Context: Vortioxetine (Lu AA21004) is an antidepressant with a mechanism of action thought to be related to a combination of 2 pharmacologic actions: direct modulation of several receptors and inhibition of the serotonin transporter.Objective: To evaluate the efficacy of vortioxetine 10 and 20 mg once daily in outpatients with major depressive disorder.Design, Setting, and Participants: This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted from July 2010 to January 2012 among adults with a primary diagnosis of recurrent major depressive disorder (DSM-IV-TR).Intervention: Eligible subjects were randomized in 1:1:1 ratio to 1 of 3 treatment arms: vortioxetine 10 mg, vortioxetine 20 mg, or placebo once daily for 8 weeks. Subjects who completed the 8-week trial entered a 2-week blinded discontinuation period to assess potential discontinuation symptoms. Main Outcome Measure:The primary endpoint was the least squares mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline. Key secondary outcomes were analyzed in the following prespecified sequential order: MADRS response (≥ 50% decrease from baseline in total score), Clinical Global Impressions-Improvement score, change from baseline in MADRS total score in subjects with baseline Hamilton Anxiety Rating Scale score ≥ 20, MADRS remission (total score ≤ 10), and change from baseline in Sheehan Disability Scale total score (all at week 8).Results: A total of 462 subjects were randomized to placebo (n = 157), vortioxetine 10 mg (n = 155), and vortioxetine 20 mg (n = 150). Mean (SE) reductions from baseline in MADRS total score (week 8) were -10.77 (± 0.807), -12.96 (± 0.832), and -14.41 (± 0.845) for the placebo, vortioxetine 10 mg (P = .058 vs placebo), and vortioxetine 20 mg (P = .002 vs placebo) groups. MADRS response/remission was achieved in 28.4%/14.2%, 33.8%/21.4%, and 39.2%/22.3% of subjects, respectively, in the 3 groups. Only MADRS response for vortioxetine 20 mg significantly separated from placebo (P = .044). Treatment was well tolerated, with the most frequently reported adverse events consisting of nausea, headache, diarrhea, and dizziness.Conclusions: Vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in this study population. Overall, vortioxetine was well tolerated in this study.Trial Registration: ClinicalTrials.gov identifier: NCT01163266 Clin Psychiatry 2015;76(5):575-582 J

RationaleVortioxetine has reduced depressive symptoms in adults with major depressive disorder (MDD) in multiple clinical trials.ObjectivesThe aim of this study is to evaluate the efficacy, safety, and tolerability of vortioxetine 15 and 20 mg vs placebo in adults with MDD.MethodsPatients were randomized 1:1:1:1 to vortioxetine 15 mg, vortioxetine 20 mg, duloxetine 60 mg (active reference), or placebo. The primary efficacy endpoint was mean change in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at week 8 (MMRM). Safety/tolerability assessments included physical examinations, vital signs, laboratory evaluations, electrocardiograms, adverse events (AEs), Columbia–Suicide Severity Rating Scale, Arizona Sexual Experiences Scale, and Discontinuation–Emergent Signs and Symptoms checklist.ResultsSix hundred and fourteen patients were randomized. Mean changes in MADRS scores were −12.83 (±0.834), −14.30 (±0.890), −15.57 (±0.880), and −16.90 (±0.884) for placebo, vortioxetine 15 mg (P = .224), vortioxetine 20 mg (P = .023), and duloxetine 60 mg (P < .001) (P vs placebo), respectively. AEs reported by ≥5 % of vortioxetine patients included nausea, headache, diarrhea, dizziness, dry mouth, constipation, vomiting, insomnia, fatigue, and upper respiratory infection. Treatment-emergent sexual dysfunction, suicidal ideation or behavior, and discontinuation symptoms were not significantly different between vortioxetine and placebo.ConclusionsVortioxetine 20 mg significantly reduced MADRS total scores after 8 weeks of treatment. Both vortioxetine doses were well tolerated.Clinical trial registrationClinicalTrials.gov identifier NCT01153009; www.clinicaltrials.gov/.

Background: This 8-week, randomized, double-blind, placebo-controlled study, conducted August 2010-May 2012 in the United States, evaluated the safety and efficacy of vortioxetine 10 mg and 15 mg in patients with major depressive disorder (MDD). The mechanism of action of vortioxetine is thought to be related to direct modulation of serotonin (5-HT) receptor activity and inhibition of the serotonin transporter.Method: Adults aged 18-75 years with MDD (DSM-IV-TR) and Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 26 were randomized (1:1:1) to receive vortioxetine 10 mg or 15 mg or placebo once daily, with the primary efficacy end point being change from baseline at week 8 in MADRS analyzed by mixed model for repeated measures. Adverse events were recorded during the study, suicidal ideation and behavior were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), and sexual dysfunction was assessed using the Arizona Sexual Experience (ASEX) scale. Results:Of the 1,111 subjects screened, 469 subjects were randomized: 160 to placebo, 157 to vortioxetine 10 mg, and 152 to vortioxetine 15 mg. Differences from placebo in the primary efficacy end point were not statistically significant for vortioxetine 10 mg or vortioxetine 15 mg. Nausea, headache, dry mouth, constipation, diarrhea, vomiting, dizziness, and flatulence were reported in ≥ 5% of subjects receiving vortioxetine. Discontinuation due to adverse events occurred in 7 subjects (4.4%) in the placebo group, 8 (5.2%) in the vortioxetine 10 mg group, and 12 (7.9%) in the vortioxetine 15 mg group. ASEX total scores were similar across groups. There were no clinically significant trends within or between treatment groups on the C-SSRS, laboratory values, electrocardiogram, or vital sign parameters. Conclusions:In this study, vortioxetine did not differ significantly from placebo on MADRS total score after 8 weeks of treatment in MDD subjects. Even among agents indicated for MDD treatment, only 53% of trials demonstrate superiority over placebo. 1 The reasons for such inconsistent results have not been fully elucidated and appear to be multifactorial. A recent meta-analysis 1 found that the baseline severity of symptoms had a stronger correlation with study outcomes than did sample size, study duration, flexible versus fixed dosing, and geographic location of study sites. A similar positive correlation between symptom severity and outcomes was shown in another meta-analysis. 2 In a third analysis, symptom severity was not a significant predictor of the difference between active treatment and placebo, whereas enrollment at academic sites was strongly predictive of positive treatment effects.3 This study suggested that raters in nonacademic settings may have a tendency to overestimate baseline scores that, in turn, could lead to higher placebo responses. Consistent with this observation, results of a study by Kobak et al 4 showed that site-based raters were more likely to assign higher 17-item Hamilton Depression Rating Scale score...

Background and ObjectiveThe identification and quantification of potential drug–drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor).MethodsThe ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration–time curve [AUC] and maximum plasma concentration [Cmax]) was used to assess pharmacokinetic interactions.ResultsCo-administration of vortioxetine had no effect on the AUC or Cmax of ethinyl estradiol/levonorgestrel or 5′-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80–125 %. Steady-state AUC and Cmax of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity.ConclusionDosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-013-0117-6) contains supplementary material, which is available to authorized users.