Sex-related differences in nortriptyline-induced side-effects among depressed patients

1. Men and women may differ in their pharmacokinetic responses to tricyclic antidepressants (TCAs), in a number of autonomic indices, and in various a drenergic receptor mediated responses. Emerging evidence also suggests that women may have a lower rate of serotonin synthesis in brain and a greater sensitivity to the depressant effects of tryptophan depletion, relative to men. However, sex-related differences in TCA-induced side-effects, includin g increases in heart rate (HR), dry mouth, constipation, and difficulty uri nating, has not been systematically investigated. 2. The authors examined potential sex-related differences in the pattern of side-effects during treatment with nortriptyline (NT), a TCA that is still widely used. Seventy-eight healthy outpatients who met Research Diagnostic Criteria and DSM-III-R criteria for major depression participated in a dou ble-blind, randomized parallel trial of NT versus placebo. 3. Each subject was acutely challenged with either placebo or 50 mg NT prio r to and after a 6-week treatment with NT. NT doses were adjusted weekly to maintain therapeutic plasma levels. Patients were assessed at multiple tim e points to detect the presence of NT-induced side-effects. 4. The initial, single (50 mg) dose of NT significantly increased supine HR . Six-week treatment with NT was found to significantly increase supine and sitting HRs, irrespective of sex. In rechallenge with the single NT dose, there were no significant effects on HR. 5. When sex-related differences were examined, HR increases were greater in men than women during weeks 4 through 6 of the NT treatment, although no s ex-related differences were present in plasma NT levels or metabolites. In addition, there was a significant NT to placebo difference in self-rated dr y mouth for women during all 6-weeks of treatment, whereas men showed a sig nificant NT-placebo difference during weeks 3 and 5. 6. The results suggest the presence of sex-related differences in elevated supine HR response during the course of 6-week NT treatment. Depressed men may be more susceptible to NT-induced increases in supine HR than women.