Augmentative effects of fluvoxamine on duloxetine plasma levels in depressed patients

Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake with weak activity on dopamine reuptake. Enzymes involved in duloxetine-metabolism are cytochrome P450 isoenzymes (CYP) CYP1A2 and to a lesser extent CYP2D6 whereas the selective serotonin reuptake inhibitor Fluvoxamine is known to be a potent inhibitor of CYP1A2. Changes in plasma levels of duloxetine revealing pharmacokinetic interactions with fluvoxamine, clinical effects and adverse effects of adding fluvoxamine in twelve patients with a steady-state duloxetine treatment by intraindividual comparisons were analyzed in this retrospective survey. Patients had been treated with a monotherapy of duloxetine under steady-state conditions until fluvoxamine was added. Serum duloxetine levels were measured at steady-state of different daily doses due to lacking experience with the combination of DLX and FLX. Adding 25 mg of fluvoxamine (FLX) per day to a steady-state treatment with 30 mg of duloxetine (DLX) in eight patients led to an average increase of duloxetine plasma levels that was threefold with a magnitude of 50% to 506%. Our findings indicate that duloxetine-plasma levels can be enhanced by a potent CYP1A2 inhibition by FLX and DLX, even in higher plasma levels, seems to be well tolerated. The use of combined treatments, however, underscores the importance of understanding pharmacokinetic interactions.