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Association of SARS-CoV-2 Infection With Psychological Distress, Psychotropic Prescribing, Fatigue, and Sleep Problems Among UK Primary Care Patients

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Is SARS-CoV-2 infection associated with risk of subsequent psychiatric morbidity, sleep problems, or fatigue?

Findings  In this cohort study of the health care records of 11 923 105 patients, including 226 521 patients with SARS-CoV-2 infection, while infection was associated with increased risk of sleep problems and fatigue, associations with subsequent psychiatric morbidity were mixed.

Meaning  These findings suggest that psychiatric morbidity associated with SARS-CoV-2 infection may be overstated in analyses of health care records that do not sufficiently control for confounding.


Importance  Infection with SARS-CoV-2 is associated with fatigue and sleep problems long after the acute phase of COVID-19. In addition, there are concerns of SARS-CoV-2 infection causing psychiatric illness; however, evidence of a direct effect is inconclusive.

Objective  To assess risk of risk of incident or repeat psychiatric illness, fatigue, or sleep problems following SARS-CoV-2 infection and to analyze changes according to demographic subgroups.

Design, Setting, and Participants  This cohort study assembled matched cohorts using the Clinical Practice Research Datalink Aurum, a UK primary care registry of 11 923 499 individuals aged 16 years or older. Patients were followed-up for up to 10 months, from February 1 to December 9, 2020. Individuals with less than 2 years of historical data or less than 1 week follow-up were excluded. Individuals with positive results on a SARS-CoV-2 test without prior mental illness or with anxiety or depression, psychosis, fatigue, or sleep problems were matched with up to 4 controls based on sex, general practice, and year of birth. Controls were individuals who had negative SARS-CoV-2 test results. Data were analyzed from January to July 2021.

Exposure  SARS-CoV-2 infection, determined via polymerase chain reaction testing.

Main Outcomes and Measures  Cox proportional hazard models estimated the association between a positive SARS-CoV-2 test result and subsequent psychiatric morbidity (depression, anxiety, psychosis, or self-harm), sleep problems, fatigue, or psychotropic prescribing. Models adjusted for comorbidities, ethnicity, smoking, and body mass index.

Results  Of 11 923 105 eligible individuals (6 011 020 [50.4%] women and 5 912 085 [49.6%] men; median [IQR] age, 44 [30-61] years), 232 780 individuals (2.0%) had positive result on a SARS-CoV-2 test. After applying selection criteria, 86 922 individuals were in the matched cohort without prior mental illness, 19 020 individuals had prior anxiety or depression, 1036 individuals had psychosis, 4152 individuals had fatigue, and 4539 individuals had sleep problems. After adjusting for observed confounders, there was an association between positive SARS-CoV-2 test results and psychiatric morbidity (adjusted hazard ratio [aHR], 1.83; 95% CI, 1.66-2.02), fatigue (aHR, 5.98; 95% CI, 5.33-6.71), and sleep problems (aHR, 3.16; 95% CI, 2.64-3.78). However, there was a similar risk of incident psychiatric morbidity for those with a negative SARS-CoV-2 test results (aHR, 1.71; 95% CI, 1.65-1.77) and a larger increase associated with influenza (aHR, 2.98; 95% CI, 1.55-5.75).

Conclusions and Relevance  In this cohort study of individuals registered at an English primary care practice during the pandemic, there was consistent evidence that SARS-CoV-2 infection was associated with increased risk of fatigue and sleep problems. However, the results from the negative control analysis suggest that unobserved confounding may be responsible for at least some of the positive association between COVID-19 and psychiatric morbidity.

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Article Information

Accepted for Publication: September 22, 2021.

Published: November 16, 2021. doi:10.1001/jamanetworkopen.2021.34803

Correction: This article was corrected on March 7, 2022, to fix the title of Figure 1.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Abel KM et al. JAMA Network Open.

Corresponding Author: Matthias Pierce, PhD, Centre for Women’s Mental Health, University of Manchester, Oxford Road, Jean McFarlane Building, Room 3.307, Manchester M13 9PL, United Kingdom (matthias.pierce@manchester.ac.uk).

Author Contributions: Drs Carr and Pierce had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Abel, Ashcroft, Chalder, Chew-Graham, Kapur, McManus, Steeg, Webb, Pierce.

Acquisition, analysis, or interpretation of data: Abel, Carr, Ashcroft, Chalder, Hope, Kapur, McManus, Steeg, Webb, Pierce.

Drafting of the manuscript: Abel, Chalder, Kapur, McManus, Pierce.

Critical revision of the manuscript for important intellectual content: Carr, Ashcroft, Chalder, Chew-Graham, Hope, Kapur, McManus, Steeg, Webb, Pierce.

Statistical analysis: Carr, Pierce.

Obtained funding: Ashcroft.

Administrative, technical, or material support: Carr, Ashcroft, Hope, McManus, Steeg.

Supervision: Kapur.

Conflict of Interest Disclosures: Prof Chalder reported receiving grants from National Institute for Health Research (NIHR) Biomedical Research Centre at South London, Maudsley National Health Service (NHS) Foundation Trust, and King’s College London during the conduct of the study and grants from Guy’s and St Thomas’ Charity; personal fees from Sheldon Press, Constable and Robinson, and NHS England for workshops; and serving as a member of the COVID-19 Rapid Guidelines committee for the National Institute for Health and Care Excellence outside the submitted work. Dr Kapur reported receiving grants and personal fees from the Department of Health and Social Care, NIHR, National Institute of Health and Care Excellence outside the submitted work. No other disclosures were reported.

Funding/Support: This work was funded by the NIHR through the Greater Manchester Patient Safety Translational Research Centre (award No. PSTRC-2016-003). Prof Chew-Graham is partly funded by the NIHR West Midlands Applied Research Collaboration. Dr Kapur is also supported by Greater Manchester Mental Health NHS Foundation Trust.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The interpretation and conclusions contained in this study are those of the authors alone, and not necessarily those of the Medicines and Healthcare products Regulatory Agency, NHS, NIHR, or the UK Department of Health and Social Care.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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