Skip to main content Accessibility help
×
Home

Suicidal ideation and behavior in adults with major depressive disorder treated with vortioxetine: post hoc pooled analyses of randomized, placebo-controlled, short-term and open-label, long-term extension trials

  • Atul R. Mahableshwarkar (a1), John Affinito (a2), Elin Heldbo Reines (a3), Judith Xu (a4), George Nomikos (a5) and Paula L. Jacobsen (a6)...

Abstract

Objectives

This study aimed to evaluate the risk of suicidal ideation and behavior associated with vortioxetine treatment in adults with major depressive disorder (MDD).

Methods

Suicide-related events were evaluated post hoc using 2 study pools: one short-term pool of 10 randomized, placebo-controlled studies (6–8 weeks) and another long-term pool that included 3 open-label extension studies (52 weeks). Evaluation of suicide-related events was performed using Columbia-Suicide Severity Rating Scale (C-SSRS) scores and treatment-emergent adverse events (TEAEs) data.

Results

At baseline, the percentage of patients reporting any C-SSRS ideation or behavior events in short-term studies was similar between placebo (14.7%), vortioxetine (19.8%, 13.0%, 11.2%, and 13.7% for 5-, 10-, 15-, and 20-mg groups, respectively), and duloxetine active reference (13.2%) and did not change throughout the 6- to 8-week treatment period for placebo (17.0%), vortioxetine (19.3%, 13.5%, 12.6%, and 15% for 5-, 10-, 15-, and 20-mg groups, respectively), or duloxetine (11.3%). The incidence of suicide-related events for TEAEs in the short-term pool was 0.4% for placebo, 0.2% or 1.0% for vortioxetine 5 mg or 10 mg, and 0.7% each for vortioxetine 15 mg and 20 mg, as well as duloxetine. After 52-week treatment with vortioxetine, suicidal ideation based on C-SSRS was 9.8%, C-SSRS suicidal behavior was 0.2%, and the incidence of suicide-related events based on TEAEs was <1%. There were no completed suicides in any study.

Conclusions

Vortioxetine is not associated with increased risk of suicidal ideation or behavior in MDD patients.

Copyright

Corresponding author

*Address correspondence to: Paula L. Jacobsen, Neuroscience, Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL 60015, USA. (Email: pjakes1@gmail.com)

Footnotes

Hide All

Assistance with manuscript preparation was provided by Andrea McReynolds, PhD, and Martina Schwarzkopf, PhD, of inVentiv Medical Communications, LLC, a Syneos Health™ group company, and supported by Takeda Pharmaceutical Company, Ltd., and H. Lundbeck A/S. All authors assume full responsibility for the scientific content of the manuscript. The study was funded by Takeda Pharmaceutical Company, Ltd., and H. Lundbeck A/S.

Footnotes

References

Hide All
1.National Institutes of Mental Health website. 2015. Major Depression among Adults. https://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adults.shtml/index.shtml. Accessed September 7, 2017.
2.Oquendo, MA, Perez-Rodriguez, MM, Poh, E, et al. Life events: a complex role in the timing of suicidal behavior among depressed patients. Mol Psychiatry. 2014; 19(8): 902909.
3.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
4.Zalsman, G, Hawton, K, Wasserman, D, et al. Suicide prevention strategies revisited: 10-year systematic review. Lancet Psychiatry. 2016; 3(7): 646659.
5.Hillhouse, TM, Porter, JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015; 23(1): 121.
6.American Foundation for Suicide Prevention. 2017. About suicide: risk factors and warning signs. https://afsp.org/about-suicide/risk-factors-and-warning-signs/. Accessed December 13, 2017.
7.Castelpietra, G, Gobbato, M, Valent, F, et al. Antidepressant use in suicides: a case-control study from the Friuli Venezia Giulia Region, Italy, 2005–2014. Eur J Clin Pharmacol. 2017; 73(7): 883890.
8.Pratt, L, Brody, DJ, Gu, Q. Antidepressant use among persons aged 12 and over: United States, 2011–2014. NCHS Data Brief, No. 283. Hyattsville, MD: National Center for Health Statistics; 2017.
9.Organisation for Economic Co-operation and Development. Antidepressant consumption, 2000 and 2014 (or nearest year). In: Gautam, A, ed. Tackling Wasteful Spending on Health. Paris, France: OECD Publishing; 2017. http://dx.doi.org/10.1787/9789264266414-graph13-en. Accessed October 9, 2017.
10.US Food and Drug Administration. 2004. Labeling Change Request Letter for Antidepressant Medications. https://wayback.archive-it.org/7993/20170723172451/https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm096352.htm. Accessed November 2, 2017.
11.Hammad, TA, Laughren, T, Racoosin, J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006; 63(3): 332339.
12.FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications [news release]. Silver Spring, MD: US Food and Drug Administration; May 2, 2007. http://wayback.archive-it.org/7993/20161024000444/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108905.htm. Accessed April 17, 2018.
13.Stone, M, Laughren, T, Jones, ML, et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ. 2009; 339:b2880.
14.Hammad, TA, Laughren, TP, Racoosin, JA. Suicide rates in short-term randomized controlled trials of newer antidepressants. J Clin Psychopharmacol. 2006; 26(2): 203207.
15.Acharya, N, Rosen, AS, Polzer, JP, et al. Duloxetine: meta-analyses of suicidal behaviors and ideation in clinical trials for major depressive disorder. J Clin Psychopharmacol. 2006; 26(6): 587594.
16.Pedersen, AG. Citalopram and suicidality in adult major depression and anxiety disorders. Nord J Psychiatry. 2006; 60(5): 392399.
17.Pedersen, AG. Escitalopram and suicidality in adult depression and anxiety. Int Clin Psychopharmacol. 2005; 20(3): 139143.
18.Gibbons, RD, Brown, CH, Hur, K, et al. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012; 69(6): 580587.
19.Tollefson, GD, Fawcett, J, Winokur, G, et al. Evaluation of suicidality during pharmacologic treatment of mood and nonmood disorders. Ann Clin Psychiatry. 1993; 5(4): 209224.
20.Fillipov, G, Christens, PF. Vortioxetine (Lu AA21004) 15 and 20 mg/day: open-label long-term safety and tolerability study in major depressive disorder. Paper presented at: 26th European College of Neuropsychopharmacology (ECNP) Congress; October 5–9, 2013; Barcelona, Spain.
21.Thase, ME, Gommoll, C, Chen, C, et al. Measures of suicidality in phase 3 clinical trials of levomilnacipran ER in adults with major depressive disorder. CNS Spectr. 2017; 22(6): 475483.
22.Kasper, S, Montgomery, SA, Moller, HJ, et al. Longitudinal analysis of the suicidal behaviour risk in short-term placebo-controlled studies of mirtazapine in major depressive disorder. World J Biol Psychiatry. 2010; 11(1): 3644.
23.Rihmer, Z, Gonda, X, Kapitany, B, et al. Suicide in Hungary: epidemiological and clinical perspectives. Ann Gen Psychiatry. 2013; 12(1): 21.
24.Cheung, K, Aarts, N, Noordam, R, et al. Antidepressant use and the risk of suicide: a population-based cohort study. J Affect Disord. 2015; 174: 479484.
25.Posner, K, Brown, GK, Stanley, B, et al. The Columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011; 168(12): 12661277.
26.Trintellix (vortioxetine) [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals, America; 2017.
27.European Medicines Agency. Human Medicines – Brintellix (vortioxetine). 2017. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002717/human_med_001714.jsp&mid=WC0b01ac058001d124. Accessed January 12, 2018.
28.Bang-Andersen, B, Ruhland, T, Jorgensen, M, et al. Discovery of 1-[2-(2, 4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011; 54(9): 32063221.
29.Sanchez, C, Asin, KE, Artigas, F. Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther. 2015; 145(Suppl C): 4357.
30.Connolly, KR, Thase, ME. Vortioxetine: a new treatment for major depressive disorder. Expert Opin Pharmacother. 2016; 17(3): 421431.
31.Baldwin, DS, Chrones, L, Florea, I, et al. The safety and tolerability of vortioxetine: analysis of data from randomized placebo-controlled trials and open-label extension studies. J Psychopharmacol. 2016; 30(3): 242252.
32.Jain, R, Mahableshwarkar, AR, Jacobsen, PL, et al. A randomized, double-blind, placebo-controlled 6-wk trial of the efficacy and tolerability of 5 mg vortioxetine in adults with major depressive disorder. Int J Neuropsychopharmacol. 2013; 16(2): 313321.
33.Mahableshwarkar, AR, Jacobsen, PL, Chen, Y. 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. Curr Med Res Opin. 2013; 29(3): 217226.
34.Henigsberg, N, Mahableshwarkar, AR, Jacobsen, P, et al. 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. J Clin Psychiatry. 2012; 73(7): 953959.
35.Mahableshwarkar, AR, Jacobsen, PL, Chen, Y, et al. 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 (Berl). 2015; 232(12): 20612070.
36.Jacobsen, PL, Mahableshwarkar, AR, Serenko, M, et al. 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. J Clin Psychiatry. 2015; 76(5): 575582.
37.Mahableshwarkar, AR, Jacobsen, PL, Serenko, M, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of 2 doses of vortioxetine in adults with major depressive disorder. J Clin Psychiatry. 2015; 76(5): 583591.
38.Boulenger, JP, Loft, H, Olsen, CK. Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder. Int Clin Psychopharmacol. 2014; 29(3): 138149.
39.Alvarez, E, Perez, V, Dragheim, M, et al. A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012; 15(5): 589600.
40.Baldwin, DS, Loft, H, Dragheim, M. A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD). Eur Neuropsychopharmacol. 2012; 22(7): 482491.
41.Katona, C, Hansen, T, Olsen, CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012; 27(4): 215223.
42.Alam, MY, Jacobsen, PL, Chen, Y, et al. Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible-dose, 52-week extension study. Int Clin Psychopharmacol. 2014; 29(1): 3644.
43.Jacobsen, PL, Harper, L, Chrones, L, et al. 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. Int Clin Psychopharmacol. 2015; 30(5): 255264.
44.U.S. Department of Health and Human Services, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials. Silver Spring, MD: U.S. Food and Drug Administration; 2012.
45.Klepper, MJ, Cobert, B. Drug Safety Data: How to Analyze, Summarize, and Interpret to Determine Risk. Westfield, NJ: Jones and Bartlett Learning LLC; 2011.
46.Thase, ME, Edwards, J, Durgam, S, et al. Effects of vilazodone on suicidal ideation and behavior in adults with major depressive disorder or generalized anxiety disorder: post-hoc analysis of randomized, double-blind, placebo-controlled trials. Int Clin Psychopharmacol. 2017; 32(5): 281288.
47.Grunebaum, MF, Ellis, SP, Duan, N, et al. Pilot randomized clinical trial of an SSRI vs bupropion: effects on suicidal behavior, ideation, and mood in major depression. Neuropsychopharmacology. 2012; 37(3): 697706.

Keywords

Type Description Title
WORD
Supplementary materials

Mahableshwarkar et al. supplementary material
Tables S1 and S2

 Word (34 KB)
34 KB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed