Comparative animal studies on cardiovascular toxicity of tri- and tetracyclic antidepressants and citalopram; relation to drug plasma levels

Abstract

The aim of the present study was to compare cardiovascular and/or cardiotoxic effects of eight anti-depressants (imipramine, chlorimipramine, amitriptyline, nortriptyline , doxepin, maprotiline, mianserin and citalopram) in anaesthetized cats after oral dosing and in conscious rabbits after intravenous infusion. In the cats drug plasma levels were determined as well. When estimated from ECG recordings, citalopram and chlorimipramine in particular, but also mianserin, appeared less cardiotoxic than the other drugs tested. The cardiovascular effects seen in the cats were with few exceptions identical for all the drugs tested but not seen at the same dose (concentration). Safety margins were defined as minimal doses or plasma levels when ECG changes (conduction or rhythm) or cardiovascular effects (+/- 10% change of initial value in a series of parameters) occurred in experimental animals divided by maximal therapeutic dose or mean plasma levels in patients. From comparisons of the safety margins it is concluded that except for citalopram and mianserin (safety margins 80 and 18 respectively in cats and greater than 15 in rabbits) all the other drugs tested (safety margins less than or equal to 9) have a cardiotoxic potential. The probability that cardiovascular side effects may occur is less pronounced for citalopram (safety margins 10-32) than for all the other drugs tested (safety margins ranging from 0.1 to less than 5).