Vortioxetine for Cognitive Impairment in Major Depressive Disorder During Post-COVID Syndrome: Real-World Evidence

Hernan F. Guillen-Burgos, MD, MSc ; Juan F. Galvez-Florez, MD ; Sergio Moreno-López, PhD ; Juan-Manuel Anaya, MD, PhD ; Angela T.H. Kwan, MSc ; Roger S. McIntyre, MD, FRCPC

J Clin Psychiatry 2025;86(2):24m15387

Abstract

Objective: To compare the effectiveness of vortioxetine versus escitalopram and sertraline as a treatment in individuals with major depressive disorder (MDD) and post-COVID syndrome (PCS).

Methods: This is a prospective, open-label, comparative effectiveness study in individuals with new-onset MDD as PCS outcome. The study was carried out in 1 clinical site. Individuals who had a history of confirmed SARS-CoV 2 infection, who met World Health Organization–defined criteria for PCS, and who met new-onset of MDD criteria according to DSM-5-TR were included. Participants that were eligible were assigned to receive vortioxetine at 10–20 mg/d, escitalopram 10–20 mg/d, or sertraline 50–200 mg/d over 8 weeks. The primary and secondary outcomes were changes from baseline to end point in Digital Symbol Substitution Test (DSST) and Montgomery-Asberg Depression Rating Scale (MADRS) or Patient Reported Outcome Measurement Information System Fatigue Short Form 7a (PROMIS 7a), respectively. Data were collected during January 2022 and December 2023.

Results: 140 participants were assigned to received vortioxetine (n = 70), escitalopram (n = 36), or sertraline (n = 34). Participants assigned to vortioxetine exhibited significant changes in DSST scores from baseline to end point compared to escitalopram or sertraline (least squares [LS] mean differences, 8.25; 95% CI, 6.25–10.25; P < .001; LS mean differences, 8.00; 95% CI, 5.95–10.06; P < .001, respectively). Participants in the vortioxetine treatment group reported significantly greater changes in total MADRS scores from baseline to end point compared to escitalopram or sertraline (LS mean differences, −4.06; 95% CI, −4.92 to −3.20; P < .001; LS mean differences, −3.94; 95% CI, −4.83 to −3.06; P < .001, respectively).

Conclusion: Vortioxetine has a significant procognitive effect. Antidepressant effects and improvement in fatigue symptoms (PROMIS 7a) also were observed.

J Clin Psychiatry 2025;86(2):24m15387

Author affiliations are listed at the end of this article.

Continue Reading...

Members enjoy unlimited free PDF downloads as part of their subscription! Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

Buy PDF for $40

Please sign in or purchase this PDF for $40.

References (64)

World Health Organization. A Clinical Case Definition of Post COVID-19 Condition by a Delphi Consensus, 6 October 2021. 2021.
Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133–146. PubMed CrossRef
Anaya JM, Rojas M, Salinas ML, et al. Post-COVID syndrome. A case series and comprehensive review. Autoimmun Rev. 2021;20(11):102947. PubMed CrossRef
Kim Y, Bae S, Chang H-H, et al. Long COVID prevalence and impact on quality of life 2 years after acute COVID-19. Sci Rep. 2023;13(1):11207. PubMed CrossRef
Taquet M, Luciano S, Geddes JR, et al. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID 19 cases in the USA. Lancet Psychiatry. 2021;8(2):130–140. PubMed CrossRef
Guillen-Burgos HF, Galvez-Florez JF, Moreno-Lopez S, et al. Factors associated with mental health outcomes after COVID-19: a 24-month follow-up longitudinal study. Gen Hosp Psychiatry. 2023;84:241–249. PubMed CrossRef
Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID 19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93–135. PubMed CrossRef
Taquet M, Sillett R, Zhu L, et al. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry. 2022;9(10):815–827. PubMed CrossRef
Taquet M, Geddes JR, Husain M, et al. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8(5):416–427. PubMed CrossRef
GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9(2):137–150. PubMed CrossRef
McIntyre RS, Phan L, Kwan ATH, et al. Vortioxetine for the treatment of post-COVID-19 condition: a randomized controlled trial. Brain. 2024;147(3):849–857. PubMed CrossRef
McIntyre R, Harrison J, Loft H, et al. The effects of vortioxetine on cognitive function in patients with major depressive disorder: a meta-analysis of three randomized controlled trials. Int J Neuropsychopharmacol. 2016;19(10):pyw055. 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
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
Lam RW, Lamy F-X, Danchenko N, et al. Psychometric validation of the Perceived Deficits Questionnaire-Depression (PDQ-D) instrument in US and UK respondents with major depressive disorder. Neuropsychiatr Dis Treat. 2018;14:2861–2877. PubMed CrossRef
Quilty LC, Robinson JJ, Rolland JP, et al. The structure of the Montgomery–Åsberg depression rating scale over the course of treatment for depression. Int J Methods Psychiatr Res. 2013;22(3):175–184. PubMed CrossRef
Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–389. PubMed
Cano JF, Gomez Restrepo C, Rondón M. Validación en Colombia del instrumento para evaluación de la depresión Montgomery-Åsberg Depression Rating Scale (MADRS). Rev Colomb Psiquiatr. 2016;45(3):146–155. PubMed CrossRef
Ganesh R, Ghosh AK, Nyman MA, et al. PROMIS scales for assessment of persistent post-COVID symptoms: a cross sectional study. J Prim Care Community Health. 2021;12:21501327211030413. PubMed CrossRef
Yang M, Keller S, Lin J-MS. Psychometric properties of the PROMIS^®Fatigue Short Form 7a among adults with myalgic encephalomyelitis/chronic fatigue syndrome. Qual Life Res. 2019;28(12):3375–3384. PubMed CrossRef
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):1266–1277. PubMed CrossRef
von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573–577. PubMed CrossRef
Talmon M, Rossi S, Pastore A, et al. Vortioxetine exerts anti-inflammatory and immunomodulatory effects on human monocytes/macrophages. Br J Pharmacol. 2018;175(1):113–124. PubMed CrossRef
McIntyre RS, Cha DS, Soczynska JK, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30(6):515–527. PubMed CrossRef
Beck AT, Bredemeier K. A unified model of depression: integrating clinical, cognitive, biological, and evolutionary perspectives. Clin Psychol Sci. 2016;4:596–619.
Liu J, Chen Y, Xie X, et al. The percentage of cognitive impairment in patients with major depressive disorder over the course of the depression: a longitudinal study. J Affect Disord. 2023;329:511–518. PubMed CrossRef
Mazza MG, Zanardi R, Palladini M, et al. Rapid response to selective serotonin reuptake inhibitors in post-COVID depression. Eur Neuropsychopharmacol. 2022;54:1–6. PubMed CrossRef
Prado CE, Watt S, Crowe SF. A meta-analysis of the effects of antidepressants on cognitive functioning in depressed and non-depressed samples. Neuropsychol Rev. 2018;28(1):32–72. PubMed CrossRef
Boulenger J-P, 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
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
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
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
Alboni S, Benatti C, Colliva C, et al. Vortioxetine prevents lipopolysaccharide induced memory impairment without inhibiting the initial inflammatory cascade. Front Pharmacol. 2020;11:603979. PubMed CrossRef
Li Y, Abdourahman A, Tamm JA, et al. Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice. Pharmacol Biochem Behav. 2015;135:70–82. PubMed CrossRef
Guilloux J-P, Mendez-David I, Pehrson A, et al. Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Neuropharmacology. 2013;73:147–159. PubMed CrossRef
Bétry C, Etiévant A, Pehrson A, et al. Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory. Prog Neuropsychopharmacol Biol Psychiatry. 2015;58:38–46.
Tedeschini E, Levkovitz Y, Iovieno N, et al. Efficacy of antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-controlled randomized trials. J Clin Psychiatry. 2011;72(12):1660–1668. PubMed CrossRef
Dale E, Zhang H, Leiser SC, et al. Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus. J Psychopharmacol. 2014;28(10):891–902. PubMed CrossRef
Jensen JB, du Jardin KG, Song D, et al. Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation. Eur Neuropsychopharmacol. 2014;24(1):148–159. PubMed CrossRef
du Jardin KG, Jensen JB, Sanchez C, et al. Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. Eur Neuropsychopharmacol. 2014;24(1):160–171. PubMed CrossRef
Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199–229. PubMed CrossRef
Hodes GE, Kana V, Menard C, et al. Neuroimmune mechanisms of depression. Nat Neurosci. 2015;18(10):1386–1393. PubMed CrossRef
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22–34. PubMed CrossRef
Del Valle DM, Kim-Schulze S, Huang HH, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636–1643. PubMed CrossRef
Iwamura APD, Tavares da Silva MR, Hümmelgen AL, et al. Immunity and inflammatory biomarkers in COVID-19: a systematic review. Rev Med Virol. 2021;31(4):e2199. PubMed CrossRef
Ponti G, Maccaferri M, Ruini C, et al. Biomarkers associated with COVID-19 disease progression. Crit Rev Clin Lab Sci. 2020;57(6):389–399. PubMed CrossRef
Anaya J-M, Herrán M, Beltrán S, et al. Is post-COVID syndrome an autoimmune disease? Expert Rev Clin Immunol. 2022;18(7):653–666. PubMed CrossRef
Lai Y-J, Liu SH, Manachevakul S, et al. Biomarkers in long COVID-19: a systematic review. Front Med. 2023;10:1085988. PubMed CrossRef
Renaud-Charest O, Lui LMW, Eskander S, et al. Onset and frequency of depression in post-COVID-19 syndrome: a systematic review. J Psychiatr Res. 2021;144:129–137. PubMed CrossRef
Mazza MG, Palladini M, De Lorenzo R, et al. Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up. Brain Behav Immun. 2021;94:138–147. PubMed CrossRef
Hazumi M, Usuda K, Okazaki E, et al. Differences in the course of depression and anxiety after COVID-19 infection between recovered patients with and without a psychiatric history: a cross-sectional study. Int J Environ Res Public Health. 2022;19(18):11316. PubMed CrossRef
Di Nicola M, Pepe M, De Mori L, et al. Physical and cognitive correlates, inflammatory levels, and treatment response in post-COVID-19 first-onset vs. recurrent depressive episodes. Eur Arch Psychiatry Clin Neurosci. 2024;274(3):583–593. PubMed CrossRef
Villarreal-Zegarra D, Paredes-Angeles R, Mayo-Puchoc N, et al. An explanatory model of depressive symptoms from anxiety, post-traumatic stress, somatic symptoms, and symptom perception: the potential role of inflammatory markers in hospitalized COVID-19 patients. BMC Psychiatry. 2022;22(1):638. PubMed CrossRef
Badinlou F, Lundgren T, Jansson-Fröjmark M. Mental health outcomes following COVID-19 infection: impacts of post-COVID impairments and fatigue on depression, anxiety, and insomnia - a web survey in Sweden. BMC Psychiatry. 2022;22(1):743. PubMed
Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 2007;28(12):551–558. PubMed CrossRef
Youssef J, Badr M. Role of peroxisome proliferator-activated receptors in inflammation control. BioMed Res Int. 2004;2004(3):156–166. PubMed CrossRef
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association Publishing; 2022.
McMorris T, Barwood M, Hale BJ, et al. Cognitive fatigue effects on physical performance: a systematic review and meta-analysis. Physiol Behav. 2018;188:103–107. PubMed CrossRef
Van Cutsem J, Marcora S, De Pauw K, et al. The effects of mental fatigue on physical performance: a systematic review. Sports Med. 2017;47(8):1569–1588. PubMed CrossRef
Badulescu S, Le GH, Wong S, et al. Impact of vortioxetine on psychosocial functioning moderated by symptoms of fatigue in post-COVID-19 condition: a secondary analysis. Neurol Sci. 2024;45(4):1335–1342. PubMed CrossRef
Zhang X, Qi S, Lin Z, et al. Pre-operative administration of butorphanol mitigates emergence agitation in patients undergoing functional endoscopic sinus surgery: a randomized controlled clinical trial. Front Psychiatry. 2022;13:1090149. 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
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
Tan SN, Tan C. Vortioxetine improves cognition in mild cognitive impairment. Int Clin Psychopharmacol. 2021;36(6):279–287. PubMed CrossRef