Long-term effects of tricyclic antidepressants on norepinephrine kinetics in humans

The nature of the discrepancy between short-term pharmacokinetic data (hour s) on the one hand and long-term pharmacodynamic effects and the clinical l atency of therapeutic amelioration on the other hand by tricyclic antidepre ssants is still unclear. A relapsed sensibilization of neuronal, immunologi c, and endocrinologic systems by changes in receptor sensitivity has been p roposed. However, the discrepancy may have a strong influence on many aspec ts of antidepressive therapy in humans. The aim of our study was to demonst rate long-term pharmacodynamic effects by single-dose antidepressive treatm ent in humans by measuring heart rate parameters in response to neurochemic al parameters. 25 young healthy probands, divided into three treatment grou ps (amitriptyline, n = 10; clomipramine, n 10; placebo, n = 5), were challe nged by a noradrenaline infusion test at baseline and one and 21 days after a single dose of antidepressant. Heart rate and blood pressure as well as plasma levels of antidepressants and of noradrenaline and adrenaline were m easured in response to noradrenaline infusion test. Noradrenaline infusion rate to reach an increase in blood pressure of RR > 30 mmHg was significant ly decreased for both antidepressants on day 1. The same effect was true fo r the amitriptyline group on day 21. Furthermore, pretreated probands respo nd to antidepressants in a different way when compared to untreated proband s. Like depressed patients under therapy they respond with a dramatic incre ase in sensitivity of the al-adrenergic receptor. We could demonstrate that the long-term pharmacodynamic effects have a strong influence on antidepre ssive therapy. A prolonged pharmacodynamic effect influences further clinic al studies as well as our thinking about adverse drug effects. In clinical studies, washout periods may be to short to overcome the benefits of a prev ious medication. Adverse drug effects are often seen during periods when dr ugs were changed. The negative effect may be due to an additional effect of both medicaments.