Depression in gastric cancer patients: Integrated therapeutic strategies and clinical implications

Abstract

Depression is a common comorbidity in gastric cancer (GC) patients, with prevalence rates reaching up to 57%, particularly in advanced stages and during active treatment. While prior studies have explored the bidirectional relationship between GC and depression, this editorial provides a structured synthesis of therapeutic strategies including pharmacological, psychotherapeutic, integrative, and biomarker-driven interventions, within a multidisciplinary care framework. Depression may exacerbate tumor progression through chronic stress and neurotransmitter dysregulation, such as β2-adrenergic receptor activation, while the cancer burden deepens psychological distress. Antidepressants, especially selective serotonin reuptake inhibitors, have demonstrated efficacy in alleviating depressive symptoms in up to 70% of cases, particularly when used alongside chemotherapy. Psychotherapeutic modalities, including cognitive-behavioral therapy and family-based interventions, help reduce depressive symptoms, improve coping mechanisms, and prevent relapse. Integrative strategies like music therapy, mindfulness, and physical activity further support emotional well-being, particularly in mild-to-moderate depression. Multidisciplinary care that combines nutritional support, pain control, and psychosocial interventions is essential. Notably, the integration of interventional therapies with traditional Chinese medicine has shown potential in stabilizing tumor growth and improving mental health, enabling functional “tumor-bearing survival”. Emerging immunotherapies such as cadonilimab may also contribute indirectly to depression alleviation by enhancing treatment efficacy and extending survival. Future research should focus on biomarker-guided approaches, such as targeting β2-adrenergic signaling, and developing personalized psychosocial care models. A holistic approach that integrates both physical and psychological care is vital to improving outcomes and quality of life in GC patients.

Key Words: Gastric cancer; Depression comorbidity; Psychosocial interventions; Integrated therapeutic strategies; Biomarker-driven therapies

Core Tip: Depression is a common and impactful comorbidity in gastric cancer patients, significantly affecting treatment adherence, quality of life, and survival. A bidirectional relationship exists between depression and gastric cancer, where psychological distress exacerbates cancer progression, and cancer-related burdens worsen depressive symptoms. Effective management requires a holistic, integrated approach, combining pharmacological treatments, psychotherapeutic interventions, and complementary therapies. Multidisciplinary care, incorporating emotional support, pain management, and nutritional strategies, is crucial for improving both psychological and physical outcomes. Future research should focus on personalized therapies targeting both stress-related pathways and individualized psychosocial support to optimize patient well-being and treatment efficacy.

INTRODUCTION

Gastric cancer (GC) is one of the leading causes of cancer-related morbidity and mortality worldwide. Depression, a prevalent comorbidity in GC patients, has emerged as a significant psychological challenge, with reports indicating a high prevalence of up to 57%. Depression in GC patients not only worsens their quality of life (QoL) but also negatively impacts treatment adherence and overall survival outcomes. The multifaceted relationship between GC and depression necessitates a deeper understanding of their bidirectional interactions, which has been explored in recent work by Christodoulidis et al[1]. However, while their editorial focused primarily on the conceptual bidirectionality between psychological distress and tumor biology, this editorial expands upon this foundation by integrating the latest clinical and translational evidence into a therapeutic framework that emphasizes multimodal and personalized interventions. This article aims to synthesize the current evidence on the etiology, therapeutic interventions, and clinical management of depression in GC patients, highlighting the importance of integrating physical and mental health strategies for optimal patient outcomes. Recent studies suggest that targeted interventions, such as Bifidobacterium triple viable bacteria-assisted mirtazapine, can effectively alleviate depressive symptoms and improve prognosis post-surgery. These emerging treatments, along with conventional approaches, emphasize the need for a comprehensive care model in managing depression in GC patients[2].

EPIDEMIOLOGY OF DEPRESSION IN GC PATIENTS

Depression is a frequent comorbidity in GC patients, with varying prevalence rates depending on factors such as cancer stage, treatment phase, assessment tools, and diagnostic criteria. Studies differentiate between depressive symptoms, typically identified via self-report scales, and major depressive disorder (MDD), which requires formal psychiatric diagnosis. For example, Zamani and Alizadeh-Tabari[3] reported a pooled prevalence of 43% for depressive symptoms in GC patients, while Kouhestani et al[4] focused specifically on MDD and found lower rates. These discrepancies reflect the heterogeneous nature of depression definitions across studies. A recent meta-review by Martinez-Calderon et al[5] has emphasized the lack of uniformity in the operationalization of depression in oncology literature, where many meta-analyses conflate MDD and subclinical depressive states. Similarly, Saracino et al[6] demonstrated that prevalence in cancer populations can vary widely depending on whether structured interviews, clinician assessments, or self-report tools are used.

In this editorial, we report a range of prevalence estimates, including a maximum rate of 57% cited in the abstract, which reflects depressive symptoms rather than clinically diagnosed MDD. This rate is consistent with findings in high-burden subgroups such as advanced-stage patients. To avoid confusion, we have clarified the nature of each prevalence figure throughout the text and standardized terminology accordingly. In evaluating prevalence data on depression in GC patients, it is important to recognize the methodological heterogeneity underlying existing studies. For example, the use of self-reported symptom scales (e.g., Patient Health Questionnaire 9, Hospital Anxiety and Depression Scale) typically yields higher prevalence rates compared to structured diagnostic interviews (e.g., severe combined immune deficiency, Mini International Neuropsychiatric Interview), which more strictly define MDD. As highlighted by Saracino et al[6], prevalence estimates of depression among cancer patients can vary significantly-up to threefold-depending on the assessment tool used and the population sampled. Additionally, many meta-analyses do not adequately stratify findings by diagnostic method or cancer stage, thereby limiting the interpretability of pooled estimates. These issues underscore the need for critical appraisal of study quality and cautious interpretation when generalizing prevalence figures across settings and populations. Future research should prioritize standardized diagnostic criteria and stratified analyses to better reflect real-world burden.

ETIOLOGY AND PATHOPHYSIOLOGY OF DEPRESSION IN GC

The pathophysiology of depression in GC patients is complex and involves both biological and psychosocial factors, with the interaction between these dimensions playing a crucial role in disease progression. Depression in GC patients is not only a consequence of the cancer diagnosis and treatment but may also exacerbate cancer progression through various biological pathways. Understanding this bidirectional relationship requires a layered analysis that begins with molecular and neuroimmune mechanisms and extends to psychological and environmental stressors. Therefore, this section first explores the biological mechanisms underlying GC-related depression and then transitions to the psychosocial factors that contribute to symptom severity and clinical outcomes.

Biological mechanisms

Neurotransmitter dysregulation, inflammatory signaling and genetic alterations interact in a complex network that underlies the pathophysiology of depression in GC patients. Chronic psychological stress activates the sympathoadrenal axis, increasing levels of circulating catecholamines such as norepinephrine and epinephrine. These neurotransmitters bind to β2-adrenergic receptors (β2-AR) on both immune and tumor cells, initiating downstream signaling cascades that include MACC1 overexpression, phosphatidylinositol-3-kinase/protein kinase B pathway activation, and enhancement of epithelial-mesenchymal transition-hallmarks of tumor progression and metastasis in GC patients[7]. At the same time, β2-AR signaling promotes the release of pro-inflammatory cytokines (e.g., interleukin-6 and tumor necrosis factor-α), generating a pro-tumorigenic and neuroinflammatory microenvironment[8]. This inflammatory state can exacerbate central neurotransmitter imbalance and induce behavioral symptoms of depression.

The chronic inflammatory burden and sustained stress response also lead to the accumulation of oxidative stress, which modifies redox-sensitive pathways and contributes to the activation of proto-oncogenes such as ABL1. ABL1 is involved in cytoskeletal reorganization, DNA damage response, and resistance to apoptosis, thereby reinforcing tumor aggressiveness. Moreover, ABL1 has been shown to interact with β-catenin and signal transducer of activation signaling, further promoting tumor cell survival and proliferation[9]. Additionally, psychological stress modulates tryptophan metabolism through the kynurenine pathway, reducing serotonin biosynthesis and increasing production of neurotoxic metabolites such as quinolinic acid. This not only contributes to depressive symptoms but also impacts immune tolerance and neuroplasticity. Together, these findings suggest that stress-induced neurotransmitter imbalance, inflammation, oxidative damage, and gene dysregulation form a neuroimmune-oncogenic feedback loop. This loop links psychological distress and tumor biology, establishing depression as both a consequence and a potential driver of cancer progression. Therapeutically, disrupting this loop via β-blockers, anti-inflammatory agents, or ABL1 inhibitors may provide novel strategies to simultaneously mitigate depressive symptoms and inhibit GC progression.

While biological mechanisms provide a foundational understanding of how stress and tumor biology are intertwined, they represent only one facet of this complex disorder. Depression in GC is also shaped by a range of psychosocial determinants, including emotional distress, social isolation, and perceived helplessness. These factors not only affect psychological resilience but can also modulate biological responses, forming a feedback loop between mind and body. The following section will elaborate on these psychosocial dimensions and their influence on disease course and patient well-being.

Psychosocial factors

Psychosocial stressors, such as uncertainty about the future, social isolation, and a perceived loss of control over one’s life, are central to the onset and exacerbation of depression in GC patients. The emotional distress caused by the diagnosis of GC, along with the physical challenges of treatment, such as pain, fatigue, and nausea, often lead to feelings of helplessness and hopelessness. Notably, emotional support plays a significant role in mental health outcomes, with patients who receive strong emotional support, particularly after treatment completion, demonstrating better mental health compared to those still undergoing treatment[10].

Certain demographic groups, including older adults and females, are more vulnerable to depression post-diagnosis[11,12]. Moreover, lifestyle factors such as poor diet and sedentary behavior, which are often exacerbated by depression, can contribute to poorer mental health and even increase the risk of developing GC in the first place. A healthy diet rich in vitamins and minerals may mitigate depressive symptoms, creating a bidirectional relationship between diet, mental health, and cancer risk[13]. Together, these psychological and biological factors highlight the complexity of depression in GC patients. The interplay between psychological distress and biological mechanisms requires a holistic approach to patient care that integrates psychological support with medical treatment to improve both mental and physical outcomes.

THERAPEUTIC APPROACHES TO DEPRESSION IN GC PATIENTS

The management of depression in GC patients requires a multifaceted approach that integrates pharmacological, psychological, and integrative therapies. Depression in these patients not only impacts their mental well-being but also has a significant effect on their cancer treatment outcomes, making effective management crucial to improving both psychological and physical health.

Pharmacological interventions

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and sertraline, are among the most commonly prescribed antidepressants for patients with cancer-related depression, including those with GC. These medications act by modulating serotonergic neurotransmission, which is often dysregulated in patients experiencing chronic stress or depressive symptoms. However, high-quality evidence supporting the efficacy of SSRIs in cancer-specific populations remains limited. According to a recent Cochrane review by Vita et al[14], studies examining antidepressant use in cancer patients generally suffer from small sample sizes and methodological heterogeneity, leading to uncertain effect estimates. Therefore, while SSRIs are widely used in practice, their effectiveness in GC populations should be interpreted with caution. Close monitoring is warranted, particularly when combined with chemotherapy or immunotherapy, due to potential pharmacokinetic interactions.

Psychotherapeutic interventions

Psychotherapy plays a crucial role in managing depression in GC patients. Among available modalities, cognitive-behavioral therapy (CBT) has shown robust efficacy in alleviating depressive symptoms by targeting maladaptive thought patterns and enhancing coping mechanisms. Interpersonal therapy and family therapy are also beneficial, particularly in enhancing social functioning and interpersonal relationships, which are frequently disrupted in cancer patients. A recent network meta-analysis compared the effectiveness of multiple psychotherapeutic approaches across patients with gastrointestinal cancers[15]. The findings suggest that CBT and interpersonal therapy demonstrate the strongest evidence for reducing both depression and anxiety, with moderate-to-large effect sizes. Family therapy and mindfulness-based interventions also exhibited benefits, although the evidence base was comparatively smaller.

However, patient responsiveness to psychotherapy varies considerably depending on age, cancer stage, psychiatric history, and cultural background. For instance, GC patients from Eastern societies may be less likely to express psychological distress openly and may prefer family-based interventions or traditional belief-aligned models. Barriers such as stigma, limited access to trained psychotherapists, and high treatment costs may further reduce engagement, especially in low-resource settings. Personalized strategies are therefore essential. Hu et al[16] demonstrated that acceptance and commitment therapy, when combined with personalized nutrition, significantly improved psychological resilience, treatment adherence, and chemotherapy tolerance in patients with advanced GC. Such models highlight the value of culturally contextualized and symptom-adaptive psychotherapeutic delivery. Furthermore, combination strategies, integrating CBT with pharmacotherapy or supportive care can enhance response and prevent relapse. Remote or hybrid formats, caregiver-inclusive models, and short-term structured interventions are also gaining traction as accessible and scalable options in GC psycho-oncology.

Integrative strategies

In addition to traditional pharmacological and psychotherapeutic treatments, complementary and integrative therapies (CITs) are gaining recognition for their potential to alleviate mild-to-moderate depressive symptoms and improve QoL in GC patients. These include music therapy, mindfulness-based stress reduction, acupuncture, and exercise-based rehabilitation. A recent review by Ribeiro and Conter[17] emphasized the benefits of integrative oncology in improving both symptom burden and psychological outcomes across gastrointestinal cancers. Similarly, the Chinese Anti-Cancer Association (CACA) Guidelines advocate for integrative modalities in GC care, especially when tailored to cultural expectations and individual preferences[18].

However, the evidence base for CITs remains limited in GC-specific populations. While some patients experience meaningful improvement in mood, fatigue, or anxiety, others may show minimal response. These disparities may stem from differences in cultural receptivity, personal belief systems, and baseline psychological traits. For example, certain patients may view mindfulness as spiritually incongruent or music therapy as emotionally uncomfortable. Thus, cultural sensitivity and pre-intervention screening for acceptability are important in CITs implementation. Despite these caveats, personalized and flexible integration of CITs, especially when combined with conventional treatment, may enhance self-efficacy and reduce psychological burden. Future studies should stratify outcomes by sociodemographic factors, belief orientation, and treatment setting to better understand who benefits most from which integrative approaches.

Multidisciplinary care

The complexity of managing depression in GC patients necessitates a multidisciplinary care model that aligns physical and mental health services. A team-based approach, comprising oncologists, psycho-oncologists, nutritionists, and palliative care specialists, has been shown to improve treatment adherence and psychological outcomes. According to the CACA Guidelines for holistic integrative management of GC, effective multidisciplinary care requires not only coordination across specialties but also incorporation of psychosocial screening tools, nutritional risk assessments, and personalized care plans[18]. Integration of emotional intelligence training and structured communication protocols further strengthens team function and patient engagement.

Practical challenges, such as time constraints, referral inefficiencies, and uneven access to psycho-oncology, remain barriers. These issues could be addressed via nurse-led coordination, telehealth-based counseling, and system-level restructuring for more inclusive mental health care access in oncology. This collaborative approach has proven to improve treatment compliance and enhance patient outcomes, highlighting the importance of treating both the psychological and physical aspects of cancer care. As noted by Zhao et al[19], interventions aimed at improving emotional intelligence also have a positive correlation with QoL and lower depression scores in GC patients, further emphasizing the value of psychological support in managing cancer-related depression.

EMERGING THERAPIES AND FUTURE DIRECTIONS

Recent advances in immunotherapy and molecular profiling have opened new possibilities for addressing both the oncologic and psychological needs of GC patients. For example, cadonilimab, a bispecific antibody targeting programmed death 1 and cytotoxic T-lymphocyte antigen-4, has demonstrated favorable outcomes in advanced GC cases, potentially reducing psychological distress via prolonged survival and symptom control. A phase I/II trial conducted in patients with advanced GC showed that cadonilimab combined with chemotherapy yielded an objective response rate of 42%, with manageable toxicity and improved symptom control[20]. Although depression-specific outcomes were not measured, improved tumor control and reduced inflammatory load may translate to better psychological well-being in future integrative trials. While data on immunotherapy’s direct psychological impact remain limited, integrative frameworks such as those proposed by Ribeiro and Conter[17] and the CACA holistic care model have called for the inclusion of psychosocial endpoints in future clinical evaluations[18]. Incorporating standardized depression and QoL scales in immunotherapy trials may provide a clearer picture of how disease control influences psychological resilience in GC patients.

Beyond immunotherapy, biomarker-driven strategies targeting neuroendocrine stress pathways, particularly the β2-AR axis, have attracted increasing attention. β2-AR activation is known to promote GC progression via mechanisms such as MACC1-induced epithelial-mesenchymal transition, phosphatidylinositol-3-kinase/protein kinase B signaling, and stress-related cytokine production. Preclinical studies have shown that β2-AR antagonists like propranolol can inhibit tumor proliferation and reduce metastatic potential in animal models of GC. These findings suggest a mechanistic link between chronic psychological stress, tumor biology, and potential therapeutic intervention.

However, it is important to emphasize that the application of β2-AR antagonists in GC remains experimental and largely supported by preclinical data. To date, no randomized clinical trials have investigated the clinical efficacy of β2-AR blockade in GC patients, nor its direct impact on depressive symptoms or stress-modulated disease progression. Therefore, while the rationale is biologically sound, current recommendations for their use remain hypothesis-generating, and further translational research is required. Future clinical trials investigating β2-AR antagonists in GC could adopt an adaptive design with stratification based on baseline stress biomarker levels (e.g., cortisol, norepinephrine). Sample size estimation should consider moderate effect sizes on both progression-free survival and validated depression scales (e.g., Patient Health Questionnaire 9), with endpoints including tumor response, QoL, and depressive symptom reduction to assess dual efficacy.

Future directions should include the integration of neuropsychological and immunological endpoints into early-phase trials of stress-targeting interventions. Such studies may utilize multi-omic biomarker profiling, capturing the dynamic interplay between neurotransmitter signaling, inflammatory load, and tumor response. A precision psycho-oncology framework, stratifying patients based on both psychological vulnerability and molecular phenotype, could help identify individuals most likely to benefit from dual-targeted strategies. Ultimately, these approaches will help determine whether modulation of stress pathways can simultaneously improve survival and mental well-being in GC patients.

INTEGRATED THERAPEUTIC MODEL AND CLINICAL MANAGEMENT

The management of depression in GC patients requires a holistic, integrative therapeutic model that aligns biological, psychological, and social dimensions of care. This model emphasizes the synergistic application of pharmacological treatments, psychotherapeutic interventions, and supportive strategies such as nutrition and symptom management. In clinical settings, sequencing and personalization of these components are crucial for optimizing outcomes. For instance, pharmacological interventions like SSRIs are often initiated in cases of moderate to severe depression, particularly when somatic symptoms such as fatigue or appetite loss predominate. Once acute symptoms stabilize, or in patients presenting with higher cognitive readiness, structured psychotherapeutic interventions such as CBT or acceptance and commitment therapy may be implemented. Conversely, in milder cases or in patients with strong social supports, psychotherapy or integrative approaches may serve as first-line options, with pharmacologic escalation reserved for nonresponse.

Personalization of the treatment plan depends on a variety of clinical and sociodemographic factors, including cancer stage, psychiatric history, age, social support, health literacy, and patient preferences. The use of screening instruments, such as distress thermometers, electronic mood tracking applications, or brief validated questionnaires, can facilitate early identification of psychological needs and guide treatment selection. However, real-world implementation of this integrated approach remains challenging, particularly in resource-constrained environments such as low- and middle-income countries, where mental health services are often underfunded or structurally disconnected from oncology.

Multiple systemic barriers complicate the execution of multidisciplinary care. These include the limited availability of trained psycho-oncologists, high patient volume in oncology clinics that restricts consultation time, poor communication between psychiatric and oncologic services, and the fragmentation of care delivery systems. Furthermore, cultural stigma surrounding mental health, lack of reimbursement for psychosocial services, and the prioritization of physical over psychological care further hinder access to timely and adequate mental health support.

Despite these challenges, several pragmatic solutions have emerged. Telemedicine-based interventions, such as app-delivered CBT and remote psychological consultations, can extend mental health support to patients in geographically isolated or underserved areas. Nurse-led triage systems that incorporate routine distress screening into oncology workflows have shown promise in enabling early detection and referral. In parallel, collaborative models that integrate dietitians and psychologists into the same clinical setting allow for simultaneous management of nutritional and emotional needs, especially beneficial for patients experiencing treatment-related cachexia and mood disturbance. In contexts with severe workforce limitations, brief, culturally adapted psychotherapeutic protocols, including mindfulness-based stress reduction or behavioral activation, can be delivered in group settings or via caregiver involvement, thus reducing individual provider burden. For example, the Shanghai Mental Health Center’s integrative care program embedded psychological screening into oncology visits and reported increased early intervention uptake and improved distress scores. Similarly, a nurse-led coordination model in rural Sichuan used brief electronic mood scales with automatic referral triggers, demonstrating operational feasibility and enhanced patient engagement.

To ensure sustainability and scalability, institutional and policy-level commitment is essential. This includes the development of standardized referral protocols, cross-training of oncology nurses in basic psychosocial assessment, and incentivizing participation in interdisciplinary team discussions. Health systems should also consider integrating psychosocial care into quality metrics and value-based payment models to align financial structures with the goal of whole-person care. Ultimately, building a truly operational, patient-centered integrative model requires not only sound evidence base but also alignment with local resource capacities, cultural norms, and administrative frameworks. Future implementation research, especially in low- and middle-income countries and diverse sociocultural contexts, will be vital to refine care pathways, ensure equitable access, and optimize both psychological and clinical outcomes for GC patients.

CONCLUSION

Depression in GC patients is a serious and prevalent comorbidity that negatively impacts treatment adherence, QoL, and survival outcomes. Addressing depression requires a multifaceted approach that includes pharmacological treatments, psychotherapeutic interventions, and integrative care strategies. An integrated therapeutic model that incorporates both physical and mental health interventions is essential for optimizing patient outcomes. Future research should focus on personalized and biomarker-driven therapies, as well as personalized psychosocial support frameworks to better manage depression in GC patients.