EFFECTS OF TRAZODONE AND FLUOXETINE IN THE TREATMENT OF MAJOR DEPRESSION - THERAPEUTIC PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTIONS THROUGH FORMATION OF META-CHLOROPHENYLPIPERAZINE

It has been suggested that (1) the clinical efficacy of the heterocycl ic antidepressant trazodone in depression may, in part, be attributed to its metabolite meta-chlorophenylpiperazine (mCPP); and (2) the enha ncement of the efficacy of trazodone by the addition of fluoxetine, a selective serotonin reuptake inhibitor, may, in part, be ascribed to f luoxetine-induced plasma concentrations of trazodone. After a washout period of 10 days, 27 inpatients with major depression were treated wi th trazodone 100 mg/day (orally). One week later (T0), fluoxetine 20 m g/day, placebo, or pindolol 7.5 mg/day was added. Plasma concentration s of mCPP and trazodone were determined at T0 and 2 and 4 weeks later. Although placebo and pinodolol had no significant effect on the plasm a concentrations of mCPP and trazodone, there was a significant increa se of the concentrations of these compounds associated with the combin ation of trazodone + fluoxetine. The results suggest that fluoxetine-i nduced increases in plasma mCPP and trazodone concentrations contribut e to the clinical efficacy of the combination of fluoxetine + trazodon e. It is suggested that desensitization of 5-HT2C receptor function by mCPP as well as fluoxetine may contribute to the antidepressant effec ts of this combination.