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Depressive symptoms and sex differences in the risk of post-COVID-19 persistent symptoms: a prospective population-based cohort study

Nature Mental Health volume 2, pages 1053–1061 (2024) Cite this article

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Abstract

Women are unexplainedly more affected than men by post-COVID-19 persistent symptoms. Depressive symptoms may partially explain these sex differences. In the French population-based CONSTANCES cohort, depressive symptoms were measured with the nine-item Patient Health Questionnaire between April 6 and May 4, 2020. Between December 2020 and January 2021, among 2,093 infected participants (mean (s.d.) age, 43.0 years (11.9); 55.3% women), 453 (21.6%) reported ≥1 new persistent symptom that emerged from March 2020. Accounting for several confounders, women were more likely than men to have ≥1 symptom (odds ratio (95% confidence interval), 1.45 (1.17–1.80)). Further adjusting for the nine-item Patient Health Questionnaire, participants in the highest (versus lowest) quartile were more likely to have ≥1 symptom (2.97 (2.09–4.23)), while the association with female sex substantially dropped (1.28 (1.02–1.60)). Depressive symptoms mediated 41.5–45.4% of this association. A biopsychosocial model, integrating gender and mental health, is warranted to understand long COVID and inform preventive and therapeutic strategies.

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Fig. 1: Mediation analysis of the association of female sex with having at least one symptom at follow-up by depressive symptoms at the beginning of the pandemic.
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Data availability

Data may be obtained from a third party and are not publicly available. The data of the CONSTANCES cohort study are protected by the French national regulatory agency (‘Commission nationale de l’informatique et des libertés’, n°910486). However, the CONSTANCES cohort study is an ‘open epidemiological laboratory’ and access to study protocols and data is available for researchers through a permanent call to proposals (https://www.constances.fr/en/scientific-area/access-to-constances/).

Code availability

The full code of the statistical analysis is available via Zenodo at https://zenodo.org/records/11669929 (ref. 35).

References

  1. Robineau, O. et al. Long-lasting symptoms after an acute COVID-19 infection and factors associated with their resolution. JAMA Netw. Open 5, e2240985 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ballering, A. V., van Zon, S. K. R., Olde Hartman, T. C., Rosmalen, J. G. M. & Lifelines Corona Research Initiative. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. Lancet 400, 452–461 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Al-Aly, Z., Bowe, B. & Xie, Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat. Med. 28, 1461–1467 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sylvester, S. V. et al. Sex differences in sequelae from COVID-19 infection and in long COVID syndrome: a review. Curr. Med. Res. Opin. 38, 1391–1399 (2022).

    Article  PubMed  Google Scholar 

  5. Luo, D. et al. Prevalence and risk factors for persistent symptoms after COVID-19: a systematic review and meta-analysis. Clin. Microbiol. Infect. 30, 328–335 (2024).

    Article  PubMed  Google Scholar 

  6. Tsampasian, V. et al. Risk factors associated with post-COVID-19 condition: a systematic review and meta-analysis. JAMA Intern. Med. 183, 566–580 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bechmann, N. et al. Sexual dimorphism in COVID-19: potential clinical and public health implications. Lancet Diabetes Endocrinol. 10, 221–230 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gebhard, C. E. et al. Impact of sex and gender on post-COVID-19 syndrome, Switzerland, 2020. Euro Surveill. 29, 2300200 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Platt, J. M., Bates, L., Jager, J., McLaughlin, K. A. & Keyes, K. M. Is the US gender gap in depression changing over time? A meta-regression. Am. J. Epidemiol. 190, 1190–1206 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bottemanne, H. et al. Do anxiety and depression predict persistent physical symptoms after a severe COVID-19 episode? A prospective study. Front. Psychiatry 12, 757685 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wang, S. et al. Associations of depression, anxiety, worry, perceived stress, and loneliness prior to infection with risk of post-COVID-19 conditions. JAMA Psychiatry 79, 1081–1091 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Matta, J. et al. Depression and anxiety before and at the beginning of the COVID-19 pandemic and incident persistent symptoms: a prospective population-based cohort study. Mol. Psychiatry. 28, 4261–4271 (2023).

    Article  PubMed  Google Scholar 

  13. Zins, M., Goldberg, M. & CONSTANCES team. The French CONSTANCES population-based cohort: design, inclusion and follow-up. Eur. J. Epidemiol. 30, 1317–1328 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Carrat, F. et al. Antibody status and cumulative incidence of SARS-CoV-2 infection among adults in three regions of France following the first lockdown and associated risk factors: a multicohort study. Int. J. Epidemiol. 50, 1458–1472 (2021).

    Article  PubMed  Google Scholar 

  15. Kroenke, K., Spitzer, R. L. & Williams, J. B. The PHQ-9: validity of a brief depression severity measure. J. Gen. Intern. Med. 16, 606–613 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Soriano, J. B. et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect. Dis. 22, e102–e107 (2022).

    Article  PubMed  Google Scholar 

  17. VanderWeele, T. J. & Ding, P. Sensitivity analysis in observational research: introducing the E-value. Ann. Intern. Med. 167, 268–274 (2017).

    Article  PubMed  Google Scholar 

  18. VanderWeele, T. J. & Mathur, M. B. Commentary: developing best-practice guidelines for the reporting of E-values. Int. J. Epidemiol. 49, 1495–1497 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Simon, G. E., VonKorff, M., Piccinelli, M., Fullerton, C. & Ormel, J. An international study of the relation between somatic symptoms and depression. N. Engl. J. Med. 341, 1329–1335 (1999).

    Article  PubMed  Google Scholar 

  20. Kohli, M. A. et al. Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients. Arch. Gen. Psychiatry 67, 348–359 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Choutka, J., Jansari, V., Hornig, M. & Iwasaki, A. Unexplained post-acute infection syndromes. Nat. Med. 28, 911–923 (2022).

    Article  PubMed  Google Scholar 

  22. Köhler, C. A. et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr. Scand. 135, 373–387 (2017).

    Article  PubMed  Google Scholar 

  23. Lemogne, C., Gouraud, C., Pitron, V. & Ranque, B. Why the hypothesis of psychological mechanisms in long COVID is worth considering. J. Psychosom. Res. 165, 111135 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ballering, A. V., Wardenaar, K. J., Olde Hartman, T. C. & Rosmalen, J. G. M. Female sex and femininity independently associate with common somatic symptom trajectories. Psychol. Med. 52, 2144–2154 (2022).

    Article  PubMed  Google Scholar 

  25. Samulowitz, A., Gremyr, I., Eriksson, E. & Hensing, G. ‘Brave men’ and ‘emotional women’: a theory-guided literature review on gender bias in health care and gendered norms towards patients with chronic pain. Pain Res. Manag. 2018, 6358624 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. van Wijk, C. M. & Kolk, A. M. Sex differences in physical symptoms: the contribution of symptom perception theory. Soc. Sci. Med. 45, 231–246 (1997).

    Article  PubMed  Google Scholar 

  27. Afari, N. et al. Psychological trauma and functional somatic syndromes: a systematic review and meta-analysis. Psychosom. Med. 76, 2–11 (2014).

    Article  PubMed  Google Scholar 

  28. Sun, Y. et al. Comparison of mental health symptoms before and during the COVID-19 pandemic: evidence from a systematic review and meta-analysis of 134 cohorts. BMJ 380, e074224 (2023).

    Article  PubMed  Google Scholar 

  29. Penninx, B. W. J. H., Benros, M. E., Klein, R. S. & Vinkers, C. H. How COVID-19 shaped mental health: from infection to pandemic effects. Nat. Med. 28, 2027–2037 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Saunders, C., Sperling, S. & Bendstrup, E. A new paradigm is needed to explain long COVID. Lancet Respir. Med. 11, e12–e13 (2023).

    Article  PubMed  Google Scholar 

  31. Lemogne, C. et al. National committee statement as a missed opportunity to acknowledge the relevance of a biopsychosocial approach in understanding long COVID. J. Psychosom. Res. https://doi.org/10.1016/j.jpsychores.2024.111596 (2024).

  32. Matta, J. et al. Trust in sources of information on COVID-19 at the beginning of the pandemic’s first wave and incident persistent symptoms in the population-based CONSTANCES cohort: a prospective study. J. Psychosom. Res. 169, 111326 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Pignon, B. et al. Psychological burden associated with incident persistent symptoms and their evolution during the COVID-19 pandemic: a prospective population-based study. BMJ Ment. Health 27, e300907 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Valeri, L. & Vanderweele, T. J. Mediation analysis allowing for exposure–mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol. Methods 18, 137–150 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zenodo https://zenodo.org/records/11669929 (2024).

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Acknowledgements

The CONSTANCES cohort benefits from grant ANR-11-INBS-0002 from the French National Research Agency. CONSTANCES is supported by the Caisse Nationale d’Assurance Maladie, the French Ministry of Health, the Ministry of Research and the Institut National de la Santé et de la Recherche Médicale (INSERM). CONSTANCES is also partly funded by AstraZeneca, Lundbeck, L’Oréal and Merck Sharp & Dohme Corp. The SAPRIS and SAPRIS-Sérologie (SERO) study was supported by grants ANR-10-COHO-06 and ANR-20-COVI-000 from the Agence Nationale de la Recherche; grant 20DMIA014-0 from Santé Publique France; grant 20RR052-00 from the Fondation pour la Recherche Médicale; and grant C20-26 from INSERM. The present study was supported by a grant ‘AAP Covid long 2022-1’ from the Agence nationale de recherches sur le sida et les hépatites virales (ANRS) | Maladies infectieuses émergentes. C.G. and C.L. were supported by a grant from ‘la Fondation de l’Assistance Publique - Hôpitaux de Paris’. The funding sources had no role in the study design, data acquisition, statistical analysis, interpretation of the results or writing of the manuscript.

Author information

Authors and Affiliations

  1. Population-based Cohorts Unit, Université Paris Cité, Paris Saclay University, UVSQ, INSERM, Paris, France

    Joane Matta, Baptiste Pignon, Sofiane Kab, Emmanuel Wiernik, Marcel Goldberg & Marie Zins

  2. Institut Pierre-Louis d’Epidémiologie et de Santé Publique, Sorbonne Université, INSERM, Paris, France

    Olivier Robineau & Fabrice Carrat

  3. Centre Hospitalier de Tourcoing, EA2694, Université de Lille, Lille, France

    Olivier Robineau

  4. Département de santé publique, Hôpital Saint-Antoine, AP-HP, Paris, France

    Fabrice Carrat

  5. Gustave Roussy, Université Paris-Saclay, UVSQ, INSERM, CESP U1018, Villejuif, France

    Gianluca Severi

  6. Department of Statistics, Computer Science, Applications ‘G. Parenti’, University of Florence, Florence, Italy

    Gianluca Severi

  7. Sorbonne Paris Nord University, INSERM U1153, INRAE U1125, Cnam, Nutritional Epidemiology Research Team, Centre of Research in Epidemiology and Statistics – Université Paris Cité, Bobigny, France

    Mathilde Touvier

  8. Fondation Jean Dausset-Centre d’Etude du Polymorphisme Humain, Paris, France

    Hélène Blanché & Jean-François Deleuze

  9. Service de Psychiatrie de l’adulte, Hôpital Hôtel-Dieu, AP-HP, Paris, France

    Clément Gouraud, Charles Ouazana Vedrines & Cédric Lemogne

  10. Center for Research in Epidemiology and Statistics, Université Paris Cité and Université Sorbonne Paris Nord, INSERM, INRAE, Paris, France

    Charles Ouazana Vedrines, Brigitte Ranque & Cédric Lemogne

  11. VIFASOM (Vigilance Fatigue Sommeil et Santé Publique), Université Paris Cité, Paris, France

    Victor Pitron

  12. Centre du Sommeil et de la Vigilance-Pathologie professionnelle, Hôtel-Dieu, AP-HP, Paris, France

    Victor Pitron

  13. Institut de Psychiatrie et Neuroscience de Paris, Université Paris Cité, INSERM U1266, Paris, France

    Sarah Tebeka & Nicolas Hoertel

  14. Service de Psychiatrie et Addictologie, Hôpital Louis-Mourier, AP-HP, Colombes, France

    Sarah Tebeka

  15. Service de Médecine interne, Hôpital européen Georges-Pompidou, AP-HP, Université de Paris, Paris, France

    Brigitte Ranque

  16. Service de Psychiatrie et Addictologie, DMU Psychiatrie et Addictologie, Hôpital Corentin-Celton, AP-HP, Issy-les-Moulineaux, France

    Nicolas Hoertel

Authors
  1. Joane Matta
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Contributions

J.M. and C.L. take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. C.L. designed the study; F.C., G.S., M.T., M.G. and M.Z. acquired the data; J.M. and C.L. performed statistical analysis. All authors contributed to the interpretation of data. J.M. and C.L. drafted the article; B.P., E.W., O.R., F.C., G.S., M.T., H.B., J.-F.D., C.G., C.O.-V., V.P., N.H., S.T., B.R., N.H., S.K., M.G. and M.Z. revised it critically for important intellectual content. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Cédric Lemogne.

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Competing interests

O.R. reported personal fees and nonfinancial support from Gilead, ViiV Healthcare and Merck Sharp & Dohme Corp, outside the submitted work. V.P. reported personal fees from Grunenthal, outside the submitted work. C.L. reported nonfinancial support from Nordic Pharma, outside the submitted work. No other disclosures were reported.

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Nature Mental Health thanks Chloe Saunders and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1

Selection of the study population.

Extended Data Fig. 2

Proportion of participants affected for each incident persistent symptom by sex.

Extended Data Fig. 3

Time frame of the assessment of depressive symptoms, history of SARS-CoV-2 infection, and incident persistent symptoms.

Extended Data Table 1 Standardized direct effects from the mediation analysis according to the structure displayed in Fig. 1
Full size table

Supplementary information

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Matta, J., Pignon, B., Kab, S. et al. Depressive symptoms and sex differences in the risk of post-COVID-19 persistent symptoms: a prospective population-based cohort study. Nat. Mental Health 2, 1053–1061 (2024). https://doi.org/10.1038/s44220-024-00290-6

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