OBJECTIVE: Vortioxetine (Lu AA21004) is an investigational antidepressant. In 
vitro studies indicate that vortioxetine is a 5-HT(3), 5-HT(7), and 5-HT(1D) 
receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor 
agonist and inhibitor of the 5-HT transporter. This trial assessed the efficacy 
and tolerability of 2.5 and 5 mg vortioxetine for the treatment of MDD.
RESEARCH DESIGN AND METHODS: Adults (N = 611) with MDD were randomized to 8 
weeks of double-blind treatment with placebo, vortioxetine (2.5 or 5 mg) or 
active reference (duloxetine 60 mg). The primary measure was change from 
baseline in the 24-item Hamilton Depression Scale (HAM-D24). Secondary endpoints 
included responder rate, Clinical Global Impression Scale-Global Improvement 
scale (CGI-I), and remission rate. Participants were monitored for adverse 
events (AEs), and treatment-emergent sexual dysfunction using the Arizona Sexual 
Experiences (ASEX) scale.
RESULTS: Both doses of vortioxetine were associated with declines in HAM-D24 
total scores compared to placebo but were not statistically significant. At 8 
weeks, changes from baseline were [mean (SE)]: -10.50 (0.76) placebo, -12.04 
(0.74) 2.5 mg vortioxetine, and -11.08 (0.74) 5 mg vortioxetine. Secondary 
outcome measures in the vortioxetine groups, including responder rate, CGI-I, 
and remission rate, were also not significantly different from placebo. 
Duloxetine treatment was associated with declines in HAM-D24 total score 
[-13.47(0.75); p = 0.005] as well as significant improvements in secondary 
outcome measures versus placebo (p ≤ 0.05). The most common AEs for vortioxetine 
were nausea, dry mouth, and headache. Rates of sexual dysfunction (ASEX) were 
51.0%, 37.5%, 46.9%, and 33.3% in the vortioxetine 2.5 mg, vortioxetine 5 mg, 
duloxetine, and placebo groups, respectively.
CONCLUSIONS: In this study of adults with MDD treated for 8 weeks with 
vortioxetine 2.5 mg or 5 mg per day, reductions in depression symptoms were not 
statistically significant compared with placebo. Study limitations are 
discussed, including patient characteristics, MDD severity, drug dosing, and 
aspects of trial design. Both doses of vortioxetine were well tolerated. This 
trial has been registered at clinicaltrials.gov #NCT00672620.