Pharmacokinetic and pharmacodynamic interactions between fluoxetine and moclobemide in the investigation of development of the "serotonin syndrome"

Objective: To assess the tolerability, safety, pharmacokinetics, and pharmacodynamics of combined treatment with fluoxetine and moclobemide in healthy subjects. Methods: Fluoxetine (20 to 40 mg/day) was administered for 23 days to 18 subjects. At (nor)fluoxetine steady state, subjects were randomized in a 2:1 ratio to receive in addition either moclobemide (ascending doses up to 600 mg/day) or placebo. A single 300 mg dose of moclobemide was administered before and at the end of the fluoxetine regimen to assess the effects of the latter on the pharmacokinetics and pharmacodynamics of moclobemide. Adverse events and vital signs were recorded and pharmacokinetic parameters of fluoxetine and moclobemide were determined. Plasma concentrations of 3,4-dihydroxyphenylglycol, 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and serotonin uptake into platelets were assessed as pharmacodynamic measures. Results: The number, intensity, or type of adverse events did not change when moclobemide was added to fluoxetine, No clinically relevant changes in safety parameters occurred. Fluoxetine markedly inhibited the metabolism of moclobemide. However, multiple dosing of moclobemide did not lead to excessive accumulation, 3,4-Dihydroxyphenylglycol, 5-hydroxyindoleacetic acid, and 3,4-dihydroxyphenylacetic acid plasma levels and serotonin uptake did not reveal a pharmacodynamic interaction, Conclusions: Combination treatment with fluoxetine and moclobemide did not provide any indication of development of the "serotonin syndrome."