHQ-9 total scores of 5, 10, 15, and 20 represent valid thresholds of mild, moderate, moderately severe, and severe depression, respectively. PHQ-9 is in the public domain and the scale can be used free of charge [18]. Following previous studies on depressive symptoms using KNHANES data [19][20][21], the presence of depressive symptoms was de ned as a PHQ-9 ≥5 in this study [22]. All participants were categorized into two groups depending on whether they had depressive symptoms according to this cutoff score.

Assessment of Covariates
We included socio-demographic variables: gender, age, educational attainment, equalized household income, living status, economic activity, and residential area. Age groups were divided into ve categories as 40-49, 50-59, 60-69, 70-79, and 80 or older. Educational attainment was categorized as 'elementary school or below,' 'middle school graduate,' 'high school graduate,' or 'college or above.' Equalized household income was categorized into quartiles from 'quartile 1 (low income)' to 'quartile 4 (high income).' Living status was categorized as 'living alone' or 'living together.' Economic activity was categorized as 'employed' or 'unemployed.' Residential area was categorized as 'urban' or 'rural.' We also included health-related variables as additional potential confounders: alcohol consumption status, smoking status, chronic medical diseases, and GOLD Stage. Alcohol consumption and smoking status were categorized as 'never use,' 'former use,' or 'current use.' Chronic medical diseases, including hypertension, diabetes mellitus, angina, myocardial infarction, and stroke, were collected via self-reported doctor diagnosis. The total number of diseases was summed and classi ed into three groups as 'zero,' 'one,' and 'two or more.' For analyses, GOLD Stages III and IV were combined into one, resulting in three categories, 'Stage I,' 'Stage II,' and 'Stage III/IV.'

Statistical Analysis
All data are presented as numbers and percentages. Categorical comparisons were performed using the chi-square test. Multivariable analysis was performed using multivariable logistic regression analysis with prespeci ed covariates. Odds ratios (ORs) and 95% con dence intervals (CIs) were also calculated. A p-value <0.05 was considered signi cant for all analyses. Data analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA).

Ethical Approval
The research protocol was approved by the Institutional Review Board (IRB) of Severance Hospital (IRB number: 4-2019-0854)

Baseline Characteristics of the Study Participants
The baseline characteristics of the study participants are summarized in Table 1  Note: Data are presented as numbers (%) or mean ± SD Abbreviations: PHQ-9, Patient Health Questionnaire-9; BMI, body mass index; GOLD, Global Initiative for Chronic Obstructive Lung Disease; OR, odds ratio; CI, con dence interval.
Factors Associated with Depressive Symptoms   Abbreviations: PHQ-9, Patient Health Questionnaire-9; BMI, body mass index; GOLD, Global Initiative for Chronic Obstructive Lung Disease; OR, odds ratio; CI, con dence interval.

Discussion
In this study, we investigated the prevalence and risk factors of depressive symptoms in adults with COPD, nding that the incidence of depressive symptoms was 17.8 (156/877), and that lower BMI, female gender, living alone, being a current smoker, and having a high severity of COPD (GOLD Stage III/IV) were signi cant risk factors of depressive symptoms. Furthermore, we found that the risk factors of depressive symptoms in COPD patients were different with respect to gender. In men, low BMI, low income, living alone, and combined chronic medical disease were related with the occurrence of depressive symptoms, whereas low educational attainment, living in an urban setting, and being a current smoker were risk factors in women.
Depression is common in patients with chronic disease, including COPD, heart disease, stroke, and diabetes, and screening and providing interventions for depression early should be emphasized to prevent worsening of the disease [23]. In COPD patients speci cally, depression is one of the most common comorbidities with a prevalence of 10 to 57% [6], and is related to a higher risk of acute exacerbation, frequent hospitalization, and mortality [24,25]. Therefore, early detection of depression followed by proper interventions in COPD patients are important to control depressive symptoms and clinical prognosis in COPD patients [26].
The PHQ-9 is a brief version, composed of nine items, of a longer depression scale, the Patient Health Questionnaire (PHQ), that is based on the DSM-IV diagnosis of depressive disorders [27]. This brief screening instrument can easily be used in primary healthcare centers and is considered to have comparable sensitivity and speci city to other depression screening instruments [7]. Many studies have been conducted to determine an appropriate cut-off value of the PHQ-9 when screening for depression [28], with some reporting that a cut-off value over 10, which is classi ed as moderate depression severity on the scale, is considered to be reliable for screening for depressive disorders [29,30]. However, Lesley et al. reported that PHQ-9 ≥5 was the optimal cut-off value to detect depression in patients with coronary artery disease, which was lower than even the recommended cut-off score [31]. Likewise, Han et al. also recommended that a PHQ-9 score of 5, based on the Korean version, was appropriate to detect depression in elderly patients [22]. In our study, 76.9% (674/877) of participants were elderly patients over 60 years old. Moreover, the prevalence of depression in our participants with COPD was 17.8%, which is similar to other previous studies that also de ned depressive symptoms based on a PHQ-9 score of ≥5. Therefore, in this study, we chose this value to de ne the presence of depressive symptoms. While this value may be lower than those in previous reports, the bene t is that we may be able to detect depressive symptoms in COPD patients earlier and initiate the proper intervention.
In previous studies, severity of COPD, living alone, respiratory symptoms [10], and lower BMI [32] were signi cantly related to the development of depression in patients with COPD. Additionally, Jasmin et al.
found that factors including female sex, low socioeconomic status, lower FEV1, the degree of dyspnea, smoking, obesity, low social support, and loneliness were associated with an increase of depression in obstructive lung disease [11]. In the current study, low BMI, female gender, living alone, being a current smoker, and having a GOLD Stage III/IV were also signi cant risk factors for depressive symptoms. However, low income, educational attainment, and household income were not signi cantly different between patients with COPD comorbid with depression.
COPD is no longer a disease more commonly found in men owing to increased tobacco use in women and exposure to air pollution [33]. It has been demonstrated that the susceptibility to COPD, related risk factors, clinical presentation, comorbidities, and response to treatment differ between men and women [34]. Among them, depression and other psychological disorders, including anxiety and irritability, are more prevalent in women [35]. Therefore, greater effort should be made in identifying and managing these conditions [36]. In a subgroup analysis, we found that there were differences in the risk factors of depression in COPD patients by gender, indicating that different approaches may be needed to predict depression in COPD patients depending on their gender.
This study has several limitations. The rst is that this was a retrospective study based on data from the KNHANES, a nationwide survey that evaluated the health and nutritional status of the Korean population.
Hence, it is possible that COPD patients with moderate to high severity were not included, as this data included the results of healthy patients for medical screening. However, our ndings could help in detecting depressive symptoms early and prevent disease progression in mild COPD patients. Second, the severity of symptoms and the treatment the patients received, aspects that could affect the patients' quality of life and the development of depression, were not able to be investigated. Further study regarding this point should be undertaken to support our ndings.
Nevertheless, our research also has its strengths, in that it shows the risk factors associated with the occurrence of depressive symptoms in COPD patients, including a difference in risk factors between men and women. Furthermore, we demonstrated that there is an opportunity to detect and manage depressive symptoms at an early stage by analyzing the data of patients with mild severity of COPD, though prospective and large-sample studies are needed for validation.

Conclusion
We found that the incidence of depressive symptoms was not lower even in patients with mild COPD, and lower BMI, female gender, living alone, being a current smoker, and having a GOLD Stage III/IV might be considered signi cant risk factors of depressive symptoms. Furthermore, the risk factors of depressive symptoms in COPD patients were different according to gender. We suggest that COPD patients found to have these risk factors should be kept under close observation to prevent depression and exacerbation of disease-related symptoms.