Association of GnRH agonists with depression and suicide/self-injury: a FAERS pharmacovigilance study

Background: The relationship between gonadotropin-releasing hormone agonists (GnRH-as) and depression and suicide/self-injury (DASSI) remains controversial. This study aimed to investigate this potential association using data from the FDA Adverse Event Reporting System (FAERS) database. Methods: Instances of DASSI linked with GnRH-as were identified from FAERS (2004Q1 to 2024Q1). Time-to-onset (TTO) analyses and disproportionality analysis (DPA) were employed to assess onset timing and signal values for adverse events. The influence of concurrent medications on DASSI was evaluated using the Ω shrinkage measure. Results: A total of 5,454 DASSI cases linked to GnRH-as were identified. TTO analyses showed earlier onset of DASSI in females, children (65) (females vs males: 3.5 (0.5-29.5) vs 120.5 (0.5-441.5) days, P < 0.001; children vs elders: 10.5 (0.5-78.5) vs 129.5 (0.5-490.5) days, P < 0.001; adults vs elders: 7.0 (0.5-81.0) vs 129.5 (0.5-490.5) days, P < 0.001). DPA revealed stronger signals for depression and suicide/self-injury in females and oncology patients compared to males and non-oncology patients. Co-medication analysis identified depressive interactions with multiple drug combinations. Conclusions: Although causality cannot be inferred from FAERS data and the results should be interpreted cautiously, we identified some signals of disproportionate reporting of DASSI for certain GnRH-a therapies. These hypothesis-generating findings may raise clinical awareness and inform a risk-informed monitoring framework (e.g., baseline assessment of mood and suicidality, patient/caregiver education on warning signs, and early follow-up) but require confirmation in well-designed epidemiologic studies.