Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients

Rationale: Previous studies showed that adjunctive paroxetine increases tri cyclic antidepressant (TCA) serum levels by inhibiting cytochrome P4502D6. This effect has, however, been examined only in experimental studies using low doses of TCAs in healthy volunteers. Objective: The present study inves tigated TCA serum level changes and side-effects after the addition of paro xetine in depressed patients treated with doses customarily used for inpati ents. Method: 14 patients who had a moderate or severe depressive episode a ccording to ICD-IO and who had not sufficiently responded (less than or equ al to 25% reduction of the Hamilton depression scale) to 3-week monotherapy with amitriptyline (n=9) or imipramine (n=5) with daily doses between 125 and 200 mg/day, received 20 mg/day paroxetine additionally under steady sta te conditions. Results: After 2 weeks the serum levels of the metabolites n ortriptyline (from 88+/-49 ng/ml to 176+/-57 ng/ml) and desipramine (from 1 52+/-78 ng/ml to 338+/-104 ng/ml) had risen to a significantly greater exte nt than those of the parent compounds amitriptyline (123+/-50 ng/ml to 195/-128 ng/ml) and imipramine (from 75+/-36 ng/ml to 98+/-51 ng/ml). It is no teworthy that, with the exception of one case of incipient delirium, the co mbination therapy was well tolerated despite high TCA serum level rises. Co nclusion: The higher increase of the metabolites as compared with the paren t compounds can be explained by a paroxetine-induced inhibition of the live r enzyme cytochrome P4502D6, which catalyses the second step of the TCA met abolism, i.e. the hydroxylation of the metabolites. Blood levels should be meticulously monitored, if TCAs are combined with paroxetine.