Long-term risk of depression after sevoflurane versus propofol anesthesia: a global propensity score-matched cohort study.

Preclinical studies indicate that volatile anesthetics such as sevoflurane induce neuroinflammation and oxidative stress-mechanisms implicated in the pathophysiology of depression-whereas propofol exhibits neuroprotective properties. However, whether these pharmacological differences translate into distinct long-term psychiatric outcomes in humans remains unclear. We conducted a multinational propensity score-matched cohort study using the TriNetX Global Federated Network (2005-2024) to determine whether sevoflurane anesthesia is associated with a higher risk of long-term depression compared with propofol. To isolate the effect of anesthetic choice, we applied a new-user design with a one-year latency washout, excluding patients with preexisting depression or antidepressant use. The primary outcome was new-onset depression diagnosed more than one year after anesthesia. The matched cohort included 37,936 patients balanced across more than 100 covariates. Sevoflurane exposure was associated with a higher risk of new-onset depression compared with propofol (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.41-1.61). The association remained consistent across severity strata (aHR, 1.51 for moderate-to-severe depression) and surgical subgroups. Notably, we observed a graded dose-response relationship, where repeated sevoflurane exposures conferred progressively higher risk (aHR, 1.75 for ≥2 exposures), consistent with a biologic gradient. In this large multinational cohort, sevoflurane use was associated with a higher long-term risk of incident depression compared with propofol. These findings align with preclinical evidence of anesthetic-related neuroinflammatory mechanisms and indicate that anesthetic selection may have implications for long-term neuropsychiatric risk. Further mechanistic and prospective studies are warranted.