Frontiers in pharmacology · 2026
SSRIs-induced liver injury adverse events: a data-based retrospective study and investigation of potential toxicological mechanisms.
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Wu Jianru, Ding Chufeng, Ma Yicong, Huang Qiaoying, Wu Qimin, Zhang Zhenpo, Liang Yankun, Zheng Jingping, Wu Wenyu, Liu Xiaoyu, Wei Fenfang, Wang Qian, Su Ling
Аннотация
AIM: To systematically evaluate safety signals of selective serotonin reuptake inhibitors (SSRIs) associated with drug-induced liver injury (DILI) using the FAERS database, and to explore potential toxicological mechanisms through drug-gene interaction network analysis.
METHODS: Adverse event data for six SSRIs (2013-2023) were extracted from FAERS. Descriptive analysis and disproportionality signal detection (ROR, BCPNN) were performed. Time to DILI onset and factors influencing mortality were analyzed. Network pharmacology explored drug-gene interactions. Due to the absence of individual-level clinical data in FAERS, we could not apply the updated RUCAM, the gold standard for DILI causality assessment.
RESULTS: DILI reports were most frequent in patients aged 18-64 years and in females. Sertraline had the highest number of reports; fluvoxamine the fewest. Common signals across SSRIs included hepatocellular injury and necrosis. Fluoxetine showed unique signals for hepatic steatosis, paroxetine for chronic active hepatitis, and sertraline for severe liver failure (e.g., primary biliary cholangitis, hemorrhagic hepatic cyst). Median time to onset was within the first month of treatment. Age 18-44 years (OR = 3.03, 95% CI: 1.12-8.18) and low body weight ≤60 kg (OR = 0.45, 95% CI: 0.18-1.14) were significant predictors of mortality. Network analysis suggested shared mechanisms (e.g., CYP450 dysfunction, apoptosis dysregulation) and drug-specific pathways (e.g., PI3K-Akt for sertraline, IL-17 signaling for fluoxetine/fluvoxamine).
CONCLUSION: DILI safety signals for SSRIs are most frequent within the first month of treatment, particularly in female patients. Considerable variability in hepatotoxicity profiles among SSRIs supports drug-specific monitoring. These hypothesis-generating findings provide a basis for personalized risk assessment and require confirmation in prospective studies.
METHODS: Adverse event data for six SSRIs (2013-2023) were extracted from FAERS. Descriptive analysis and disproportionality signal detection (ROR, BCPNN) were performed. Time to DILI onset and factors influencing mortality were analyzed. Network pharmacology explored drug-gene interactions. Due to the absence of individual-level clinical data in FAERS, we could not apply the updated RUCAM, the gold standard for DILI causality assessment.
RESULTS: DILI reports were most frequent in patients aged 18-64 years and in females. Sertraline had the highest number of reports; fluvoxamine the fewest. Common signals across SSRIs included hepatocellular injury and necrosis. Fluoxetine showed unique signals for hepatic steatosis, paroxetine for chronic active hepatitis, and sertraline for severe liver failure (e.g., primary biliary cholangitis, hemorrhagic hepatic cyst). Median time to onset was within the first month of treatment. Age 18-44 years (OR = 3.03, 95% CI: 1.12-8.18) and low body weight ≤60 kg (OR = 0.45, 95% CI: 0.18-1.14) were significant predictors of mortality. Network analysis suggested shared mechanisms (e.g., CYP450 dysfunction, apoptosis dysregulation) and drug-specific pathways (e.g., PI3K-Akt for sertraline, IL-17 signaling for fluoxetine/fluvoxamine).
CONCLUSION: DILI safety signals for SSRIs are most frequent within the first month of treatment, particularly in female patients. Considerable variability in hepatotoxicity profiles among SSRIs supports drug-specific monitoring. These hypothesis-generating findings provide a basis for personalized risk assessment and require confirmation in prospective studies.