The Effects of Vortioxetine on Cognitive Function in Patients with Major Depressive Disorder: A Meta-Analysis of Three Randomized Controlled Trials

R S McIntyre, J Harrison, H Loft, W Jacobson, C K Olsen, R S McIntyre, J Harrison, H Loft, W Jacobson, C K Olsen

Abstract

Background: Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD.

Methods: Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5-20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen's d ) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only).

Results: Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25-0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial ( p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04).

Conclusions: Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.

Keywords: cognitive function; duloxetine; major depressive disorder; meta-analysis; vortioxetine.

© The Author 2016. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Total, direct, and indirect effects of vortioxetine and duloxetine on Digital Symbol Substitution Test adjusted for change from baseline in MADRS score (path analysis). *p < 0.05, **p < 0.01, ***p < 0.001 vs placebo. Numbers above bars are standardized total effect size versus placebo. P-values refer to results from unmediated ANCOVA model that did not include change in MADRS. Meta 3 studies: meta-analysis based on Mahableshwarkar et al. (2015), McIntyre et al. (2014), and Katona et al. (2012). Meta 2 studies: meta-analysis based on Mahableshwarkar et al. (2015) and Katona et al. (2012). Indirect effect: correlated with MADRS; direct effect: not correlated with MADRS. ANCOVA, analysis of covariance; DUL, duloxetine; MADRS, Montgomery-Åsberg Depression Rating Scale; VOR, vortioxetine.
Figure 2.
Figure 2.
Change in DSST (number of correct symbols; SES versus placebo) from baseline to 8 weeks after adjustment for change in MADRS total score. Data are full analysis set (FAS), ANCOVA, last observation carried forward (LOCF). ANCOVA, analysis of covariance; CI, confidence interval; DSST, Digital Symbol Substitution Test; DUL, duloxetine; MADRS, Montgomery-Åsberg Depression Rating Scale; PBO, placebo; SES, standardized effect size; VOR, vortioxetine.

References

    1. Alexopoulos GS, Meyers BS, Young RC, Mattis S, Kakuma T. (1993) The course of geriatric depression with “reversible dementia”: a controlled study. Am J Psych 150:1693–1699.
    1. American Psychiatric Association (2000. a) Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psych 157(Supp 4):1–45.
    1. American Psychiatric Association (2000. b) Diagnostic and statistical manual of mental disorders. Text revision, 4th ed Washington, DC: American Psychiatric Association.
    1. Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB. (2011) 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 54: 3206–3221.
    1. Bortolato B, Carvalho AF, McIntyre RS. (2014) Cognitive dysfunction in major depressive disorder: a state-of-the-art clinical review. CNS Neurol Disord Drug Targets 13: 1804–1818.
    1. Cohen J. (1988) Statistical power analysis for the behavioral sciences. Section 2.2, pp 20–27. Hillsdale, NJ: Lawrence Erlbaum Associates.
    1. Ditlevsen S, Christensen U, Lynch J, Damsgaard MT, Keiding N. (2005. a). The mediation proportion: a structural equation approach for estimating the proportion of exposure effect on outcome explained by an intermediate variable. Epidemiology 16:114–120.
    1. Ditlevsen S, Christensen U, Lynch J, Damsgaard MT, Keiding N. (2005. b). The mediation proportion: a structural equation approach for estimating the proportion of exposure effect on outcome explained by an intermediate variable. Appendix A, The mediation proportion: details of the basic statistical regression model. Epidemiology 16:114–120.
    1. Florea I, Danchenko N, Brignone M, Loft H, Rive B, Abetz-Webb L. (2015) The effect of vortioxetine on health-related quality of life in patients with major depressive disorder. Clin Ther 37:2309–2323.
    1. Haddjeri N, Etievant A, Pehrson A, Sanchez C, Betry C. (2012) Effects of the multimodal antidepressant Lu AA21004 on rat synaptic and cellular hippocampal plasticity and memory recognition. Eur Neuropsychopharmacol 22:S303.
    1. Hammar A, Ardal G. (2009) Cognitive functioning in major depression – a summary. Front Hum Neurosci 3:26.
    1. Higgins JP, Thompson S, Deeks JJ, Altman DG. (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560.
    1. Katona C, Hansen T, Olsen CK. (2012) 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 27:215–223.
    1. Korczyn AD, Halperin I. (2009) Depression and dementia. J Neurol Sci 283:139–142.
    1. Lam RW, Kennedy SH, Mclntyre RS, Khullar A. (2014) Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment. Can J Psychiatry 59:649–654.
    1. Lee RS, Hermens DF, Porter MA, Redoblado-Hodge MA. (2012) A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder. J Affect Disord 140:113–124.
    1. Leucht S, Hierl S, Kissling W, Dold M, Davis JM. (2012) Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry 200:97–106.
    1. Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. (2015) A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology 40:2025–2037.
    1. Mattila MJ, Mattila-Evenden ME. (1997) Effects of alcohol and hypnosedative drugs on digit-symbol substitution: comparison of two different computerized tests. J Psychopharmacol 11:313–317.
    1. Matsunaga S, Kishi T, Iwata N. (2015) Memantine monotherapy for Alzheimer’s disease: a systematic review and meta-analysis. PLOS One 10:e0123289.
    1. McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Kudlow P, Alsuwaidan M, Baskaran A. (2013) Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety 30:515–527.
    1. McIntyre RS, Lophaven S, Olsen CK. (2014) A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychop 17:1557–1567.
    1. McIntyre RS, Xiao H, Syeda K, Vinberg M, Carvalho AF, Mansur RB, Maruschak N, Cha DS. (2015. a) The prevalence, measurement, and treatment of the cognitive dimension/domain in Major Depressive Disorder. CNS Drugs 29:577–589.
    1. McIntyre RS, Soczynska JZ, Woldeyohannes, Alsuwaidan MT, Cha DS, Carvalho AF, Jerrell JM, Dale RM, Gallaugher LA, Muzina DJ, Kennedy SH2. (2015. b). The impact of cognitive impairment on perceived workforce performance: results from the International Mood Disorders Collaborative Project. Compr Psychiatry 56:279–282.
    1. Mioni G, Stablum F, Cantagallo A. (2013) Time discrimination in traumatic brain injury patients. J Clin Exp Neuropsychol 35:90–102.
    1. Montgomery S, Åsberg M. (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389.
    1. National Academies of Sciences, Engineering, and Medicine (2015). Enabling discovery, development, and translation of treatments for cognitive dysfunction in depression. Workshop summary. Washington, DC: National Academies Press (US) Available at: Accessed October 2015.
    1. Patten SB, Kennedy SH, Lam RW, O’Donovan C, Filteau MJ, Parikh SV, Ravindran AV; Canadian Network for Mood and Anxiety Treatments (2009) Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. I. Classification, burden and principles of management. J Affect Disord 117(Suppl 1):S5–14.
    1. Patterson TL, Goldman S, McKibbin CL, Hughs T, Jeste DV. (2001) UCSD Performance-Based Skills Assessment: development of a new measure of everyday functioning for severely mentally ill adults. Schizophr Bull 27:235–245.
    1. Pehrson AL, Leiser SC, Gulinello M, Dale E, Li Y, Waller JA, Sanchez C. (2015) Treatment of cognitive dysfunction in major depressive disorder – a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetine. Eur J Pharmacol 753:19–31.
    1. Pompeia S, Pradella-Hallinan M, Manzano GM, Bueno OF. (2008) Effects of lorazepam on visual perceptual abilities. Hum Psychopharmacol 23:183–192.
    1. Raskin J, Wiltse C, Siegal A, Sheikh J, Xu J, Dinkel JJ, Rotz BT, Mohs RC. (2007) Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psych 164:900–909.
    1. Riga MS, Celada P, Sanchez C, Artigas F. (2013) Role of 5-HT3 receptors in the mechanism of action of the investigational antidepressant vortioxetine. Eur Neuropsychopharmacol 23:S393–394.
    1. Rock PL, Roiser JP, Riedel WJ, Blackwell AD. (2014) Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med 44:2029–2040.
    1. Rosenblat JD, Kakar R, McIntyre RS. (2015) The cognitive effects of antidepressants in major depressive disorder: a systematic review and meta-analysis of randomized clinical trials. Int J Neuropsychop. Advance online publication. doi: 10.1093/ijnp/pyv082.
    1. Roth T, Roehrs T, Koshorek G, Sicklesteel J, Zorick F. (1987) Sedative effects of antihistamines. J Allergy Clin Immunol 80:94–98.
    1. Sáez-Fonseca JA, Lee L, Walker Z. (2007) Long-term outcome of depressive pseudodementia in the elderly. J Affect Disord 101:123–129.
    1. Sanchez C, Asin K, Artigas F. (2015) Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther 145:43–57.
    1. Snyder HR. (2013) Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: a meta-analysis and review. Psychol Bull 139:81–132.
    1. Tyson BT, Pham MT, Brown NT, Mayer TR. (2012) Patient safety considerations in the rehabilitation of the individual with cognitive impairment. Phys Med Rehabil Clin N Am 23:315–334.
    1. Wallace A, Pehrson AL, Sánchez C, Morilak DA. (2014) Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats. Int J Neuropsychop 17:1695–1706.
    1. Ward RD, Kellendonk C, Kandel ER, Balsam PD. (2012) Timing as a window on cognition in schizophrenia. Neuropharmacology 62:1175–1181.
    1. Wykes T, Reeder C, Landau S, Everitt B, Knapp M, Patel A, Romeo R. (2007) Cognitive remediation therapy in schizophrenia: randomised controlled trial. Br J Psychiatry 190:421–427.
    1. Xiang X, An R. (2015) The impact of cognitive impairment and comorbid depression on disability, health care utilization, and costs. Psychiatr Serv 66:1245–1248.

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