Review of: Solmi M et al, Schizophr Bull 2024;50(6):1471–1481 

Study Type: Retrospective case-control study

People with severe mental illness face a shortened life expectancy for various reasons, including higher rates of cardiovascular disease and limited access to medical care. Could the long-term use of certain antipsychotic medications also increase the risk of breast cancer? 

The efficacy of antipsychotics has been linked to dopamine blockade in the striatum. However, simultaneous blockade of dopamine receptors in other brain pathways can lead to hyperprolactinemia, which has been associated with an increased risk of breast cancer in animal studies (Johnston AN et al, Breast Cancer Res 2018;20(1):42). This study explores the potential link between antipsychotic use and breast cancer risk among women with severe mental illness.

Using Swedish national health registers, researchers identified women with schizophrenia, schizoaffective disorder, other nonaffective psychotic disorders, or bipolar disorder (n=132,061). Among these, women diagnosed with breast cancer between 2010 and 2021 (n=1,642) were matched with controls (n=8,173) by age, primary psychiatric diagnosis, and disease duration.

Antipsychotic medications were categorized as prolactin-sparing (clozapine, quetiapine, aripiprazole, brexpiprazole, and cariprazine) or prolactin-raising (all others). Duration of use was classified as <1 year, 1–4 years, or ≥5 years. The analysis considered cumulative doses and adjusted for confounding factors such as medical comorbidities and use of other medications.

Women exposed to prolactin-raising antipsychotics for 1–4 years had a 20% increased risk of developing breast cancer, and those with ≥5 years of exposure had 47% increased risk. Women taking prolactin-sparing antipsychotics did not show an increase in breast cancer risk regardless of the duration of use. The study also found consistent results across cancer types, with prolonged exposure to prolactin-raising antipsychotics associated with an increased risk of both ductal and lobular adenocarcinoma.

CARLAT TAKE
This study strengthens the evidence linking long-term use of prolactin-raising antipsychotics with an increased risk of breast cancer. While it does not establish causality, the dose-response relationship—showing higher risk with longer duration of exposure—adds indirect evidence supporting a possible causal link. Unmeasured confounders, such as obesity and health care utilization patterns, may have inflated the observed risks, which should temper our confidence in the findings.

Nonetheless, these findings highlight the importance of closely monitoring prolactin levels in female patients who are prescribed prolactin-raising antipsychotics, even if the patients are asymptomatic. Be sure to encourage regular breast cancer screenings (eg, mammograms) to detect potential issues early. For women who have additional breast cancer risk factors, such as a family history of breast cancer, obesity, or smoking, consider prescribing prolactin-sparing antipsychotics (eg, clozapine, quetiapine, aripiprazole, brexpiprazole, and cariprazine) as an alternative.