To our knowledge, our study is the first to prospectively investigate the association between depressive symptoms and subsequent cancer risk in mainland China. In this population-based, nationally representative longitudinal cohort of 11,974 Chinese adults, we found that a high CES-D score and severe depressive symptoms were independently associated with increased cancer risk. Overall cancer morbidity was positively associated with depression in women but not in men. The association of depressive symptoms and cancer risk was more pronounced for female hormone-related cancers.
It was reported that clinically diagnosed depression was more likely to be associated with subsequent cancer risk than elevated depressive symptoms . Clinically diagnosed depression, also known as major depression or major depressive disorder (MDD), is the most severe form of depression. It is characterized by depressed mood, diminished interests, impaired cognitive function, and vegetative symptoms . Previous studies found a positive association between clinical depression and cancer incidence [22, 23]. However, it remains debatable whether depressive symptoms associated with cancer development [12, 24]. In our study, when CES-D score was treated as a continuous variable, it suggested a small but significant association between depressive symptoms and subsequent overall cancer risk. When we used a cut-off CES-D score of 10 and 20 to define moderate and severe depressive symptoms, which offered a more stringent approach to the classification of depressive symptoms, we found severe depressive symptoms were associated with a 75% increased cancer risk. This result was similar with a previous U.S. study , which suggested that a certain threshold of severe depressive symptoms might exist in the relation of depression and subsequent cancer. Thus, in our study, this may explain that severe depressive symptoms, rather than moderate depressive symptoms, were significantly associated with overall cancer risk. Individuals with severe depressive symptoms, who were always ignored and unnoticed for years, were more likely to develop clinical depression. Although increased cancer risks were found for patients with depression, most cancer screening programs excluded people with mental illness. Thus, we suggest that individuals with very high depressive symptoms could be considered as high-risk population in cancer screening programs.
We found a positive association and a dose-response relationship between depressive symptoms and cancer risk among women, while a null association among man, which is inconsistent with a previous South Korean study , This discrepancy can be explained by the differences in study methods and settings. The gender difference in the present study may result from gender differences in unmeasured factors such as biological mechanisms, including the immune system. Interestingly, there is evidence suggesting women could be more vulnerable to inflammation-induced depression . Thus, depression or severe depressive symptoms may be associated with cancer incidence to a greater extent in women than in men. Besides, it could possibly be attributable to menopausal transition in women’s life. The changed level of sex hormones could be related to both cancer and depression [28, 29].
This study found that restless sleep, depression, stress, and fear were significantly with cancer risk among women. Compared with women whose sleep were restless rarely or none of the time, women with restless sleep most or all of the time during the last week were more likely to develop cancer. A recent study suggests that poor sleep quality is significantly associated with the risk of subsequent cancer, especially for women, at 8-year follow-up . The mechanisms included reduction in production of melatonin, sleep disruption, and lifestyle disturbance. When living with a lot of stress, people would feel everything did was an effort. Studies in animals and human have suggested that stress and depression may lead to an impairment of the immune response and might promote the initiation and progression of some types of cancer . Literature on the effect of fear on cancer is even scarcer. However, fear itself may affect behavior, although its behavioral effects are not yet clear. Some studies have shown that people are more afraid of cancer than any other diseases, and suggested that it prevents help-seeking and screening for cancers , and others have shown that it has a motivating effect [31, 32].
Among specific cancer types, we found severe depressive symptoms were significantly associated with an increased risk of hormone-related cancers among women. There is more evidence to support the hypothesis that cancers are not biologically homogenous, and as such depression may influence different types of cancer in different ways . Previous studies also indicated that depression was associated with an increased cancer risk of lung, prostate, and a decreased cancer risk of cervical [22, 26]. It is worth noting that our study found an increased risk of hormone-related cancers. Although some previous studies didn’t report significant associations between depression and hormone-related cancers [10, 11, 33, 34], several studies identified a significant association between depression and hormone-sensitive cancers, including breast, ovarian, uterus, cervical, and prostate cancers [8, 25, 26, 35]. The different results across studies may be attributable to patient heterogeneity, cultural factors, socio-economic levels, and the state of medical care . In addition, various prevalence of depression and cancer among countries may also affect the estimate of the association between depression and cancer risk .
Several mechanisms may be responsible for the association between depression and subsequent cancer development. One plausible pathway involves the hypothalamic-pituitary-adrenal (HPA) axis. The persistent activation of the HPA axis and exorbitant levels of cortisol in the chronic stress response and depression probably impairs the immune response and contributes to the development and progression of cancer [7, 37]. Changes in the secretion and regulation of cytokines could be another possible pathway through which exposure to depression may be associated with incident cancer risk. It found that patients with MDD had increased serum levels of cytokines, such as tumor necrosis factor (TNF) and IL-6 . It is well established that TNF and IL-6 promote tumor development through direct effects on premalignant cells and by orchestrating a tumor-promoting microenvironment through effects on many different cell types .
To our knowledge, this is the first study to prospectively investigate the association between total CES-D score, individual depressive symptoms and subsequent cancer risk in mainland China. The strength of this study included prospective and complex survey design and statistical control for many confounding information. Due to the multistage stratified probability-proportional-to-size sampling technique, the sample can be fully to represent Chinese adults aged 45 and above. There are also limitations to be noted. First, we used a self-reported questionnaire to ascertain depression status and cancer cases, thus there may be misclassifications. In order to reduce this bias, we confirmed the incident cancer cases through surveys of wave 2 and wave 3. Second, our study has a limited follow-up period of about 7 years. We cannot investigate the long-term cumulative effect of depression on cancer development. Third, our study is limited by small number of site-specific cancers. Finally, although we adjusted for the sociodemographic characteristics, lifestyle factors, and medical history in the study, residual confounding is still possible.
In summary, we found severe depressive symptoms were significantly associated with incident cancer risk among Chinese adults, especially for women. Further investigations are warranted to validate the result and understand the underlying mechanisms.