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Meta-Analysis
. 2017 Jul 5;7(7):CD011520.
doi: 10.1002/14651858.CD011520.pub2.

Vortioxetine for depression in adults

Markus Koesters  1 , Giovanni Ostuzzi, Giuseppe Guaiana, Johanna Breilmann, Corrado Barbui
Affiliations
Meta-Analysis

Vortioxetine for depression in adults

Markus Koesters et al. Cochrane Database Syst Rev. .

Abstract

Background: Major depressive disorder is a common mental disorder affecting a person's mind, behaviour and body. It is expressed as a variety of symptoms and is associated with substantial impairment. Despite a range of pharmacological and non-pharmacological treatment options, there is still room for improvement of the pharmacological treatment of depression in terms of efficacy and tolerability. The latest available antidepressant is vortioxetine. It is assumed that vortioxetine's antidepressant action is related to a direct modulation of serotonergic receptor activity and inhibition of the serotonin transporter. The mechanism of action is not fully understood, but it is claimed to be novel. Vortioxetine was placed in the category of "Other" antidepressants and may therefore provide an alternative to existing antidepressant drugs.

Objectives: To assess the efficacy and acceptability of vortioxetine compared with placebo and other antidepressant drugs in the treatment of acute depression in adults.

Search methods: We searched Cochrane's Depression, Anxiety and Neurosis Review Group's Specialised Register to May 2016 without applying any restrictions to date, language or publication status. We checked reference lists of relevant studies and reviews, regulatory agency reports and trial databases.

Selection criteria: We included randomised controlled trials comparing the efficacy, tolerability, or both of vortioxetine versus placebo or any other antidepressant agent in the treatment of acute depression in adults.

Data collection and analysis: Two review authors independently selected the studies and extracted data. We extracted data on study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability. We analysed intention-to-treat (ITT) data only and used risk ratios (RR) as effect sizes for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Meta-analyses used random-effects models.

Main results: We included 15 studies (7746 participants) in this review. Seven studies were placebo controlled; eight studies compared vortioxetine to serotonin-norepinephrine reuptake inhibitors (SNRIs). We were unable to identify any study that compared vortioxetine to antidepressant drugs from other classes, such as selective serotonin reuptake inhibitors (SSRIs).Vortioxetine may be more effective than placebo across the three efficacy outcomes: response (Mantel-Haenszel RR 1.35, 95% CI 1.22 to 1.49; 14 studies, 6220 participants), remission (RR 1.32, 95% CI 1.15 to 1.53; 14 studies, 6220 participants) and depressive symptoms measured using the Montgomery-Åsberg Depression Scale (MADRS) (score range: 0 to 34; higher score means worse outcome: MD -2.94, 95% CI -4.07 to -1.80; 14 studies, 5566 participants). The quality of the evidence was low for response and remission and very low for depressive symptoms. We found no evidence of a difference in total dropout rates (RR 1.05, 95% CI 0.93 to 1.19; 14 studies, 6220 participants). More participants discontinued vortioxetine than placebo because of adverse effects (RR 1.41, 95% CI 1.09 to 1.81; 14 studies, 6220 participants) but fewer discontinued due to inefficacy (RR 0.56, 95% CI 0.34 to 0.90, P = 0.02; 14 studies, 6220 participants). The quality of the evidence for dropouts was moderate.The subgroup and sensitivity analyses did not reveal factors that significantly influenced the results.In comparison with other antidepressants, very low-quality evidence from eight studies showed no clinically significant difference between vortioxetine and SNRIs as a class for response (RR 0.91, 95% CI 0.82 to 1.00; 3159 participants) or remission (RR 0.89, 95% CI 0.77 to 1.03; 3155 participants). There was a small difference favouring SNRIs for depressive symptom scores on the MADRS (MD 1.52, 95% CI 0.50 to 2.53; 8 studies, 2807 participants). Very low quality evidence from eight studies (3159 participants) showed no significant differences between vortioxetine and the SNRIs as a class for total dropout rates (RR 0.89, 95% CI 0.73 to 1.08), dropouts due to adverse events (RR 0.74, 95% CI 0.51 to 1.08) and dropouts due to inefficacy (RR 1.52, 95% CI 0.70 to 3.30).Against individual antidepressants, analyses suggested that vortioxetine may be less effective than duloxetine in terms of response rates (RR 0.86, 95% CI 0.79 to 0.94; 6 studies, 2392 participants) and depressive symptoms scores on the MADRS scale (MD 1.99, 95% CI 1.15 to 2.83; 6 studies; 2106 participants). Against venlafaxine, meta-analysis of two studies found no statistically significant differences (response: RR 1.03, 95% CI 0.85 to 1.25; 767 participants; depressive symptom scores: MD 0.02, 95% CI -2.49 to 2.54; 701 participants). In terms of number of participants reporting at least one adverse effect (tolerability), vortioxetine was better than the SNRIs as a class (RR 0.90, 95% CI 0.86 to 0.94; 8 studies, 3134 participants) and duloxetine (RR 0.89, 95% CI 0.84 to 0.95; 6 studies; 2376 participants). However, the sensitivity analysis casts some doubts on this result, as only two studies used comparable dosing.We judged none of the studies to have a high risk of bias for any domain, but we rated all studies to have an unclear risk of bias of selective reporting and other biases.

Authors' conclusions: The place of vortioxetine in the treatment of acute depression is unclear. Our analyses showed vortioxetine may be more effective than placebo in terms of response, remission and depressive symptoms, but the clinical relevance of these effects is uncertain. Furthermore, the quality of evidence to support these findings was generally low. In comparison to SNRIs, we found no advantage for vortioxetine. Vortioxetine was less effective than duloxetine, but fewer people reported adverse effects when treated with vortioxetine compared to duloxetine. However, these findings are uncertain and not well supported by evidence. A major limitation of the current evidence is the lack of comparisons with the SSRIs, which are usually recommended as first-line treatments for acute depression. Studies with direct comparisons to SSRIs are needed to address this gap and may be supplemented by network meta-analyses to define the role of vortioxetine in the treatment of depression.

PubMed Disclaimer

Conflict of interest statement

MK: none.

GO: none.

GG: none.

JB: none.

CB: none.

Figures

1
1
Study flow diagram.
2
2
Countries participating in trials. The categories represent the number of studies randomising participants within a country.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
5
5
Forest plot of comparison: 1 Vortioxetine versus placebo, outcome: 1.1 Response.
6
6
Forest plot of comparison: 1 Vortioxetine versus placebo, outcome: 1.2 Total number of dropouts.
7
7
Forest plot of comparison: 3. Vortioxetine versus serotonin‐norepinephrine reuptake inhibitors, outcome: 3.1 Response.
8
8
Forest plot of comparison: 3. Vortioxetine versus serotonin‐norepinephrine reuptake inhibitors, outcome: 3.2 Total number of dropouts.
See this image and copyright information in PMC

Comment in

  • Network meta-analysis of antidepressants.
    Fox J, Zhang P. Fox J, et al. Lancet. 2018 Sep 22;392(10152):1011. doi: 10.1016/S0140-6736(18)31787-2. Epub 2018 Sep 20. Lancet. 2018. PMID: 30264702 No abstract available.

References

References to studies included in this review

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Boulenger 2014 {published data only}
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Henigsberg 2012 {published data only}
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Jacobsen 2015 {published data only}
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Jain 2013 {published data only}
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Katona 2012 {published data only}
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Mahableshwarkar 2013 {published data only}
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Mahableshwarkar 2015a {published data only}
    1. Mahableshwarkar AR, Jacobsen PL, Chen Y, Serenko M, Trivedi MH. 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. Psychopharmacology 2015;232(12):2061‐70. - PMC - PubMed
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Mahableshwarkar 2015b {published data only}
    1. Jacobson W, Harvey P, Merikle E, Zhong W, Nomikos G, Olsen CK, et al. Impact of vortioxetine on functional capacity in MDD patients with subjective cognitive dysfunction: performance on the University of California San Diego performance‐based skills assessment (UPSA). 54th Annual Meeting of the American College of Neuropsychopharmacology, ACNP; 2015 Dec 6‐10; Hollywood (FL). 2015:S150‐1.
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Mahableshwarkar 2015c {published data only}
    1. Mahableshwarkar AR, Jacobsen PL, Serenko M, Chen Y, Trivedi MH. A randomized, double‐blind, placebo‐controlled study of the efficacy and safety of 2 doses of vortioxetine in adults with major depressive disorder. Journal of Clinical Psychiatry 2015;76(5):583‐91. - PubMed
    1. NCT01179516. A phase 3, randomized, double‐blind, parallel‐group, placebo‐controlled, fixed‐dose study comparing the efficacy and safety of 2 doses (10 and 15 mg) of Lu AA21004 in acute treatment of adults with major depressive disorder. clinicaltrials.gov/show/NCT01179516 Date first received: 9 August 2010.
McIntyre 2014 {published data only}
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    1. NCT01422213. Randomised, double‐blind, parallel‐group, placebo‐controlled, fixed dose study on the efficacy of [vortioxetine] Lu AA21004 on cognitive dysfunction in adult patients with major depressive disorder (MDD). clinicaltrials.gov/show/NCT01422213 Date first received: 22 August 2011.
NCT01255787 {published data only}
    1. Euctr2010‐022257‐41‐Lv. A multinational, randomized, double‐blind, placebo‐controlled, dose ranging study to assess the efficacy and safety of Lu AA21004 in patients with major depressive disorder ‐ efficacy and safety of Lu AA21004 for treatment of major depressive disorder. www.clinicaltrialsregister.eu/ctr‐search/search?query=eudract_number:201... 2010.
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Takeda 2011 {published data only}
    1. Jprn‐Japiccti‐111492. A randomized, double‐blind, placebo‐controlled, phase III study to assess the efficacy and safety of LuAA21004 in patients with major depressive disorder. www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI‐111492 Date first received: 9 May 2011.
    1. NCT01355081. A randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study to assess the efficacy and safety of Lu AA21004 in patients with major depressive disorder. clinicaltrials.gov/show/NCT01355081 Date first received: 16 May 2011.
Wang 2015 {published data only}
    1. Kct0000432. Randomised, double‐blind, parallel‐group, active‐comparator (venlafaxine extended release), fixed‐dose study of LuAA21004 in major depressive disorder in Asian countries. cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=2532 Date first approved: 16 August 2011.
    1. NCT01571453. Randomised, double‐blind, parallel‐group, active‐comparator (venlafaxine extended release), fixed‐dose study of [vortioxetine] Lu AA21004 in major depressive disorder in Asian countries. clinicaltrials.gov/show/NCT01571453 Date first received: 28 March 2012.
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References to studies excluded from this review

Boulenger 2012 {published data only}
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Browning 2014 {published data only}
    1. Browning M, Smith J, Conen S, Smallman R, Buchbjerg J, Larsen Kg, et al. Vortioxetine reduces BOLD signal during performance of the N‐back task in subjects remitted from depression and healthy control participants. 28th European College of Neuropsychopharmacology, ECNP Congress; 2015 Aug 29 to Sep 1; Amsterdam, Netherlands. 2015:S314‐5.
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Jacobsen 2015a {published data only}
    1. Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, Clayton AH. Effect of vortioxetine vs. escitalopram on sexual functioning in adults with well‐treated major depressive disorder experiencing SSRI‐induced sexual dysfunction. Journal of Sexual Medicine 2015;12(10):2036‐48. - PubMed
Jacobsen 2015b {published data only}
    1. Jacobsen PL, Harper L, Chrones L, Chan S, Mahableshwarkar AR. Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open‐label, flexible‐dose, 52‐week extension study. International Clinical Psychopharmacology 2015;30(5):255‐64. - PMC - PubMed
Montgomery 2014 {published data only}
    1. Haggstrom L, Nielsen RZ, Danchenko N, Poulsen L. A randomised, double‐blind, study of vortioxetine versus agomelatine in adults with major depressive disorder (MDD) with inadequate response to SSRI/SNRI treatment. 26th European College of Neuropsychopharmacology, ECNP Congress; 2013 Oct 5‐9; Barcelona, Spain. 2013:S412.
    1. Haggstrom L, Nielsen RZ, Dragheim M. Randomized, double‐blind, study of vortioxetine versus agomelatine in adults with MDD after inadequate response to SSRI or SNRI treatment. European Psychiatry 2013;28(Suppl 1):3009.
    1. Montgomery SA, Nielsen RZ, Poulsen LH, Haggstrom L. A randomised, double‐blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin‐noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine. Human Psychopharmacology 2014;29(5):470‐82. [EUCTR2011‐002362‐21; NCT01488071] - PMC - PubMed
    1. NCT01488071. A randomised, double‐blind, parallel‐group, active‐controlled, flexible dose study evaluating the effects of Lu AA21004 versus agomelatine in adult patients suffering from major depressive disorder with inadequate response to antidepressant treatment. clinicaltrials.gov/show/NCT01488071 Date first received: 29 November 2011.
    1. Papakostas G, Dragheim M, Nielsen RZ. Efficacy and tolerability of vortioxetine is independent of previous treatment in MDD patients switched after an inadequate response. European Neuropsychopharmacology 2014;24:S466. - PubMed
NCT02371980 {published data only}
    1. NCT02371980. A randomized, double‐blind, placebo‐controlled, phase 4, relapse prevention study evaluating the efficacy and safety of vortioxetine (5, 10 and 20 mg) in adults with major depressive disorder. clinicaltrials.gov/show/NCT02371980 Date first received: 20 February 2015.

References to studies awaiting assessment

NCT02272517 {published data only}
    1. NCT02272517. An interventional, randomised, double‐blind, parallel‐group, active‐comparator, flexible‐dose study on the efficacy of vortioxetine versus escitalopram on cognitive dysfunction in patients with inadequate response to current antidepressant treatment of major depressive disorder. clinicaltrials.gov/show/NCT02272517 Date first received: 21 October 2014.
NCT02279966 {published data only}
    1. NCT02279966. An interventional, randomised, double‐blind, parallel‐group, placebo‐controlled, active‐referenced (paroxetine), fixed‐dose study on the efficacy of vortioxetine on cognitive dysfunction in working patients with major depressive disorder. clinicaltrials.gov/show/NCT02279966 Date first received: 21 October 2014.

References to ongoing studies

NCT02294305 {published data only}
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NCT02389816 {published data only}
    1. Jprn‐Japiccti‐152831. A randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study to assess the efficacy and safety of Lu AA21004 in patients with major depressive disorder. www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI‐152831 Date first received: 4 March 2015.
    1. NCT02389816. A randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study to assess the efficacy and safety of Lu AA21004 in patients with major depressive disorder. clinicaltrials.gov/show/NCT02389816 Date first received: 10 March 2015.

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