Association of Second-generation Antiandrogens with Depression among Patients with Prostate Cancer

Importance: Previous studies have shown a consistent association between hormone therapy (HT), such as androgen deprivation therapy, to treat prostate cancer and depression risk. However, the association between second-generation antiandrogens (AAs) and depression is unknown. Objective: To test the a priori hypothesis that second-generation AAs are associated with an increased risk of depression, including compared with traditional forms of HT. Design, Setting, and Participants: This retrospective cohort study analyzed patients aged 66 years and older who were diagnosed with prostate cancer without a second cancer in 12 months from January 2011 to December 2015. Patients with continuous Medicare Parts A, B, and D coverage were included. Individuals who received any form of HT prior to prostate cancer diagnosis and those previously diagnosed with depression were excluded. Data were collected from the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare linked databases. Data were analyzed from February to May 2021. Exposures: The following treatment groups were compared: (1) no HT group, (2) traditional HT group (HT without second-generation AA exposure), and (3) second-generation AA group. Main Outcomes and Measures: Risk of depression in the second-generation AA group compared with the no HT and traditional HT groups, determined prior to data collection, stratified by diagnosis stage. Results: Of 210804 patients diagnosed with prostate cancer during the study window, 30069 men (11484 [38%] aged 66-70 years; 22594 [75%] White) who met inclusion criteria were identified. Overall, 17710 (59%) received no HT, 11311 (38%) received traditional HT only, and 1048 (3%) received a second-generation AA. Those receiving a second-generation AA were more likely to be older (aged ≥81 years: second-generation AA group, 246 [24%]; traditional HT group, 1997 [18%]; no HT group, 1173 [7%]) and present with advanced disease (eg, distant disease: second-generation AA group, 562 [24%]; traditional HT group, 876 [8%]; no HT group, 129 [0.7%]). Multivariable Cox proportional hazards analysis showed that the second-generation AA group had an increased risk of depression compared with the no HT group (hazard ratio [HR], 2.15; 95% CI, 1.79-2.59; P <.001) and the traditional HT group (HR, 2.26; 95% CI, 1.88-2.73; P <.001), including specifically among those with metastatic disease at diagnosis (HR, 2.40; 95% CI, 1.38-4.15; P =.002). Conclusions and Relevance: In this cohort study, patients with prostate cancer who received a second-generation AA had a large and clinically significant increased risk of depression compared with patients who received traditional HT alone or no HT, including when limiting our analysis to individuals with metastatic disease at diagnosis.