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Cited by 98Treatment of Major DepressionAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesBipolar Disorder and Treatment

A randomized, double-blind, duloxetine-referenced study comparing efficacy and tolerability of 2 fixed doses of vortioxetine in the acute treatment of adults with MDD

Open access
Mahableshwarkar, Atul R., Jacobsen, Paula L., Chen, Yinzhong, Serenko, Michael, Trivedi, Madhukar H.·2015·Psychopharmacology
DOI 10.1007/s00213-014-3839-0PMC PMC4432084
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Abstract

RATIONALE: Vortioxetine has reduced depressive symptoms in adults with major depressive disorder (MDD) in multiple clinical trials. OBJECTIVES: The aim of this study is to evaluate the efficacy, safety, and tolerability of vortioxetine 15 and 20 mg vs placebo in adults with MDD. METHODS: Patients 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. RESULTS: Six 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. CONCLUSIONS: Vortioxetine 20 mg significantly reduced MADRS total scores after 8 weeks of treatment. Both vortioxetine doses were well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01153009; www.clinicaltrials.gov/ .

AI snapshot

Written from the paper’s full text.

TL;DR

In this 8-week phase 3 trial, vortioxetine 20 mg significantly reduced MADRS total score versus placebo in adults with MDD, while vortioxetine 15 mg did not. Both vortioxetine doses were generally well tolerated, with no significant differences from placebo on sexual dysfunction, suicidal ideation/behavior, or discontinuation symptoms.

Key findings

  • Among 614 randomized patients, week-8 MADRS mean changes were −12.83 for placebo, −14.30 for vortioxetine 15 mg (P=.224), −15.57 for vortioxetine 20 mg (P=.023), and −16.90 for duloxetine 60 mg (P<.001); vortioxetine 20 mg had an LS mean difference from placebo of −2.75 (95% CI −5.12 to −0.38).
  • Key secondary efficacy endpoints did not separate from placebo for either vortioxetine dose (P>.050); duloxetine 60 mg separated from placebo on the primary endpoint, confirming assay sensitivity.
  • AEs reported by ≥5% of vortioxetine patients included nausea, headache, diarrhea, dizziness, dry mouth, constipation, vomiting, insomnia, fatigue, nasopharyngitis, and upper respiratory infection; discontinuation due to AEs occurred in 2.5% of placebo, 9.5% of vortioxetine 15 mg, 9.1% of vortioxetine 20 mg, and 6.6% of duloxetine patients.
  • Treatment-emergent sexual dysfunction, suicidal ideation or behavior, and discontinuation symptoms were not significantly different between vortioxetine and placebo; sexual dysfunction developed in 36.2% of placebo, 35.6% of vortioxetine 15 mg, 35.6% of vortioxetine 20 mg, and 53.2% of duloxetine patients without baseline sexual dysfunction.

Methods

  • This was an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, duloxetine-referenced phase 3 study at 58 sites in the USA; adults aged 18–75 with recurrent MDD, MADRS total score ≥26, and CGI-S ≥4 were randomized 1:1:1:1 to placebo, vortioxetine 15 mg, vortioxetine 20 mg, or duloxetine 60 mg once daily.
  • The primary efficacy endpoint was change from baseline MADRS total score at week 8, analyzed using MMRM ANCOVA; sensitivity analyses used ANCOVA with LOCF and OC methods.
  • Safety/tolerability assessments included AEs, vital signs, laboratory evaluations, electrocardiograms, C-SSRS, ASEX, and DESS.

Limitations

  • Stated: the study was not powered for direct efficacy comparisons; the paper also notes possible methodological issues in MDD trials, including large multisite trials and multiple raters, as possible reasons for negative results.
  • Evident from the text: the trial was acute (8 weeks) and conducted only in the USA, with a predominantly White sample (77%) and high mean BMI (31.2 kg/m²), which may limit generalizability.
  • Evident from the text: vortioxetine 15 mg did not separate from placebo on the primary endpoint, and neither vortioxetine dose separated from placebo on key secondary endpoints; in LOCF and OC ANCOVA sensitivity analyses, neither vortioxetine dose separated from placebo.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00213-014-3839-0

Cites

27 of 27 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 21 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Suicidal ideation or behavior was not significantly different between vortioxetine and placebo.

    “Treatment-emergent sexual dysfunction, suicidal ideation or behavior, and discontinuation symptoms were not significantly different between vortioxetine and placebo.”
    Quote in the paperSubstantial claim
  • Findingown data

    In this study, 32% of patients had no sexual dysfunction at baseline.

    “In this study, 32 % of patients had no sexual dysfunction at baseline.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Duloxetine 60 mg separated from placebo on the primary endpoint.

    “Duloxetine 60 mg separated from placebo (-16.90 ± 0.884 vs -12.83 ± 0.834; P<.001) on the primary endpoint, confirming assay sensitivity.”
    Quote in the paperSubstantial claim
  • Findingown data

    Although some improvements in SDS total scores were apparent in the vortioxetine 20-mg and duloxetine 60-mg groups, the differences from placebo did not reach statistical significance.

    “Although some improvements in SDS total scores were apparent in the vortioxetine 20-mg and duloxetine 60-mg groups, the differences from placebo did not reach statistical significance.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The missing data are missing at random.
  • Findingown data

    Two serious AEs (a stress fracture and suicidal ideation) occurred in the vortioxetine 15-mg group during the study.

    “Two serious AEs (a stress fracture and suicidal ideation) occurred in the vortioxetine 15-mg group during the study.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 13
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingnone given

    The prevalence of nausea in this trial was transient and highest during the first week of treatment.

    “The prevalence of nausea was transient and highest during the first week of treatment.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In the duloxetine treatment group, approximately one half (53%) of patients who had no sexual dysfunction at baseline developed TESD.

    “In the duloxetine treatment group, approximately one half (53 %) developed TESD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Change from baseline in MADRS total score in the vortioxetine 15-mg group demonstrated improvement over time and was numerically greater than placebo but not statistically significant at week 8.

    “Change from baseline in MADRS total score in the vortioxetine 15-mg group demonstrated improvement over time and was numerically greater than placebo but not statistically significant at week 8.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The missing data are missing at random.

  • May combine two claims.

    Findingown data

    The vortioxetine 15- and 20-mg groups had a 0.7% lower rate of sexual dysfunction compared with placebo and a 17.6% lower rate of sexual dysfunction compared with duloxetine.

    “The vortioxetine 15-and 20-mg groups had a 0.7 % lower rate of sexual dysfunction compared with placebo and a 17.6 % lower rate of sexual dysfunction compared with duloxetine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Changes in serum chemistry, hematology, vital signs, and electrocardiogram parameters were distributed evenly across vortioxetine and placebo groups; no discernible patterns of concern were noted for any of the treatment groups.

    “Changes in serum chemistry, hematology, vital signs, and electrocardiogram parameters were distributed evenly across vortioxetine and placebo groups; no discernible patterns of concern were noted for any of the treatment groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Discontinuation due to AEs occurred in 4 (2.5%) patients in the placebo group, 14 (9.5%) in the vortioxetine 15-mg group, 14 (9.1%) in the vortioxetine 20-mg group, and 10 (6.6%) in the duloxetine 60-mg group.

    “Discontinuation due to AEs occurred in 4 (2.5 %) patients in the placebo group, 14 (9.5 %) in the vortioxetine 15-mg group, 14 (9.1 %) in the vortioxetine 20-mg group, and 10 (6.6 %) in the duloxetine 60-mg group (Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During the study, one patient in the vortioxetine 15-mg group and one patient in the vortioxetine 20-mg group had active suicidal ideation compared with no patients in the placebo group and two patients in the duloxetine group; no suicidal behavior-related events were reported during the study.

    “During the study, one patient in the vortioxetine 15-mg group and one patient in the vortioxetine 20-mg group had active suicidal ideation compared with no patients in the placebo group and two patients in the duloxetine group; no suicidal behavior-related events were reported during the study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mean changes from baseline in SDS total score (MMRM) were numerically larger in the vortioxetine treatment groups compared with placebo; however, neither dose separated from placebo statistically.

    “The mean changes from baseline in SDS total score (MMRM) were numerically larger in the vortioxetine treatment groups compared with placebo; however, neither dose separated from placebo statistically.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The missing data are missing at random.

  • May combine two claims.

    Premisecitation

    Vortioxetine 20 mg is significantly superior to placebo on multiple depression endpoints (MADRS total score, response rate, CGI-I, SDS, and MADRS in patients with high baseline HAM-A) after 8 weeks of treatment in two other studies, one conducted in the USA and one outside the USA.

    “Vortioxetine 20 mg has been shown to be significantly superior to placebo on multiple depression endpoints (MADRS total score, response rate, CGI-I, SDS, and MADRS in patients with high baseline HAM-A) after 8 weeks of treatment in two other studies, one conducted in the USA and the other conducted outside of the USA”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jacobsen et al. 2013

      Not checked in the free run.

    • cites Boulenger et al. 2014 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To control for two-sided type I error, the primary efficacy endpoint and key secondary endpoints were tested for each dose in a sequential order.

    “To control for two-sided type I error, the primary efficacy endpoint and key secondary endpoints were tested for each dose in the following sequential order:”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Vortioxetine 20-mg treatment was statistically significantly superior to placebo on the primary efficacy analysis and demonstrated continual improvement over the 8-week study.

    “Vortioxetine 20-mg treatment was statistically significantly superior to placebo on the primary efficacy analysis and demonstrated continual improvement over the 8-week study.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The missing data are missing at random.

  • May combine two claims.

    Interpretationown data

    These results are consistent with vortioxetine having a favorable tolerability profile and a low risk of TESD.

    “These results are consistent with vortioxetine having a favorable tolerability profile and a low risk of TESD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Even after multiple antidepressant therapies, over 30% of patients remain symptomatic in the short term.

    “Moreover, even after multiple antidepressant therapies, over 30 % of patients remain symptomatic in the short term (Rush et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rush et al. 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Of the 1141 patients screened, 614 (54%) were randomized.

    “Of the 1141 patients screened, 614 (54 %) were randomized (placebo, n=161; vortioxetine 15 mg, n=147; vortioxetine 20 mg, n=154; and duloxetine 60 mg, n=152) (Fig. 1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Eligible patients were randomized 1:1:1:1 to receive placebo, vortioxetine 15 mg, vortioxetine 20 mg, or duloxetine 60 mg once daily during the 8-week, double-blind treatment period, using an interactive voice response system.

    “Eligible patients were randomized (1:1:1:1) to receive placebo, vortioxetine 15 mg, vortioxetine 20 mg, or duloxetine 60 mg once daily during the 8-week, double-blind treatment period, using an interactive voice response system.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Randomization was stratified by patients' sexual function status (normal vs abnormal) as determined at baseline by the ASEX scale.

    “Randomization was stratified by patients' sexual function status (normal vs abnormal) as determined at baseline by the Arizona Sexual Experiences (ASEX) scale (McGahuey et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McGahuey et al. 2000 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Methodological issues have been previously proposed as possible reasons for negative clinical trials in MDD.

    “methodological issues, including aspects of study design and conduct (i.e., issues with identifying appropriate patients, large multi-site trials, multiple raters) that have been previously proposed as possible reasons for negative clinical trials in MDD”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bridge et al., 2009 source

      Not checked in the free run.

    • cites Brunoni et al., 2009 source

      Not checked in the free run.

    • cites Khan et al., 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study was an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, duloxetine-referenced, phase 3 study conducted at 58 sites in the USA.

    “This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, duloxetine-referenced, phase 3 study was conducted at 58 sites in the USA.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    SIB was prospectively monitored using the C-SSRS scores in all vortioxetine clinical trials.

    “SIB was prospectively monitored using the C-SSRS scores in all vortioxetine clinical trials”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The reasons for failure of the vortioxetine 15-mg dose to separate from placebo in the current study remain unclear.

    “The reasons for failure of the vortioxetine 15-mg dose to separate from placebo in the current study remain unclear”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The active reference, duloxetine 60 mg, separated from placebo, confirming assay sensitivity.

    “The active reference, duloxetine 60 mg, separated from placebo, confirming assay sensitivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Only about one third of patients treated with an antidepressant achieve remission in the acute phase of major depressive disorder.

    “Although numerous antidepressants are available for the treatment of major depressive disorder (MDD), only about one third of patients treated with an antidepressant achieve remission in the acute phase (Trivedi et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Trivedi et al. 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Atypical antidepressants such as bupropion, mirtazapine, and nefazodone are less likely to cause TESD.

    “Atypical antidepressants such as bupropion, mirtazapine, and nefazodone are less likely to cause TESD”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Serretti and Chiesa 2009 source

      Not checked in the free run.

23 of 23

  • The authors state this as an assumption.

    The missing data are missing at random.

    “Based on missing data at random assumption, this analysis was performed using observed case (OC) data only.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The incidence rate of adverse events is similar to that of previous clinical studies at around 30%.

    “The incidence rate is similar to that of previous clinical studies at around 30%.17,34”

    From A Randomized Controlled Study of Efficacy and Cognitive Function Improvement of Vortioxetine and Escitalopram in Patients with Depression in Chinese Han Nationality (2024) · cites this paper as [17]

    Table 3 (Discussion; page unavailable) reports that any treatment-emergent adverse event occurred in 73.5% and 81.2% of the two vortioxetine groups, not around 30%. Nausea occurred in 35.4% and 33.1%, but that is one specific adverse event, not the overall incidence claimed. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Clinical studies in many countries have reported the clinical effects of Vortioxetine on cognitive function in patients with depression.

    “Clinical studies in many countries have reported the clinical effects of Vortioxetine on cognitive function in patients with depression.15–18”

    From A Randomized Controlled Study of Efficacy and Cognitive Function Improvement of Vortioxetine and Escitalopram in Patients with Depression in Chinese Han Nationality (2024) · cites this paper as [17]

    The Introduction and Discussion describe vortioxetine studies in the USA and elsewhere, but report effects on depressive symptoms rather than cognitive function. The Efficacy measures section lists depression, anxiety, global-impression and disability scales; a search for cognitive function and cognitive tests found no passage addressing the claimed outcome. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Duloxetine nasopharyngitis percentage is incorrect

    Minor

    The table reports 5 cases among 150 duloxetine patients as 5.3%, but 5/150 is 3.3%.

    Reported 5.3 · recomputed 3.333333

  • SDS row has a CGI-I footnote

    Minor

    Footnote d is attached to the SDS change row but describes a treatment difference in CGI-I score instead.

2 of 2

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Related

Authors
Mahableshwarkar, A. R., Jacobsen, P. L., Chen, Y., Serenko, M., & Trivedi, M. H.
Affiliations
  • Takeda (United States) (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Mahableshwarkar, Atul R.
ORCID
Venue
Psychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2015-01-11
Volume
232
Issue
12
Pages
2061-2070
ISSN
  • 0033-3158 (ISSN-L)
  • 1432-2072
DOI
10.1007/s00213-014-3839-0
PMC
PMC4432084
OpenAlex
W1986102787
Semantic Scholar
6ea6c33a1a09b7274e011d882dc24d7493c1de37
Cited by
98
References
27
Citations by year
2025: 12 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 4 · 2019: 10 · 2018: 12 · 2017: 9 · 2016: 10 · 2015: 11
FWCI
10.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Psychopharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Takeda Pharmaceuticals U.S.A.
  • H. Lundbeck A/S
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Keywords
vortioxetine, major depressive disorder, duloxetine, acute treatment, antidepressant efficacy, tolerability, dose comparison, sexual dysfunction, suicidal ideation, discontinuation symptoms, adverse events
MeSH terms
Duloxetine Hydrochloride, Vortioxetine, Adolescent, Adult, Aged, Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Dose-Response Relationship, Drug, Double-Blind Method, Electrocardiography, Fatigue, Female, Humans, Sleep Initiation and Maintenance Disorders, Male, Middle Aged, Piperazines, Psychiatric Status Rating Scales, Sulfides, Selective Serotonin Reuptake Inhibitors, Young Adult, Suicidal Ideation

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