Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day

Abstract

This study assessed the efficacy, tolerability and safety of vortioxetine versus placebo in adults with recurrent major depressive disorder. This double-blind, randomized, placebo-controlled study included 608 patients [Montgomery–Åsberg Depression Rating Scale (MADRS) total score≥26 and Clinical Global Impression – Severity score≥4]. Patients were randomly assigned (1 : 1 : 1 : 1) to vortioxetine 15 mg/day, vortioxetine 20 mg/day, duloxetine 60 mg/day or placebo. The primary efficacy endpoint was change from baseline in MADRS total score at week 8 (mixed model for repeated measurements). Key secondary endpoints were: MADRS responders; Clinical Global Impression – Improvement scale score; MADRS total score in patients with baseline Hamilton Anxiety Rating Scale ≥20; remission (MADRS≤10); and Sheehan Disability Scale total score at week 8. On the primary efficacy endpoint, both vortioxetine doses were statistically significantly superior to placebo, with a mean difference to placebo (n=158) of −5.5 (vortioxetine 15 mg, P<0.0001, n=149) and −7.1 MADRS points (vortioxetine 20 mg, P<0.0001, n=151). Duloxetine (n=146) separated from placebo, thus validating the study. In all key secondary analyses, both vortioxetine doses were statistically significantly superior to placebo. Vortioxetine treatment was well tolerated; common adverse events (incidence≥5%) were nausea, headache, diarrhea, dry mouth and dizziness. No clinically relevant changes were seen in clinical safety laboratory values, weight, ECG or vital signs parameters. Vortioxetine was efficacious and well tolerated in the treatment of patients with major depressive disorder.

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). …”

“…In preclinical studies, vortioxetine has demonstrated effects on serotonergic, noradrenergic, dopaminergic, cholinergic, norepinephrinergic, acetylcholinergic, histaminergic, gabanergic, and glutamatergic neurotransmission (Bang‐Andersen et al., 2011; Mork et al., 2012; Sanchez, Asin, & Artigas, 2015). 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).…”