The Impact of Depression on Survival and Treatment Adherence in Cancer Patients: A Systematic Review

doi:10.21203/rs.3.rs-8484915/v1

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Systematic Review

The Impact of Depression on Survival and Treatment Adherence in Cancer Patients: A Systematic Review

https://doi.org/10.21203/rs.3.rs-8484915/v1

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Depression is prevalent among cancer patients and has been proposed as a prognostic factor for survival, yet its impact across cancer types remains unclear. This systematic review evaluates the association between depression, survival outcomes, and treatment adherence in adult cancer patients. A structured search of PubMed and SpringerLink identified peer-reviewed cohort studies, meta-analyses, and narratives published between 2000 and 2025. Eligible studies included adults with histologically confirmed cancer in whom depression was assessed using clinical diagnostic criteria or validated symptom-based instruments. Outcomes of interest included overall survival (OS) and cancer-specific survival (CSS). Due to methodological heterogeneity, a narrative synthesis was utilized. Twelve studies met the inclusion criteria. Across nearly all studies, depression was associated with worse OS, with reported hazard ratios generally ranging from 1.2 to 1.8. Clinically diagnosed depression and depression occurring after cancer diagnosis were associated with stronger adverse survival effects. Persistent or severe depressive symptoms were linked to higher mortality, whereas remission of symptoms and adherence to depression treatment were associated with improved survival. In conclusion, depression is consistently associated with poorer survival in cancer patients and appears to represent a potentially modifiable prognostic factor. These findings suggest routine depression screening and integrated mental health care in oncology practice. This review was conducted following PRISMA 2020 guidelines.

Oncology

Depression is a common and serious mood disorder characterized by persistent feelings of sadness, loss of interest in activities, and a range of cognitive, behavioral and physical symptoms that can significantly impair daily functioning (Mayo Clinic, 2025; Cleveland Clinic, 2016). While depression affects millions of individuals worldwide, its impact extends beyond mental health, contributing to adverse outcomes in patients with chronic medical conditions, including cancer (Smith, 2015). Among cancer patients, depression is highly prevalent, affecting an estimated 10–40% of individuals depending on cancer type, stage, and demographic factors, with pancreatic and lung cancers demonstrating particularly high rates (Walker et al., 2021; Smith, 2015). Depression in these patients is often triggered by the psychological stress of a cancer diagnosis, maladaptive coping strategies, social isolation, prior mental health conditions, and biological mechanisms such as chronic inflammation, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, and immune suppression (Smith, 2015; Mössinger & Kostev, 2023).

Evidence suggests that depression not only affects quality of life but also has prognostic significance in cancer, influencing both overall and cancer-specific survival. Large cohort studies and meta-analyses have consistently demonstrated that patients with depression experience higher mortality risk across multiple cancer types. For example, Walker et al. (2021) reported a 41% increase in mortality among cancer patients diagnosed with major depression, while Pinquart and Duberstein (2010) found a significant association between depression and cancer mortality across 76 prospective studies. Other meta-analyses have confirmed these findings, with depression associated with 23–83% increased mortality depending on cancer type, including breast, colorectal, lung, and prostate cancers (Ungvari et al., 2025; Wang et al., 2020; Xia et al., 2024). Importantly, the effect of depression on patient outcomes seems to be separate from major clinical factors like cancer stage, treatment type, and other health conditions. This suggests that depression may be a risk factor on its own, rather than just a sign of more severe disease.

Furthermore, longitudinal studies indicate that the timing and persistence of depressive symptoms are important for survival outcomes. Patients with new-onset or persistent depression after cancer diagnosis exhibit higher mortality risk, whereas symptom remission is associated with survival similar to non-depressed patients (Sullivan et al., 2016; Yen et al., 2022). These findings suggest that depression is a potentially modifiable factor, and that systematic screening and treatment adherence may improve not only psychological well-being but also survival outcomes in cancer patients. Together, these studies underscore the clinical importance of integrating routine depression assessment and targeted psychosocial interventions into comprehensive oncology care.

A structured literature search was conducted to identify studies examining the prognostic significance of depression in cancer patients. Peer-reviewed studies were identified through searches of PubMed and SpringerLink. The search was limited to studies published between 2000 and 2025. Search terms included combinations of “depression,” “cancer,” “overall survival,” “mortality,” and “prognosis.”

Studies were included if they included adult patients with histologically confirmed cancer, assessed depression using a clinical diagnosis (DSM or ICD criteria) or validated symptoms scales, or reported survival outcomes, including overall survival (OS) and/or cancer-specific survival (CSS). Studies with a cohort design or were meta-analyses of cohort studies were also a part of the inclusion criteria. Narratives were also included for context purposes.

Studies were excluded if they were case reports, editorials, or interventional trials without survival outcomes. Studies that focused exclusively on quality of life without mortality data were also excluded. Non-English publications were not included.

Data extraction was performed by one reviewer. Extracted variables included author and year of publication, study design, sample size, cancer type, method of depression assessment, timing of depression measurement, length of follow-up, and reported hazard ratios (HRs) or relative risks (RRs) for survival outcomes.

Study quality was assessed using principles consistent with the preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Key factors evaluated included clarity of study design, adjustment for major confounders, validity of depression assessment, and completeness of follow-up. Most included studies demonstrated moderate to high methodological quality. No studies were excluded based on quality assessment.

Due to heterogeneity in cancer type, depression assessment, and follow-up duration, a narrative synthesis approach was used. Effect estimates for OS and CSS were summarized descriptively, and trends were compared across studies.

Across the 12 included studies, depression was assessed using either validated symptom-based instruments or a structured clinical diagnostic criteria. Clinically diagnosed depression was typically defined using DSM or ICD criteria derived from psychiatric interviews or medical records (Satin et al., 2009; Walker et al., 2021; Yen et al., 2022). Symptom-based assessments most commonly used the Hospital Anxiety and Depression Scale (HADS), Center for Epidemiologic Studies Depression Scale (CES-D), and Patient Health Questionnaire (PHQ) instruments (Vodermaier et al., 2013; Sullivan et al., 2016; Lan et al., 2024).

Follow-up duration ranged from approximately 3 years to over 15 years across cohorts. Most studies adjusted survival analyses for key clinical covariates, including age, cancer stage, treatment modality, and comorbidity burden, allowing evaluation of depression as an independent prognostic factor (Pinquart & Duberstein, 2010; Walker et al., 2021; Xia et al., 2024).

Across nearly all the included studies, depression was associated with significantly worse overall survival (OS) among patients with cancer. Early meta-analytic evidence by Satin et al. (2009), which included 25 studies with clinically diagnosed depression and 26 studies using symptom scales, demonstrated that depression was associated with a significantly increased risk of mortality. The pooled effect size was strongest for studies using clinical diagnoses, with hazard ratios approaching 1.39, while symptom-based measures showed smaller but still significant effects.

Pinquart and Duberstein (2010) further expanded upon this evidence in a meta-analysis of 76 prospective studies, reporting a pooled relative risk of 1.17 for cancer mortality among depressed patients. Importantly, this association remained significant after controlling for demographic variables, disease stage, and treatment factors in the majority of included cohorts, supporting depression as an independent prognostic factor rather than a simple correlation of disease severity.

More recent large-scale cohort studies reinforced these findings. Walker et al. (2021) analyzed over 20,000 cancer patients using a two-stage psychiatric diagnostic process and found that major depression was independently associated with increased all-cause mortality across multiple cancer types (adjusted HR 1.41). The association persisted when analyses were restricted to cancer-specific mortality, suggesting that the observed effect was not driven solely by non-cancer causes of death.

The prognostic impact of depression varied based on timing and severity. Several studies demonstrated that depression diagnosed after cancer diagnosis had a stronger association with mortality than pre-existing depression (Satin et al., 2009; Walker et al., 2021). This suggests that depression emerging in response to cancer diagnosis or treatment may reflect biological or behavioral processes more directly relevant to disease progression.

Severity and persistence of depressive symptoms further modified risk. Sullivan et al. (2016), in a longitudinal study of lung cancer patients, identified distinct depression trajectories and showed that patients with persistent or worsening depressive symptoms experienced significantly higher mortality compared to patients with transient or remitting depression. In contrast, patients whose depressive symptoms resolved over time had survival outcomes comparable to those of non-depressed patients.

Similarly, Lan et al. (2024) reported that moderate-to-severe depressive symptoms were associated with markedly increased long-term mortality among cancer survivors, whereas mild symptoms showed weaker and less consistent associations.

Evidence for the prognostic role of depression was consistent across several cancer types. In breast cancer cohorts, depression at diagnosis or during early treatment was associated with worse OS and increased recurrence risk (Vodermaier et al., 2013; Wang et al., 2020). Wang et al. (2020), in a meta-analysis of over 280,000 breast cancer patients, reported that depression significantly increased the risk of both mortality and disease recurrence, with the strongest effects observed in patients with comorbid anxiety.

In lung cancer, depression demonstrated particularly strong prognostic significance. Sullivan et al. (2016) reported that persistent depression was associated with significantly higher mortality independent of disease stage and treatment. These findings are consistent with earlier observations that psychological distress may be especially impactful in cancers with aggressive disease courses.

In colorectal cancer, Xia et al. (2024) analyzed a large population-based cohort and found that depression independently predicted all-cause mortality after adjustment for tumor stage, treatment, and comorbidities. Although associations with cancer-specific mortality were weaker, the overall survival disadvantage remained significant.

Several studies provided evidence that depression is a potentially modifiable prognostic factor. Yen et al. (2022) examined over 19,000 cancer patients with diagnosed depression and demonstrated that adherence to antidepressant treatment or psychiatric care was associated with significantly improved survival compared to untreated depressed patients. Notably, untreated depression was associated with the highest mortality risk, exceeding that observed in non-depressed patients.

Similarly, Sullivan et al. (2016) observed that remission of depressive symptoms over time mitigated excess mortality risk, suggesting that effective treatment may reverse some of the adverse prognostic effects associated with depression.

This systematic review synthesizes evidence from cohort studies and meta-analyses demonstrating that depression is consistently associated with poorer survival outcomes in patients with cancer. Across diverse cancer types, study designs, and assessment methods, depression emerged as an independent prognostic factor, with hazard ratios generally ranging from 1.2 to 1.8 (Satin et al., 2009; Pinquart & Duberstein, 2010; Walker et al., 2021).

Importantly, the strength of the association varied based on how depression was measured. Clinically diagnosed depression consistently demonstrated stronger associations with mortality than symptom-based measures, suggesting that diagnostic severity and chronicity play a critical role (Satin et al., 2009; Walker et al., 2021). This pattern mirrors findings in other prognostic domains, where more precise phenotyping yields stronger predictive value.

Timing also appears to be an important moderating factor. Depression assessed after a cancer diagnosis shows a stronger association with mortality than depression present before diagnosis. This suggests that depression related to the cancer diagnosis or its treatment may be more relevant to disease progression and survival (Walker et al., 2021). Persistent depressive symptoms are especially harmful, whereas remission of depression reduces the excess risk of mortality (Sullivan et al., 2016).

Several biological and behavioral mechanisms may explain these findings. Depression has been associated with chronic inflammation, immune dysregulation, and alterations in stress hormone signaling, all of which may influence tumor growth and metastasis. Behaviorally, depression may reduce adherence to cancer treatment and follow-up care, delay symptom reporting, and impair overall health behaviors (Pinquart & Duberstein, 2010; Yen et al., 2022). The observation that depression treatment adherence improves survival supports the contribution of modifiable behavioral pathways.

This review has limitations. All included studies were observational, limiting causal inference. Depression assessment methods varied widely, contributing to heterogeneity. Additionally, study selection and data extraction were performed by a single reviewer, which may increase the risk of bias. Nonetheless, the consistency of findings across large cohorts and meta-analyses strengthens confidence in the overall conclusions.

This systematic review shows that depression is an independent prognostic factor for survival among cancer patients. Across multiple cancer types, depression was consistently linked to higher mortality, especially when it was clinically diagnosed, persistent, or left untreated (Satin et al., 2009; Walker et al., 2021; Yen et al., 2022). Evidence that remission of depressive symptoms and adherence to depression treatment are associated with better survival outcomes suggests that depression is a modifiable risk factor.

These results support the inclusion of routine depression screening and mental health care in standard oncology practice. Future research should focus on prospective studies using standardized measures of depression, as well as randomized controlled trials to determine whether treating depression can directly improve cancer survival. Including psychological health in prognostic models may enhance risk assessment and contribute to more personalized cancer care.

Acknowledgments

Artificial intelligence tools, such as ChatGPT, were used to assist with language, editing, organization, and clarity of the manuscript. The study selection, data extraction, data interpretation, and conclusions were performed by the authors.

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The authors declare no competing interests.

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Table including data of studies
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