Skip to main content
SpringerLink
Log in

Assessing the Effects of Metabolic Disruption, Body Mass Index and Inflammation on Depressive Symptoms in Post-COVID-19 Condition: A Randomized Controlled Trial on Vortioxetine

  • Original Research
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

To date, there are no therapeutics that have gained regulatory approval by the United States Food and Drug Administration (FDA) for the treatment of post-COVID-19 condition (PCC), a debilitating condition characterized by cognitive impairment and mood symptoms. Additionally, persistent inflammation, metabolic dysfunction, and risks associated with an elevated body mass index (BMI) have been observed. Herein, we aimed to assess the efficacy of vortioxetine in improving depressive symptoms among individuals with PCC,  as modulated by inflammation, metabolic dysfunction, and BMI.

Methods

In this post-hoc analysis, we present preliminary data obtained from an 8-week randomized, double-blind, placebo-controlled trial. Participants included  adults aged 18 years and older residing in Canada who were experiencing symptoms of World Health Organization (WHO)-defined PCC. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled, 147 were randomized (1:1) to receive vortioxetine (5–20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change from baseline to endpoint in the 16-Item Quick Inventory of Depressive Symptomatology Self-Report Questionnaire (QIDS-SR-16).

Results

Our findings revealed significant effects for time (χ2 = 9.601, p = 0.002), treatment (χ2 = 9.135, p = 0.003), and the treatment × time × CRP × TG-HDL × BMI interaction (χ2 = 26.092, p < 0.001) on PCC-related depressive symptoms in the adjusted model. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint as compared to placebo (mean difference = − 5.41, SEM = 1.335, p < 0.001).

Conclusion

Overall, vortioxetine significantly improved depressive symptoms among participants with PCC in the adjusted model. Notably, individuals with baseline markers of increased inflammation, metabolic disruption, and elevated BMI exhibited a more pronounced antidepressant effect at endpoint.

Trial Registration Number

NCT05047952 (ClinicalTrials.gov).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

The data and research materials that support the findings of this study are available from the corresponding author, Roger S. McIntyre, upon reasonable request and will be anonymized.

References

  1. McIntyre RS, Rasgon NL, Kemp DE, et al. Metabolic syndrome and major depressive disorder: co-occurrence and pathophysiologic overlap. Curr Diab Rep. 2009;9(1):51–9.

    Article  PubMed  Google Scholar 

  2. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28(3):583–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cruz Neto J, Frota Cavalcante T, de Carvalho Félix ND. Post-COVID-19 metabolic syndrome: a new challenge for nursing care. Invest Educ Enferm. 2023. https://doi.org/10.17533/udea.iee.v41n1e01.

    Article  PubMed  Google Scholar 

  4. Su Y, Yuan D, Chen DG, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022;185(5):881–95.e20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Siddiqi HK, Libby P, Ridker PM. COVID-19—a vascular disease. Trends Cardiovasc Med. 2021;31(1):1–5.

    Article  CAS  PubMed  Google Scholar 

  6. Frere JJ, tenOever BR. Cardiometabolic syndrome—an emergent feature of long COVID? Nat Rev Immunol. 2022;22(7):399–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. World Health Organization. Клиничecкoe oпpeдeлeниe cлyчaя cocтoяния пocлe COVID-19 мeтoдoм дeльфийcкoгo кoнceнcyca. https://apps.who.int/iris/bitstream/handle/10665/345824/WHO-2019-nCoV-Post-COVID-19-condition-Clinical-case-definition-2021.1-rus.pdf. Accessed 11 Aug 2023.

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. World Health Organization. A clinical case definition for post COVID-19 condition in children and adolescents by expert consensus. https://apps.who.int/iris/bitstream/handle/10665/366126/WHO-2019-nCoV-Post-COVID-19-condition-CA-Clinical-case-definition-2023.1-eng.pdf. Accessed 11 Aug 2023.

  10. McIntyre RS, Phan L, Kwan ATH, et al. Vortioxetine for the treatment of post-COVID-19 condition: a randomized controlled trial. Brain. 2023. https://doi.org/10.1093/brain/awad377.

    Article  Google Scholar 

  11. 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. https://doi.org/10.1007/s10072-024-07377-z.

    Article  PubMed  Google Scholar 

  12. Le GH, Kwan ATH, Wong S, et al. Impact of elevated body mass index (BMI) on hedonic tone in persons with post-COVID-19 condition: a secondary analysis. Adv Ther. 2024;41(2):686–95.

    Article  PubMed  Google Scholar 

  13. Maamar M, Artime A, Pariente E, et al. Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study. Curr Med Res Opin. 2022;38(6):901–9.

    Article  CAS  PubMed  Google Scholar 

  14. Lacavalerie MR, Pierre-Francois S, Agossou M, et al. Obese patients with long COVID-19 display abnormal hyperventilatory response and impaired gas exchange at peak exercise. Future Cardiol. 2022;18(7):577–84.

    Article  CAS  PubMed  Google Scholar 

  15. Scherer PE, Kirwan JP, Rosen CJ. Post-acute sequelae of COVID-19: a metabolic perspective. Elife. 2022. https://doi.org/10.7554/eLife.78200.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Haroon E, Daguanno AW, Woolwine BJ, et al. Antidepressant treatment resistance is associated with increased inflammatory markers in patients with major depressive disorder. Psychoneuroendocrinology. 2018;95:43–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fenton C, Lee A. Antidepressants with anti-inflammatory properties may be useful in long COVID depression. Drugs Ther Perspect. 2023;39(2):65–70.

    Article  PubMed  Google Scholar 

  18. Heitmann J, Kreutz J, Aldudak S, Schieffer E, Schieffer B, Schäfer AC. A practical approach for the treatment of post-COVID symptoms. Herz. 2023;48(3):243–6.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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):1127–33.

    Article  CAS  PubMed  Google Scholar 

  20. McIntyre RS, Harrison J, Loft H, Jacobson W, Olsen CK. 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. https://doi.org/10.1093/ijnp/pyw055.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Talmon M, Rossi S, Pastore A, Cattaneo CI, Brunelleschi S, Fresu LG. Vortioxetine exerts anti-inflammatory and immunomodulatory effects on human monocytes/macrophages. Br J Pharmacol. 2018;175(1):113–24.

    Article  CAS  PubMed  Google Scholar 

  22. Kwan ATH, Arfaie S, Therriault J, Azizi Z, Lussier FZ, Tissot C, Chamoun M, Bezgin G, Servaes S, Stevenon J, Rahmouni N, Pallen V, Gauthier S, Rosa-Neto P (2023) Medial temporal tau predicts memory decline in cognitively unimpaired elderly. Brain Commun 5(1):fcac325. https://doi.org/10.1093/braincomms/fcac325

  23. Fourrier C, Sampson E, Mills NT, Baune BT. Anti-inflammatory treatment of depression: study protocol for a randomised controlled trial of vortioxetine augmented with celecoxib or placebo. Trials. 2018;19(1):447.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jones BDM, Farooqui S, Kloiber S, Husain MO, Mulsant BH, Husain MI. Targeting metabolic dysfunction for the treatment of mood disorders: review of the evidence. Life. 2021. https://doi.org/10.3390/life11080819.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lu Y, Ho CS, Liu X, et al. Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression. PLoS ONE. 2017;12(10):e0186700.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jeon SW, Kim YK. Neuroinflammation and cytokine abnormality in major depression: cause or consequence in that illness? World J Psychiatry. 2016;6(3):283–93.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Talmon M, Chaudhari RD, Suryavanshi H, et al. Design, synthesis and biological evaluation of vortioxetine derivatives as new COX-1/2 inhibitors in human monocytes. Bioorg Med Chem. 2020;28(23):115760.

    Article  CAS  PubMed  Google Scholar 

  28. Benedetti F, Palladini M, D’Orsi G, et al. Mood-congruent negative thinking styles and cognitive vulnerability in depressed COVID-19 survivors: a comparison with major depressive disorder. J Affect Disord. 2022;1(308):554–61.

    Article  Google Scholar 

  29. Di Nicola M, Pepe M, Montanari S, et al. Vortioxetine improves physical and cognitive symptoms in patients with post-COVID-19 major depressive episodes. Eur Neuropsychopharmacol. 2023;70:21–8.

    Article  PubMed  PubMed Central  Google Scholar 

  30. De Filippis S, Pugliese A, Christensen MC, et al. Effectiveness of vortioxetine in patients with major depressive disorder in real-world clinical practice in Italy: results from the RELIEVE study. Neuropsychiatr Dis Treat. 2022;9(18):1665–77.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all of the participants within the present study, as well as the staff members of the Brain and Cognition Discovery Foundation (BCDF) for their role in the data collection.

Medical Writing, Editorial and Other Assistance

The authors did not use any medical writing or editorial assistance for this article.

Funding

No funding was received for the publication of this article.

Author information

Authors and Affiliations

  1. Brain and Cognition Discovery Foundation, Toronto, ON, Canada

    Angela T. H. Kwan, Ziji Guo, Felicia Ceban, Gia Han Le, Sabrina Wong, Kayla M. Teopiz, Joshua D. Di Vincenzo, Sebastian Badulescu, Shakila Meshkat, Joshua D. Rosenblat, Donovan A. Dev, Lee Phan & Mehala Subramaniapillai

  2. Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Angela T. H. Kwan

  3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Ziji Guo & Roger S. McIntyre

  4. Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada

    Felicia Ceban

  5. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Gia Han Le, Sabrina Wong & Sebastian Badulescu

  6. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Taeho Greg Rhee

  7. Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, USA

    Taeho Greg Rhee

  8. Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Roger Ho

  9. Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore

    Roger Ho

  10. Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, 400715, People’s Republic of China

    Bing Cao

  11. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Joshua D. Rosenblat & Roger S. McIntyre

  12. Department of Neuroscience, Imaging and Clinical Sciences, University “G. d’Annunzio”, Chieti, Italy

    Giacomo d’Andrea

  13. Brain and Cognition Discovery Foundation, 77 Bloor Street West, Suite 617, Toronto, ON, M5S 1M2, Canada

    Roger S. McIntyre

Authors
  1. Angela T. H. Kwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ziji Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Felicia Ceban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gia Han Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sabrina Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kayla M. Teopiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Taeho Greg Rhee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Roger Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joshua D. Di Vincenzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sebastian Badulescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shakila Meshkat
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bing Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Joshua D. Rosenblat
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Giacomo d’Andrea
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Donovan A. Dev
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lee Phan
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Mehala Subramaniapillai
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Roger S. McIntyre
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: Angela T.H. Kwan and Roger S. McIntyre; Data Curation: Angela T.H. Kwan, Lee Phan and Mehala Subramaniapillai; Formal Analysis: Angela T.H. Kwan; Funding Acquisition: Roger S. McIntyre; Investigation: Angela T.H. Kwan; Methodology: Angela T.H. Kwan; Project Administration: Angela T.H. Kwan, Lee Phan, Mehala Subramaniapillai and Roger S. McIntyre; Resources: Angela T.H. Kwan and Roger S. McIntyre; Software: Angela T.H. Kwan; Supervision: Angela T.H. Kwan and Roger S. McIntyre; Validation: Angela T.H. Kwan, Gia Han Le and Ziji Guo; Visualization: Angela T.H. Kwan; Writing-Original Draft: Angela T.H. Kwan and Roger S. McIntyre; Writing-Review & Editing: All authors.

Corresponding author

Correspondence to Roger S. McIntyre.

Ethics declarations

Conflict of Interest

Dr. Roger S. McIntyre has received research grant support from CIHR, GACD, National Natural Science Foundation of China (NSFC), and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Dr. Roger S. McIntyre is an editor-in-chief/editorial board member of Advances in Therapy. Dr. Roger S. McIntyre was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Felicia Ceban, Kayla M. Teopiz and Mehala Subramaniapillai received fees from Braxia Scientific Corp. Dr. Taeho Greg Rhee was supported in part by the National Institute on Aging (NIA) (#R21AG070666; R21AG078972), National Institute of Mental Health (#R21MH117438), National Institute on Drug Abuse (#R21DA057540) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. Dr. Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). Dr. Rhee is currently a co-Editor-in-Chief of Mental Health Science and has received honorarium payments annually from the publisher, John Wiley & Sons, Inc. Dr. Roger Ho has received funding from the National University of Singapore iHeathtech Other Operating Expenses (A-0001415-09-00).

Ethical Approval

A local research ethics board (REB) approved the primary study, which is currently published (NCT05047952). The study adhered to the guidelines of Good Clinical Practice (ICH, 1996) and the Declaration of Helsinki (WMA, 2008), with the trial design receiving approval from a local research ethics board (REB). The protocol and dataset presented herein are derived from the primary study, which aimed to investigate the efficacy of vortioxetine in treating cognitive deficits in individuals with PCC and is currently published (ClinicalTrials.gov number NCT05047952). All procedures involving human subjects/patients were approved by Advarra (Pro00055939).

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 126 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kwan, A.T.H., Guo, Z., Ceban, F. et al. Assessing the Effects of Metabolic Disruption, Body Mass Index and Inflammation on Depressive Symptoms in Post-COVID-19 Condition: A Randomized Controlled Trial on Vortioxetine. Adv Ther 41, 1983–1994 (2024). https://doi.org/10.1007/s12325-024-02826-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-024-02826-9

Keywords

Search

Navigation