Paula L. Jacobsen

A randomized, double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple doses of Lu AA21004 in adults with major depressive disorder.

OBJECTIVE Lu AA21004 is an investigational multimodal antidepressant. This randomized controlled trial evaluated the efficacy and tolerability of multiple doses of Lu AA21004 versus placebo in adults with major depressive disorder (MDD). METHOD Adults diagnosed with MDD (based on DSM-IV-TR criteria) with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 26 were randomly assigned (1:1:1:1) to receive Lu AA21004 1 mg, 5 mg, or 10 mg or placebo for 8 weeks (between August 2008 and August 2009). The primary endpoint was reduction in 24-Item Hamilton Depression Rating Scale (HDRS-24) total score after 8 weeks of treatment compared with placebo for Lu AA21004 10 mg. Additional outcomes included response and remission rates, Sheehan Disability Scale (SDS), Clinical Global Impressions-Global Improvement scale (CGI-I), MADRS total score, and HDRS-24 total score in subjects with baseline Hamilton Anxiety Rating Scale (HARS) score ≥ 20. Adverse events were assessed throughout the study. RESULTS A total of 560 subjects (mean age = 46.4 years) were randomized. There was a statistically significant reduction from baseline in HDRS-24 total score at week 8 for Lu AA21004 10 mg vs placebo (P < .001). There were improvements (nominal P values < .05 with no adjustment for multiplicity) in HDRS-24 total score, response and remission rates, CGI-I score, MADRS total score, and HDRS-24 total score in subjects with baseline HARS score ≥ 20 at week 8 for all Lu AA21004 treatment groups vs placebo. No significant differences were seen in SDS scores between any dose of Lu AA21004 and placebo. The most common adverse events were nausea, headache, and dizziness. CONCLUSIONS After 8 weeks of treatment with Lu AA21004 10 mg, there was a significant reduction in HDRS-24 total score compared with placebo in adults with MDD. Lu AA21004 was well tolerated in this study. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00735709.

A randomized, double-blind, placebo-controlled 6-wk trial of the efficacy and tolerability of 5 mg vortioxetine in adults with major depressive disorder.

Vortioxetine (Lu AA21004) is a multi-modal antidepressant in clinical development for the treatment of major depressive disorder (MDD). The current study evaluated the efficacy and tolerability of 5 mg vortioxetine compared to placebo after 6 wk of treatment in adults with MDD in an out-patient setting. Adults aged 18-75 yr, with a diagnosis of MDD and a baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥30, were randomized to receive either 5 mg vortioxetine or placebo over 6 wk, followed by a 2-wk medication-free discontinuation period. The primary efficacy measure was change from baseline in Hamilton Rating Scale for Depression (HAMD)-24 total score at week 6 compared to placebo. Additional measures included response and remission rates, Clinical Global Impression Scale - Improvement scores, HAMD-24 total score in subjects with baseline Hamilton Anxiety Scale (HAMA) >19 and MADRS-S total score. Adverse events (AEs) were assessed throughout the study. A total of 600 adults were randomized. There were no significant differences in efficacy measures between subjects in the 5 mg vortioxetine and placebo groups at week 6. HAMD-24 total score in subjects with baseline HAMA >19 in the 5 mg vortioxetine group was improved at weeks 3-6 compared to the placebo group (nominal p value <0.05). The most common AEs for the vortioxetine and placebo groups were nausea (19.1 and 9.4%), headache (17.1 and 15.1%) and diarrhoea (11.4 and 7.0%), respectively. In this study of adults with MDD, 5 mg vortioxetine did not differ significantly from placebo in reducing depression symptoms after 6 wk of treatment.

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.

Abstract 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

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.

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.

Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible-dose, 52-week extension study.

Patients with major depressive disorder often experience relapse after responding to treatment; therefore, maintenance therapy with antidepressants is recommended for maintaining response or remission. This multicenter, open-label, flexible-dose, 52-week extension study evaluated the long-term safety, tolerability, and maintenance of efficacy in study participants who had completed one of two randomized, double-blind, placebo-controlled, 8-week dose-ranging vortioxetine trials in study participants with major depressive disorder. At the open-label baseline, all study participants were switched to vortioxetine 5 mg/day for the first week, with subsequent dose adjustments from 2.5 to 10 mg/day on the basis of response and tolerability. Treatment with vortioxetine for 52 weeks was well tolerated, with no new safety signals identified. Among the 834 evaluable study participants, treatment-emergent adverse events were reported in 70.6%, with the most common in the combined (all doses) population of nausea (15.2%), headache (12.4%), nasopharyngitis (9.8%), diarrhea (7.2%), and dizziness (6.8%). The rate of adverse events related to sexual dysfunction was low and weight gain was minimal. Laboratory values, vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale results showed no trends of clinical concern. The change in the severity of depressive and anxiety symptoms was maintained throughout the study as reflected by a 24-item Hamilton Depression Scale total score of 8.2 at week 52 (from 17.6 at open-label baseline) in the observed case data set.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of 2 doses of vortioxetine in adults with major depressive disorder.

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. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01179516.

Vortioxetine (Lu AA21004) in generalized anxiety disorder: Results of an 8-week, multinational, randomized, double-blind, placebo-controlled clinical trial

Vortioxetine is a multimodal antidepressant, with anxiolytic properties observed in preclinical studies. The goal of the current study was to evaluate the efficacy and tolerability of vortioxetine 5mg vs placebo in adults with generalized anxiety disorder (GAD). Adults with a primary diagnosis of GAD (HAM-A total score ≥20 and MADRS score ≤16) received vortioxetine 5mg or placebo for 8 weeks. The primary efficacy endpoint was reduction in HAM-A total scores from baseline after 8 weeks of treatment compared with placebo. Key secondary measurements were HAD anxiety subscore, CGI-I, SDS total score, HAM-A response rates, HAM-A total score for subjects whose baseline HAM-A total score was ≥25, and SF-36 social functioning subscore. HAM-A remission rates were also measured. Adverse events (AEs) were assessed throughout the study. In total, 301 subjects (mean age, 45.2 years; 31% male) were randomized (1:1) to receive vortioxetine 5mg (n=150) or placebo (n=151). After 8 weeks of treatment, there was a statistically significant difference in reduction from baseline in HAM-A total score for the vortioxetine group (-14.30) compared with placebo recipients (-10.49) (P<0.001). Statistically significant differences were observed for all key secondary outcomes favoring vortioxetine treatment (vs placebo), using a mixed model for repeated measurements (MMRM) analysis. Active treatment resulted in a significantly higher rate of remission. Vortioxetine was well tolerated. The most common treatment-related AEs were nausea, headache, dizziness, and dry mouth. In sum, vortioxetine was safe and effective in treating adults with GAD in this multinational population.

Vortioxetine (Lu AA21004) 5 mg in generalized anxiety disorder: Results of an 8-week randomized, double-blind, placebo-controlled clinical trial in the United States

The goal of the current clinical study, conducted in the United States (US), was to evaluate the efficacy and tolerability of vortioxetine 5mg vs placebo in adults with a primary diagnosis of generalized anxiety disorder (GAD; HAM-A total score ≥20 and MADRS score ≤16). Subjects were randomized (1:1) to receive vortioxetine 5mg (n=152) or placebo (n=152) for 8 weeks. Efficacy was assessed using change from baseline in HAM-A total scores after 8 weeks of treatment compared with placebo, using mixed-model repeated measures (MMRM) analyses. Adverse events (AEs) were assessed throughout the study. A total of 304 subjects were randomized (mean age, 41.2 years). After 8 weeks of treatment, there was no statistically significant difference in the reduction in HAM-A total score from baseline between the Vortioxetine (n=145) and placebo (n=145) groups. There were no statistically significant differences in any key secondary efficacy outcome between vortioxetine and placebo. Factors potentially contributing to the differences between the results of this study and those of one of identical design conducted outside the US are discussed. The most common treatment-emergent AEs were nausea, headache, dizziness, and dry mouth. Nausea was more frequently reported in the vortioxetine group (25% vs 4.6% for the placebo group). Most AEs were mild to moderate in severity. In conclusion, in this trial, vortioxetine did not improve symptoms of GAD (compared with placebo) over 8 weeks of treatment. Vortioxetine was well tolerated in this study.

Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well‐Treated Major Depressive Disorder Experiencing SSRI‐Induced Sexual Dysfunction

INTRODUCTION Sexual dysfunction is common with serotonergic antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and does not resolve in most patients. Vortioxetine, an antidepressant with a multimodal mechanism of action, has shown low rates of sexual dysfunction in previous major depressive disorder (MDD) trials. AIM This study compared the effects of vortioxetine and escitalopram on sexual functioning in adults with well-treated MDD experiencing treatment-emergent sexual dysfunction (TESD). METHODS Participants treated with, and responding to, citalopram, paroxetine, or sertraline were randomized to switch to either vortioxetine (10/20 mg; n = 225) or escitalopram (10/20 mg; n = 222) for 8 weeks. Sexual function was assessed using the Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14), and antidepressant efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions (CGI) scale, and Profile of Mood States brief form (POMS-brief). Safety and tolerability were also assessed. MAIN OUTCOME MEASURES The primary endpoint was change from baseline in the CSFQ-14 total score after 8 weeks of treatment. The MADRS, CGI, and POMS-brief were used to assess antidepressant efficacy. Safety was assessed via adverse events, vital signs, electrocardiograms, laboratory values, weight, and physical examination findings. RESULTS Vortioxetine showed significantly greater improvements in CSFQ-14 total score (8.8 ± 0.64, mean ± standard error) vs. escitalopram (6.6 ± 0.64; P = 0.013). Benefits vs. escitalopram were significant on four of five dimensions and all three phases of sexual functioning assessed by the CSFQ-14 (P < 0.05). Antidepressant efficacy continued in both groups, with similar, but slight, improvements in MADRS and CGI scores. Vortioxetine and escitalopram had similar clinical efficacy profiles in this study, with safety profiles similar to previous trials. Nausea (n = 9, 4.0%) was the most common treatment-emergent adverse event leading to discontinuation of vortioxetine. CONCLUSION Switching antidepressant therapy to vortioxetine may be beneficial for patients experiencing sexual dysfunction during antidepressant therapy with SSRIs.

A randomized, double‐blind, fixed‐dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10 mg in acute treatment of adults with generalized anxiety disorder

Vortioxetine is a recently approved multimodal antidepressant with anxiolytic properties in preclinical studies.