To assess the potential benefit of adding antidepressants that inhibit acid sphingomyelinase (ASM) to standard-of-care therapy for treatment of glioblastoma (GBM).

GBM is the most common malignant primary brain tumor in adults and remains difficult to treat. Though still under investigation, ASM has been implicated in GBM lipid raft formation, which facilitates cancer signaling. We sought to verify if, and if so what kinds of ASM inhibitors (ASMis) improve outcomes in GBM. 

We conducted a retrospective study of GBM patients treated between 2015 and 2024 at one academic center. ASMi impact on overall survival (OS) and progression-free survival (PFS) was assessed using Kaplan-Meier analysis and Cox proportional hazards models adjusting for age, sex, tumor location, use of tumor-treating fields (TTFs), and MGMT promoter methylation status. Propensity score matching was performed to account for baseline imbalances.

ASMi use alone was not associated with a statistically significant OS benefit (HR = 0.81, 95% CI 0.55-1.2, p = 0.26). Stratifying by ASMi revealed fluoxetine as the only antidepressant that significantly improved OS (HR = 0.36, 95% CI 0.15-0.9, p = 0.03). In a fluoxetine-only multivariate analysis (n = 17 vs. 186 controls), the survival benefit remained significant (HR = 0.38, 95% CI 0.15–94, p = 0.04). This effect persisted in the propensity-matched cohort (HR = 0.20, 95% CI 0.05–0.78, p = 0.02). Age and unmethylated MGMT promoter status were independently associated with decreased survival.

Fluoxetine was associated with increased survival in GBM patients, whereas other antidepressant ASMis and ASMi use overall was not. These findings seem to support utilization of fluoxetine for adjunct benefits in GBM treatment and justify further investigation.