Plasma concentrations of risperidone and 9-hydroxyrisperidone during combined treatment with paroxetine

The effects of paroxetine on steady-state plasma concentrations of risperid one and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) were studied in 10 patients with schizophrenia or schizoaffective disorder. Pati ents stabilized using risperidone therapy (4-8 mg/d) also received paroxeti ne (20 mg/d) for 4 weeks. During paroxetine administration, mean plasma con centrations of risperidone increased significantly (P < 0.01), whereas leve ls of 9-OH-risperidone decreased slightly but not significantly. After 4 we eks of paroxetine treatment, the sum of the concentrations of risperidone a nd 9-OH-risperidone (active moiety) increased significantly by 45% (P < 0.0 5) over baseline. The mean plasma risperidone/9-OH-risperidone ratio was al so significantly modified (P < 0.001) during paroxetine treatment. The drug combination was generally well tolerated with the exception of one patient who developed Parkinsonian symptoms in the second week of adjunctive thera py. In this patient total plasma levels of risperidone and its active metab olite increased by 62% during paroxetine co-administration. The authors' fi ndings indicate that paroxetine, a potent inhibitor of CYP2D6, may impair t he elimination of risperidone, primarily by inhibiting CYP2D6-mediated 9-hy droxylation and to a lesser extent by simultaneously affecting the further metabolism of 9-OH-risperidone or other pathways of risperidone biotransfor mation. Careful clinical observation and possibly monitoring of plasma risp eridone levels may be useful whenever paroxetine is co-administered with ri speridone.