The Binomy Antidepressants and ROS with Breast Cancer: Reanalysis of Evidence from Over Two Million Women with a Randomised Meta-analytic Approach

Introduction The use of antidepressants is steadily increasing worldwide. This trend has a significant impact on public health and socioeconomic conditions. Although studies have looked for a possible link between antidepressants and breast cancer risk, findings remain unpredictable. Variations depend on drug class, treatment duration, dosage, number of prescriptions, and patient characteristics. This meta-analysis aims to provide overall and stratified estimates of the association with cancer incidence risk. It evaluates different pharmacological mechanisms and the main clinical and epidemiological factors involved. Methods A meta-analysis was conducted following PRISMA guidelines. Searches were performed in PubMed, Embase, and Web of Science, from inception to September 2025, including observational studies (cohort and case-control) and randomised controlled trials (RCTs), without restrictions on sex or geographic location. Screening was independently performed by two reviewers; disagreements were resolved by a third author. Eligible studies required well-defined criteria and a validated data source (health registries, electronic prescription databases, national cancer registries, structured interviews conducted by qualified health professionals, or medical records). Studies with unobjective exposure or inadequate definitions were excluded. Outcome definition The primary outcome was the incidence of breast cancer, confirmed through cancer registries (e.g., SEER, GPRD, national registries), medical records, histological reports, or ICD codes. When available, analyses were stratified by hormone receptor status (ER, PR), histological subtype (ductal, lobular), and disease stage. Effect measures (OR, RR, HR) were extracted and converted to their natural logarithm for comparability and symmetry. Subgroup analyses were performed by drug class, treatment duration and intensity, patient characteristics, and tumour immunophenotype. Robustness was evaluated per Galbraith plots, while heterogeneity was assessed using I², τ², and H² statistics; publication bias was explored by funnel plot. All analyses were conducted using R 4.3. Methodological quality was calculated with the Modified Newcastle-Ottawa Scale (mNOS). Results Twenty-four studies with 2,145,493 participants were included. We analysed 184 antidepressant-related variables. Patients discontinuing SSRI therapy prior to study baseline showed a reduced breast cancer risk (OR = 0.82; 95% CI: 0.69-0.96). Cumulative SSRI exposure of 0-1 year correlated with increased risk (OR = 1.08; 95% CI: 1.04-1.12), notable among current users with less than 1 year of use (OR = 1.18; 95% CI: 1.08-1.29). Paroxetine appeared protective, with a lower risk among current users (OR = 0.62; 95% CI: 0.43-0.88) and among those undergoing therapy for over 2 years (OR = 0.60; 95% CI: 0.36-0.99). Conclusions This meta-analysis of over two million individuals suggests that the relationship between antidepressant use and breast cancer risk varies depending on patient and treatment factors. Short-term use of SSRIs was related to increased breast cancer risk, whereas previous use appeared protective. Paroxetine demonstrated a protective effect, especially with long-term use. These findings inform risk assessment and therapeutic planning for women requiring antidepressants. These results support a personalised approach to antidepressant prescribing, especially for long-term therapy and for patients with breast cancer risk factors. Risk-benefit assessment in clinical practice should consider both antidepressant efficacy and potential effects on breast carcinogenesis. Further research is warranted to clarify underlying biological mechanisms, supporting evidence-based, individualised treatment decisions.