Impact of COVID-19 on mental illness in vaccinated and unvaccinated people: a population-based cohort study in OpenSAFELY

Background: COVID-19 is associated with subsequent mental illness in both hospital- and population-based studies. Evidence regarding effects of COVID-19 vaccination on mental health consequences of COVID-19 is limited. Methods: With the approval of NHS England, we used linked electronic health records (OpenSAFELY-TPP) to conduct analyses in a 'pre-vaccination' cohort (17,619,987 people) followed during the wild-type/Alpha variant eras (January 2020-June 2021), and 'vaccinated' and 'unvaccinated' cohorts (13,716,225 and 3,130,581 people respectively) during the Delta variant era (June-December 2021). We estimated adjusted hazard ratios (aHRs) comparing the incidence of mental illness after diagnosis of COVID-19 with the incidence before or without COVID-19. Outcomes: We considered eight outcomes: depression, serious mental illness, general anxiety, post-traumatic stress disorder, eating disorders, addiction, self-harm, and suicide. Incidence of most outcomes was elevated during weeks 1-4 after COVID-19 diagnosis, compared with before or without COVID-19, in each cohort. Vaccination mitigated the adverse effects of COVID-19 on mental health: aHRs (95% CIs) for depression and for serious mental illness during weeks 1-4 after COVID-19 were 1.93 (1.88-1.98) and 1.42 (1.24-1.61) respectively in the pre-vaccination cohort and 1.79 (1.68-1.91) and 2.21 (1.99-2.45) respectively in the unvaccinated cohort, compared with 1.16 (1.12-1.20) and 0.91 (0.84-0.98) respectively in the vaccinated cohort. Elevation in incidence was higher, and persisted for longer, after hospitalised than non-hospitalised COVID-19. Interpretation: Incidence of mental illness is elevated for up to a year following severe COVID-19 in unvaccinated people. Vaccination mitigates the adverse effect of COVID-19 on mental health. Funding: Medical Research Council (MC\_PC\_20059) and NIHR (COV-LT-0009). ### Competing Interest Statement NC is remunerated for participation in Data Safety and Monitoring Boards for AstraZeneca. AM was paid for three days of consultancy for https://inductionhealthcare.com/ in Feburary 2022. No other conflicts of interest to be disclosed. ### Clinical Protocols ### Funding Statement This work was supported by the COVID-19 Longitudinal Health and Wellbeing National Core Study, which is funded by the Medical Research Council (MC\_PC\_20059) and NIHR (COV-LT-0009). VW is also supported by the Medical Research Council Integrative Epidemiology Unit at the University of Bristol [MC\_UU\_00032/03]. YW was supported by an UKRI MRC Fellowship awarded to YW (MC/W021358/1) and received funding from UKRI EPSRC Impact Acceleration Account (EP/X525789/1). AM received funding from the Bennett Foundation, Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, Mohn-Westlake Foundation. The OpenSAFELY Platform is supported by grants from the Wellcome Trust (222097/Z/20/Z) and MRC (MR/V015737/1, MC\_PC\_20059, MR/W016729/1). In addition, development of OpenSAFELY has been funded by the Longitudinal Health and Wellbeing strand of the National Core Studies programme (MC\_PC\_20030: MC\_PC\_20059), the NIHR funded CONVALESCENCE programme (COV-LT-0009), NIHR (NIHR135559, COV-LT2-0073), and the Data and Connectivity National Core Study funded by UK Research and Innovation (MC\_PC\_20058) and Health Data Research UK (HDRUK2021.000). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Health Research Authority [REC reference 22/PR/0095] and by the University of Bristol's Faculty of Health Sciences Ethics Committee [reference 117269]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data were linked, stored and analysed securely within the OpenSAFELY platform: https://www.opensafely.org/. Data include pseudonymised data such as coded diagnoses, medications and physiological parameters. No free text data are included. All code and code lists are shared openly for review and re-use under an MIT open license (https://github.com/opensafely/post-covid-mentalhealth). Detailed pseudonymised patient data is potentially re-identifiable and therefore not shared.