A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of 2 Doses of Vortioxetine in Adults With Major Depressive Disorder

Abstract

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...

The effect of vortioxetine on overall patient functioning in patients with major depressive disorder

“…In the current analysis, functional remission (SDS total score ≤6) at week 6/8 was 25.5%, 30.4%, 30.9%, and 31.2% for vortioxetine 5, 10, 15, and 20 mg, respectively. Symptomatic remission rates (MADRS total score ≤10) at these doses in the individual studies ranged from 28.8% to 36.0% for vortioxetine 5 mg, 21.4%–36.0% for vortioxetine 10 mg, 23.9%–34.9% for vortioxetine 15 mg, and 29.3%–38.4% for vortioxetine 20 mg, respectively (Baldwin et al., 2012; Boulenger et al., 2014; Henigsberg et al., 2012; Jacobsen et al., 2015; Jain et al., 2013; Mahableshwarkar, Jacobsen, Chen, et al., 2015; Mahableshwarkar, Jacobsen, Serenko, et al., 2015; Mahableshwarkar et al., 2013). …”

“…Additionally, vortioxetine 10 mg daily demonstrated clinically significant benefits on all aspects of functioning (SDS single‐item scores) in the total population as well as on overall functioning (SDS total score) in patients with severe MDD and/or significant functional impairment or high anxiety symptoms at baseline. These findings are consistent with the results of the individual studies, where vortioxetine administration was associated with improvements in patient functioning as well as in depressive symptoms (Baldwin et al., 2012; Boulenger et al., 2014; Henigsberg et al., 2012; Jacobsen et al., 2015; Jain et al., 2013; Mahableshwarkar, Jacobsen, Chen, et al., 2015; Mahableshwarkar, Jacobsen, Serenko, et al., 2015; Mahableshwarkar et al., 2013; Takeda, 2013). …”

“…Thus, data from nine short‐term (6/8 weeks) multicenter, double‐blind, randomized, placebo‐controlled, parallel‐group, fixed‐dose clinical studies of vortioxetine conducted in adults (aged 18–75 years) with MDD were analyzed. The details of the study design and the results of the nine included trials have been previously published (Baldwin et al., 2012; Boulenger et al., 2014; Henigsberg et al., 2012; Jacobsen et al., 2015; Jain et al., 2013; Mahableshwarkar, Jacobsen, Chen, et al., 2015; Mahableshwarkar, Jacobsen, Serenko, et al., 2015; Mahableshwarkar et al., 2013; Takeda, 2013). Table 1 provides a summary of treatment dosages, number of participants in each dosage arm, treatment duration, and key inclusion criteria for each of the trials included in this meta‐analysis.…”

“…All patients enrolled in these studies met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM‐IV‐TR; American Psychiatric Association (APA), 2000) criteria for a major depressive episode lasting ≥3 months and were ≥18 years old. Additionally, patients were required to have Montgomery‐Åsberg Depression Rating Scale (MADRS; Montgomery & Asberg, 1979) scores ≥22 (NCT00672620, Mahableshwarkar et al., 2013), ≥30 (NCT00672958, Jain et al., 2013) or ≥26 (all other trials; Baldwin et al., 2012; Boulenger et al., 2014; Henigsberg et al., 2012; Jacobsen et al., 2015; Mahableshwarkar, Jacobsen, Chen, et al., 2015; Mahableshwarkar, Jacobsen, Serenko, et al., 2015; Takeda, 2013; Table 1). …”

“…The efficacy and safety of vortioxetine in patients with MDD has been demonstrated in a series of short‐ and long‐term studies (Alvarez et al., 2012; Boulenger, Loft, & Olsen, 2014; Henigsberg et al., 2012; Jacobsen et al., 2015; Katona, Hansen, & Olsen, 2012; Mahableshwarkar, Jacobsen, Chen, et al., 2015; McIntyre, Lophaven, & Olsen, 2014; Montgomery, Nielsen, et al., 2014). The effects of vortioxetine on general functioning were assessed (with the SDS) as secondary measures in a subset of short‐term clinical trials (Baldwin, Loft, & Dragheim, 2012; Boulenger et al., 2014; Henigsberg et al., 2012; Jacobsen et al., 2015; Jain et al., 2013; Mahableshwarkar, Jacobsen, & Chen, 2013; Mahableshwarkar, Jacobsen, Chen, et al., 2015; Mahableshwarkar, Jacobsen, Serenko, et al., 2015; Takeda, 2013). The purpose of this post hoc meta‐analysis was to analyze the SDS results from these studies to determine the effect of vortioxetine on overall patient functioning as well as the proportion of patients who achieved functional remission versus placebo.…”