Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder.

An early clinical trial suggested that the substance P (neurokinin(1) receptor) antagonist, aprepitant, might provide a unique mechanism of antidepressant activity. Phase III trials were conducted to confirm these findings. Five 8-week, randomized, double-blind, parallel-groups, placebo-controlled, multicenter trials in outpatients with Major Depressive Disorder were performed. Aprepitant 160 mg and placebo were included in all trials. Aprepitant 80 mg and paroxetine 20 mg (active comparator) were included in three trials. Approximately 150 patients were enrolled per treatment group in each trial. The primary end point was the mean change-from-baseline of the first 17 items of the Hamilton Rating Scale for Depression (HAM-D(17)) score at 8 weeks. A positron emission tomography (PET) study was also performed in normal subjects to determine the relationship between neurokinin(1) receptor occupancy and aprepitant plasma concentrations in dosing regimens relevant to the trials. No statistically significant differences from placebo on the HAM-D(17) were observed at week 8 for either dose of aprepitant in any of the trials, whereas paroxetine 20 mg was significantly (p