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

Rakesh Jain, Atul R. Mahableshwarkar, Paula L. Jacobsen, Yinzhong Chen, Michael E. Thase
DOI: http://dx.doi.org/10.1017/S1461145712000727 313-321 First published online: 1 March 2013

Abstract

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.

Key words
  • vortioxetine
  • multi-modal
  • randomized clinical trial

Introduction

Despite the large number of medications available to treat major depressive disorder (MDD), there remain considerable unmet needs in pharmacological treatment (Papakostas, 2007; Warden et al. 2007). Significant reductions in depression symptoms occur in <50% of patients treated with the most commonly prescribed antidepressants and it can take up to 6 wk to achieve a clinically significant response [defined as a 50% reduction from baseline in the Hamilton Depression Scale – 24 Items (HAMD-24) or Montgomery Åsberg Depression Rating Scale (MADRS); (Hansen et al. 2005; Rosenzweig-Lipson et al. 2007)]. Tolerability issues (e.g. treatment-emergent sexual dysfunction, weight gain, insomnia, cognitive deficits, nausea and vomiting) can lead to poor medication adherence and are among the leading causes of discontinuation of treatment (Ashton et al. 2005; Papakostas, 2007). Medications with greater efficacy and faster onset of action with improved tolerability are needed for the treatment of MDD, which is estimated to affect between 13 and 16% of the US population at some point in their lives and can have serious effects on overall health status and quality of life (Hasin et al. 2005; Judd et al. 2000; Katon & Ciechanowski, 2002; Kessler et al. 2003; Zlotnick et al. 2000). Medications that act on multiple neurotransmitter systems and receptor subtypes, and that are targeted to specific aspects of the neurobiology of depression, may offer advantages in efficacy and tolerability over currently available antidepressants (Schechter et al. 2005).

Vortioxetine (Lu AA21004) is a multi-modal antidepressant that functions as a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter in vitro (Bang-Andersen et al. 2011; Mork et al. 2011). In vivo non-clinical studies have demonstrated that vortioxetine enhances levels of the neurotransmitters serotonin, noradrenaline, dopamine, acetylcholine and histamine in specific areas of the brain (Bang-Andersen et al. 2011). In a previous clinical trial in subjects with MDD, 5 and 10 mg vortioxetine demonstrated significant improvement in MADRS total score after 6 wk of treatment compared to placebo (p < 0.0001 for both doses) and was well tolerated (Alvarez et al. 2011). Additional short-term efficacy trials have demonstrated mixed results with various vortioxetine doses (from 1 to 10 mg) and between geographic regions (Baldwin et al. 2011; Boulenger et al. 2012; Henigsberg et al. 2011; Katona et al. 2012). The goal of the current study was to evaluate the efficacy and tolerability of 5 mg vortioxetine (as a previously demonstrated efficacious dose) compared to placebo after 6 wk of treatment in subjects with MDD in the United States.

Method

This was a multi-centre, randomized, double-blind, placebo-controlled, parallel-group study in the United States of 5 mg vortioxetine in subjects with MDD. The study was conducted between April and November 2008 on subjects recruited by psychiatrists or primary care physicians working in private practice, at research centres or at academic sites. Adults aged 18–75 yr with a diagnosis of MDD (major depressive episode of at least 3 months’ duration, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revised) were eligible for the study. Subjects underwent screening prior to the start of the study. Demographic information, medical history and medication history were collected. Subjects underwent a physical examination, clinical laboratory testing, 12-lead electrocardiogram (ECG) and psychological assessments including the Mini International Neuropsychiatric Interview (MINI), HAMD-24, MADRS and Columbia-Suicide Severity Rating Scale (C-SSRS). All subjects were required to have a baseline MADRS total score ⩾30 with no co-morbid psychiatric disorder, as assessed by the MINI. Subjects were excluded from the study if they had failed two previous antidepressant treatments (of at least 6 wk in duration) or if they were considered by the investigator to pose a significant risk of suicide, had a score ⩾5 on item 10 (suicidal thoughts) of the MADRS or had made a suicide attempt in the previous 6 months. Subjects were also excluded from the study if they had a history of a neurological or substance abuse disorder, current clinically significant medical illness or clinically significant abnormalities in vital signs or laboratory values. Concomitant use of any neuroactive medication was prohibited 2–5 wk (depending on drug half-life) prior to the start of the study and throughout the treatment period.

Subjects who met all the qualifications were subsequently randomized (1:1) to receive either 5 mg vortioxetine or placebo once daily for 6 wk on an out-patient basis. A centralized computer system was used for subject randomization and study medication assignments. Subjects returned to the study site weekly to receive wallet cards of either 5 mg vortioxetine or placebo capsules (beginning at baseline) and for efficacy and safety assessments. Blinding of all participants was maintained throughout the study. All study medication was identical in appearance and dispensed using unique identification numbers.

The primary endpoints were change from baseline in the HAMD-24 total score after 6 wk of treatment and change from baseline in HAMD-24 total score assessed at each week in sequential fashion. Additional assessments included response rate (⩾50% decrease in the HAMD-24 total score from baseline), remission rate (MADRS total score ⩽10), Clinical Global Impression Scale – Improvement (CGI-I) score, Clinical Global Impression Scale – Severity of Illness (CGI-S) score, HAMD-24 total score in subjects with baseline Hamilton Anxiety Scale (HAMA) total score >19, MADRS-S (self-assessment) total score, MADRS total score and the Sheehan Disability Scale (SDS).

Safety was assessed during the treatment period via collection of adverse events (AEs), vital signs, weight, ECGs, laboratory values and physical examinations. AEs were collected through subject spontaneous reports, physician observation and responses to non-leading questions. The C-SSRS was administered at each visit in order to assess any potential suicidal ideation or behaviour during the study. Potential discontinuation symptoms were assessed at 1 and 2 wk of the medication-free discontinuation period after study completion. A safety follow-up phone call was placed 4 wk after the last dose of double-blind study drug.

This study was conducted according to the protocol, the World Medical Association Declaration of Helsinki, the ICH Harmonised Tripartite Guideline for GCP and all applicable local or regional regulatory requirements. An institutional review board at each site approved the protocol and written informed consent was obtained from each subject prior to any study procedures.

In order to detect possible early effects, the sample size was based on statistical comparison at week 1. Assuming s.d. 6.0 for the change from baseline in HAMD-24 total score at week 1, a total of 600 subjects (300 per treatment group) would achieve at least 85% power to detect a difference of 1.5 in change from baseline in HAMD-24 total score at week 1 between the vortioxetine and placebo group using a two-sample t test with a 0.05 two-sided significance level.

Statistical analyses were performed using SAS® Version 9.1.3. Before unblinding the data, centres with fewer than eight subjects were pooled with geographically similar centres to minimize artefacts in the statistical analyses. Demographic data were compared using the Cochran–Mantel–Haenszel test for categorical data and using a two-way ANOVA model for continuous data with effects for centre and treatment. Efficacy analyses were based on the full analysis set, which included all randomized subjects who received at least one dose of study drug and had at least one valid post-baseline value for assessment of primary efficacy. Safety analyses were based on the safety set, which included all subjects who were randomized and received at least one dose of double-blind study medication. Data for each efficacy assessment were evaluated using analysis of covariance, with treatment and centre as fixed factors and baseline value as covariate, using the last-observation-carried-forward method. Standardized effect sizes were calculated using the difference of mean change between vortioxetine and placebo divided by the pooled standard deviation. The HAMD-24 response rate and MADRS remission rate were analysed at each week using logistic regression, adjusting for baseline score and treatment. Post-hoc comparisons of individual sites (grouped by screen failure rate, enrolment rate) and subsets of subjects [by body mass index (BMI), number of raters] were performed in a similar manner.

To control two-sided type I error, a hierarchical testing procedure was used. The testing sequence was as follows: step 1 – change from baseline in HAMD-24 total score at week 6 tested at significance level 0.05; step 2 – endpoints tested in two sequential orders at significance level 0.025. Sequence 1 tested the change from baseline in HAMD-24 total score at each week starting with week 5, then weeks 4, 3, 2 and 1. Sequence 2 tested the HAMD-24 response rate at week 6 followed by the MADRS remission rate at week 6, CGI-I score at week 6, change from baseline in HAMD-24 total score at week 6 in subjects with baseline HAMA total score >19, change from baseline in MADRS-S total score at week 6, change from baseline in SDS total score at week 6 and change from baseline in MADRS-S total score at weeks 4 and 1. Once an endpoint was considered not significant, the testing procedure was stopped for all subsequent endpoints. For endpoints that occurred after the pre-specified statistical testing procedure was stopped or were outside the testing procedure, nominal p values with no adjustment for multiplicity were reported. The phrase ‘separation from placebo’ was used to describe findings with nominal p values <0.05.

Results

A total of 600 subjects in the US (47 sites) were randomized into the study (n = 300 per group) and 480 completed the treatment (236/300 placebo, 244/300 5 mg vortioxetine; Fig. 1). Subject demographics are shown in Table 1. There were no statistically significant differences between treatment groups in demographic or clinical characteristics at baseline.

Fig. 1

CONSORT diagram. AE, Adverse event; IMP, investigational medicinal product.

View this table:
Table 1

Subject demographics (all randomized subjects)

CharacteristicPlacebo n = 3005 mg vortioxetine n = 300
Sex, n (%)
  Male136 (45.3)114 (38.0)
  Female164 (54.7)186 (62.0)
Mean age, yr (s.d.) 42.4 (12.7) 42.5 (13.0)
Race, n (%)
  White216 (72.0)209 (69.7)
  Black 78 (26.0) 81 (27.0)
  Asian  4 (1.3)  8 (2.7)
  American Indian/Alaskan  2 (0.7)  1 (0.3)
  Pacific Islander  0 (0.0)  1 (0.3)
BMI, kg/m2 30.8 (7.7) 30.5 (8.2)
Mean baseline HAMD-24, total score (s.d.) 32.2 (5.5) 32.7 (5.4)
Mean baseline MADRS, total score (s.d.) 34.0 (3.4) 34.1 (3.4)
  • BMI, Body mass index; HAMD-24, Hamilton Rating Scale for Depression – 24 Items; MADRS, Montgomery–Asberg Depression Rating Scale.

There were no significant differences between vortioxetine and placebo in change from baseline in HAMD-24 total score at any time-point (Fig. 2). There were no significant differences between vortioxetine and placebo in change from baseline in MADRS total score, change from baseline in MADRS-S total score, HAMD-24 response rate, MADRS remission rate, CGI-I, change from baseline in CGI-S or SDS total score at week 6 (Table 2). There was a reduction in HAMD-24 total score at weeks 3–6 (nominal p value <0.05 compared to placebo) in subjects with HAMA >19 (Fig. 3, Table 2).

Fig. 2

Hamilton Rating Scale for Depression – 24 Item (HAMD-24) total score change from baseline for the 6-wk treatment period for the 5 mg vortioxetine and placebo groups. Data for each efficacy assessment were evaluated using analysis of covariance, with treatment and centre as fixed factors and baseline value as covariate, using the last-observation-carried-forward method.

Fig. 3

Hamilton Rating Scale for Depression – 24 Item (HAMD-24) total score change from baseline for the 6-wk treatment period in subjects with Hamilton Anxiety Scale >19 at baseline for the 5 mg vortioxetine and placebo groups. Data for each efficacy assessment were evaluated using analysis of covariance, with treatment and centre as fixed factors and baseline value as covariate, using the last-observation-carried-forward method. *Nominal p < 0.05.

View this table:
Table 2

Efficacy endpoints at week 6 (FAS)

EndpointPlacebo5 mg vortioxetine
HAMD-24 total score
  LS mean change from baseline (s.e.)−13.87 (0.662)−14.61 (0.650)
  LS mean difference from placebo (s.e.)−0.74 (0.887)
  p value0.407
  95% CI(−2.48 to 1.01)
  Standardized effect size0.09
MADRS-S total score
  LS mean change from baseline (s.e.)−4.56 (0.313)−4.97 (0.307)
  LS mean difference from placebo (s.e.)−0.41 (0.419)
  p value0.326
  95% CI(−1.23 to 0.41)
  Standardized effect size0.04
MADRS total score
  LS mean change from baseline (s.e.)−15.48 (0.708)−15.80 (0.698)
  LS mean difference from placebo (s.e.)−0.32 (0.950)
  p value0.736
  95% CI(−2.19 to 1.55)
  Standardized effect size0.04
HAMD-24 response rate
  n (%)132 (46.2)135 (46.2)
  p value0.927
  Odds ratio vs. placebo1.015
  95% CI(0.731 to 1.410)
MADRS remission
  n (%)92 (32.2)85 (29.1)
  p value0.443
  Odds ratio vs. placebo0.869
  95% CI(0.607 to 1.244)
CGI-I
  LS mean (s.e.)2.61 (0.076)2.57 (0.075)
  LS mean difference from placebo (s.e.)−0.04 (0.103)
  p value0.688
  95% CI(−0.24 to 0.16)
  Standardized effect size0.02
SDS
  LS mean change from baseline (s.e.)−6.61 (0.548)−6.69 (0.557)
  LS mean difference from placebo (s.e.)−0.09 (0.753)
  p value0.908
  95% CI(−1.57 to 1.39)
  Standardized effect size0.05
CGI-S
  LS mean (s.e.)−1.46 (0.085)−1.46 (0.083)
  LS mean difference from placebo (s.e.)0.01 (0.114)
  p value0.962
  95% CI(−0.22 to 0.23)
  Standardized effect size0.00
HAMD-24 total score with HAM-A >19
  LS mean change from baseline (s.e.)−13.41 (1.164)−16.18 (1.170)
  LS mean difference from placebo (s.e.)−2.77 (1.397)
 p value0.049
 95% CI(−5.52 to −0.02)
 Standardized effect size0.21
  • FAS, Full analysis set; HAMD-24, Hamilton Rating Scale for Depression – 24 Items; LS, least squares; 95% CI, 95% confidence intervals; MADRS-S, Montgomery–Asberg Depression Rating Scale – Self-Assessment; CGI-I, Clinical Global Impression Scale – Improvement; SDS, Sheehan Disability Scale; CGI-S, Clinical Global Impression Scale – Severity of Illness.

Of the 597 subjects in the safety set, 401 (67.2%) experienced a total of 1055 AEs during the study. The incidence of AEs was similar between treatment groups (69.9% with vortioxetine and 64.4% with placebo). The majority of AEs were considered by the investigators to be mild to moderate in intensity. All treatment-emergent AEs occurring in ⩾5% of subjects in any group during the entire study period are shown in Table 3. The number of subjects reporting sexual dysfunction AEs was low in both groups. There was one subject in the placebo group (decreased libido) and four subjects in the vortioxetine group (one anorgasmia, one ejaculation disorder, one decreased libido and one abnormal orgasm) with sexual dysfunction AEs.

View this table:
Table 3

Treatment-emergent adverse events occurring in ⩾5% of subjects for any treatment condition

Adverse eventPlacebo n (%)5 mg vortioxetine n (%)
Total192 (64.4)209 (69.9)
Nausea  28 (9.4) 57 (19.1)
Headache 45 (15.1) 51 (17.1)
Diarrhoea  21 (7.0) 34 (11.4)
Dry mouth  19 (6.4)  25 (8.4)
Dizziness  22 (7.4)  19 (6.4)

Eleven subjects (1.8%) reported a serious AE during the study, seven (2.3%) in the vortioxetine group (drug hypersensitivity, herpes zoster, injury, colon cancer, renal cell carcinoma, cerebrovascular accident, convulsion) and four (1.3%) in the placebo group (puncture site infection, laryngeal cancer, abortion spontaneous, ectopic pregnancy). All serious AEs were considered by the investigator to be not related to study drug. No deaths occurred during the study.

There were no clinically significant changes in clinical laboratory values or vital signs. No clinically meaningful differences between treatment groups were observed at any time-point for systolic or diastolic blood pressure, pulse, body temperature or weight. There were no significant differences between vortioxetine and placebo in suicidal ideation or behaviour using the C-SSRS.

By the end of the treatment period, 18/597 subjects (3%) had discontinued treatment due to AEs. There were no differences between the vortioxetine and placebo groups with regard to the number of subjects who discontinued the study because of an AE [nine subjects (3.0%) in each group]. During the 2-wk discontinuation period, the incidence of AEs was similar for the two treatment groups (8.9% in the placebo group and 8.2% in the vortioxetine group). None of the AEs had an incidence ⩾2% in either treatment group during the discontinuation period.

Several post-hoc analyses were undertaken in order to gain a better understanding of the data and assess potential reasons for the lack of separation from placebo for vortioxetine. A post-hoc analysis using BMI differentiation showed no difference in the reduction of HAMD-24 total score from baseline with vortioxetine compared to placebo for subjects with a BMI >30 and those ⩽30. Comparisons of individual sites demonstrated that subjects from sites with screen failure rates >25% had greater differences from placebo on HAMD-24 total score at week 6 [−1.89 (n = 308) vs. 0.0 (n = 270)] than seen in sites with screen failure rates <25%. Subjects from slow enrolling sites (<4 subjects/month; 41%) did not demonstrate any difference from placebo in HAMD-24 total score at week 6 but did have lower baseline HAMD-24 total scores compared to those from fast enrolling sites. Reduction from baseline in HAMD-24 total score at week 6 in subjects with one consistent rater (n = 197) and those with >1 rater throughout the trial (n = 381) showed a difference between the two groups in subjects randomized to placebo (single rater −13.4, multiple raters −16.4) but no difference in those randomized to vortioxetine (single rater −15.2, multiple raters −14.9).

Discussion

There were no significant differences in reduction of depression symptoms between subjects in the 5 mg vortioxetine and placebo groups after 6 wk of treatment. In the subgroup of subjects with high baseline anxiety (HAMA >19), there was a reduction in the HAMD-24 total score beginning at week 3, with a nominal p value <0.05. The lack of significant improvement is in contrast with a previous 6-wk study demonstrating significant reductions in MDD symptoms with 5 and 10 mg vortioxetine (Alvarez et al. 2011) and a similar 8-wk study of 1, 5 and 10 mg vortioxetine that showed significant reductions in HAMD-24 (Henigsberg et al. 2011). Many issues such as study population, dose and aspects of study design and conduct (including the inclusion of inappropriate subjects) may contribute to a large placebo response masking potential effects of treatment and have been previously proposed as possible reasons for negative clinical trials in MDD (Bridge et al. 2009; Brunoni et al. 2009; Khan et al. 2010; Mundt et al. 2007). Data on several of these aspects from the current study were analysed in an attempt to understand the discrepancy between the results of this study and other clinical trials of vortioxetine.

The characteristics of a study population including the identification of appropriate subjects and expectations for treatment can greatly affect the results of any clinical trial. Because clinical trials for MDD often specify high depression scores for inclusion, there may be a tendency to inflate baseline scores to get subjects into a clinical trial, which can in turn overestimate subsequent response (Mundt et al. 2007). In the current study, there was a reduction in HAMD-24 total scores from baseline to week 1 of 5.9 points for the vortioxetine group and 5.2 points for the placebo group. This indicates that a significant subgroup of participants began to improve early in the course of study participation, although the extent to which this observation is related to pretreatment score inflation is unclear. Data from post-hoc analyses of individual sites by number of screen failures and speed of enrolment did indicate possible inclusion of inappropriate subjects and rater inflation at sites that had fast enrolment or a low percentage of screen failures. The expectations of subjects (i.e. prior clinical trial experience, previous antidepressant use and the number of previous depressive episodes) may also influence subject's response to treatment (Stewart-Williams & Podd, 2004). In the current study, the majority of subjects had >1 previous depressive episode, which may have influenced their expectations for treatment. Additional information that might have affected expectations (i.e. number of clinical trials previously participated in, experience with selective serotonin reuptake inhibitors/serotonin–norepinephrine reuptake inhibitors prior to the current trial) were not collected in this study, so it is unknown if they had any impact on the overall results.

Dose may also be a factor in this study, which only evaluated 5 mg vortioxetine. While two other international studies demonstrated efficacy at 5 mg (Alvarez et al. 2011; Henigsberg et al. 2011), the current study was conducted solely in the US, whose population tends to have a higher BMI than most other countries. However, there was no apparent difference in effect for subjects with a BMI >30 vs. ⩽30 in the current study, so an inadequate dosage for the specific study population may not be the critical factor.

Other aspects of clinical trial design and study conduct may also impact the overall outcome of a trial. The current study was a large multi-site trial (47 sites) that involved many different raters to evaluate the effects of treatment (197 subjects were evaluated by multiple raters). The growing reliance on large multi-site trials and the use of multiple raters have been identified in the literature as possibly contributing to a large placebo response in MDD trials (Bridge et al. 2009; Mundt et al. 2007). Subjects with multiple raters in this study did demonstrate a larger placebo response than those with a single rater. In addition, complications with rater consistency and unintentional bias may arise when multiple raters are used for a single subject (Bridge et al. 2009; Mundt et al. 2007). Rater qualifications and experience are important considerations and may contribute to some of the differences seen in trials conducted with multiple raters vs. centralized rating and in those conducted in different countries or regions where qualification and education requirements differ (Mallinckrodt et al. 2011).

Overall, it is not clear if any one or a combination of factors including study population, dose or study design and conduct led to the inability of vortioxetine to separate from placebo in this trial. Future studies of vortioxetine in the treatment of MDD may address these issues by improving selection of appropriate study subjects, evaluating higher doses, including a positive control, and improving rater consistency and study conduct.

Even though there were no significant differences in efficacy between the placebo and vortioxetine groups, the large number of subjects in this study provides important information on the safety and tolerability of vortioxetine at the 5 mg dose. Tolerability issues are one of the most frequently cited reasons for discontinuation of antidepressant treatment (Ashton et al. 2005). A study by Hu et al. (2004) asked patients to rank the most bothersome side-effects of antidepressants. Sexual dysfunction was the most frequently rated (16.7%), followed by drowsiness/fatigue (16.5%), weight gain (11.5%), insomnia (11.2%) and nausea (5.7%). In the current study, gastrointestinal complaints (i.e. nausea, diarrhoea) were the most common AEs in the vortioxetine group, with a higher incidence than in the placebo group. However, the reports of sexual side-effects, somnolence, weight gain and insomnia were low overall (⩽5%) and the incidence was similar between the vortioxetine and placebo groups. Since no specific sexual dysfunction questionnaire was used in this study, the incidence of sexual side-effects may be under-represented and additional studies using validated scales may be needed to fully understand the sexual side-effect profile of vortioxetine. Only 18 subjects withdrew from the study due to AEs, with no differences between the vortioxetine and placebo groups (nine subjects in each group). There were also no significant discontinuation symptoms detected during the 2-wk follow-up period after the end of the 6-wk treatment. A dose of 5 mg vortioxetine was well tolerated in this study of adults with MDD.

In conclusion, in this study of adults with MDD conducted in the US, 5 mg vortioxetine did not differ significantly from placebo in reducing depression symptoms after 6 wk of treatment. Treatment with 5 mg vortioxetine was well tolerated in this population. Additional studies are needed to fully define the efficacy and optimal doses of vortioxetine for the treatment of MDD.

Statement of Interest

R. J. has been a consultant for Addrenex, Forest, Eli Lilly, Merck, Pamlab, Pfizer, Shionogi, Shire, Sunovion and Takeda. R. J. has received research funding support from AstraZeneca, Forest, Eli Lilly, Pfizer, Shire and Takeda. R. J. has received honoraria from Addrenex, Forest, Eli Lilly, Merck, Pamlab, Pfizer, Shionogi, Shire and Sunovion. R. J. has participated in speaker/advisory boards for Addrenex, Forest, Eli Lilly, Merck, Pamlab, Pfizer, Shionogi, Shire, Sunovion and Takeda. A. M., P. J. and Y. C. are employees of Takeda Global Research and Development Center. M. T. has been a consultant/advisor for Alkermes, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Dey Pharma, Forest, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, Lundbeck, MedAvante, Merck, Neuronetics, Novartis, Otsuka, Ortho-McNeil, Pamlab, Pfizer, PGx Health, Shire, Supernus, Takeda and Transcept. M. T. has received grant support from the Agency for Healthcare Research and Quality, Eli Lilly, Forest, GlaxoSmithKline, National Institute of Mental Health, Otsuka and Sepracor. M. T. has participated as a speaker for AstraZeneca, Bristol-Myers Squibb, Dey Pharma, Eli Lilly, Merck and Pfizer. M. T. has equity holdings in MedAvante and receives royalties from the American Psychiatric Foundation (Guilford Publications).

Acknowledgements

This study was sponsored by the Takeda Pharmaceutical Company Ltd as part of a joint clinical development programme with H. Lundbeck A/S. Assistance with writing and manuscript preparation was provided by Sara Sarkey, PhD, an employee of Takeda Pharmaceuticals. The authors are entirely responsible for the scientific content of this paper.

Footnotes

  • * This trial has been registered at clinicaltrials.gov #NCT00672958.

References

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