Hemodynamic effects of duloxetine at supratherapeutic dosages

Background/Aims Hemodynamic effects of duloxetine, a potent dual inhibitor of serotonin and norepinephrine uptake, were evaluated in a study designed to definitively establish the absence of QT prolongation at supratherapeutic exposures. Methods Vital signs were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy women aged 19–74 years. Duloxetine dosages escalated from 60 mg BID to 200 mg BID. Supine and postural vital signs were monitored at baseline, prior to morning dosing, and at steady state. Results Initiation of duloxetine at 60 mg BID caused a 5–7 mmHg increase in supine systolic and diastolic blood pressures that remained stable despite continued dose-escalation. Supine heart rate also increased upon dosing with duloxetine 60 mg BID, but the increase was more gradual and dose-dependent, reaching 10–12 bpm above baseline levels by the end of the 200-mg BID dosing period. Dose-dependent postural changes occurred with duloxetine, which increased throughout dose escalation. Of 11 subjects who met predefined criteria for outliers, only 5 had associated symptoms. All vital signs returned to normal by 1–2 days after stopping the drug. Conclusions Supratherapeutic duloxetine exposures produce minor and generally asymptomatic changes in supine and postural vital signs. Some prehypertensive subjects may become hypertensive upon initial dosing with duloxetine, but this can be predicted from predose values. Clinical Pharmacology & Therapeutics (2005) 77, P27–P27; doi: 10.1016/j.clpt.2004.11.104