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-OHrisperidone
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.