Effect of 3 Different Doses of Trazodone on QT Interval Length
Patients diagnosed with depression often also suffer from cardiovascular diseases, including heart failure. Given the increased risk of death in such comorbid patients, the safety and efficacy of the antidepressant must be considered when choosing one.
Introduction
Trazodone is characterized by a multifunctional mechanism of action and unique therapeutic flexibility. It is indicated for the treatment of major depressive disorder with or without anxiety. It acts against a wide range of depression comorbidities and in non-depressive indications such as anxiety, insomnia, dementia, Alzheimer's disease, substance abuse, schizophrenia, bulimia, and fibromyalgia.
Its cardiovascular safety profile appears favorable, but in vitro it shows strong inhibition of potassium channels, which correlates with the prolongation of the QT/QTc interval. Therefore, the aim of the Swiss Phase I randomized double-blind crossover study was to evaluate the effect of 3 different single doses of trazodone on the QT interval in healthy volunteers.
Study Methodology
The study included 17 participants. Trazodone was administered as a 6% oral solution of trazodone hydrochloride. Volunteers received doses of 20, 60, and 140 mg of trazodone, placebo as a negative control, and 400 mg of moxifloxacin as a positive control, each after a 7-day washout phase. Trazodone and placebo were administered double-blind, and moxifloxacin without blinding.
The primary objective was to evaluate the relationship between plasma concentration of trazodone and changes in the QT interval according to Fridericia's formula (QTcF) after accounting for changes in the QT interval that occurred with placebo administration. ECG was recorded during the 24 hours following the dose and compared with the pre-dose recording.
Results
The measured maximum concentration (Cmax) of trazodone was 413.4 ng/ml at a dose of 20 mg, 1269.0 ng/ml at a dose of 60 mg, and 2083.5 ng/ml at a dose of 140 mg. At the specified Cmax of trazodone, the ΔΔQTcF values of 4.5 ms, 12.3 ms, and 19.8 ms were found. No QTc prolongation occurred at the 20 mg dose. The upper limit of the 90% confidence interval exceeded 10 ms (as specified in guideline E14) at doses of 60 and 140 mg. Considering the administration of trazodone on an empty stomach, this represents the evaluation of the effect that could occur in the worst-case scenario. No significant influence of trazodone on heart rate or the length of PR and QRS intervals or clinically significant new morphological changes was found.
Conclusion
This moxifloxacin and placebo-controlled study conducted in healthy volunteers demonstrated that trazodone in 3 different single doses has a mild, dose-dependent effect on cardiac repolarization that does not pose a clinical risk for ventricular proarrhythmia. Caution is recommended only when co-administering drugs that prolong QT or increase trazodone exposure.
(lkt)
Sources: Tellone V., Rosignoli M. T., Picollo R. et al. Effect of 3 single doses of trazodone on QTc interval in healthy subjects. J Clin Pharmacol 2020 Jun 2, doi: 10.1002/jcph.1640 [Epub ahead of print].
Did you like this article? Would you like to comment on it? Write to us. We are interested in your opinion. We will not publish it, but we will gladly answer you.
