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

Rationale: Previous studies showed that adjunctive paroxetine increases tricyclic 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 investigated TCA serum level changes and side-effects after the addition of paroxetine in depressed patients treated with doses customarily used for inpatients. Method: 14 patients who had a moderate or severe depressive episode according to ICD-10 and who had not sufficiently responded (≤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 state conditions. Results: After 2 weeks the serum levels of the metabolites nortriptyline (from 88±49 ng/ml to 176±57 ng/ml) and desipramine (from 152±78 ng/ml to 338±104 ng/ml) had risen to a significantly greater extent 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 noteworthy that, with the exception of one case of incipient delirium, the combination therapy was well tolerated despite high TCA serum level rises. Conclusion: The higher increase of the metabolites as compared with the parent compounds can be explained by a paroxetine-induced inhibition of the liver enzyme cytochrome P4502D6, which catalyses the second step of the TCA metabolism, i.e. the hydroxylation of the metabolites. Blood levels should be meticulously monitored, if TCAs are combined with paroxetine.