Association between Depressive Symptoms and the Risk of Cancer in Middle-Aged and Older Chinese Adults：a population-based cohort study

doi:10.21203/rs.3.rs-5308711/v1

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Association between Depressive Symptoms and the Risk of Cancer in Middle-Aged and Older Chinese Adults：a population-based cohort study

https://doi.org/10.21203/rs.3.rs-5308711/v1

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IMPORTANCE Depressive symptoms may heighten the risk of cancer, however, little evidence is available on the association of depressive symptoms and cancer in China.

OBJECTIVE To evaluate the association between depressive symptoms and risk of cancer among middle-aged and older Chinese adults.

DESIGN, SETTING, AND PARTICIPANTS This study was based on data collected by the China Health and Retirement Longitudinal Study (CHARLS). Our cohort included 7,090 middle-aged and older Chinese adults with no cancer diagnosis at baseline. Information on depressive symptoms and cancer were collected at four waves of CHARLS investigations conducted in 2011, 2013, 2015, 2018 and 2020, respectively.

EXPOSURE Depressive symptoms were assessed using the Chinese version of the 10-item Center for Epidemiologic Studies Depression Scale (CES-D). Participants scoring ≥12 on CES-D at all four waves of investigations were classified as persistent depressive.

MAIN OUTCOMES AND MEASURE Follow-up ended when the participant reported a physician diagnosis of cancer or death or when the study period ended (September 30, 2023).

RESULTS Of the 7,090 individuals, 3,672 (51.8%) were female and 5,687(80.2%) were 45-60 years old. During the seven years of follow-up, 156 new cancer cases were identified. Persistent depressive symptoms were independently associated with an increased risk of cancer (adjusted HR: 2.27; 95%CI: 1.5-3.45) after adjusting for potential confounding factors. The association between persistent depressive symptoms and cancer was not moderated by sociodemographic characteristics.

CONCLUSIONS AND RELEVANCE The presence of depressive symptoms was significantly associated with the risk of cancer among middle-aged and older Chinese adults. Future risk management and preventive services of cancer should consider incorporating screening and providing psychosocial therapies for the elder population to identify and ameliorate depressive symptoms.

Depressive Symptoms

risk of cancer

Middle-Aged and Older Adults

Question

Are depressive symptoms associated with risk of cancer among middle-aged and older Chinese adults?

Findings

In this cohort study of 7 090 Chinese adults, participants with persistent depressive symptoms had higher incident rates of cancer compared with those without such symptoms. This association persisted after adjusting for potential confounding factors.

Meaning

This study suggests that persistent depressive symptoms may be associated with cancer among middle-aged and older Chinese adults.

There were an estimated 18.1 million new cases of cancer and 9.9 million cancer-related deaths reported in 2020.¹ Depression often occur concomitantly with cancer, approximately one-third of cancer patients may experience depression or adjustment disorder within the first five years of cancer diagnosis.² In recent years, growing evidence supported that depression might be a risk factor for cancer occurrence and that depression was involved in immune function, cancer metastasis, and other processes. ^3,4 Correspondingly, some researchers investigated the possible association between depressive symptoms and the risks of certain specific subtypes of cancer such as breast cancer and lung cancer. ^5–7 Some studies have shown an etiological association, whereas others have identified a trend toward a small, barely significant relationship between depression and subsequent overall cancer risk.^8,9A recent meta-analysis reported that depression had a positive association with the overall risk of cancer, as well as with liver cancer and lung cancer risks, though the findings indicated moderate heterogeneity. ¹⁰ Empirical findings on the association thus remain mixed and controversial.^11,12These inconclusive and controversial results indicate the need to long-term follow-up and more convincing evidence to provide more explicit information for clinical use and for psychological interventions.

Continued examination of the association between depression and cancer risk is relevant and significant, given the high and rising prevalence of depressive disorders. In China, nearly 4.3 million new cancer cases and a crude incidence rate of 201.7 per 100,000 population were reported in 2018.¹³ Meanwhile, depression has become increasingly common and presented a high prevalence among elderly adults. A national survey showed that 32.5–74.5% of persons aged 45 years and older experienced noticeable depressive symptoms. ¹⁴The potential cancer risk attributed to depression may sizably contribute to overall morbidity and mortality in the population as a whole.¹⁵ However, few studies have been conducted on cancer risks among individuals with depression in China, most of the existing findings were obtained from Western societies. Therefore, our study takes advantage of national longitudinal database to prospectively examine the relationship in a sample of middle-aged and older Chinese adults.

Data source

This cohort study was a secondary analysis of the China Health and Retirement Longitudinal Study (CHARLS) survey, which is an ongoing survey of a nationally representative sample of Chinese individuals aged 45 years or older and their partners.¹⁶ The baseline survey of CHARLS included 17,708 individuals from 10,257 households recruited from 450 villages or urban communities across 150 counties in 28 provinces in China based on a multistage stratified cluster probability sampling design. The first wave of CHARLS was collected in 2011 with a response rate of 80.5%. It collected information on sociodemographic indicators, lifestyle factors, and health status.^16,17 Individuals were then followed up in 2013, 2015, 2018 and 2020 and had a response rate of 82.7% or more in each wave.¹⁸

The CHARLS study was approved by the ethics committee of the Peking University Health Science Center .^16,19 Written informed consent was obtained from each participant before completing the CHARLS survey and the current study was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines.²⁰

Sample Selection

We included all middle-aged and older Chinese adults (older than 45 years), and excluded individuals who met one of the three criteria: i) was a cancer patient at baseline; ii) had missing socio-demographic and health information at baseline; iii) had incomplete information on depressive symptoms and cancer before the date of cancer diagnosis.

Follow-up

Follow-up started on the date of baseline survey conducted between 2011 and 2012 and ended when the participant reported a physician diagnosis of cancer or death or when the study period ended (September 30, 2020).

Assessment of Depressive Symptoms

Depressive symptoms were assessed at each wave using the Chinese version of the 10-item Center for Epidemiologic Studies Depression Scale (CES-D), which had been validated among middle-aged and older adults in China to screen for depressive symptoms.^21,22 The CES-D scores 0 − 30, with higher scores reflecting severer depressive symptoms.²³ Based on previous studies, we used a total score of 12 as the threshold to identify participants with different levels of depressive symptoms.^24,25 Participants were categorized into three groups according to their scores on the CES-D survey: never depression (scoring < 12 on CES-D at all waves of CHARLS investigation); persistent depression (scoring > = 12 on CES-D at all waves); the others were classified into episodic depression.

Identification of cancer patients

Information on cancer was collected during each survey based on self-reports or report from a close informant in the case of patient death. All participants were asked if they had a doctor diagnosis of cancer or of a malignant tumor. Participants who answered “yes” were classified as having cancer and were further asked about the site of cancer (including the origins and metastasis of tumor).

Covariates

For each individual, socio-demographics collected included sex (female or male), age (≤ 60 or > 60 years), residence (urban or rural), education level (illiterate or primary school or middle school or above), marital status (married or other), region (eastern, central, or western), and health insurance (yes or no). Behavioral factors and health indicators were collected by trained interviewers using structured questionnaires at baseline. Behavioral factors included self-reported smoking and drinking status (never or current). Health indicators included self-reported presence of chronic diseases (hypertension, dyslipidemia, diabetes or high blood sugar, chronic lung diseases, liver disease, heart problems, stroke, kidney disease, stomach or other digestive disease) and body mass index (BMI) (< 25 or ≥ 25 kg/m²) calculated by height and weight measured at the interview.

Statistical Analysis

Data were described in terms of frequency and percentage for categorical variables. Baseline characteristics were summarized according to the three levels of depressive symptoms and compared using the Chi-squared test. The incidence rates of cancer per 1,000 person-years were calculated based on depression status. To examine the association between depressive symptoms and cancer, Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for different covariates in the three models. The first model included sex, age, residence, education level, marital status, region, and health insurance. The second multivariable model included smoking, drinking, and covariates in the first model. The third multivariable model included BMI, concomitant chronic diseases, and covariates in the second model. Subgroup analyses were conducted to determine the interaction between depressive symptoms and cancer moderated by all sociodemographic characteristics. The interactions between depressive symptoms and covariates were examined using interaction terms and likelihood ratio tests. We conducted a sensitivity analysis using a CES-D scores cut-off point of 10. All analyses were conducted using Stata/MP version 15.0 (Stata Corp LLC, College Station, Texas, USA). Two-side P-values of < 0.05 were considered statistically significant.

A total of 17,708 participants were included in the CHARLS at baseline. We excluded 387 with cancer and 1,043 with missing sociodemographic information at baseline, 185 participants younger than 45 years, 8 329 with incomplete information on depressive symptoms (2013 ,2015, 2018, 2020), and 674 who provided no answers to the questions on physician-diagnosed cancer during follow-up.

A total of 7,090 participants were included in our final analysis. Of these, 3672 (51.8%) were female, and 5687 (80.2%) were 45–60 years old. Table 1 shows participants’ characteristics. A total of 3,101 participants (43.7%) developed depressive symptoms. Univariate analysis revealed that there were significant differences in sex(p < 0.001), age(p = 0.004), residence(p < 0.001), educational level (p < 0.001), marital status(p < 0.001), region(p < 0.001) among the three groups presenting different levels of depressive symptoms.

Table 1

Characteristics of Sample According to Depressive Symptoms Status
	Participants, No. (%)
	Total sample(N = 7090)	Depressive Symptoms
Characteristics	Total sample(N = 7090)	Never (n = 3989)	Episodic (n = 2491)	Persistent(n = 610)	P Value
Sex					< 0.001
Male	3418(48.2)	2241(56.2)	1002(40.2)	175(28.7)
Female	3672(51.8)	1748(43.8)	1489(59.8)	435(71.3)
Age (years)					0.004
45–60	5687(80.2)	3254(81.6)	1951(78.3)	482(79.0)
> 60	1403(19.8)	735(18.4)	540(21.7)	128(21.0)
Annual household income (CNY)					< 0.001
≤ 4000	4011(56.6)	2,421(60.7)	1401(56.2)	289(47.4)
4001–25000	2344(33.1)	1107(27.8)	902(36.2)	235(38.5)
≥ 25000	735(10.4)	461(11.6)	188(7.5)	86(14.1)
Residence					< 0.001
Rural	5846(82.5)	3121(78.2)	2167(87.0)	558(91.5)
Urban	1244(17.5)	868(21.8)	324(13.0)	52(8.5)
Educational level					< 0.001
Illiterate and Primary school	6259(88.3)	3363(84.3)	2309(92.7)	587(96.2)
Middle school or above	831(11.7)	626(15.7)	182(7.3)	23(3.8)
Marital status					< 0.001
Married	657(9.3)	285(7.1)	289(11.6)	83(13.6)
Other	6433(90.7)	3704(92.9)	2202(88.4)	527(86.4)
Region					< 0.001
Eastern	2397(33.8)	1596(40.0)	668(26.8)	133(21.8)
Central	2456(34.6)	1320(33.1)	926(37.2)	210(34.4)
Western	2237(31.6)	1073(26.9)	897(36.0)	267(43.8)
Health insurance					0.122
No	360(5.1)	190(4.8)	144(5.8)	26(4.3)
Yes	6730(94.9)	3799 (95.2)	2347(94.2)	584 (95.7)
Smoking					< 0.001
Never	4286(60.5)	2252(56.5)	1597(64.1)	437(71.6)
Current	2804(39.5)	1737(43.5)	894(35.9)	173(28.4)
Drinking					< 0.001
Never	4093(57.7)	2152(53.9)	1540(61.8)	401(65.7)
Current	2997(42.3)	1837(46.1)	951(38.2)	209(34.3)
BMI(kg/m² )					0.003
< 25	4770(67.3)	2620(65.7)	1716(68.9)	434(71.1)
>=25	2320(32.7)	1369(34.3)	775(31.1)	176(28.9)
Concomitant chronic diseases*					< 0.001
No	2367(33.4)	1609(40.3)	665(26.7)	93(15.2)
Yes	4723(66.6)	2380(59.7)	1826(73.3)	517(84.8)
P value was based on x². Abbreviation: BMI ,Body mass index, Calculated as weight in kilograms divided by height in meters squared.
*Concomitant chronic diseases included hypertension; dyslipidemia; diabetes or high blood sugar; chronic lung diseases; liver disease; heart problems; stroke; kidney disease; stomach or other digestive disease.

A total of 156 new cancer cases were recorded during the three waves of follow-up. The incidence of cancer was 8.52/1,000 person-years for participants with persistent depressive symptoms, 1.44/per 1,000 person-years for participants with episodic depressive symptoms, and 3.48/1,000 person-years for those without depressive symptoms. Table 2 shows the association between depressive symptoms and the risk of cancer. After adjusting for all potential confounding factors in model 4, persistent depressive symptoms were independently associated with a 127% increased risk of cancer (adjusted HR: 2.27; 95%CI: 1.5–3.45). The presence of episodic depressive symptoms was independently associated with a 61.0% decreased risk of cancer (adjusted HR, 0.39; 95%CI, 0.25–0.62).

Table 2

Incidence of cancer According to Depressive Symptoms Status
		Incidence Rate, per 1000 Person-Years	HR (95%CI)
Outcome	Cases	Incidence Rate, per 1000 Person-Years	model 1^a	model 2^b	model 3^c	model 4^d
Depressive Symptoms
Never	96	3.48	1[reference]	1[reference]	1[reference]	1[reference]
Episodic	25	1.44	0.41(0.27–0.64)	0.42(0.29–0.74)	0.42(0.29–0.70)	0.39(0.27–0.64)
Persistent	35	8.52	2.44(1.65–3.50)	2.58(1.72–3.86)	2.57(1.70–3.85)	2.27(1.49–3.41)
Abbreviation: HR, hazard ratio.
^a Model 1 Non-adjusted.
^b Model 2 was adjusted for age, sex, residence, marital status, educational level, region and health insurance. income level
^c Model 3 was adjusted as model 2 plus smoking status, and drinking status.
^d Model 4 was adjusted as model 3 plus BMI and concomitant chronic diseases

Figure 1 and Fig. 2 provides the association between depressive symptoms and cancer, stratified by potential risk factors. The association between persistent depressive symptoms and cancer was not moderated by sociodemographic characteristics (all P > 0.05).

eTable 1 shows the association between depressive symptoms and the risk of cancer in the sensitivity analysis. After adjusting for all potential confounding factors, persistent depressive symptoms were independently associated with a 98% increased risk of cancer (adjusted HR: 1.98; 95%CI: 1.34–2.92). The presence of episodic depressive symptoms was independently associated with a 61.0% decreased risk of cancer (adjusted HR, 0.39; 95%CI, 0.25–0.60).

To our knowledge, this is the first study to assess the relationship between depressive symptoms and risk of cancer in a nationally representative cohort in China. The results showed that persistent depressive symptoms were associated with an increased risk of cancer. This association persisted after adjusting for potential confounding factors such as sociodemographic characteristics, behavioral factors and health indicators.

The underlying mechanisms of the association between depression and the risk of cancer remain unclear, and there are possible biological and behavioral explanations.^26–27 Depression may lead to an abnormal activation of the hypothalamic-pituitary-adrenal axis and exorbitant plasma cortisol levels and thus suppression of immune responses to tumor cells. ²⁸ Depression is also associated with alterations in inflammatory cytokine secretion, such as interleukin 1, 6, and the C-reactive protein, ²⁹ which may be related to the risk of cancer. ³⁰ Furthermore, health-related behaviors and lifestyle may underpin the risk of cancer as individuals with depression tended to lead unhealthy lifestyles, including a lack of physical activity and poor diet. ³¹ In addition, these individuals were also less likely to receive preventive care, such as cancer screening, and may have decreased access to primary medical care. ³²

We found that episodic depressive symptoms decreased the risk of cancer as compared with the absence of depressive symptoms in our study. One potential explanation is that people with episodic depressive symptoms are more likely to take antidepressants to relieve their symptoms. Studies have shown that antidepressant use may decrease the risk of specific cancers. ^33,34 For example, the use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) was associated with a reduced risk of oral cancer. ³³ The use of any antidepressant may be associated with a reduced risk of colorectal cancer and the associations were similar for persons who used SSRIs and TCAs exclusively. ³⁴ This is consistent with the outcomes of another nested case-control study involving patients aged 40–84 years, which found a protective effect of antidepressant use on cancer. ³⁵

As China's population is rapidly aging, the high prevalence of depressive symptoms, especially among elder populations, has become increasingly pressing. ^7,36 In this study, approximately one third of middle-aged and older adults experienced depressive symptoms. This is consistent with the findings of a previous meta-analysis on the prevalence of depressive symptoms among seniors in China and the prevalence gradually increased.³⁷ Our findings provide a future reference for the role of depression in cancer etiology. Early screening and effective interventions for depression among older patients can prevent the occurrence or persistence of depressive symptoms. Cognitive-behavioral therapy and appropriate use of antidepressants thus have clinical and public health implications for cancer prevention and relief. Therefore, the prevention and treatment of depression need to be incorporated into risk management and primary prevention strategies of cancer.

The strengths of our study include the use of a large national representative sample of middle-aged and older adults, their detailed demographic information, and a prospective cohort design. In addition, multiple potential confounding or causal factors were included in the analyses and a subgroup analysis was conducted to avoid reverse causality. However, several limitations of this study need to be acknowledged. First, our study was based on the CES-D scale for depression ascertainment, which might not truly reflect depression in the sample. Although the diagnosis of depression through standardized diagnostic interviews is the golden standard, the CES-D was widely used in similar population studies for its convenience and the Chinese version of CES-D had been proved valid to screen for depressive symptoms in the Chinese population.^38,39 The short screening survey also has the advantage of quick identification of mild depressions as many individuals with depression often do not approach psychiatric professionals until more severe symptoms develop. Acknowledging that depression symptoms tend to develop and can fluctuate over a long period of time, we used the category of persistent depressive symptoms to capture and consolidate fluctuating and transient depressive symptoms. Thus, our use of CES-D scores as a proxy for depression to remains valid for the aim of this study. Second, our study was based on self-reported data, which might have introduced recall bias of the elderly respondents and thus distorted estimation of outcomes. However, other cohort study in comparison with data from State Cancer Registries have found a high accuracy for self-reported cancer with the sensitivity up to 0.93 and the calculated specificity up to 0.98.⁴⁰ Finally, our findings are also limited by the high dropout rate (50.8%), which might affect the reliability of the results.

In conclusion, our study showed that the presence of depressive symptoms may be associated with an increased risk of cancer among middle-aged and older Chinese adults. Future risk management and preventive services of cancer should consider incorporating screening and providing psychosocial therapies for the elder population to identify and target depressive symptoms.

Conflict of Interest Disclosures

The authors have no financial relationships to disclose

Additional Contributions

The authors thank the China Center for Economic Research, National School of Development at Peking University for providing the CHARLS data and simple training in using the database.

Ethical approval

Not required

Author Contribution

XZ and YL conceptualized and designed the study. YL rechecked the data. YL conducted the data analysis. XZ drafted the manuscript. XZ and YL provided critical revision of the manuscript. YL supervised the study and provided administrative support.

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No competing interests reported.

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Association between Depressive Symptoms and the Risk of Cancer in Middle-Aged and Older Chinese Adults：a population-based cohort study

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Abstract

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Introduction

Materials and Methods

Data source

Sample Selection

Follow-up

Assessment of Depressive Symptoms

Identification of cancer patients

Covariates

Statistical Analysis

Results

Discussion

Conclusion

Declarations

Conflict of Interest Disclosures

Additional Contributions

Ethical approval

Author Contribution

References

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