It has been suggested that (1) the clinical efficacy of the heterocyclic antidepressant trazodone in depression may, in part, be attributed to its metabolite meta-chlorophenylpiperazine (mCPP); and (2) the enhancement of the efficacy of trazodone by the addition of fluoxetine, a selective serotonin reuptake inhibitor, may, in part, be ascribed to fluoxetine-induced plasma concentrations of trazodone. After a washout period of 10 days, 27 inpatients with major depression were treated with trazodone 100 mg/day (orally). One week later (T0), fluoxetine 20 mg/day, placebo, or pindolol 7.5 mg/day was added. Plasma concentrations of mCPP and trazodone were determined at T0 and 2 and 4 weeks later. Although placebo and pindolol had no significant effect on the plasma concentrations of mCPP and trazodone, there was a significant increase of the concentrations of these compounds associated with the combination of trazodone + fluoxetine. The results suggest that fluoxetine-induced increases in plasma mCPP and trazodone concentrations contribute to the clinical efficacy of the combination of fluoxetine + trazodone. It is suggested that desensitization of 5-HT2C receptor function by mCPP as well as fluoxetine may contribute to the antidepressant effects of this combination. (J Clin Psychopharmacol 1997;17:358-364).
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