A randomized, double-blind, placebo-controlled study of the efficacy and safety of vortioxetine 10 mg and 20 mg in adults with major depressive disorder

OBJECTIVE: Vortioxetine (LuAA21004) is an investigational antidepressant. The mechanism of action of vortioxetine is thought to be related to its multimodal activity, which is a combination of two pharmacological modes of action: direct modulation of receptor activity and inhibition of the serotonin transporter. This placebo-controlled study investigated the efficacy of vortioxetine 10mg and 20mg in the treatment of major depressive disorder (MDD). METHODS: In this 8-week, multicenter, randomized, doubleblind, parallel-group, placebo-controlled trial in the US, adults with MDD were randomized (1:1:1) to placebo, vortioxetine 10mg, or vortioxetine 20mg daily. The primary efficacy endpoint, mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 8, was analyzed separately for each dose using mixed model for repeated measures (MMRM). Primary and key secondary outcomes were analyzed in the following prespecified sequential order: MADRS response (?50% decrease from baseline in total MADRS score at week 8), last observation carried forward (LOCF); Clinical Global Impressions–Improvement (CGI-I) score at week 8 (MMRM); change from baseline in MADRS total score at week 8 in subjects with baseline Hamilton Anxiety Rating Scale (HAM-A) ?20 (MMRM); MADRS remission (MADRS total score ?10 at week 8), LOCF; and change from baseline in Sheehan Disability Scale (SDS) total score at week 8 (MMRM). Safety assessments included adverse events (AEs), vital signs, weight, Columbia-Suicide Severity Rating Scale (C-SSRS), Arizona Sexual Experience (ASEX) scale, and the Discontinuation-Emergent Signs and Symptoms (DESS) checklist. RESULTS: 462 patients were randomized to placebo (157), vortioxetine 10mg (155), and vortioxetine 20mg (150). The leastsquares mean declines from baseline in MADRS total score at week 8 were -10.77 (± 0.807), -12.96 (±0.832), and -14.41 (±0.845), respectively, for the placebo, vortioxetine 10mg, and vortioxetine 20mg groups (P=0.002 for vortioxetine 20mg vs placebo; P=0.058 for 10mg vs placebo). MADRS response at 8 weeks was achieved in 28.4%, 33.8%, and 39.2%, of patients, respectively, in the 3 groups. Vortioxetine 20mg was also significantly improved in HAM-A, CGI-I, and SDS scores at week 8 vs placebo (nominal P<0.05). Treatment was well tolerated; the most frequently reported AEs (?5%) were nausea, headache, diarrhea, dizziness, constipation, vomiting, viral upper respiratory infection, and fatigue. Incidences of treatment-emergent AEs were 62.4%, 73.5%, and 68.7%, respectively, in the placebo, vortioxetine 10mg, and 20mg dose groups. There were no differences between the vortioxetine groups and placebo in the change from baseline of ASEX total score at week 8, or C-SSRS or DESS scores. CONCLUSIONS: In this study of adults with MDD in the US, vortioxetine 20mg significantly reduced MADRS total score at 8 weeks and improved symptoms of MDD. Overall vortioxetine was well tolerated.