As dopamine antagonists, antipsychotics are associated with increased prolactin levels by inhibiting the binding of dopamine-to-dopamine D2 receptors. Although most second-generation antipsychotics do not bind as tightly to D2-receptors as conventional antipsychotics, atypical antipsychotics, such as risperidone and paliperidone, are associated with increased prolactin levels. Elevated prolactin levels have been linked to an increased risk for the development of breast cancer (BC). However, the role of antipsychotics in BC development remains inconclusive.
Investigators conducted a systematic review and meta-analysis of observational studies identified in PubMed, Embase, and Web of Science to determine the association of antipsychotic use with BC. Cohort and case-controlled observational studies that investigated and quantified the association of antipsychotic use in patients aged 16 years and older with BC were included in the analyses. Exclusion criteria included non-English published studies, noncohort or noncase-controlled trials, BC development prior to antipsychotic exposure, and studies that did not compare antipsychotic use to nonuse.
Nine studies representing 2,031,380 women were included for qualitative synthesis and quality assessment in the systematic review. Seven studies (n = 1,557,013) were included in the meta-analysis and provided a pooled estimate of the association in question.
Of the nine studies, five were cohort studies and four were case-controlled studies. Studies were of moderate to high quality. Various methods were used to identify the outcome of interest (i.e., first-time diagnosis of BC, including International Classification of Diseases codes, histological or pathologic verification, or autopsy). Confounders considered included those involving clinical history (e.g., age, use of drugs such as lithium oral contraceptives, or hormone replacement therapy which can affect BC risk), lifestyle (e.g., obesity, smoking, BMI, and substance misuse), and socioeconomic factors (e.g., occupation, income, education status, a summarized Townsend score—which is a measure of material deprivation within a population).
Among the included clinical trials, exposure duration was examined in three of the studies and ranged from having received at least two prescriptions for an antipsychotic to prior exposure until 1 year before a BC diagnosis. Stratification to further define the extent of exposure was conducted and assessed cumulative doses, average yearly dosages, prescription count, duration, and prolactin-elevating propensity. Six of the nine studies (five that stratified participants and one that did not) reported significant associations between the use of antipsychotics and BC.
Among the specific findings, long-term use (i.e., having a cumulative dose of >10,000 mg of olanzapine equivalents) was found to have a small association with BC development. There was a 74% increase in the odds of developing BC following the use of an antipsychotic for more than 5 years (odds ratio [OR] = 1.74; 95% CI, 1.38-2.21). Another study found a hazard ratio (HR) of 2.37 (95% CI, 1.25-4.47) when antipsychotics were used for at least 6 years. A dose-response relationship was not found for the atypical antipsychotic subgroup. Paradoxically, there was an association between lower exposure and increased BC risk with mean antipsychotic exposure of <28 g/year associated with a HR of 2.49 (95% CI, 1.69-3.66) and a nonsignificant association for exposures of >245 g/year.
Exposure to antipsychotics with prolactin-elevating properties showed an increased risk of BC occurrence. Antipsychotics with both medium and high prolactin-elevating properties were associated with a significant 1.56-fold increased odds of BC development (OR = 1.56; 95% CI, 1.27-1.92) among those exposed for at least 5 years. Among the antipsychotics with the highest prolactin-elevating potential, i.e., risperidone, paliperidone, and amisulpride, risk of BC development was increased almost twofold (HR = 1.96; 95% CI, 1.36-2.82).
The pooled estimates of HRs from cohort studies showed a 1.39-fold increased BC risk, but ORs for case-controlled studies were not statistically significant. The authors concluded that there was a moderate association between BC risk and antipsychotic use, although they caution that their findings were based on observational studies.
As patient advocates, pharmacists should help to identify those women most at risk for BC development or recurrence (i.e., past history or family history of BC), educate fellow health professionals about the potential risk of BC associated with the use of these psychotropics, and encourage eligible women to get yearly screening mammograms.
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