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.

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). . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 3

SARS-CoV-2 infection, and consequent COVID-19, are associated with subsequent mental illness in both hospital and population-based studies1,2; for both common mental health difficulties, such as anxiety and depressive symptoms3, and serious mental illness, including psychotic disorders4. Potential mechanisms for these adverse effects of COVID-19 include physiological pathways, such as inflammation and microvascular changes, and psychosocial effects, such as anxiety about the consequences of COVID-19 including long COVID. Previous studies identified associations of COVID-19 with mental illness in both hospitalised patients5,6 and the general population1,7,8. Differentiating between hospitalised and non-hospitalised groups can provide insights into the role of COVID-19 severity.9 Rapid rollout of COVID-19 vaccination within a year of the start of the pandemic was a crucial component of the public health response. Although the impacts of vaccination in preventing and reducing the severity of COVID-19 are well-established10,11, there is limited evidence regarding the implications of vaccination for other adverse health consequences of COVID-19, including mental illness. Several studies reported short-term improvements in population mental health following vaccination rollout.12,13 However, we did not identify any studies investigating differences in mental illness outcomes following COVID-19 by vaccination status. Rates of SARS-CoV-2 infection, vaccination, and disease severity were patterned by socio-demographic and health factors including age, sex, ethnicity, income and prior mental illness.14–18 Mental health consequences of COVID-19 may also vary between subgroups. For example, older people are at higher risk of more severe COVID-19, and hence may have experienced higher levels of psychological distress. Using linked primary and secondary care data from over 17 million people, we examined associations of COVID-19 with subsequent mental illness in the pre-vaccination period of the pandemic and for unvaccinated and vaccinated people after vaccination became available. We compared rates of common and severe mental illness after a diagnosis of COVID-19 with rates before or without COVID-19. We also investigated variation in these associations between subgroups defined by COVID-19 severity, age, sex, ethnicity, prior mental illness, and prior SARS-COV-2 infection. Follow-up of those diagnosed with COVID-19 during the first year of the pandemic was for up to two years post-diagnosis.

Study design and data sources Our study used OpenSAFELY-TPP, which provides secure, privacy-protecting access to linked data from 24 million people registered with English general practices (GPs) using TPP SystmOne software. These data include primary care data linked via pseudonymised NHS number to Secondary Uses Service (SUS) secondary care data, Office of National Statistics (ONS) Death Registry, Second Generation Surveillance System (SGSS) COVID-19 testing data and the Index of Multiple Deprivation (IMD). COVID-19 vaccination records (National Immunisation Management System) are available within TPP primary care data. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 4 Outcomes were defined using the earliest of: a relevant SNOMED CT code indicating a diagnosis in primary care; start of a secondary care episode with an ICD-10 code indicating a confirmed diagnosis in any position; or death with an ICD-10 code indicating the diagnosis as either a primary or underlying cause. From the range of mental illnesses examined, we present main findings for depression and serious mental illness (composite of schizophrenia, schizo-affective disorder, bipolar disorder, and psychotic depression). We also examined general anxiety disorders, post-traumatic stress disorder (PTSD), eating disorders, addiction, self-harm and suicide, which are presented in supplementary material. Code lists are available online: https://github.com/opensafely/post-covid-mentalhealth/tree/main/codelists. The date of COVID-19 was defined as the first of: confirmed COVID-19 diagnosis recorded in primary care; positive SARS-COV-2 PCR or antigen test recorded in SGSS; start of an episode with a confirmed diagnosis in any position in SUS; or death with SARS-COV-2 infection listed in any position on the ONS death registry. People with a hospital admission record in SUS that included a confirmed diagnosis in the primary position within 28 days of first COVID-19 were defined as having had ‘hospitalised COVID-19’. All other COVID-19 diagnoses were defined as ‘non-hospitalised’. Covariates identified as potential confounders included age, sex, ethnicity, area socioeconomic deprivation, smoking status, care home residence, health care work, number of GP-patient interactions in 2019, and binary indicators for history of comorbidities (Supplementary Table 1). Study population Three cohorts were defined (Supplementary Table 2; Supplementary Figure 1). The ‘pre-vaccination’ cohort was followed from January 1st 2020 (baseline) until the earliest of December 14th 202119, outcome event date and date of death. Exposure was defined as recorded COVID-19 between baseline and the earliest date of eligibility for COVID-19 vaccination, date of first vaccination and June 18th 2021 (when all adults became eligible for vaccination). Follow-up in the ‘vaccinated’ cohort started at the later of baseline and two weeks after a second COVID-19 vaccination and ended at the earliest of December 14th 2021, outcome event date and date of death. The ‘unvaccinated’ cohort had not received a COVID-19 vaccine by 12 weeks after they became eligible for vaccination. Follow-up started at the later of baseline and 12 weeks after vaccination eligibility and ended at the earliest of December 14th 2021, outcome event date, date of death and date of first vaccination. People eligible for each cohort were registered with an English GP for at least six months before baseline and were alive with a known age between 18 and 110 years, sex, deprivation, and region at baseline. People were excluded from each cohort if they had any record of SARS-CoV-2 infection before baseline. In the vaccinated cohort, people were excluded if they received a vaccination before the start of the vaccine rollout on December 8th 2020 (indicating an error or participation in a randomized trial); their second dose was dated before their first dose vaccination (contradictory vaccine record); their second dose was less than three weeks after their first dose; or they received mixed vaccine brands before this was permitted on May 7th 2021. In the unvaccinated cohort, people were excluded if they had any record of a COVID-19 vaccination before June 1st 2021. Vaccine eligibility was defined using the Joint Committee on Vaccination and Immunisation (JCVI) groupings. People who could not be assigned to a JCVI group were excluded. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 5 Statistical analyses For each cohort, baseline characteristics were described, and numbers of outcome events, person-years of follow-up and incidence rates (per 100,000 person-years) before and after all, hospitalised and non- hospitalised COVID-19 were tabulated. Time to first event was analysed for each outcome. Cox models were fitted with calendar time scale using the cohort-specific baseline as the origin. Hazard ratios (HRs) for follow- up after, versus before or without COVID-19, were estimated, splitting follow-up into the day of COVID-19 diagnosis (‘day 0’), the remainder of 1-4 weeks, and 5-28 weeks after COVID-19 for all cohorts and additionally 29-52 and 53-102 weeks after COVID-19 for the pre-vaccination cohort. For computational efficiency, we used sampling for analyses containing >4,000,000 people: we included all people with the outcome event, all people with the exposure, and a 10% (for general anxiety, depression, serious mental illness) or 20% (for all other outcomes) random sample of non-case-non-exposed people. We used inverse probability weights to adjust for the sampling and derived confidence intervals using robust standard errors when sampling had occurred. For each outcome and cohort, we estimated: (i) age and sex adjusted; and (ii) maximally adjusted HRs including all covariates listed above. Restricted cubic splines were used to account for age unless otherwise specified. All models were stratified by region so that risk sets were constructed within region, hence accounting for between-region variation in the baseline hazard. Subgroup analyses according to prior history of the outcome event, age group, sex, ethnicity, and COVID-19 history were conducted for depression and serious mental illness. We calculated absolute excess risk 28 weeks after COVID-19, including outcome events recorded on the day of COVID-19 diagnosis (‘day 0’) and weighted by the proportion of people in age and sex strata in the pre-vaccination cohort. Further details of the statistical methods are in the supplement. Data management and analyses were conducted in Python version 3.8.10, R version 4.0.2 and Stata/MP version 16.1 according to a pre-specified protocol. The protocol, analysis code and code lists are available online: https://github.com/opensafely/post-covid-mentalhealth.

The pre-vaccination cohort included 17,619,987 people of whom 975,429 received a COVID-19 diagnosis (Table 1, Supplementary Figure 2). The median (interquartile range (IQR)) age was 49 (34-64) years. The cohort was 50.2% female and 79.3%, 6.3%, and 2.1% were recorded as of White, South Asian, and Black ethnicities respectively. The vaccinated and unvaccinated cohorts included 13,716,225 and 3,130,581 people respectively, of whom 850,023 and 147,315 received a COVID-19 diagnosis. Differences in demographic characteristics between the vaccinated and unvaccinated cohorts reflect predictors of COVID-19 vaccine uptake.20 Supplementary Table 3 summarises participants’ medical history by cohort. In each cohort, the incidence of mental illness was higher after diagnosis of COVID-19 than before or without COVID-19 (Table 2). The highest incidence rates were after hospitalised COVID-19. Depression was the most common outcome with a total of 1,278,363, 343,371, and 56,403 diagnoses in the pre-vaccination, vaccinated . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 6 and unvaccinated cohorts respectively. There were 379,275, 84,981, and 18,039 diagnoses of serious mental illness in the pre-vaccination, vaccinated and unvaccinated cohorts respectively. Comparisons of event rates after diagnosis of COVID-19 versus before or without COVID-19 Maximally adjusted HRs (aHRs) comparing the incidence of each outcome after diagnosis of COVID-19 with the incidence before or without COVID-19 did not differ substantially from the age- and sex-adjusted HRs in all cohorts (Supplementary Figure 3). The incidence of all outcomes was extremely high on day zero (Table 3). The incidence of most outcomes was elevated during the remainder of 1-4 weeks after COVID-19, compared with before or without COVID-19, in each cohort. Depression The incidence of depression was elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, in the pre-vaccination and unvaccinated cohorts (1.93 (95% CI 1.88-1.98) and 1.79 (1.68-1.91) respectively) and, to a lesser extent, in the vaccinated cohort (1.16 (1.12-1.20)) (Figure 1, Table 3). The incidence of depression remained elevated during weeks 5-28 in the vaccinated and unvaccinated cohorts (aHRs 1.11 (1.08-1.14) and 1.28 (1.22-1.36) respectively) and up to weeks 53-102 in the pre-vaccination cohort (aHR 1.17 (1.13-1.20)). aHRs during weeks 1-4 were considerably higher after hospitalised COVID-19 (pre- vaccination: 16.5 (15.8-17.3); vaccinated: 13.0 (12.0-14.0); unvaccinated: 15.6 (14.1-17.2)) than after non- hospitalised COVID-19 (pre-vaccination: 1.22 (1.17-1.26); vaccinated: 0.92 (0.88-0.95); unvaccinated: 1.11 (1.02-1.20)) (Figure 1, Supplementary Tables 4-5). In the pre-vaccination cohort, aHRs remained higher after hospitalised than non-hospitalised COVID-19 throughout follow-up. Serious mental illness The incidence of serious mental illness was elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, in the pre-vaccinated and unvaccinated cohorts (1.48 (95% CI 1.40-1.56) and 1.42 (1.24- 1.61) respectively) (Figure 1, Table 3). However, the incidence of serious mental illness was lower during weeks 1-4 in the vaccinated cohort (0.91 (0.84-0.98)). Incidence remained slightly elevated during weeks 5-28 in the vaccinated and unvaccinated cohorts (1.07 (1.01-1.1) and 1.14 (1.02-1.27)) and up to weeks 53-102 in the pre-vaccination cohort (1.13 (1.06-1.19)). The incidence of serious mental illness during weeks 1-4 was considerably higher after hospitalised COVID-19 (pre-vaccination: 9.65 (8.71-10.7); vaccinated: 6.38 (5.21- 7.80); unvaccinated: 8.76 (7.02-10.9)) than after non-hospitalised COVID-19: (pre-vaccination: 1.04 (0.97- 1.11); vaccinated: 0.79 (0.73-0.86); unvaccinated: 0.98 (0.83-1.15)) (Figure 1, Supplementary Tables 4-5). Subgroup analyses aHRs for depression were highest during weeks 1-4 after COVID-19, versus before or without COVID-19, for people with prior history of the condition that was recorded more than six months ago (Figure 2, Supplementary Tables 6-8). For example, in the pre-vaccination cohort, aHRs were 2.16 (2.08-2.23) for prior history more than six months ago, 1.66 (1.52-1.80) for prior history within six months, and 1.58 (1.50-1.67) for no prior history. aHRs for serious mental illness were also highest during weeks 1-4 after COVID-19 for people with prior history of the condition that was recorded more than six months ago in the unvaccinated cohort (1.56 (1.30-1.88)). However, aHRs for serious mental illness were highest during weeks 1-4 after COVID-19 for . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 7 people with prior history within six months for the pre-vaccination (1.88 (1.57-2.26)) and vaccinated cohorts (1.07 (0.87-1.33)). Beyond 5 weeks, incidence attenuated for those with prior history both within six months and more than six months ago. For the vaccinated cohort, incidence of serious mental illness during weeks 5- 28 after COVID-19 was consistent with before or without COVID-19 (prior history more than six months ago: 1.00 (0.93-1.08); prior history within six months: 1.07 (0.87-1.33)). In the vaccinated cohort, aHRs for depression and serious mental illness after COVID-19, versus before or without COVID-19 were similar in people with and without a with prior history of COVID-19 (Supplementary Figure 4, Supplementary Table 9). aHRs for depression during weeks 1-4 and 5-12 were greater in the 60-79 and 80-110 age groups than the 18-39 and 40-59 age groups: those serious mental illness were greater in the 60-79 and 80-110 age groups than the 18-39 and 40-59 age groups across all time periods (Supplementary Figure 5, Supplementary Tables 10-13). aHRs for depression and serious mental illness were marginally higher for men than women during weeks 1-4 after COVID-19 (Supplementary Figure 6, Supplementary Tables 14- 15). aHRs for depression after COVID-19, versus before or without COVID-19, were generally comparable between ethnic groups (Supplementary Figure 7, Supplementary Tables 16-20), except that in the vaccinated cohort aHRs for depression were higher for the Black ethnic group than other ethnic groups. aHRs for serious mental illness after COVID-19 were broadly comparable by ethnic group for the pre-vaccination cohort. aHRs for serious mental illness could only be estimated for the White and South Asian ethnic groups in the vaccinated cohort, and for the White ethnic group in the unvaccinated cohort, due to low event counts. Other mental illnesses aHRs for other mental illnesses were broadly similar to those for depression and serious mental illness, both overall (Figure 3, Table 3) and for hospitalised and non-hospitalised COVID-19 (Supplementary Tables 4-5). An exception was that aHRs for post-traumatic stress disorder after hospitalised COVID-19, versus before or without COVID-19, were higher during weeks 1-4 in the vaccinated cohort than the other two cohorts (pre- vaccination: 19.9 (15.6-25.5); vaccinated: 26.3 (19.3-35.8); unvaccinated: 14.0 (8.40-23.4)). This pattern was not present for non-hospitalised COVID-19 or overall. Absolute excess risk Estimated excess risks of depression 28 weeks after COVID-19, standardised to the age and sex distribution of the pre-vaccination cohort, were 1020, 449, and 1009 per 100,000 people in the pre-vaccination, vaccinated and unvaccinated cohorts respectively (Figure 4, Supplementary Table 21). Up to 32% of the estimated excess events occurred on the day of COVID-19 diagnosis (‘day 0’). Estimated excess risks of serious mental illness 28 weeks post-COVID-19, standardised to the age and sex distribution of the pre-vaccination cohort, were 227, 60, and 199 per 100,000 people in the pre-vaccination, vaccinated and unvaccinated cohorts respectively. Up to 43% of the estimated excess events occured on the day of COVID-19 diagnosis (‘day 0’). . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 8

In a study of more than 17 million people followed for up to two years of the pandemic, rates of most mental illnesses were markedly elevated during the first four weeks after diagnosis of COVID-19. This elevation was less marked in people who were vaccinated before diagnosis of COVID-19. In people diagnosed with COVID-19 before vaccination was available, incidence of mental illness remained elevated more than four weeks after diagnosis, particularly in people who were hospitalised with COVID-19. In subgroup analyses according to prior history of depression and serious mental illness, associations 1-4 weeks after COVID-19 were greater in those with than without prior history of each outcome, but more than 4 weeks after COVID-19 associations were greater in people with no prior history of the outcome. Subgroup analyses also suggested stronger associations in older age groups and in men. The effect of COVID-19 on mental illness did not differ markedly between ethnic groups. The attenuation of adverse effects of COVID-19 on mental illness in those who were vaccinated, compared to those unvaccinated, may be explained by reduced disease severity due to vaccination.21 This might be due to lower levels of systemic inflammation, as well as psychological benefits of vaccination such as reduced worry about the consequences of COVID-19, increased social engagement, and resuming previous activities.22 A previous cross-cohort study found that associations varied by COVID-19 severity, with poorer mental illness outcomes only found among those who were bedridden with COVID-19, as a marker of more severe illness.3 Those hospitalised due to COVID-19, especially people in intensive care and requiring ventilator support, may have been at greater risk of developing post-traumatic stress disorder23; though this could not be examined in the present study. Elevation in rates of mental illness outcomes declined with increasing time since diagnosis of COVID-19, although for those diagnosed in in the pre-vaccination era incidence remained elevated up to a year after hospitalised COVID-19. Previous findings regarding long-term effects have been mixed, with a review reporting no clear long-term associations between COVID-19 and mental illness24, whereas a recent multi-cohort study found an association between COVID-19 and mental illness with little evidence of attenuation over time1. Persisting effects of COVID-19 on mental illness could partly reflect ongoing impacts of long COVID25,26. In line with previous research1, we found stronger associations between COVID-19 and mental illness among older age groups. This is likely to reflect the increased risk of severe COVID-19 among older people and resulting increased anxiety about the consequences of infection. The association between COVID-19 and mental illness was slightly stronger among men, who have been found to be at greater risk of severe mental illness outcomes than women27. These patterns contrast with the wider impacts of the pandemic on mental health. For instance, overall mental health impacts of the pandemic were found to be greatest in adults aged 25-44 years, women, and those with higher degrees28; indicating that the mechanisms linking COVID-19 disease and mental health may differ from those underpinning wider effects of the pandemic. Our findings highlight the wider public health benefits of the vaccination programme. Prior mental illness may influence vaccine uptake, which highlights the importance of actively encouraging vaccine uptake in people . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 9 with mental health difficulties.20,29,30 Our analyses suggested that the adverse effects of COVID-19 on mental illness were greater during the first year of the pandemic, prior to the availability of vaccination. This may reflect greater uncertainty and public concern around consequences of COVID-19 and treatment effectiveness at the beginning of the pandemic. Strengths of this study include the very large sample size, availability of detailed linked electronic health record data, relatively long duration of follow-up, and the opportunity to examine the role of vaccination in the relationship between COVID-19 and mental illness. We also note several limitations. First, those who were unvaccinated may have been less likely to contact health services and to test for SARS-CoV-2, which might have led to underestimated effects in unvaccinated people not hospitalised with COVID-19. Those with recorded COVID-19, particularly those who were hospitalised, may have been more likely to have their mental illness recorded due to greater contact with health services. This may have underpinned the particularly high HRs observed initially following diagnosis, especially in those hospitalised, and the rapid fall thereafter as service contact is likely to be highest in the early post-diagnosis period. However, this is unlikely to fully explain the adverse effect of COVID-19 on mental illness, given the persistent elevation of incidence of mental illness following hospitalised COVID-19 and the variation in associations with different mental illnesses. Also, those with prior recorded mental health diagnoses may not have had additional diagnostic codes added to their record at every visit, even if their mental health had deteriorated due to COVID-19. Additionally, data on mental health in primary and secondary care is generally incomplete, as it does not include access to mental health services data or NHS Talking Therapies (formerly ‘Improving Access to Psychological Therapies (IAPT)’), which patients can self-refer to. A further limitation is that we could only assess COVID-19 severity according to whether patients were hospitalised and did not consider the potential role of repeated infections. We cannot exclude the possibility of unmeasured confounding, although we controlled for a wide range of demographic characteristics and prior morbidities. A previous study found that the mental health impacts of COVID-19 were less apparent when using a negative control group, suggesting that observed associations may have been, at least in part, due to residual confounding2. Finally, other viruses may have consequences for mental illness. Our findings may therefore reflect a phenomenon that occurs after many viruses rather than being specific to SARS-CoV-2. Our findings add to a growing body of evidence highlighting the increased risk of mental illness following COVID-19 diagnosis, with stronger associations found in relation to non-vaccination and more severe COVID- 19 disease, and longer-term associations relating mainly to new-onset mental illness. This has important implications for public health and mental health service provision, as serious mental illnesses in particular are associated with more intensive healthcare needs and longer-term health and other adverse effects. Our

highlight the importance of accessing vaccination among those with mental illness, who may be at higher risk of both SARS-CoV-2 infection and adverse health outcomes following COVID-19. They also emphasise the widespread public health benefits of COVID-19 vaccination in the general population. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 10

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Longitudinal course and predictors of health-related quality of life, mental health, and fatigue, in non-hospitalized individuals with or without post COVID-19 syndrome. In Review, 2023 DOI:10.21203/rs.3.rs-3221088/v1. 27 Pijls BG, Jolani S, Atherley A, et al. Demographic risk factors for COVID-19 infection, severity, ICU admission and death: a meta-analysis of 59 studies. BMJ Open 2021; 11: e044640. 28 Patel K, Robertson E, Kwong ASF, et al. Psychological Distress Before and During the COVID-19 Pandemic Among Adults in the United Kingdom Based on Coordinated Analyses of 11 Longitudinal Studies. JAMA Netw Open 2022; 5: e227629. 29 Hassan L, Sawyer C, Peek N, et al. COVID-19 vaccination uptake in people with severe mental illness: a UK- based cohort study. World Psychiatry 2022; 21: 153–4. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 12 30 Hassan L, Peek N, Lovell K, et al. Disparities in COVID-19 infection, hospitalisation and death in people with schizophrenia, bipolar disorder, and major depressive disorder: a cohort study of the UK Biobank. Mol Psychiatry 2022; 27: 1248–55.

We are very grateful for all the support received from the TPP Technical Operations team throughout this work, and for generous assistance from the information governance and database teams at NHS England and the NHS England Transformation Directorate. We thank the CONVALESCENCE Study Long COVID PPIE group for their input and for sharing their experiences and expertise throughout the duration of the project. CONFLICTS OF INTEREST 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. FUNDING 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). DATA AVAILABILITY STATEMENT 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. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 13 ETHICAL APPROVAL AND INFORMATION GOVERNANCE 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]. Authors involved in data management/analysis successfully passed information governance training and obtained ONS safe researcher accreditation. NHS England is the data controller of OpenSAFELY-TPP. All outputs underwent disclosure checks and were approved by NHS England. Further details of OpenSAFELY information governance are provided in supplemental methods. AUTHOR CONTRIBUTIONS VW, PP, RD, AWo, NC, JMac, AJ, JACS contributed to Conceptualization. VW, RD, JACS contributed to Methodology. VW, JICC, TP, AWa, LF, JMas, SD, AM, SB, BG contributed to Software. VW, JICC, RD, HF, JS, BM, ET, KT, GC, EH, YW, MAA, RK, JMac, AJ contributed to Validation. VW, JICC contributed to Formal analysis. VW, JICC contributed to Investigation. TP, AWa, LF, JMas, SD, AM, SB, BG contributed to Resources. VW, JICC, HF contributed to Data Curation. VW, PP, JACS contributed to Writing - Original Draft. All authors contributed to Writing - Review & Editing. VW, JICC contributed to Visualization. VW, RD, BG, AWo, NC, JMac, AJ, JACS contributed to Supervision. VW, PP, RD, BG, AWo, NC, JMac, AJ, JACS contributed to Project administration. NC, JACS contributed to Funding acquisition. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 2 Table 1: Patient characteristics in the pre-vaccination, vaccinated and unvaccinated cohorts. Characteristic Pre-vaccination cohort Vaccinated cohort Unvaccinated cohort N (%) COVID-19 diagnoses N (%) COVID-19 diagnoses N (%) COVID-19 diagnoses All 17619987 975429 13716225 850023 3130581 147315 Sex Female 8847327 (50.2%) 524127 7140045 (52.1%) 472455 1313967 (42%) 77943 Male 8772657 (49.8%) 451299 6576177 (47.9%) 377571 1816611 (58%) 69375 Age, years 18-29 2968245 (16.8%) 230823 1695351 (12.4%) 92115 948093 (30.3%) 39417 30-39 3018537 (17.1%) 197505 1914075 (14%) 146811 939573 (30%) 49947 40-49 2921427 (16.6%) 185643 2162535 (15.8%) 232005 593535 (19%) 32889 50-59 3135621 (17.8%) 180213 2663187 (19.4%) 200301 361947 (11.6%) 16545 60-69 2452011 (13.9%) 90525 2270565 (16.6%) 103599 175419 (5.6%) 5535 70-79 1990863 (11.3%) 49467 1940685 (14.1%) 53013 76089 (2.4%) 1899 80-89 940581 (5.3%) 29667 889707 (6.5%) 17853 28389 (0.9%) 879 90+ 192699 (1.1%) 11583 180123 (1.3%) 4323 7527 (0.2%) 219 Ethnicity White 13965363 (79%) 737295 11361897 (83%) 726897 1946799 (62%) 112497 S. Asian 1109529 (6.3%) 114231 769293 (5.6%) 40809 311121 (9.9%) 9381 Black 368835 (2.1%) 25845 212187 (1.5%) 9405 166593 (5.3%) 7443 Other 371805 (2.1%) 19137 228615 (1.7%) 10377 180609 (5.8%) 3951 Mixed 197745 (1.1%) 13467 124425 (0.9%) 7383 77583 (2.5%) 3789 Missing 1606707 (9.1%) 65451 1019811 (7.4%) 55149 447873 (14.3%) 10257 IMD quintile (lower: more deprived) 1 3395079 (19.3%) 239709 2229885 (16.3%) 133593 933093 (29.8%) 45183 2 3478545 (19.7%) 211725 2563539 (18.7%) 156321 750447 (24%) 34959 3 3801099 (21.6%) 194859 3032523 (22.1%) 183045 627477 (20%) 29079 4 3606213 (20.5%) 176199 2999331 (21.9%) 188019 479739 (15.3%) 22113 5 3339045 (19%) 152931 2890947 (21.1%) 189039 339819 (10.9%) 15981 Smoking Never 682269 (3.9%) 38217 412623 (3%) 15945 356319 (11.4%) 8247 Former 8051205 (45.7%) 485781 6381579 (46.5%) 414003 1295349 (41.4%) 58611 Current 5870427 (33.3%) 318777 5000223 (36.5%) 327639 625515 (20%) 43167 Missing 3016083 (17.1%) 132645 1921797 (14%) 92433 853395 (27.3%) 37287 Region East 4088403 (23.2%) 221181 3209673 (23.4%) 180231 704565 (22.5%) 33441 E.Midlands 3121905 (17.7%) 185739 2431149 (17.7%) 158091 513993 (16.4%) 28311 London 1116735 (6.3%) 64383 715353 (5.2%) 37059 446763 (14.3%) 10929 North East 852093 (4.8%) 58887 652491 (4.8%) 48537 132987 (4.2%) 7185 North West 1568139 (8.9%) 104913 1233741 (9%) 85629 211239 (6.7%) 11697 South East 1159293 (6.6%) 47829 943521 (6.9%) 55689 188109 (6%) 8757 South West 2490369 (14.1%) 76029 2136165 (15.6%) 129291 313809 (10%) 17235 W.Midlands 693339 (3.9%) 52617 481725 (3.5%) 29205 172029 (5.5%) 7941 Yorkshire 2529699 (14.4%) 163839 1912395 (13.9%) 126285 447087 (14.3%) 21819 Care home resident 82575 (0.5%) 14391 56451 (0.4%) 2775 2889 (0.1%) 105 Healthcare worker 552441 (3.1%) 63351 480825 (3.5%) 38709 20157 (0.6%) 1947 IMD: Index of Multiple Deprivation . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 3 Table 2: Mental illness events following diagnosis of COVID-19 in the pre-vaccination, vaccinated and unvaccinated cohorts, overall and by COVID-19 severity. Outcome COVID-19 severity Pre-vaccination cohort N=17,619,987 Vaccinated cohort N=13,716,225 Unvaccinated cohort N=3,130,581 Event/person-years Incidence rate Event/person-years Incidence rate Event/person-years Incidence rate Depression No COVID-19 1229103/31815936 3863 332523/6177768 5383 53547/1178058 4545 Hospitalised COVID-19 6123/40514 15113 1359/2379 57128 831/1614 51475 Non-hospitalised COVID-19 43137/875165 4929 9489/153403 6186 2025/24665 8210 Serious mental illness No COVID-19 364809/32692824 1116 82479/6242112 1321 17325/1185912 1461 Hospitalised COVID-19 1581/46044 3434 207/2651 7809 165/1771 9319 Non-hospitalised COVID-19 12885/921950 1398 2295/156141 1470 549/25091 2188 General anxiety disorders No COVID-19 898383/32181914 2792 221499/6207309 3568 39285/1181444 3325 Hospitalised COVID-19 4695/42625 11015 1017/2481 40994 873/1615 54045 Non-hospitalised COVID-19 34569/891502 3878 6795/154561 4396 1689/24774 6818 Post-traumatic stress disorder No COVID-19 35325/33027918 107 8061/6260421 129 2733/1189246 230 Hospitalised COVID-19 303/47761 634 57/2695 2115 57/1798 3170 Non-hospitalised COVID-19 1281/939590 136 225/156887 143 93/25218 369 Eating disorders No COVID-19 18273/33044280 55 4539/6261356 72 903/1189653 76 Hospitalised COVID-19 63/48018 131 Sep-07 333 15/1808 830 Non-hospitalised COVID-19 765/940251 81 129/156909 82 33/25239 131 Addiction No COVID-19 36615/33023855 111 5481/6261035 88 4131/1188788 347 Hospitalised COVID-19 165/47887 345 21/2704 777 51/1799 2835 Non-hospitalised COVID-19 879/939847 94 105/156925 67 87/25220 345 Self-harm No COVID-19 85761/32977385 260 15027/6258886 240 4977/1188790 419 Hospitalised COVID-19 237/47754 496 27/2703 999 15/1808 830 Non-hospitalised COVID-19 2955/936599 316 507/156793 323 141/25205 559 Suicide No COVID-19 39951/33023812 121 6135/6260977 98 1935/1189437 163 Hospitalised COVID-19 159/47888 332 15/2706 554 9/1810 497 Non-hospitalised COVID-19 1359/939065 145 219/156893 140 57/25232 226 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 4 Table 3: Maximally adjusted hazard ratios and 95% CIs for mental illness events following diagnosis of COVID-19 in the pre-vaccination, vaccinated and unvaccinated cohorts. Outcome Time since COVID-19 Pre-vaccination cohort Vaccinated cohort Unvaccinated cohort Depression Day 0 32.9 (31.8-34.0) 8.52 (8.05-9.03) 19.1 (17.5-20.8) 1-4 weeks 1.93 (1.88-1.98) 1.16 (1.12-1.20) 1.79 (1.68-1.91) 5-28 weeks 1.25 (1.23-1.26) 1.11 (1.08-1.14) 1.28 (1.22-1.36) 29-52 weeks 1.16 (1.14-1.18) - - 53-102 weeks 1.17 (1.13-1.20) - - Serious mental illness Day 0 29.4 (27.6-31.3) 7.61 (6.74-8.59) 19.1 (16.2-22.5) 1-4 weeks 1.48 (1.40-1.56) 0.91 (0.84-0.98) 1.42 (1.24-1.61) 5-28 weeks 1.20 (1.17-1.23) 1.07 (1.01-1.12) 1.14 (1.02-1.27) 29-52 weeks 1.15 (1.12-1.18) - - 53-102 weeks 1.13 (1.06-1.19) - - General anxiety Day 0 33.7 (32.4-34.9) 8.55 (7.98-9.17) 25.3 (23.3-27.5) 1-4 weeks 2.19 (2.13-2.26) 1.26 (1.21-1.31) 2.29 (2.15-2.44) 5-28 weeks 1.26 (1.24-1.28) 1.12 (1.09-1.16) 1.36 (1.28-1.45) 29-52 weeks 1.14 (1.12-1.16) - - 53-102 weeks 1.15 (1.11-1.19) - - Post-traumatic stress disorder Day 0 43.3 (36.8-51.0) 12.3 (9.13-16.4) 30.0 (22.1-40.5) 1-4 weeks 1.84 (1.56-2.16) 1.01 (0.81-1.26) 1.42 (1.06-1.92) 5-28 weeks 1.13 (1.04-1.23) 1.01 (0.86-1.18) 1.05 (0.81-1.36) 29-52 weeks 1.06 (0.97-1.16) - - 53-102 weeks 1.17 (0.99-1.38) - - Eating disorders Day 0 29.2 (22.7-37.6) 5.59 (3.26-9.59) 20.9 (11.8-37.0) 1-4 weeks 1.96 (1.61-2.39) 0.88 (0.64-1.21) 1.56 (0.97-2.52) 5-28 weeks 1.26 (1.13-1.41) 0.91 (0.71-1.16) 1.14 (0.73-1.77) 29-52 weeks 1.09 (0.96-1.24) - - 53-102 weeks 1.24 (0.98-1.57) - - Addiction Day 0 66.2 (56.9-77.1) 17.0 (12.0-24.1) 44.8 (34.9-57.5) 1-4 weeks 1.45 (1.19-1.78) 0.98 (0.72-1.33) 1.04 (0.73-1.47) 5-28 weeks 0.95 (0.86-1.05) 0.69 (0.53-0.91) 0.77 (0.57-1.05) 29-52 weeks 1.00 (0.89-1.12) - - 53-102 weeks 1.00 (0.79-1.26) - - Self-harm Day 0 22.3 (19.2-26.0) 10.9 (8.61-13.9) 12.1 (8.28-17.6) 1-4 weeks 1.21 (1.06-1.37) 1.02 (0.86-1.20) 1.09 (0.83-1.44) 5-28 weeks 1.15 (1.09-1.22) 1.17 (1.04-1.31) 0.92 (0.73-1.15) 29-52 weeks 1.17 (1.10-1.25) - - 53-102 weeks 1.14 (1.01-1.29) - - Suicide Day 0 850 (742-975) † † 1-4 weeks 4.18 (2.94-5.94) † † 5-28 weeks 0.85 (0.60-1.19) † † 29-52 weeks 0.83 (0.57-1.20) - - 53-102 weeks 0.86 (0.45-1.65) - - † Insufficient events for estimation . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 5 Figure 1: Maximally adjusted hazard ratios and 95% CIs for depression and serious mental illness following diagnosis of COVID-19 in the pre-vaccination, vaccinated and unvaccinated cohorts, overall and by COVID-19 severity. Events on the day of COVID-19 diagnosis (day 0) were excluded. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 6 Figure 2: Maximally adjusted hazard ratios and 95% CIs for depression and serious mental illness following diagnosis of COVID-19 in the pre-vaccination, vaccinated and unvaccinated cohorts, by prior history of the outcome. Events on the day of COVID-19 diagnosis (day 0) were excluded. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 7 Figure 3: Maximally adjusted hazard ratios and 95% confidence intervals for other mental illness events following diagnosis of COVID-19 in the pre-vaccination, vaccinated and unvaccinated cohorts. Events on the day of COVID-19 diagnosis (day 0) were excluded. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint 8 Figure 4: Absolute excess risk up to 28 weeks for depression and serious mental illness following diagnosis of COVID-19 in the pre-vaccination, vaccinated and unvaccinated cohorts. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted December 7, 2023. ; https://doi.org/10.1101/2023.12.06.23299602doi: medRxiv preprint