Vortioxetine Versus Placebo for Major Depressive Disorder: A Comprehensive Analysis of the Clinical Trial Dataset

Nadia Iovieno, MD; George I. Papakostas, MD; Anna Feeney, MD; Maurizio Fava, MD; Sanjay J. Mathew, MD; Dan I. Iosifescu, MD, MSc; James W. Murrough, MD, PhD; Matthew Macaluso, DO; Rebecca S. Hock, PhD; Manish K. Jha, MD

J Clin Psychiatry 2021;82(4):20r13682

ABSTRACT

Objective: To conduct a meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD).

Data Sources: Abstracts were identified using PubMed by cross-referencing vortioxetine with placebo and randomized. No language or publication year restrictions were used.

Study Selection: Randomized, double-blind, placebo-controlled clinical trials comparing oral vortioxetine monotherapy with placebo for acute treatment of MDD.

Data Extraction: Data were extracted with a pre-coded form, as follows: number of patients randomized, treatment group, Montgomery-Asberg Depression Rating Scale (MADRS) response and remission rates, and mean change in scores from baseline and standard errors for the MADRS, Hamilton Anxiety Rating Scale (HARS), and Digit Symbol Substitution Test (DSST).

Results: 7,269 subjects randomized to vortioxetine (n = 3,630) or placebo (n = 3,639) from 17 studies were included. The probability of receiving placebo did not predict difference in change in MADRS scores between vortioxetine and placebo (estimate = 4.1, P = .54). The standardized mean difference (SMD) (95% CI) for change in MADRS score for vortioxetine overall versus placebo was 0.33 (0.24 to 0.41) and was 0.24 (0.08 to 0.39), 0.33 (0.19 to 0.47), 0.26 (−0.06 to 0.58), and 0.44 (0.27 to 0.62) for 5-mg, 10-mg, 15-mg, and 20-mg doses, respectively. Greater difference in efficacy between drug and placebo was observed in studies with a low rather than a high placebo response rate.

Conclusions: Vortioxetine is more effective than placebo in improving depression, anxiety, and cognition. Less informative or uninformative studies obscured the true treatment effect.

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References (60)

Papakostas GI, Jackson WC, Rafeyan R, et al. Inadequate response to antidepressant treatment in major depressive disorder. J Clin Psychiatry. 2020;81(3):OT19037COM5. PubMed
Papakostas GI, Jackson WC, Rafeyan R, et al. Overcoming challenges to treat inadequate response in major depressive disorder. J Clin Psychiatry. 2020;81(3):OT19037BR4. PubMed
Rafeyan R, Papakostas GI, Jackson WC, et al. Inadequate response to treatment in major depressive disorder: augmentation and adjunctive strategies. J Clin Psychiatry. 2020;81(3):OT19037BR3. PubMed CrossRef
Jackson WC, Papakostas GI, Rafeyan R, et al. Recognizing inadequate response in patients with major depressive disorder. J Clin Psychiatry. 2020;81(3):OT19037BR2. PubMed CrossRef
Trivedi MH, Papakostas GI, Jackson WC, et al. Implementing measurement-based care to determine and treat inadequate response. J Clin Psychiatry. 2020;81(3):OT19037BR1. PubMed CrossRef
Trivedi MH. How can measurement-based care help improve treatment outcomes for major depressive disorder in primary care? J Clin Psychiatry. 2020;81(2):UT17042BR2C. PubMed CrossRef
Trivedi MH. Major depressive disorder in primary care: strategies for identification. J Clin Psychiatry. 2020;81(2):UT17042BR1C. PubMed CrossRef
Citrome L, Gaynes BN, Goldberg JF, et al. New mechanisms, new opportunities: integrating novel antidepressants in the treatment of major depressive disorder. J Clin Psychiatry. 2019;80(5):TK18061AS2C. PubMed CrossRef
Thase ME. Current and emerging treatments to address unmet needs in MDD. J Clin Psychiatry. 2019;80(1):AL18009BR1C. PubMed
Zhang J, Mathis MV, Sellers JW, et al. The US Food and Drug Administration’s perspective on the new antidepressant vortioxetine. J Clin Psychiatry. 2015;76(1):8–14. PubMed CrossRef
Connolly KR, Thase ME. Vortioxetine: a new treatment for major depressive disorder. Expert Opin Pharmacother. 2016;17(3):421–431. PubMed CrossRef
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):138–149. PubMed CrossRef
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):575–582. PubMed CrossRef
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):583–591. PubMed CrossRef
Baune BT, Brignone M, Larsen KG. A network meta-analysis comparing effects of various antidepressant classes on the Digit Symbol Substitution Test (DSST) as a measure of cognitive dysfunction in patients with major depressive disorder. Int J Neuropsychopharmacol. 2018;21(2):97–107. PubMed CrossRef
Inoue T, Sasai K, Kitagawa T, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and safety of vortioxetine in Japanese patients with major depressive disorder. Psychiatry Clin Neurosci. 2020;74(2):140–148. PubMed CrossRef
Papakostas GI. Antidepressants and their effect on cognition in major depressive disorder. J Clin Psychiatry. 2015;76(8):e1046. PubMed CrossRef
Papakostas GI, Culpepper L. Understanding and managing cognition in the depressed patient. J Clin Psychiatry. 2015;76(4):418–425. PubMed CrossRef
Berhan A, Barker A. Vortioxetine in the treatment of adult patients with major depressive disorder: a meta-analysis of randomized double-blind controlled trials. BMC Psychiatry. 2014;14(1):276. PubMed CrossRef
Meeker AS, Herink MC, Haxby DG, et al. The safety and efficacy of vortioxetine for acute treatment of major depressive disorder: a systematic review and meta-analysis. Syst Rev. 2015;4(1):21. PubMed CrossRef
Pae CU, Wang SM, Han C, et al. Vortioxetine: a meta-analysis of 12 short-term, randomized, placebo-controlled clinical trials for the treatment of major depressive disorder. J Psychiatry Neurosci. 2015;40(3):174–186. PubMed CrossRef
Baldwin DS, Florea I, Jacobsen PL, et al. A meta-analysis of the efficacy of vortioxetine in patients with major depressive disorder (MDD) and high levels of anxiety symptoms. J Affect Disord. 2016;206:140–150. PubMed CrossRef
Thase ME, Mahableshwarkar AR, Dragheim M, et al. A meta-analysis of randomized, placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in adults. Eur Neuropsychopharmacol. 2016;26(6):979–993. PubMed CrossRef
Koesters M, Ostuzzi G, Guaiana G, et al. Vortioxetine for depression in adults. Cochrane Database Syst Rev. 2017;7(7):CD011520. PubMed
Nomikos GG, Tomori D, Zhong W, et al. Efficacy, safety, and tolerability of vortioxetine for the treatment of major depressive disorder in patients aged 55 years or older. CNS Spectr. 2017;22(4):348–362. PubMed CrossRef
Christensen MC, Florea I, Lindsten A, et al. Efficacy of vortioxetine on the physical symptoms of major depressive disorder. J Psychopharmacol. 2018;32(10):1086–1097. PubMed CrossRef
Zheng J, Wang Z, Li E. The efficacy and safety of 10 mg/day vortioxetine compared to placebo for adult major depressive disorder: a meta-analysis. Afr Health Sci. 2019;19(1):1716–1726. PubMed CrossRef
Papakostas GI, Charles D, Fava M. Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? a meta-analysis of randomized, double-blind, placebo-controlled, dose-finding studies in major depressive disorder. World J Biol Psychiatry. 2010;11(2 pt 2):300–307. PubMed CrossRef
Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? a meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2009;19(1):34–40. PubMed CrossRef
Iovieno N, Nierenberg AA, Parkin SR, et al. Relationship between placebo response rate and clinical trial outcome in bipolar depression. J Psychiatr Res. 2016;74:38–44. PubMed CrossRef
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134(4):382–389. PubMed CrossRef
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–55. PubMed CrossRef
Jaeger J. Digit symbol substitution test: the case for sensitivity over specificity in neuropsychological testing. J Clin Psychopharmacol. 2018;38(5):513–519. PubMed CrossRef
Lenze EJ, Stevens A, Waring JD, et al. Augmenting computerized cognitive training with vortioxetine for age-related cognitive decline: a randomized controlled trial. Am J Psychiatry. 2020;177(6):548–555. PubMed CrossRef
Vieta E, Florea I, Schmidt SN, et al. Intravenous vortioxetine to accelerate onset of effect in major depressive disorder: a 2-week, randomized, double-blind, placebo-controlled study. Int Clin Psychopharmacol. 2019;34(4):153–160. PubMed CrossRef
Nierenberg AA, Loft H, Olsen CK. Treatment effects on residual cognitive symptoms among partially or fully remitted patients with major depressive disorder: a randomized, double-blinded, exploratory study with vortioxetine. J Affect Disord. 2019;250:35–42. PubMed CrossRef
Smith J, Browning M, Conen S, et al. Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls. Mol Psychiatry. 2018;23(5):1127–1133. PubMed CrossRef
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(11):1408–1416. PubMed CrossRef
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):482–491. PubMed CrossRef
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):217–226. PubMed CrossRef
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):313–321. PubMed CrossRef
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):953–959. PubMed CrossRef
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):215–223. PubMed CrossRef
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):589–600. PubMed CrossRef
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):2061–2070. PubMed CrossRef
Nishimura A, Aritomi Y, Sasai K, et al. Randomized, double-blind, placebo-controlled 8-week trial of the efficacy, safety, and tolerability of 5, 10, and 20 mg/day vortioxetine in adults with major depressive disorder. Psychiatry Clin Neurosci. 2018;72(2):64–72. PubMed CrossRef
Inoue T, Nishimura A, Sasai K, et al. Randomized, 8-week, double-blind, placebo-controlled trial of vortioxetine in Japanese adults with major depressive disorder, followed by a 52-week open-label extension trial. Psychiatry Clin Neurosci. 2018;72(2):103–115. PubMed CrossRef
Baune BT, Sluth LB, Olsen CK. The effects of vortioxetine on cognitive performance in working patients with major depressive disorder: a short-term, randomized, double-blind, exploratory study. J Affect Disord. 2018;229:421–428. PubMed CrossRef
McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557–1567. PubMed CrossRef
Mahableshwarkar AR, Zajecka J, Jacobson W, et al. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology. 2016;41(12):2961. PubMed CrossRef
Liebowitz MR, Careri J, Blatt K, et al. Vortioxetine versus placebo in major depressive disorder comorbid with social anxiety disorder. Depress Anxiety. 2017;34(12):1164–1172. PubMed CrossRef
Thase M, Asami Y, Wajsbrot D, et al. A meta-analysis of the efficacy of venlafaxine extended release 75–225 mg/day for the treatment of major depressive disorder. Curr Med Res Opin. 2017;33(2):317–326. PubMed CrossRef
Ball SG, Desaiah D, Zhang Q, et al. Efficacy and safety of duloxetine 60 mg once daily in major depressive disorder: a review with expert commentary. Drugs Context. 2013;2013:212245. PubMed
Gopalakrishnan M, Zhu H, Farchione TR, et al. The trend of increasing placebo response and decreasing treatment effect in schizophrenia trials continues: an update from the US Food and Drug Administration. J Clin Psychiatry. 2020;81(2):19r12960. PubMed CrossRef
Salloum NC, Fava M, Ball S, et al. Success and efficiency of phase 2/3 adjunctive trials for MDD funded by industry: a systematic review. Mol Psychiatry. 2020;25(9):1967–1974. PubMed CrossRef
Papakostas GI, Østergaard SD, Iovieno N. The nature of placebo response in clinical studies of major depressive disorder. J Clin Psychiatry. 2015;76(4):456–466. PubMed CrossRef
Trivedi MH, South C, Jha MK, et al. A novel strategy to identify placebo responders: prediction index of clinical and biological markers in the EMBARC Trial. Psychother Psychosom. 2018;87(5):285–295. PubMed CrossRef
Zimmerman M, Balling C, Chelminski I, et al. Have treatment studies of depression become even less generalizable? applying the inclusion and exclusion criteria in placebo-controlled antidepressant efficacy trials published over 20 years to a clinical sample. Psychother Psychosom. 2019;88(3):165–170. PubMed CrossRef
Iltis AS, McCall WV, Deria R. Suicidality, depression, and the FDA: health inequities and the ethical conduct of research. J Clin Psychiatry. 2020;81(2):19m13050. PubMed CrossRef
Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342–351. PubMed CrossRef