Breast Cancer Risk Not Linked to SSRIs; Prolactin Levels Warrant Careful Prescribing

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Although a minor association was found between prolactin levels and risk of developing estrogen receptor (ER)-positive or ER-negative breast cancers, use of selective serotonin reuptake inhibitors (SSRIs) were not associated with breast cancer risk, according to a recent study.

Researchers applied a 2 sample Mendelian randomization (MR) study that focused on genetic variants assigned randomly at conception. Patients with depression are usually prescribed SSRIs as first line treatment because they increase synaptic 5-hydroxytryptamine (5-HT) concentrations that in turn elevate prolactin concentrations, often related to the proliferation and differentiation of breast cancer cells.

The study used MR analysis with genetic data to investigate the link between antidepressants, specifically SSRIs, and breast cancer risk, as well as the role of prolactin levels. They confirmed associations using statistical methods like inverse variance weighted (IVW) and MR-Egger regression, while also testing for potential biases like heterogeneity and pleiotropy. The analysis satisfied MR's 3 conditions, ensuring reliable results regarding the effects of antidepressants and prolactin levels on breast cancer risk. Single-nucleotide polymorphisms were screened from the GWAS database.

Potential links between increased breast cancer risk and prolactin levels triggered by a rise in 5-HT levels were investigated. Researchers examined this hypothesis by analyzing the relationships between these factors. They specifically focused on single-nucleotide polymorphisms (SNPs) known to influence 5-HT, prolactin, and breast cancer risk. These SNPs were used as instrumental variables to assess the causal effect of prolactin on breast cancer. Additionally, the research explored the established connection between prolactin levels and the use of SSRIs to solidify the potential link in the SSRI-prolactin-breast cancer hypothesis.

Study results found no notable risks linked between antidepressant use, including SSRIs and breast cancer with ER-positive or ER-negative types (all methods P > .05). However, the analysis did find some association between prolactin levels and breast cancer (IVW: OR, 1.058; P = .02) and ER-positive breast cancer (IVW: OR, 1.066; P = .027), with higher prolactin levels increasing ER-positive breast cancer and other forms of breast cancer.

There was no statistically significant association between SSRI use and prolactin levels (all methods P > .05). To further explore the relationship, the researchers reversed the analysis by treating prolactin levels as the exposure and SSRI use as the outcome. Even with this reversed approach, no causal connection emerged between any of the variables examined and prolactin levels (all methods P > .05).

Bidirectional Mendelian randomization suggest a causal relationship, although individual tests weren't statistically significant (P > .05).

Results of the Cochran’s Q test analysis did not find evidence of genetic factors affecting the results because the SNPs were not statistically significant in the analysis. This suggests a low chance of pleiotropy, when a single gene influences multiple traits. Additionally, a leave-one-out analysis confirmed that no single SNP significantly impacted the overall findings.

No significant influence from genes affecting other traits like horizontal pleiotropy were observed. Neither the funnel plot nor the MR-PRESSO test detected any bias or outliers after correction. This strengthens the idea that the SNPs studied only affect the trait of interest.

Study results were limited by the population sample of only European origin and did not display data from other ethnic groups. Additionally, the lack of data on genetic variations associated with antidepressant dosage hinders the potential for more precise treatment recommendations. Future studies should take these limitations into consideration along with health care professionals accounting for breast cancer risk when prescribing antidepressant classes to patients.

The 3-method MR analysis methods found no increased risk of breast cancer from antidepressant medication even though prolactin levels showed some connection to breast cancer, there was no evidence that SSRIs directly caused these changes. Further heterogeneity and sensitivity tests confirmed the strength of these findings.

The authors concluded, “Our study may provide additional information for clinical decision making and the results of the study suggest that health professionals may take less account of breast cancer risk when prescribing antidepressant-like medications to patients.”

Reference

Niu, D., Li, C., Yan, X. et al. The relationship between antidepressants and breast cancer: evidence from Mendelian randomization. Cancer Causes Control. 2024;35:55-62. doi:10.1007/s10552-023-01766-z