ELECTROCARDIOGRAPHIC EFFECTS OF FLUOXETINE AND DOXEPIN IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER

Cardiovascular adverse effects are amongst the most serious observed w ith antidepressant drugs and are often due to effects on cardiac condu ction and refractoriness. However, such electrophysiologic effects may not be evident when using conventional electrocardiographic measures. Forty patients with major depressive disorder (according to DSM-III-R criteria) were enrolled in a 6-week double-blind parallel group study of fluoxetine (N = 20) or doxepin (N = 20). Cardiac conduction (QRS d uration) and repolarization (corrected QT interval, QT(c)), were measu red using signal-averaged electrocardiograms and 12-lead electrocardio gram at baseline and after 2, 4, and 6 weeks of treatment. Patients ta king doxepin (mean daily dosage at 6 weeks 169 +/- 42 mg) were similar to those taking fluoxetine (37 +/- 18 mg) for demographic variables a nd improvement in depression scores but volunteered more side effects (p = 0.011), especially dry mouth (p < 0.001) and dizziness/lightheade dness (p = 0.005). After 6 weeks, doxepin increased heart rate (69 +/- 12 to 81 +/- 13 beats per minute; p = 0.0003) and prolonged QT(c) (fr om 417 +/- 36 to 439 +/- 28 msec;p < 0.03); overall QRS duration was n ot prolonged but was correlated with serum doxepin concentrations (r = 0.78, p < 0.0001). Fluoxetine had no effect on QT(c) (428 +/- 24 msec at baseline vs. 430 +/- 24 msec at 6 weeks) or QRS duration (97 +/- 1 2 msec at baseline vs. 94 +/- 12 msec at 6 weeks). The standard 12-lea d electrocardiogram showed no significant change in QRS or QT(c) for e ither drug. Using a sensitive measure of electrocardiographic effects, doxepin prolongs repolarization and may slow cardiac conduction. Fluo xetine has no measurable electrocardiographic effects, which suggests an increased safety margin for cardiac adverse effects. The ability of the signal-averaged electrocardiogram to resolve small changes in the electrocardiogram is useful in the assessment of drugs with subtle el ectrophysiologic effects.