A randomized, double-blind trial of 2.5 mg and 5 mg vortioxetine (Lu AA21004) versus placebo for 8 weeks in adults with major depressive disorder

Objective: Vortioxetine (Lu AA21004) is an investigational antidepressant. In vitro studies indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A 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