An open‐label, single‐arm, dose‐escalating concentration–QT study to investigate the cardiac effects and safety of paroxetine in healthy adults

Abstract Aims Paroxetine is a selective serotonin reuptake inhibitor (SSRI), approved for treatment of major depressive disorder and anxiety disorders. Some SSRIs are known to prolong the QT interval; however, clinical evidence to establish a lack of association between paroxetine and corrected QT interval (QTc) prolongation is limited. Therefore, this study aimed to characterize the relationship between paroxetine concentration and QT/QTc interval following therapeutic doses in healthy individuals. Methods This open‐label, single‐arm, dose‐escalating concentration‐QT study (NCT06065735) was performed in healthy adults (18–65 years) without a history of cardiac disease or pre‐diagnosed mood disorder. Eligible individuals (n = 38) received paroxetine 20 to 60 mg QD for 1 week per dose level. Paroxetine plasma concentrations and electrocardiogram recordings were monitored over a 12 h period on Days 1 (baseline), 7 (20 mg), 14 (40 mg) and 21 (60 mg). Results Mean change from baseline in QTcF (ΔQTcF) fluctuated between −7.1 and +4.7 ms. However, diurnal variation was also observed without treatment. A linear regression model showed no clinically significant effect of paroxetine concentrations on ΔQTcF, with a weak slope of 0.0108 ms/ng/mL (90% CI: 0.01, 0.03) and maximum ΔQTcF of +0.42 ms (90% CI: −2.68, 3.52) at 60 mg QD, corresponding to a Cmax of 221.4 (95%CI: 179.6–272.8) ng/mL. Similarly, paroxetine did not affect the mean change in PR or QRS interval, or heart rate relative to baseline. Conclusions Paroxetine does not prolong QTc interval in healthy individuals to any clinically meaningful extent at therapeutically relevant doses. This study supports the favourable cardiac safety profile of paroxetine.