Plasma risperidone concentrations during combined treatment with sertraline.

The effect of sertraline on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was studied in 11 patients with schizophrenia or schizoaffective disorder. To treat concomitant depressive symptoms, additional sertraline, at the dose of 50 mg/d, was administered for 4 weeks to patients stabilized on risperidone (4-6 mg/d). Mean plasma concentrations of risperidone, 9-OH-risperidone, and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) did not change significantly during combined treatment with sertraline. At the end of week 4, sertraline dosage was adjusted in some patients on the basis of the individual response and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the 4 patients who were still receiving the initial sertraline dose, but concentrations were slightly but not significantly increased (by a mean 15% over pretreatment) in the subgroup of 5 subjects treated with a final dose of 100 mg/d. In the 2 patients receiving the highest dose of sertraline, 150 mg/d, at week 8 total plasma risperidone concentrations were increased by 36% and 52%, respectively, as compared with baseline values. Sertraline coadministration with risperidone was well tolerated, and no patient developed extrapyramidal symptoms. These findings indicate that sertraline at dosages up to 100 mg/d is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of sertraline may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of sertraline on CYP2D6-mediated 9-hydroxylation of risperidone.

Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction.

The effect of fluoxetine on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was evaluated in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized on risperidone (4-6 mg/day) received additional fluoxetine (20 mg/day) to treat concomitant depression. One patient dropped out after 1 week due to the occurrence of akathisia associated with markedly increased plasma risperidone concentrations. In the other subjects, mean plasma concentrations of risperidone increased during fluoxetine administration from 12 +/- 9 ng/mL at baseline to 56 +/- 31 at week 4 (p < 0.001), while the levels of 9-OH-risperidone were not significantly affected. After 4 weeks of combined treatment, the levels of the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) increased by 75% (range, 9-204%, p < 0.01) compared with baseline. The mean plasma risperidone/9-OH-risperidone ratio also increased significantly. During the second week of adjunctive therapy, two patients developed Parkinsonian symptoms, which were controlled with anticholinergic medication. These findings indicate that fluoxetine, a potent inhibitor of the cytochrome P450 enzyme CYP2D6 and a less potent inhibitor of CYP3A4, reduces the clearance of risperidone by inhibiting its 9-hydroxylation or alternative metabolic pathways. This interaction may lead to toxic plasma risperidone concentrations. In addition to careful clinical observation, monitoring plasma risperidone levels may be of value in patients given adjunctive therapy with fluoxetine.