Comparison of the Effect of Amitriptyline in Standard and Sustained-Release Formulations on Cardiac Systolic Time Intervals

Eight healthy male volunteers were given single doses of 75 mg standard and sustained-release amitriptyline in a double-blind, crossover trial. Systolic time intervals (STI) were measured hourly on drug and base-line days. Plasma amitriptyline and nortriptyline were measured hourly on drug days. To correct for diurnal variations, STI values on drug days were compared with values of base-line days at the same hour. Both formulations of amitriptyline produced initial decreases in heart rate (followed by a return to normal values) and a significant decrease in ventricular electrical systole (QTc), which began before plasma amitriptyline could be detected. One of the eight volunteers showed T wave depression following amitriptyline. The preejection period (PEPc) increased significantly in three of the eight volunteers (max 19%), and this change was due to an increase in true isovolumetric contraction time (TICT). The left ventricular ejection time (LVETc) decreased significantly in all volunteers (5%, p less than 0.001), the change being greater after sustained-release amitriptyline. Standard amitriptyline produced larger changes than sustained-release amitriptyline in QTc and PEPc. The overall increase in the PEP/LVET ratio, indicating an impairment of cardiac function, was twice as large after standard than after sustained-release amitriptyline (38% and 16%, respectively). The possible mechanisms of cardiac effects of amitriptyline are discussed. Our findings indicate that a sustained-release preparation may be safer than a standard preparation of amitriptyline, particularly if there is a risk of cardiac complications.