Paroxetine potentiates the central nervous system side effects of perphenazine: Contribution of cytochrome P4502D6 inhibition in vivo

Background: Paroxetine is a frequently used antidepressant and a potent inhibitor of the CYP2D6 isozyme in vitro (inhibition constant [K-i] = 0.15 mu mol/L). Most classic antipsychotic agents such as perphenazine are metabolized by the CYP2D6 isozyme and are often coadministered with antidepressant agents, This study assessed the extent of changes in CYP2D6 isozyme activity in vivo after pretreatment with paroxetine and its consequences on perphenazine kinetics and central nervous system effects. Methods: Eight extensive metabolizers for CYP2D6 were administered a single dose of perphenazine (0.11 mg/kg orally) or placebo following a randomized double-blind design, Perphenazine plasma concentrations and effects were assessed for a period of 8 hours. Subsequently, subjects were treated with a standard therapeutic dose of paroxetine (20 mg/day orally) for 10 days and test sessions with perphenazine and placebo were repeated. Results: Paroxetine treatment resulted in a twofold to 21-fold decrease in CYP2D6 activity (p < 0.001), After pretreatment with paroxetine, perphenazine peak plasma concentrations increased twofold to 13-fold (p < 0.01). This was associated with a significant increase in central nervous system side effects of perphenazine, including oversedation, extrapyramidal symptoms, and impairment of psychomotor performance and memory (p < 0.05). Conclusion: Coadministration of perphenazine after pretreatment with a standard therapeutic dose of paroxetine increased the plasma concentration and central nervous system side effects of perphenazine, primarily as a result of inhibition of the CYP2D6 isozyme, In patients who are at steady state with paroxetine, a reduction of perphenazine dose may be required to prevent central nervous system side effects.