Abstract
Introduction:
Depressive symptoms (DS) are prevalent among cancer survivors and may be exacerbated by chemotherapy. However, longitudinal data on this relationship within the Mexican population are lacking. The current study aimed to analyze the relationship between chemotherapy and the persistence of depressive symptoms over time in cancer survivors.
Methods:
Retrospective observational study using Mexican Study of Health and Aging (MHAS) data (2012–2021). Participants aged 50+ included chemotherapy patients (n=30) and healthy controls (n=6,970). Depressive symptoms were assessed with a modified Center for Epidemiologic Studies Depression Scale. Mann-Whitney U, X2 tests, and generalized estimating equations analyzed chemotherapy's impact on depressive symptoms over time.
Results:
Chemotherapy recipients showed significantly higher depressive symptoms at early follow-ups (2012, 2015, 2018; p < 0.05), with no significant difference by 2021. Adjusted analyses indicated chemotherapy was associated with a more than twofold increase in odds of depression (OR = 2.165; 95% CI: 1.220–3.810). Lower education and comorbidities such as diabetes and hypertension were also independently linked to increased depression risk.
Conclusions:
Chemotherapy is a significant predictor of persistent depressive symptoms among Mexican cancer survivors aged 50 and above. These findings highlight the critical need for integrated mental health screening and targeted psychosocial care within oncology settings.
Keywords: Chemotherapy, Depression, Cancer Survivors, Quality of Life
Introduction
The increasing global burden of cancer has led to a greater reliance on chemotherapy, a cornerstone of oncologic treatment that targets rapidly dividing malignant cells [1]. Although chemotherapy is effective in controlling tumor growth, it is commonly associated with a range of adverse physical effects, including fatigue, nausea, and pain, that substantially diminish patients quality of life [2]. Beyond somatic symptoms, chemotherapy frequently induces psychological distress manifesting as anxiety, fear, and affective dysregulation. Although these symptoms may be transient, they can progress to clinical depression, a diagnosable psychiatric condition characterized by persistent low mood and anhedonia [3,4].
Depression is a significant comorbidity among cancer patients receiving chemotherapy, resulting from the interaction of somatic symptoms, emotional distress, psychosocial stressors associated with cancer diagnosis and treatment; and chemotherapy-induced neurotoxicity, which may contribute to affective dysregulation via systemic inflammation and disruption of neurocircuitry involved in mood regulation [5]. Challenges such as social isolation, financial hardship, altered self-identity, and existential concerns about prognosis and mortality can exacerbate both the severity and duration of depressive symptoms (DS) [3,6,7]. Notably, these symptoms often persist beyond the completion of chemotherapy, leading to reduced social functioning, poor adherence to medical recommendations, impaired occupational engagement, and diminished overall quality of life [8]. Moreover, aging further increases the risk and alters the course of depression in this context. Older adults are particularly vulnerable due to age-related physiological changes, comorbidities, and decreased resilience, all of which may amplify the neurotoxic and inflammatory effects of chemotherapy associated with depressive outcomes [3,9].
Although numerous studies have investigated the association between chemotherapy and depression across both short- and long-term periods, the majority have focused predominantly on non-Hispanic populations [8-14]. These studies commonly report a higher prevalence of depression among patients undergoing chemotherapy, with symptoms generally declining over time [8-14]. However, there remains a notable gap in the literature regarding the prolonged persistence of DS among cancer survivors in the Mexican population, where distinct cultural, socioeconomic, and healthcare-related factors may uniquely shape mental health outcomes [15-17]. The main objective of this work is to evaluate the relationship between chemotherapy treatment and the persistence of DS in cancer survivors over time.
Methods
Data Source and Design
This retrospective observational study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [18]. The present work is a secondary analysis based on the Mexican Health and Aging Study (MHAS) [19] database. Launched in 2001, this thorough longitudinal study covers adults from all 32 states, featuring follow-ups in 2003, 2012, 2015, 2018, and 2021, as well as new samples gathered in 2003, 2012, and 2018. The MHAS is managed by collaborative teams from the U.S. and Mexico and is supported by funding from the National Institute on Aging (NIH R01AG018016) and the National Institute of Statistics and Geography (INEGI). Data and methodological details about its development can be found at www.ENASEM.org.
Study Population
Participants eligible for this study were required to be either follow-ups from past MHAS samples or new individuals from the 2012 MHAS samples, with a completed face-to-face interview until the last MHAS 2021; and 50 years of age or older. The final sample consisted of two groups: cancer patients receiving chemotherapy and healthy controls. Participants were classified as chemotherapy patients if they answered to the self-reported question “during the last two years, have you received for your cancer chemotherapy or medication?”. Conversely, healthy controls were selected based on their negative responses to any inquiries about previous cancer or chemotherapy experiences. Given that there were no methodological restrictions on selecting controls, the maximum number was utilized to strengthen statistical power. Cases with missing data were excluded from the analysis.
Main Outcome
The DS were evaluated using a modified nine-item version of the Center for Epidemiologic Studies Depression Scale (CES-D), originally developed by Radloff in 1977 [20]. The CES-D is a self-administered instrument designed to assess the presence and severity of depressive symptomatology in the general population. The original scale encompasses four domains: negative affect, positive affect, somatic complaints, and interpersonal difficulties [21]. Participants were asked to indicate whether they had experienced specific symptoms during the previous week. Each affirmative response was assigned a score of one, and each negative response a score of zero. The total score ranged from 0 to 9, with scores below five interpreted as indicative of low depressive symptomatology, and scores of five or above reflecting elevated levels of DS [22]. The Spanish-language version of the CES-D has demonstrated adequate psychometric performance in older populations, with a reported sensitivity of 80.7% and specificity of 68.7% for identifying clinically relevant DS [23]. Both the number of endorsed symptoms and the overall severity of DS were evaluated in this study.
Covariates
Baseline covariates from 2012 encompassed demographic and health-related variables: age (recorded continuously at the time of the MHAS 2012 interview), sex (biologically classified as male or female), and locality size (defined as rural for populations under 100,000 and urban for populations of 100,000 or more). Educational attainment was categorized by years of formal schooling completed, ranging from no formal education to ten or more years. Marital status was based on self-reported categories of married or civil union, separated or divorced, widowed, or single. Chronic disease status was assessed via self-reported physician diagnoses of diabetes, hypertension, myocardial infarction, or respiratory diseases (including asthma and emphysema). Full definitions and classifications of all covariates and the primary outcome are detailed in Supplementary Table 1.
Statistical Analysis
The normality of the data distribution was assessed using the Kolmogorov-Smirnov test. Due to the non-normal distribution observed, non-parametric tests were used. Mann-Whitney U and chi-squared (X2) tests examined demographic and health differences between chemotherapy patients and healthy subjects. Demographic variables and chronic diseases were assessed at baseline only. In addition, mean depression symptom scores and prevalence of depression over the study years were examined. A generalized estimating equation (GEE) model was used to investigate the effects of chemotherapy over time, adjusting for relevant covariates [24]. Continuous variables are reported as means ± standard deviations (SD), and categorical variables are summarized using frequencies and percentages. Statistical significance was defined as p < 0.05, and 95% confidence intervals (CI) were reported. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, ver. 25, IBM) [25].
Ethical considerations
The Mexican Health and Aging Study (MHAS) received ethical approval from the institutional review boards and ethics committees at the University of Texas Medical Branch, INEGI, and the National Institute of Public Health in the United States and Mexico. Adhering to the Mexican standard NOM-012-SSA3-2012, robust confidentiality measures were implemented to safeguard participant data throughout the study. The present secondary analysis utilized only daintified information and this study was categorized as minimal risk according to the Mexican General Law on Health Research. Approval of this investigation was obtained from the Ethics Committee at the Women’s Hospital, Secretariat of Health (202410-61).
Results
Study Population Characteristics
Table 1 summarizes the baseline demographic and health-related characteristics of the study population. The final analytical sample consisted of 7,000 participants, including 30 individuals who received chemotherapy and 6,970 healthy controls, yielding an approximate ratio of 1:232. The average year of cancer diagnosis was 2006 (±4.2 years). Most participants (90%) had a single cancer diagnosis. The most common cancer types were breast (33.3%), cervical (15.1%), and stomach (12%), with other types including prostate, lung, colorectal, endometrial, and various others. Half of the patients were actively receiving treatment in 2012. Regarding treatment modalities alongside chemotherapy, 20% underwent surgery, 33.3% received radiotherapy, 16.7% used symptomatic medications, and only 3.3% used herbal remedies (Supplementary Table 2).
Table 1.
Baseline sociodemographic profiles of chemotherapy patients and healthy controls.
| Covariate | Category | Chemotherapy Treatment | p-valuea | |
|---|---|---|---|---|
| Yes (n = 30) | No (n = 6 970) | |||
| Overall CESD-9 Scoreb | 2012 | 4.60 ± 2.7 | 3.25 ± 2.5 | 0.008* |
| 2015 | 4.30 ± 2.9 | 3.24 ± 2.6 | 0.042* | |
| 2018 | 4.50 ± 3.2 | 3.27 ± 2.5 | 0.041* | |
| 2021 | 3.93 ± 3.0 | 3.22 ± 2.5 | 0.224 | |
| High Degree of DSc | 2012 | 17 (56.7) | 2143 (30.7) | 0.002* |
| 2015 | 15 (50) | 2032 (29.2) | 0.012* | |
| 2018 | 14 (46.7) | 2059 (29.5) | 0.040* | |
| 2021 | 12 (40) | 2053 (29.5) | 0.206 | |
| Age | 62.6 ± 7.8 | 62.1 ± 8.1 | 0.640 | |
| Sex | Male | 7 (23.3) | 2767 (39.7) | 0.065 |
| Female | 23 (76.7) | 4203 (60.3) | ||
| Size of locality | <100 000 | 9 (30) | 3020 (43.3) | 0.139 |
| ≥100 000 | 21 (70) | 3950 (56.7) | ||
| Education Years | None | 1 (3.3) | 1086 (15.6) | 0.095 |
| 1–5 years | 7 (23.3) | 2143 (30.7) | ||
| 6 years | 8 (26.7) | 1604 (23) | ||
| 7-9 years | 10 (33.3) | 1209 (17.3) | ||
| ≥10 years | 4 (13.3) | 928 (13.3) | ||
| Marital Status | Married/Civil union | 24 (80) | 5084 (72.9) | 0.479 |
| Separated/Divorced | 1 (3.3) | 557 (8) | ||
| Widowed | 5 (16.7) | 1011 (14.5) | ||
| Single | 0 (0) | 318 (4.6) | ||
| Diabetes | No | 18 (60) | 5581 (80.1) | 0.006* |
| Yes | 12 (40) | 1389 (19.9) | ||
| Hypertension | No | 15 (50) | 4008 (57.5) | 0.701 |
| Yes | 15 (50) | 2962 (42.5) | ||
| Heart Attack | No | 27 (90) | 6775 (97.2) | 0.018* |
| Yes | 3 (10) | 195 (2.8) | ||
| Respiratory Disease | No | 27 (90) | 6596 (94.6) | 0.259 |
| Yes | 3 (10) | 374 (5.4) | ||
Continuous variables are presented as mean ± standard deviation (SD), while categorical variables are presented as N (%).
Mann-Whitney U test was used for continuous variables, while the X2 test was used for categorical variables.
CESD-9: Center for Epidemiologic Studies Depression Scale (CES-D). Participants were asked about the occurrence of certain symptoms in the past week. Each positive response was scored as one, whereas a negative response was scored as zero. A total score of less than five was considered indicative of low depressive symptoms (DS), whereas a score of five or higher indicated a high level of DS.
p < 0.05.
Baseline Characteristics and Depressive Symptoms by Chemotherapy Status
The chemotherapy group exhibited significantly higher mean CES-D scores than the non-chemotherapy group (n = 6,970) at three time points: 2012 (4.60 ± 2.7 vs. 3.25 ± 2.5, p = 0.008), 2015 (4.30 ± 2.9 vs. 3.24 ± 2.6, p = 0.042), and 2018 (4.50 ± 3.2 vs. 3.27 ± 2.5, p = 0.041). By 2021, differences in depressive symptom scores were no longer statistically significant (3.93 ± 3.0 vs. 3.22 ± 2.5, p = 0.224). Similarly, the proportion of participants classified with a high degree of DS was significantly greater in the chemotherapy group in 2012 (56.7% vs. 30.7%, p = 0.002), 2015 (50% vs. 29.2%, p = 0.012), and 2018 (46.7% vs. 29.5%, p = 0.040), but this difference was not significant in 2021 (40% vs. 29.5%, p = 0.206). Regarding covariates, there were no statistically significant differences between groups for age, sex, size of locality, education level, or marital status. However, the chemotherapy group had a significantly higher prevalence of diabetes (40% vs. 19.9%, p = 0.006) and history of myocardial infarction (10% vs. 2.8%, p = 0.018). No significant differences were observed for hypertension or respiratory disease.
Temporal Trends in Depression and Chemotherapy
In Table 2, the results of the multivariate analysis using GEE for DS and covariates are shown. Chemotherapy was significantly associated with higher odds of DS in the unadjusted model (OR = 2.212; 95% CI: 1.269–3.855; p = 0.005) and this association remained robust after adjustment for multiple covariates (OR = 2.165; 95% CI: 1.220–3.810; p = 0.008). Male participants had significantly lower odds of DS than females in both unadjusted (OR = 0.443; 95% CI: 0.410–0.479; p < 0.001) and adjusted models (OR = 0.513; 95% CI: 0.473–0.557; p < 0.001).
Table 2.
Multivariate analysis of depressive symptoms and covariates using generalized estimating equations (GEE).
| Variables | Category | Unadjusted Model | Adjusted Modela | |||
|---|---|---|---|---|---|---|
| ORb (95% CI) | P-value | ORb (95% CI) | P-value | |||
| Age | 1.012 (1.007, 1.016) | 0.001* | 1.000 (0.995, 1.005) | 0.922 | ||
| Chemotherapy | Yes | 2.212 (1.269, 3.855) | 0.005* | 2.165 (1.220, 3.810) | 0.008* | |
| No | Ref. | |||||
| Sex | Male | 0.443 (0.410, 0.479) | 0.001* | 0.513 (0.473, 0.557) | 0.001* | |
| Female | Ref. | |||||
| Size of locality | <100 000 | 1.008 (0.957, 1.062) | 0.752 | 1.016 (0.963, 1.072) | 0.555 | |
| ≥100 000 | Ref | |||||
| Education Years | None | 4.059 (3.474, 4.741) | 0.001* | 3.568 (3.043, 4.184) | 0.001* | |
| 1-5 years | 3.297 (2.855, 3.808) | 0.001* | 2.919 (2.523, 3.377) | 0.001* | ||
| 6 years | 2.676 (2.304, 3.109) | 0.001* | 2.357 (2.027, 2.740) | 0.001* | ||
| 7-9 years | 1.857 (1.583, 2.179) | 0.001* | 1.593 (1.359, 1.868) | 0.001* | ||
| ≥10 years | Ref. | |||||
| Marital Status | Married/Civil union | 1.156 (0.950, 1.407) | 0.148 | 0.944 (0.778, 1.145) | 0.558 | |
| Separated/Divorced | 1.314 (1.044, 1.654) | 0.020* | 1.188 (0.946, 1.492) | 0.137 | ||
| Widowed | 1.363 (1.102, 1.685) | 0.004* | 1.014 (0.820, 1.254) | 0.898 | ||
| Single | Ref. | |||||
| Diabetes | Yes | 1.467 (1.341, 1.604) | 0.001* | 1.254 (1.145, 1.372) | 0.001* | |
| No | Ref. | |||||
| Hypertension | Yes | 1.667 (1.548, 1.795) | 0.001* | 1.396 (1.293, 1.507) | 0.001* | |
| No | Ref. | |||||
| Heart Attack | Yes | 1.692 (1.381, 2.074) | 0.001* | 1.536 (1.250, 1.880) | 0.001* | |
| No | Ref. | |||||
| Respiratory Disease | Yes | 1.746 (1.503, 2.029) | 0.001* | 1.528 (1.307, 1.787) | 0.001* | |
| No | Ref. | |||||
The model was adjusted for age, Size of locality, years of education, marital status, diabetes, hypertension, myocardial infarction, and respiratory disease.
OR: odds ratio with 95% confidence interval (CI).
p < 0.05
Education demonstrated a strong inverse association with the likelihood of DS, as participants without formal education had more than three times the adjusted odds of DS compared to those with ten or more years of education (OR = 3.568; 95% CI: 3.043–4.184; p < 0.001). Similarly, lower education levels showed progressively higher odds in a graded manner (all p < 0.001). Additionally, diabetes, hypertension, history of myocardial infarction, and respiratory disease were each significantly linked to increased odds of DS in the adjusted model, with ORs ranging from 1.254 to 1.536 (all p < 0.001). No statistically significant associations were identified between DS and age, size of locality, or marital status in the fully adjusted analysis.
Discussion
Main Outcomes
Depression persists as a leading mental health concern in cancer survivors, shaped by a combination of treatment-induced stressors and neurobiological disruptions. The present study found that cancer survivors who received chemotherapy reported significantly higher levels of DS than healthy individuals, especially early in the follow-up period. Although symptom levels gradually declined, they remained elevated until 2021, pointing to the prolonged emotional burden associated with chemotherapy. Multivariate analysis showed that chemotherapy was independently associated with more than twice the odds of experiencing DS, even after adjusting for sociodemographic and health factors.
Our findings are consistent with international literature indicating a high prevalence of depression among cancer survivors, with a global pooled estimate of 33.16% (95% CI: 27.59–38.74) [26]. In Mexico, reported prevalence of high DS among cancer survivors ranges from 11.8% to 53.3% [27-29]. Several longitudinal studies have investigated the temporal association between DS and chemotherapy. Lloyd et al. [8] reported a significant increase in risk among colorectal cancer survivors, with HRs of 2.04 (95% CI: 1.27–3.29) within two years and 6.58 (95% CI: 2.41–17.94) between two- and five-years post-diagnosis. Likewise, Boyes et al. [13] identified higher odds six months after diagnosis following recent chemotherapy (OR = 1.9; 95% CI: 1.2–3.1). Conversely, both Lee et al. [14] found a non-significant association (OR = 1.31; 95% CI: 0.87–1.97), and Zhao et al. [12] reported no significant relationship. Although the overall association between chemotherapy and depression appears consistent, discrepancies across studies may be attributed to variations in study design, population characteristics, and methodological approaches. Differences in the definition and measurement of depression further underscore the importance of contextual and methodological factors in evaluating depression in cancer survivors.
Strengths and Implications for Psychosocial Policies
The principal strength of this study lies in its distinction as the first longitudinal investigation of its kind in Mexico, providing critical insights into the long-term trajectory of DS among cancer survivors who have received chemotherapy. By employing a comparative design with a large control group, the study enhances the robustness of its findings and facilitates a nuanced understanding of the temporal relationship between chemotherapy and DS. The extended follow-up period further contributes valuable data on the long-term psychological sequelae of cancer treatment within this specific population. These findings emphasize the necessity of routine mental health screening and tailored psychosocial support for vulnerable groups, as well as the integration of psychological services into standard oncology care protocols. Continued follow-up and psychoeducational interventions may improve patient outcomes, underscoring the pivotal role of mental health in comprehensive cancer care and the pressing need for further research to inform evidence-based strategies and policy development [30].
Study Limitations
The main limitation of this study is the small sample size of chemotherapy patients. This problem is partly because the MHAS is aimed at a broader elderly population and not exclusively at cancer patients. In addition, the small number of cases may be due to the long follow-up period during which some participants may have been lost due to factors such as relocation, death, or other circumstances. In addition, information on the type and dose of chemotherapy or histopathological characteristics of the cancer was not available. Another limitation is the lack of a formal clinical diagnosis of depression, as the study is based solely on self-reported symptoms assessed using the CES-D scale. Although validated, the CES-D does not provide a definitive diagnosis. However, it has shown a moderate sensitivity of 80.7% and a specificity of 68.7% [23]. Furthermore, given that classification was determined by the question, “In the past two years, have you received chemotherapy or medication for your cancer?”, a potential bias may arise from the medication option. Nonetheless, since other response options included medications for pain management or palliative care, and multiple selections were allowed, this bias may be lessened. Furthermore, because patients self-reported their experiences, they might associate chemotherapy exclusively with intravenous treatment, which could explain the inclusion of medication to also cover oral chemotherapy, as other medication types (for pain and palliative care) were provided as separate answer options.
Conclusion
The current study provides the first longitudinal evidence in Mexico linking chemotherapy to an increased risk of DS among cancer survivors, with effects persisting for nearly a decade. These findings highlight the critical need for integrating routine mental health screening and psychosocial support into cancer care to address the long-term emotional burden of treatment.
Supplementary Material
Figure 1.
Filtering and Screening Flowchart.
aMHAS: Mexican Health and Aging Study. bCESD-9: Nine-item scale adapted from the modified Center for Epidemiologic Studies Depression Scale
Figure 2. Characteristics of depressive symptoms over the years in chemotherapy patients (colored in red) and healthy subjects (colored in green).
A. Box plots of mean depressive symptoms according to the CESD-9. The t-lines represent the 95% confidence interval of the mean (black line in each box plot). B. percentage of high-grade symptoms across years.
Funding Statement:
No funding was received for conducting this study.
Footnotes
Disclosure Statement: The authors declare that there are no conflicts of interest related to this study. They have no financial or personal relationships that could influence the work presented in this manuscript.
Data Availability Statement:
This information was obtained from publicly available resources provided by the Mexican Health Aging Study [MHAS], accessible at: https://www.mhasweb.org/. The final dataset can be provided upon reasonable request to the authors.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
This information was obtained from publicly available resources provided by the Mexican Health Aging Study [MHAS], accessible at: https://www.mhasweb.org/. The final dataset can be provided upon reasonable request to the authors.