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.