Discussion
The present meta-analysis demonstrated that patients with BC with exposure to AD had a worse prognosis compared with non-exposed patients. Sensitivity analysis demonstrated the robustness of these findings. Before interpreting the observed association as a direct effect of AD exposure, it is key to consider the primary confounding effect of depression. Notable evidence has associated depressive states with increased tumor aggressiveness, immune suppression, poor treatment adherence and elevated risk of recurrence and metastasis (23–26). According to a previous meta-analysis of 65 cohort studies published in 2025, depression is markedly associated with increased cancer-specific mortality across multiple cancer types, such as colorectal cancer, lung cancer and prostate cancer, with a 23% higher hazard for poor survival (27). Therefore, the observed associations in the present study cannot rule out the potential confounding effect of depression, and the findings should be interpreted primarily as reflecting the prognostic impact of the underlying depressive disorder rather than a direct pharmacological effect of the drugs themselves.
Several pathophysiological pathways may mediate this association, such as neuroendocrine dysregulation, chronic inflammation and alterations in the gut microbiota. Firstly, in depressive states, persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to chronically elevated cortisol levels, which can result in glucocorticoid receptor dysfunction and impaired cortisol regulation (28,29). Epidemiological studies suggested that patients with flattened cortisol rhythms have a higher risk of cancer mortality (29,30). In addition to HPA axis dysregulation, emotional stress associated with depression can activate the sympathetic nervous system and promote the release of the neurotransmitter norepinephrine (31), which has been implicated in BC pathogenesis (32). For example, a previous study by Szpunar et al (33) demonstrated that chronic administration of TCAs suppresses norepinephrine reuptake, thereby stimulating the proliferation of mammary adenocarcinoma cell lines. This dual neuroendocrine dysregulation may collectively contribute to the observed association between depression and worse cancer outcomes.
Secondly, several studies have demonstrated that postoperative depressive symptoms in patients with BC are markedly associated with elevated levels of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α (34,35). These cytokines serve a key role in tumor angiogenesis, metastatic dissemination and therapeutic resistance. For instance, IL-6 promotes cancer stem cell properties and induces epithelial-mesenchymal transition via the Janus kinase (JAK)/STAT3 signaling pathway (36), while also remodeling the immunosuppressive tumor microenvironment by modulating the regulatory T/T helper 17 cell balance (37). Clinically, elevated IL-6 levels are associated with a 2.25 times higher risk of mortality in patients with BC, compared with patients without elevated IL-6 levels (38).
Thirdly, depression alters gut microbiota composition and reduces microbial diversity, which in turn promotes BC progression (23,39). A mechanistic study by Cui et al (40) revealed that a reduction in beneficial bacteria may decrease butyrate levels, a key microbial metabolite. Butyrate deficiency can aberrantly activate the low-density lipoprotein receptor-related protein 5/β-catenin pathway, thereby enhancing cancer stem cell properties and promoting tumor growth and metastasis. Furthermore, gut-derived microbial metabolites including short-chain fatty acids, secondary bile acids and aromatic amino acid metabolites, have been implicated in BC development via the circulatory system (41). Furthermore, gut microbiota dysbiosis may contribute to immune dysfunction, affecting the response to antitumor therapy and facilitating tumor progression (42).
Notably, when interpreting the present study findings, it is key to consider not only the neuroendocrine-immunological mechanisms of depression, but also the potential impact of psychological comorbidities in patients with BC receiving AD treatment. At the prevention and early detection stage, depression may lead patients to avoid preventive medical services. Baeker Bispo et al (43) reported that women with untreated depression or anxiety had a 14–17% lower rate of timely BC screening compared with women without depression or anxiety, suggesting that psychological distress may impair cancer prevention engagement and lead to delayed diagnosis and worse prognosis. In the treatment stage, psychological states such as fear of recurrence, treatment concerns and loss of confidence may reduce adherence to standard therapies (44,45). Patients who use ADs have been reported to be 1.14 times more likely to forego standard BC treatment compared with patients who do not use ADs (10), and a TAILORx trial (46) sub analysis reported that patients with BC with a history of depression had an 82% higher risk of prematurely discontinuing adjuvant endocrine therapy, compared with those without a history of depression (47). By contrast, positive psychological resources, such as belief in treatment effectiveness and optimism, are associated with improved outcomes (48). Mindfulness-based interventions also markedly reduce depressive symptoms, such as persistent sadness, fatigue and loss of appetite (49), as well as improve the quality of life of patients with BC, highlighting the clinical relevance of addressing psychological well-being (50,51).
Beyond the confounding effect of depression, the impact of AD on malignant tumors is complex, encompassing both pro-tumorigenic and antitumorigenic potential, with inconsistent findings from in vitro and in vivo experiments. Certain ADs have reported intrinsic antitumor properties, including the induction of cancer cell apoptosis and inhibition of the PI3K/AKT/mTOR signaling axis to trigger autophagy (52–54). However, the translational relevance of these preclinical findings remains to be elucidated. The concentrations used in most in vitro studies exceed therapeutic doses, and cell line systems fail to replicate the complex in vivo microenvironment, immune surveillance and pharmacokinetics. A previous study by Taler et al (55) demonstrated that while sertraline significantly inhibited BC tumor growth in vitro, it paradoxically promoted tumor growth in vivo.
Furthermore, several studies have suggested that AD may carry a potential risk of promoting tumorigenesis (56,57). This finding was replicated in the present meta-analysis, which demonstrated that exposure to AD is associated with worse prognosis in patients with BC. Firstly, tamoxifen is a common adjuvant endocrine therapy for patients with hormone receptor-positive (HR+) BC (58). As a prodrug, tamoxifen is metabolized primarily by the hepatic cytochrome P450 (CYP) enzyme system, particularly CYP family 2 subfamily D member 6 (CYP2D6), which converts it into its active metabolite endoxifen to inhibit BC tumor growth (59–61). In patients receiving tamoxifen, concomitant use of certain SSRIs that are potent to moderate CYP2D6 inhibitors may interfere with this activation pathway (60), leading to reduced endoxifen concentrations and potentially diminished therapeutic efficacy. This pathway is relevant only to HR+ patients treated with tamoxifen and cannot explain the associations observed in HR− subtypes or in patients receiving aromatase inhibitors. In the present study, although the overall findings are consistent with this hypothesis, the limited subgroup data do not allow robust confirmation.
Secondly, SSRIs block the serotonin transporter, promoting increased extracellular 5-hydroxytryptamine (5-HT) levels, which drive tumor cell proliferation through multiple mechanisms. 5-HT activates the JAK1/STAT3 signaling cascade to drive glycolysis and the cAMP/protein kinase A cascade to promote mitochondrial biogenesis (62), both closely associated with aggressive tumor behavior and poor prognosis in BC (62,63). Furthermore, 5-HT effects are partially mediated by the upregulation of G-protein-coupled receptor 30 (GPR30) (64), which activates PI3K/AKT and ERK signaling to promote BC cell proliferation (65). Notably, certain SSRIs, such as fluoxetine, paroxetine and sertraline, may directly interact with estrogen receptors (ERs), including GPR30 and ERα (66), exerting estrogen-like effects that activate these downstream pathways.
Furthermore, the category of other ADs in the subgroup analyses of the present study warrants particular attention. This group combined mianserin with other agents. Pharmacologically, mianserin is a tetracyclic AD with a mechanism fundamentally distinct from that of SSRIs or TCAs. Ideally, mianserin would have been analyzed as a separate category; however, the limited number of studies precluded a notable subgroup analysis for this agent alone, so this classification was adopted for analytical feasibility.
Due to the limited number of studies in the drug-specific subgroup analyses, the null findings for certain SSRIs should be interpreted with caution and may reflect insufficient statistical power to detect a true association. Therefore, these results should be considered inconclusive rather than evidence of no effect. The pro-tumorigenic effects of SSRIs such as fluoxetine, paroxetine and sertraline, which are mediated via 5-HT-associated mechanisms, do not provide a complete understanding of these drugs. Of note, previous studies have also revealed antitumorigenic mechanisms: Fluoxetine inhibits eukaryotic elongation factor 2 kinase and activates the AMP-activated protein kinase-mTOR-Unc-51-like kinase complex axis (67), inducing autophagic cell death; both sertraline and paroxetine have been reported to enhance the sensitivity of tumor cells to apoptosis (52,68). This duality of pro-tumor and antitumor effects may offer a plausible explanation for the lack of a notable association observed in the subgroup analysis for these three specific agents, although this interpretation requires further investigation. By contrast, citalopram demonstrated a notable association with worse BCSS. This discrepancy may be partly explained by the intermediate CYP2D6 inhibitory potency of citalopram and its documented impact on tamoxifen metabolism (69), which could be clinically relevant in patients receiving this endocrine therapy. Furthermore, citalopram has been associated with prolongation of the QT interval (the time from the start of the QRS complex to the end of the T wave on an electrocardiogram) (70), a potential risk factor for sudden cardiac death. Nevertheless, the precise mechanism underlying this association remains speculative and warrants further study.
In the present study, geographical variation was observed in the association between AD use and BC survival. Subgroup analysis revealed that this association reached statistical significance in Europe and Asia, whereas no such association was observed in North America. However, this null finding should be interpreted with caution, as it may reflect limited statistical power due to the small number of included studies and extensive CIs, rather than a true absence of effect. Several factors may contribute to the observed geographical differences. The prevalence of depression in patients with BC is 24.9% in North America, compared with 28.9% in Europe and 34.2% in Asia (3). Therefore, the influence of depression on prognosis may be smaller in the North American cohort. Furthermore, CONCORD study data indicated that the incidence rate of locally advanced tumors in Europe is double that in North America (71), suggesting later-stage diagnosis and greater tumor burden, which inherently worsens prognosis. Similarly, in Asia, a majority of patients with BC are diagnosed at advanced stages, with limited national data available for precise quantification (72). Therefore, these findings should not be overgeneralized as evidence that AD use is safe in North American patients with BC.
To the best of our knowledge, the present meta-analysis is the first systematic evaluation of the association between AD exposure and BC prognosis. Comprehensive subgroup analyses were performed, revealing differential effects across specific AD classes and geographical regions. However, several limitations should be considered. The majority of the studies included were observational cohort designs, with only one RCT included. The inherent heterogeneity among the included studies combined with the weak causal evidence reduces the credibility of the pooled estimates. The limited number of studies precluded subgroup analyses stratified by key pathological factors, including molecular subtype (ER/progesterone receptor/HER2 status) and TNM stage. Due to the notable heterogeneity of BC in terms of prognosis across these subtypes, the inability to perform such analyses represents a major methodological constraint. Therefore, the generalizability of the present study findings across different molecular subtypes and disease stages remains to be elucidated. Notably, confounding by indication cannot be ruled out in the present meta-analysis, as the underlying depression leading to AD exposure may account for the observed survival disadvantage rather than the medication. Furthermore, a majority of the included studies lacked comprehensive adjustment for depression severity. Therefore, the observed associations should be interpreted with caution and causality cannot be inferred from the present study findings. This represents a major limitation of the present study.
In conclusion, the present study observed a statistical association between AD exposure and worse OS and BCSS in patients with BC. However, this association is hypothesized to be largely driven by depression and its associated psychosocial factors, rather than by a direct pharmacological effect of AD. The independent effects of AD could not be distinguished from those of the underlying depressive disorder based on the findings of the present study. Due to the limited sample size and the key confounding by indication, these findings should be interpreted with caution and warrant confirmation in larger-scale, well-designed prospective studies that adequately control for depression severity in the future.