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

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.

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.

A total of 5,454 DASSI cases linked to GnRH-as were identified. TTO analyses showed earlier onset of DASSI in females, children (<18), and adults (18-65) compared to males and elders (>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.

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.