Abstract Body: Clozapine is the most effective medication for treatment-resistant schizophrenia, yet its use has long been limited by concerns about rare but serious cardiac complications. Although clozapine-associated myocarditis is a recognized safety concern, with 1,802 reports identified in the FDA Adverse Event Reporting System (FAERS), the broader spectrum of cardiovascular abnormalities associated with this drug has not been fully characterized at the population level.
We hypothesized that clozapine exposure would demonstrate disproportionate pharmacovigilance signals for inflammatory and structural cardiovascular adverse events in the FAERS database.
Adverse event reports were extracted from FAERS from September 26, 1989, to January 1, 2026. A total of 16,320,175 reports were analyzed, including 123,765 involving clozapine exposure. Disproportionality analysis using reporting odds ratios (RORs) with 95% confidence intervals was performed to detect cardiovascular safety signals. Signal strength and robustness were further evaluated using information component (IC) and IC₀₂₅ values derived from a Bayesian confidence propagation neural network.
Clozapine exposure demonstrated strong pharmacovigilance signals across multiple cardiovascular adverse events. The strongest association was observed for myocarditis (ROR 32.393, 95% CI 30.758–34.116; IC 4.68, IC₀₂₅ 4.49), indicating markedly increased reporting relative to background rates and suggesting a prominent inflammatory cardiac signal. Structural abnormalities were also enriched, including left ventricular hypertrophy (ROR 8.761, 95% CI 7.558–10.156; IC 3.02, IC₀₂₅ 2.40) and congestive cardiomyopathy (ROR 6.655, 95% CI 5.763–7.713; IC 2.65, IC₀₂₅ 2.09), consistent with myocardial remodeling and ventricular dysfunction. Electrophysiologic abnormalities were similarly observed, including QT prolongation (ROR 6.010, 95% CI 5.627–6.419; IC 2.52, IC₀₂₅ 2.32) and tachycardia (ROR 5.995, 95% CI 5.763–6.237; IC 2.51, IC₀₂₅ 2.38). Positive IC₀₂₅ values across all events confirmed statistically robust signals.
These findings suggest that clozapine is associated with a spectrum of cardiovascular injury signals, spanning inflammatory myocardial damage, structural remodeling, and electrophysiologic disturbances. These observations reinforce the importance of cardiovascular monitoring during clozapine therapy and highlight the need for further mechanistic studies to elucidate underlying pathways.