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

Atul R Mahableshwarkar, Paula L Jacobsen, Yinzhong Chen, Michael Serenko, Madhukar H Trivedi, Atul R Mahableshwarkar, Paula L Jacobsen, Yinzhong Chen, Michael Serenko, Madhukar H Trivedi

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/ .

Figures

Fig. 1
Fig. 1
Patient disposition.aAll randomized patients who received ≥1 dose of double-blind study medication; bAll randomized patients who received ≥1 dose of double-blind study medication and had ≥1 valid post-baseline efficacy assessment; cAll patients in the full analysis set who had no major protocol violations
Fig. 2
Fig. 2
Least-squares change from baseline in Montgomery–Åsberg Depression Rating Scale total score by visit (full analysis set; mixed model for repeated measures). *Nominal P < .050; **Nominal P < .010; ***Nominal P < .001 vs placebo; †P < .025

References

    1. Alvarez E, Perez V, Dragheim M, Loft H, Artigas F. A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012;15:589–600. doi: 10.1017/S1461145711001027.
    1. Baldwin DS, Hansen T, Florea I. Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder. Curr Med Res Opin. 2012;28:1717–1724. doi: 10.1185/03007995.2012.725035.
    1. 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;22:482–491. doi: 10.1016/j.euroneuro.2011.11.008.
    1. Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhnog H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB. 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;54:3206–3221. doi: 10.1021/jm101459g.
    1. Boulenger JP, Loft H, Florea I. A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder. J Psychopharmacol. 2012;26:1408–1416. doi: 10.1177/0269881112441866.
    1. Boulenger JP, Loft H, Olsen CK. Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomised, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder. Int Clin Psyhcopharmacol. 2014;29:138–149. doi: 10.1097/YIC.0000000000000018.
    1. Bridge JA, Birmaher B, Iyengar S, Barbe RP, et al. Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder. Am J Psychiatr. 2009;166:42–49. doi: 10.1176/appi.ajp.2008.08020247.
    1. Brunoni AR, Lopes M, Kaptchuk TJ, Fregni F. Placebo response of non-pharmacological and pharmacological trials in major depression: a systematic review and meta-analysis. PLoS One. 2009;4:e4824. doi: 10.1371/journal.pone.0004824.
    1. Delgado PL, Brannan SK, Mallinckrodt CH, Tran PV, McNamara RK, Watkin JG, Detke MJ. Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder. J Clin Psychiatr. 2005;66:686–692. doi: 10.4088/JCP.v66n0603.
    1. Guy W (1976) Clinical global impressions (028-CGI). Revised ed. Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 217–222.
    1. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50–55. doi: 10.1111/j.2044-8341.1959.tb00467.x.
    1. Henigsberg N, Mahableshwarkar AR, Jacobsen P, Chen Y, Thase ME. 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 Psychiatr. 2012;73:953–959. doi: 10.4088/JCP.11m07470.
    1. Jacobsen P, Mahableshwarkar AR, Serenko M, Chan S, Trivedi M (2013) 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 [abstract]. American Psychiatric Association (APA) 166th Annual Meeting 2013 (manuscript submitted for publication J Clin Psych)
    1. Jain R, Mahableshwarkar A, Jacobson P, Chen Y, Thase ME. A randomized, double-blind, placebo-controlled 6-weeks trial of the efficacy and tolerability of 5 mg vortioxetine in adults with major depressive disorder. Int J Neuropsychopharmacol. 2013;16:313–321. doi: 10.1017/S1461145712000727.
    1. 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;27:215–223. doi: 10.1097/YIC.0b013e3283542457.
    1. Khan A, Bhat A, Kolts R, Thase ME, et al. Why has the antidepressant-placebo difference in antidepressant clinical trials diminished over the past three decades? CNS Neurosci Ther. 2010;16:217–226. doi: 10.1111/j.1755-5949.2010.00151.x.
    1. Mahableshwarkar AR, Jacobsen PL, Serenko M, Chen Y, Trivedi M (2013a) A duloxetine-referenced fixed dose study comparing efficacy and safety of 2 vortioxetine doses in the acute treatment of adult MDD patients [abstract]. American Psychiatric Association (APA) 166th Annual Meeting 2013 (manuscript submitted for publication J Clin Psych)
    1. 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;29:217–226. doi: 10.1185/03007995.2012.761600.
    1. McGahuey CA, Gelenberg AJ, Laukes CA, Moreno FA, Delgado PL, McKnoght KM, Manber R. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther. 2000;26:25–40. doi: 10.1080/009262300278623.
    1. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatr. 1979;134:382–389. doi: 10.1192/bjp.134.4.382.
    1. Mørk A, Pehrson A, Brennum L, Nielsen SM, Zhong H, Lassen AB, Miller S, Westrich L, Boyle NJ, Sanchez C, Fischer CW, Liebenberg N, Wegener G, Bundgaard C, Hogg S, Bang-Andersen B, Stensbøl TB. Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J Pharmacol Exp Ther. 2012;340:666–675. doi: 10.1124/jpet.111.189068.
    1. Mundt JC, Greist JH, Jefferson JW, Katzelnick DJ, et al. Is it easier to find what you are looking for if you think you know what it looks like? J Clin Psychopharmacol. 2007;27:121–125. doi: 10.1097/JCP.0b013e3180387820.
    1. Pehrson AL, Cremers T, Betry C, van der Hart MG, Jørgensen L, Madsen M, Haddjeri N, Ebert B, Sanchez C. Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters—a rat microdialysis and electrophysiology study. Eur Neuropsychopharmacol. 2013;23:133–145. doi: 10.1016/j.euroneuro.2012.04.006.
    1. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oguendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatr. 2011;168:1266–1277. doi: 10.1176/appi.ajp.2011.10111704.
    1. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatr. 2006;163:1905–1917. doi: 10.1176/ajp.2006.163.11.1905.
    1. Sanchez C, Asin K, Artigas F. Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther. 2014
    1. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009;29:259–266. doi: 10.1097/JCP.0b013e3181a5233f.
    1. Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol. 1996;11:89–95. doi: 10.1097/00004850-199606003-00015.
    1. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatr. 2006;163:28–40. doi: 10.1176/appi.ajp.163.1.28.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться