Influence of chronic diseases on the occurrence of depression: A 13-year follow-up study from the Survey of Health, Ageing and Retirement in Europe

The causal association between chronic diseases and depression remains unclear. This study aimed to explore the effects of types and number of chronic diseases on the risk of depression using data from the Survey of Health, Ageing and Retirement in Europe (SHARE). A self-admitted questionnaire was used to obtain data on 14 pre-defined chronic diseases and the European-Depression Scale (EURO-D) was used to assess depression. Among the 16,080 baseline depression-free participants aged 50 + , 31.29% (5032) developed depression over 13 years. Multivariate Cox regression models showed that individuals with any chronic diseases were at higher risk of new onset depression compared to disease-free participants. The risk of new onset depression increased with an increasing number of diseases among both younger (50 – 64) and older (65 + ) adults. Individuals with heart attack, stroke, diabetes, chronic lung disease, and arthritis were at increased risk of depression across age groups. However, some age-specific associations were observed, with cancer increasing depression risk among younger-and peptic ulcer, Parkinson ’ s disease and cataracts increasing depression risk among older adults. These findings highlight the importance of managing chronic diseases, especially among those with more than two diseases, to prevent the development of depression among middle-aged and older adults.


Introduction
Depression has become one of the most important public health problems in middle-aged and older adults (Gracia-García et al., 2015). The World Health Organization (WHO) reported that more than 280 million people of all ages suffer from depression worldwide, and that depression has already played a major role in the global burden of diseases on health (Institute of Health Metrics and Evaluation; World Health Organization, 2021).
The relationship between chronic diseases and depression has been extensively studied. A meta-analysis of 40 cross-sectional studies has indicated a relationship between chronic diseases and depression (Assari, 2014;Egede, 2007;Read et al., 2017). However, due to the cross-sectional nature of these studies, it is difficult to establish a causal relationship. Recently, several cohort studies have examined the relationship between chronic diseases at baseline and subsequent depression occurrence, but many have focused on individual disease, such as heart disease (Yang et al., 2020), diabetes (Anderson et al., 2001;de Jonge et al., 2006), stroke (Fei et al., 2016), chronic lung disease (Ren et al., 2021;Riblet et al., 2020), arthritis (Ke et al., 2021), and cancer (Krebber et al., 2014). A few cohort studies have examined the relationship between baseline multiple chronic diseases and subsequent depression occurrence, but these have only included a small number of chronic diseases (Hu et al., 2022).
To gain a better understand of the relationship between multiple chronic diseases and the occurrence of subsequent depression, some cohort studies examined the relationship between more than 12 chronic diseases and depression occurrence in middle-aged and elderly Chinese (Bi et al., 2021;Jiang et al., 2020). There is currently a lack of a comprehensive and integrated evaluation of a broader range of chronic diseases over a long follow-up period.
This study aims to investigate the effect of chronic diseases on the risk of new onset depression in middle-aged and older adults in Europe, with up to 13 years follow-up. The specific aims are: 1) whether the presence of any chronic diseases has an impact on new onset depression among younger (aged 50-64) and older (aged 65-99) participants; 2) whether there is a dose-response pattern between the number of depression-related chronic diseases and the risk of new onset depression among younger and older participants; and 3) which specific chronic diseases are independent risk factors for new onset depression among younger and older participants.

Study population
The study population was derived from the Survey of Health, Ageing and Retirement in Europe (SHARE), which collected extensive data from 27 European countries and Israel. Detailed information of this survey has been described previously (Börsch-Supan, 2022a, b, c, d, e, f). Starting in 2004, SHARE participants have been followed up every two years. Wave 3, SHARELIFE, is a retrospective wave focused on individual's life histories that links individual micro data over the respondents' entire life with institutional macro data on the welfare state. Therefore, waves 1 (baseline, 2004-2006) to 7 (2017-2019), except wave 3 data, were used in this study.
Of the 30,424 participants who participated in wave 1, individuals who were younger than 50 and with missing information on age (n = 1059) were excluded (Fig. 1). We excluded 7312 participants with baseline depression, 153 with missing information on chronic diseases, 665 on depression, and 411 on education, living status, smoke, alcohol consumption or BMI, which left 20,824 participants. We further excluded 4744 individuals who did not participate in wave 2 and waves 4 to 7, leaving 16,080 participants from 12 countries (Austria, Germany, Sweden, Netherlands, Spain, Italy, France, Denmark, Greece, Switzerland, Belgium, Israel) in the final analysis.
Data collection for SHARE were approved by the Ethics Committee of the University of Mannheim and the Ethics Committee of the Max Planck Society. Written informed consent was provided by all participants.

Chronic diseases
Chronic diseases were assessed by the question on the following 14 predefined chronic diseases: "Has a doctor ever told you that you had heart attack, high blood pressure or hypertension, high blood cholesterol, stroke or cerebrovascular disease, diabetes or high blood sugar, chronic lung disease, asthma, arthritis, osteoporosis, cancer, stomach or duodenal ulcer, peptic ulcer, Parkinson disease, cataract, hip fracture or femoral fracture". The available answers for each of the disease were 0 no disease, 1 having disease. The sum of the scores represents the number of chronic diseases that the participants have, ranging from 0 to 14. Self-reported chronic diseases have been shown to have considerable validity (Martin et al., 2000).

Depression
Depression was ascertained at both baseline and follow-up surveys using the European-Depression Scale (EURO-D), and applicable to the assessment of depression in different European countries with good internal consistency and external validity (Castro-Costa et al., 2007;Prince et al., 1999). The scale consists of a total of 12 items, including guilt, interest, appetite, concentration, depression, pessimism, suicidality, sleep, irritability, fatigue, enjoyment, and tearfulness. Each of the 12 items is categorized as a dichotomous variable, with a score of 1 for yes and 0 for no. The 12 items are summed to give a total score (0-12). Depression was categorized as a dichotomous variable, having depression (score >= 4) and not having depression (score < 4) (Castro-Costa et al., 2007;Prince et al., 1999). EURO-D encompasses all symptoms included in the DSM-5 but includes appetite loss instead of weight loss. Therefore, the EURO-D has a good capacity to capture DSM-5 depression (Guerra et al., 2015).

Covariates
Age, gender, education, marriage status and living arrangement, smoking, alcohol consumption, and body mass index (BMI) were considered in the multivariate analysis. Age was introduced into the model as continuous variable, and gender as male and female. Education level was divided into three groups according to International Standard Classification of Education-97 (ISCED-97): low education (ISCED 0-2), middle education (ISCED 3-4) and high education (ISCED 5-6) assessed using the ISCED-97. Marital status and living arrangement were assessed by the question "What is your marital status?" and the answers were dichotomized as cohabit (married and living together with spouse or registered partnership) and living alone (married, living separated from spouse, never married, or divorced and widowed). Smoking was assessed by the question "Have you ever smoked cigarettes, cigars, cigarillos, or a pipe daily for a period of at least one year?" and the answers were dichotomized as no and yes. Alcohol consumption was assessed by the question "Days a week consumed alcohol in last 6 months?" and was divided into three categories, high (almost every day; five or six days a week; three or four days a week), middle (once or twice a week; once or twice a month) and low (less than once a month, not at all in the last 6 months). BMI was divided into four categories according to WHO criteria: underweight (< 18.5 kg/m 2 ), normal (18.5-24.9 kg/ m 2 ), overweight (25-29.9 kg/m 2 ) and obese (>= 30 kg/m 2 ).
The follow-up time was calculated separately for those who did and did not develop depression during the follow-up period. For those who developed depression, the follow-up time was calculated as the date of the first occurrence of depression minus the date of participants entered the study, and for people who did not develop depression it was calculated as the date of the end of follow-up minus the date the participants entered the study.

Statistical analyses
Statistical differences between baseline demographic characteristics and chronic diseases conditions as well as new onset depression status were examined with chi-square tests for categorical variables and analysis of variance (ANOVA) for continuous variables.
Cox regression model was used to explore the relationship between baseline chronic diseases and new onset depression and time-dependent Cox regression model was used to examine the association between the number of depression-related chronic diseases and the risk of new onset depression because the pH assumption was violated (Fisher and Lin, 1999).
The variable "chronic diseases" was treated as both a dichotomous variable (the presence of chronic diseases versus the absence of chronic diseases) and a categorical variable (the presence of 0, 1, 2, and 3+ chronic diseases) in different models to investigate the effect of having at least one chronic disease and the total number of chronic diseases on the risk of new onset depression, respectively. To study the influence of specific individual chronic diseases on the risk of new onset depression, these diseases were introduced into the multivariate models one at a time, respectively. After screening for the specific chronic diseases that were associated with new onset depression, the chronic diseases that were significantly associated to new onset depression were summed up and the dose-response effect of the number of the depression-related chronic diseases was further explored. All models were adjusted for the covariates mentioned before.
Age was introduced into the model as a continuous variable, while education, alcohol consumption and BMI as categorical variables, and gender, smoking and marital status and living arrangement as dichotomous variable. Age was also divided into two groups, younger (aged 50-64) and older (aged 65+) to explore the relationship between chronic diseases and new onset depression in different age groups.
The statistical software Stata 14.0 was used to analyze the data.

Results
Of the 20,824 participants, 4744 were dropped-out during the follow-up, representing a 22.78% attrition rate. Compare to respondents, the non-respondents were more likely to be younger (age < 65), male, cohabit, no smoking, overweight and with low levels of education, with either low or high alcohol consumption. Table 1 presents the baseline characteristics of study population and chronic diseases status. Participants with chronic diseases were more likely to be older (aged >= 65), female, living alone, overweight or obese, and with low-level education and low alcohol consumption. Table 2 shows the baseline characteristics of study population and new onset depression status. Among the 16,080 participants, 5032 (31.29%) of them developed depression during an average of 7.10 ± 4.21 years of follow-up. Participants who were female, aged 65 and above, living alone, no smoking, underweight and obese, with low levels of education, low levels of alcohol consumption were at higher risks of new onset depression.
Significantly higher incident rates of depression were observed among participants with any chronic diseases and those with three and more chronic diseases, compared to participants without any chronic diseases (P < 0.001) ( Table 3). Among the 14 chronic diseases, new onset of depression was significantly associated with all of them except Parkinson's disease and cataracts among younger (aged 50-64) participants, and except stroke, asthma, cancer, Parkinson's disease, and hip fracture among older (aged 65-99) participants. Fig. 2 shows the relationship between baseline chronic diseases and new onset depression during follow-up among younger (aged 50-64) and older (aged 65-99) participants. Both younger (Hazard Ratio (HR) = 1.50) and older (HR = 1.61) participants with at least one chronic disease had a significantly higher risk of new onset depression compared to participants without any chronic diseases, after adjusting for confounders. A significant dose-response relationship was observed between the total number of chronic diseases and the risk of new onset depression among younger (one disease: HR = 1.33; two: HR = 1.54; three or more: HR = 2.14, P trend < 0.05) and older (one disease: HR = 1.44; two: HR = 1.53; three or more: HR = 1.98, P trend < 0.05) participants.
Based on the six chronic diseases that were significantly associated with new onset depression among younger (aged 50-64) participants, we further analyzed the potential dose-response relationship between the number of depression-related chronic diseases and the risk of new onset depression. The risk of new onset depression increased with the increasing number of the six types of depression-related chronic diseases (one disease: HR = 1.67; two: HR = 2.39; three and above: HR = 4.37). Similar, the risk of new onset depression also increased with the increasing number of the eight types of depression-related chronic diseases among older (aged 65-99) participants (one disease: HR = 1.63; two: HR = 1.71; three and above: HR = 2.48) (Table 4).
Furthermore, we performed sensitivity analyses with wave2, wave4, and wave5 as the baseline of assessment of exposures and covariates, respectively, and the subsequent new onset depression as outcome to take into account the time-varying variables. The results of these sensitivity analyses were consistent with the main findings of the study (Supplementary Table 2, 3 and 4).

Discussion
This study is the longest follow-up investigation to date on the relationship between a broader range of chronic diseases and the risk of new onset depression in Europe.
Previous studies have shown that multiple chronic diseases are a risk factor of depression in middle-aged and older Chinese populations over a 4-year follow-up period (Bi et al., 2021;Jiang et al., 2020). This current study not only confirmed these findings in European populations but also extended the follow-up time to 13 years. Furthermore, this study conducted stratified analyses by age. We found that the presence of any chronic diseases was significantly associated with an increased risk of new onset depression over 13 years of follow-up among both younger (aged 50-64) and older (aged 65-99) participants. These results suggest that the association between number of chronic diseases and new onset depression is not only limited to older adults, but also extends to individuals as young as 50 years old. In addition, we studied not only the number of total chronic diseases, but also the number of depression-related chronic diseases in relation to new onset depression. A significant dose-response pattern was observed between the total number of chronic diseases and the number of depression-related chronic diseases and the risk of new onset depression among both a Education: low education (ISCED code = 0, 1, 2), middle education (ISCED code = 3, 4), high education (ISCED code = 5, 6). b Alcohol consumption: low (less than once a month, not at all in the last 6 months), middle (once or twice a week; once or twice a month) and high (almost every day; five or six days a week; three or four days a week). c BMI: underweight (< 18.5 kg/m 2 ), normal (18.5-24.9 kg/m 2 ), overweight (25-29.9 kg/m 2 ) and obese (>= 30 kg/m 2 ).

Table 3
Baseline chronic diseases and new onset depression status, n (%).  younger and older participants. These findings provided further evidence of a causal association between multiple chronic diseases and new onset depression (Cox, 2018). It is possible that when individuals experienced a negative event, such as the occurrence of chronic diseases, their negative attitudes and beliefs developed during early life experiences may be activated in response to stress, thereby increasing the likelihood of depression (Beck, 2008;Sethi, 1964). Further, patients with chronic diseases are often facing limited activity and chronic pain, leading to a passive reduction in activity opportunities, which may affect mood and lead to the onset of depression (Jiang et al., 2020;Williamson, 2000). It is suggested that physical diseases may reduce the ability to implement strategies to maintain important aspects of life, causing neurochemical and neuroanatomical changes associated with the diseases, which in turn may lead to the onset of depression (Schulberg et al., 2000).
Of the 14 chronic diseases, heart attack, stroke, diabetes, chronic lung disease, and arthritis were significantly related to increased risks of new onset depression among both younger (aged 50-64) and older (aged 65-99) participants. One potential explanation for the link between heart attack and increased risk of new onset depression is the prolonged  HRs were obtained from multivariate time-dependent cox regression models and adjusted for age, gender, education, marital status and living arrangement, smoking, alcohol consumption, and BMI. *P<0.05.
stimulation of the central monoamine system, which may result in toxicity of monoamine neuron and reduced monoamine function, leading to the development of depression (Connor and Leonard, 1998;Kim, 1996;Musselman et al., 2001). The association between stroke and an increased risk of new onset depression may be due to the fact that stroke can cause physical and functional disability and damage to areas of the brain that regulate mood and emotions, leading to changes in mood and behavior and reduced quality of life, contributing to depression (Hackett and Pickles, 2014). Further, there may be underlying biological factors, such as changes in neurotransmitters or inflammation, that contribute to both stroke and depression (Spalletta et al., 2006). In addition, survivors from heart attack and stroke may need to cope with the emotional and psychological impact of experiencing these life-threatening events, which may contribute to the development of depression. Diabetic patients often experience symptoms associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, such as subclinical cortisolism, sluggish circadian cortisol rhythms or hypocortisolism with impaired glucocorticoid sensitivity and increased inflammation. HPA axis dysfunction plays a key role in the pathophysiology of depression (Champaneri et al., 2010). Patients with chronic obstructive pulmonary disease (COPD) and other lung conditions are at higher risk of disability, which can significantly limit their daily activities and productivity, ultimately leading to a reduced quality of life (Baltieri et al., 2017;Littner, 2011), which may contribute to the development of depression. Arthritis is a form of autoimmune disease that not only causes pain and dysfunction in the joints, but also damages other tissues and organs, which may eventually result in disability, impacting the normal daily life and increasing the overall burden, potentially leading to depression (Hootman et al., 2016;Ke et al., 2021).
We found that cancer was significantly related to increased risks of new onset depression among younger (50-64 years) but not older (65+ years) adults. This suggests that the impact of cancer on mental health may vary by age group. One possible explanation for the age-related difference is that young-old adults have more responsibilities and duties in their lives to fulfill and may be less prepared to copy with the negative impact of cancer compared to older adults (65+ years). In contrast, older adults who were diagnosed with cancer may have already experienced decline in both physical and cognitive functions during the aging process, which make them more psychologically prepared to accept the disease (Linden et al., 2012) than younger individuals. On the other hand, we observed that peptic ulcer, Parkinson's disease and cataracts were significantly associated with an increased risk of new onset depression among older participants. Similar results were also observed in a Korean population among participants aged >=60 in a cross-sectional study (Seo et al., 2017). It is possible that Parkinson's disease is less often among younger than older participants, the limited number of cases can lead to insufficient study power to detect a significant difference among younger participants. Cataracts are a common condition that can affect people of all ages, but they are more prevalent in older adults, who may also have other age-related health issues, such as cognitive decline or physical frailty, which may further impact their overall health and well-being, leading to a greater negative impact on mental health and increases the risk of depression. The reason why the presence of peptic ulcer is differently related to the risk of depression among younger and older adults is unclear. It could be due to a number of factors, such as differences in the underlying mechanisms of the disease or differences in the psychological and social impact of the disease on different age groups. Further research is needed to understand the underlying mechanisms of this age-specific association. These results suggest that individuals with chronic disease, especially those with more than two chronic diseases, require greater attention and emotional support, highlighting the importance of diseases management.
This study has the several strengths. First, this is a cohort study with a follow-up period of up to 13 years, providing a unique opportunity to investigate the causal relationship between baseline chronic diseases and subsequent new onset depression during the follow-up period. This is because the chronic diseases occurred prior to the new onset of depression, allowing for a temporal relationship to be established (Levin, 2006). The evidence of a dose-response association further supports the causal association between chronic diseases and the new onset depression. Second, a representative sample from 12 European countries with big sample size of more than 16,000 participants increased the generalizability of the study results in a wide range of European countries. Third, unlike many previous studies that have commonly examined a limited number of chronic diseases (typically five) (Hu et al., 2022), the inclusion of 14 chronic diseases in oue study provides a more comprehensive assessment of the association between various chronic diseases and new onset depression. Fourth, we conducted age stratified analyses, which provided age-specific evidence on the association between chronic diseases and new onset depression. Fifth, we conducted sensitivity analyses that accounted for time-varying exposure and covariates, and the results of these analyses were consistent with our findings, which enhances the credibility and robustness of our results. Finally, a number of potential confounders were considered in the analysis, which increased the accuracy of the estimation.
There are some limitations. First, information of chronic diseases and depression were self-reported, reporting bias was inevitable. Therefore, replications are required using clinical diagnoses and objective assessment scales. Second, selection bias may occur due to the exclusion of participants with incomplete information, which may bias our findings to a certain extent. Third, our analysis is limited to residents over the age of 50 in European countries, so it would be cautious to extend the conclusions to other populations and age group. Fourth, there is no information on comorbid psychiatric disorders, without adjusting for such covariate might have partially influenced the results. Fifth, nonresponse bias could have influenced our results due to differences in characteristics between respondents and non-respondents, even though the response rate in this study was higher than 70%.
In summary, this study provided evidence on the detrimental effect of chronic diseases, especially the presence of three or more diseases, on new onset depression for both younger (50-64) and older (65+) adults. In the light of the recent increase in incidence of chronic diseases, such as diabetes (Tinajero and Malik, 2021), cardiovascular diseases (Roth et al., 2020) and chronic respiratory diseases (GBD Chronic Respiratory Disease Collaborators, 2020), management of chronic diseases in preventing the development of depression among middle-aged and older adults has become increasingly crucial. Healthcare professionals should remain vigilant for signs and symptoms of depression and actively screening for depression in middle-aged and older patients with more than two chronic diseases. Early detection and treatment of depression can improve patients' quality of life and overall health outcomes.

Declaration of Competing Interest
The authors have no conflicts of interest to disclose.