Antipsychotic use tied to >30 percent increased risk of breast cancer

Antipsychotic use is moderately associated with breast cancer, with >30 percent increased observed risk, possibly mediated by prolactin-elevating properties of certain medications, researchers from the University of Hong Kong (HKU) have reported.

“Elevated breast cancer incidence has been consistently reported in patients with schizophrenia and bipolar disorder, and antipsychotic use is speculated to potentially explain at least part of the increased risk,” said the researchers. “Possible mechanisms include antipsychotic-induced hyperprolactinaemia, antipsychotic-mediated weight gain, and poorer lifestyle among antipsychotic users. With complex mechanisms and multiple interacting risk factors, evidence for the said association remains inconclusive.”

To determine this hypothesized association, the researchers have conducted the world’s first systematic review and meta-analysis of observational studies involving over two million individuals. A total of nine observational studies, including five cohort and four case-control studies, were eventually included in the review (n=2,031,380), and seven studies were included for meta-analysis (n=1,557,013) after screening for eligibility. All nine studies defined the outcome of interest as the first-time diagnosis of breast cancer. [Epidemiol Psychiatr Sci 2022;31:e61]

“All these studies were rated as high quality [7–9 out of 10 stars] according to the Newcastle-Ottawa Scale, a standardized study quality assessment instrument,” noted the researchers. Six studies reported a significant association between antipsychotic use and breast cancer.

Results of pool estimates suggested a moderate association of antipsychotic use with breast cancer, with >30 percent increased risk observed (hazard ratio [HR] generated from four individual cohort studies, 1.39; 95 percent confidence interval [CI], 1.11–1.73; I²=75 percent; p=0.004), although the pooled odds ratio (OR) did not reach statistical significance (OR generated from three individual case-control studies, 1.37; 95 percent CI, 0.90–2.09; I²=93 percent; p=0.15).

Notably, three studies demonstrated that a further extent of exposure to antipsychotics (eg, longer duration of use) was associated with a higher risk of breast cancer, especially for antipsychotics with prolactin-elevating properties. “This is supported by a widely adopted working hypothesis of the hyperprolactinaemia-inducing properties of antipsychotics,” explained the researchers. As dopamine receptor antagonists, antipsychotics prohibit dopamine from binding to dopamine D2 receptors, thereby increasing prolactin secretion and eventually leading to an increased risk of breast cancer.

Compared with typical antipsychotics, atypical antipsychotics were reported to cause less hyperprolactinaemia, which could be explained by their lower affinity for and occupancy of the D2 receptors. [Neuropsychopharmacology 2005;30:765-774; Ann Clin Psychiatry 2002;14:163-173]

This study on the potentially elevated risk of breast cancer adds to the current knowledge of adverse events associated with antipsychotic use, such as stroke and myocardial infarction. [BMC Psychiatry 2019;19:189; Br J Clin Pharmacol 2016;82:624-632]

“With the increasingly prevalent use of antipsychotics worldwide, including off-label use, we believe comprehensive clinical assessment should be performed for patients based on the overall safety profile of antipsychotics before prescription,” commented Dr Francisco Lai of the Department of Pharmacy at HKU.

“Based on the findings of this study, antipsychotics with known prolactin-elevating properties should preferably be avoided in patients with breast cancer risk factors,” suggested the researchers. “Appropriate counselling is warranted before prescribing prolactin-elevating antipsychotics, and prolactin level monitoring may be considered. Prompt management of antipsychotic-induced hyperprolactinaemia is essential.”