Effect of 3 Single Doses of Trazodone on QTc Interval in Healthy Subjects

Abstract

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone-matched placebo in 5 periods separated by 7-day washouts, according to a double-blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration-QTc relationship assessed on placebo-adjusted change from baseline for Fridericia-corrected QT (QTcF) was the primary end point. QTcF values of 4.5, 12.3, and 19.8 ms for the 20-, 60-, and 140-mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60-and the 140-mg doses. Time-matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin-validated ECG trial, trazodone had a modest, dose-dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20-mg dose and an effect exceeding the values set in E14 guideline with the 60-and 140-mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure.

Psychotherapeutic drug‐induced life‐threatening arrhythmias: A retrospective analysis using the Japanese adverse drug event report database

“…Trazodone, a serotonin antagonist and reuptake inhibitor, is used only in Japan and Belgium and is a prescribed antidepressant as well as hypnotic drug in Japan. Although trazodone did not significantly prolong QTc in a thorough QT/QTc study, 15 a retrospective case analysis of data from a poison center found that trazodone was associated with QT prolongation (QTc >500 ms) 16 . There have also been case reports of QT prolongation associated with trazodone overdose 17–19 .…”

The effects of orally administered trazodone on ambulation and recumbency in healthy horses

“…To determine whether trazodone caused QT interval prolongation as described in humans, 8 QT intervals were measured 30 minutes before the 1st trazodone dose and 1 hour after the 4th trazodone dose. The QT interval was measured in milliseconds from the start of the Q wave to the end of the T wave where it intersects baseline, as previously described 9 .…”

Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia

“…Studies looking at safety in large prescription datasets show trazodone to be similar to atypical antipsychotics and benzodiazepines in terms of fall and fracture risk in demented patients, but with a lower overall mortality risk [61,62]. The largest study of cardiac side effects of trazodone in older people found no effect on QTc and minimal effect on pulse or other ECG parameters [63,64]. Similarly, trazodone may be less likely to result in hyponatraemia than other antidepressants [65].…”