Long-term mental health outcomes after SARS-CoV-2 infection: prospective cohort study

Despite previous evidence from retrospective cohorts suggest that survivors of COVID-19 may be at increased risk of psychiatric sequelae, questions remain on the incidence and absolute risk of psychiatric outcomes, and on the potential protective effect of vaccination. Addressing these knowledge gaps will help public health and clinical service planning during the ongoing pandemic. Based on UK Biobank prospective data, we constructed a SARS-CoV-2 infection cohort including participants with a positive PCR test for SARS-CoV-2 between March 1, 2020 and September 30, 2021; a contemporary control cohort with no evidence of SARS-CoV-2, and a historical control cohort predating the COVID-19 pandemic. Additional control cohorts were constructed for benchmarking, including participants diagnosed with other respiratory tract infection, or with a negative SARS-CoV-2 test. We used propensity score weighting using predefined (clinically informed) and data-driven covariates to minimize confounding. We then estimated incidence rates and risk of first psychiatric disorders diagnosed by ICD-10 codes and psychotropic prescriptions after SARS-CoV-2 infection using cause-specific Cox models. In this prospective cohort including 406,579 adults (224,681 women, 181,898 men; mean [SD] age 66.1 [8.4] years), 26,181 had a SARS-CoV-2 infection. Compared with contemporary controls (n=380,398), COVID-19 survivors had increased risks of subsequent psychiatric diagnoses (HR: 2.02, 95% CI 1.85-2.21; difference in incidence rate: 24.85, 95 CI 20.69-29.39 per 1000 person-years) and psychotropic prescriptions (HR: 1.61, 95% CI 1.48-1.75; difference in incidence rate: 21.77, 95% CI 16.59-27.54 per 1000 person-years). Regarding individual mental health related outcomes, the SARS-CoV-2 infection cohort showed an increased risk of psychotic disorders (2.26, 1.28-3.98), mood disorders (2.19, 1.92-2.50), anxiety disorders (2.08, 1.82-2.38), substance use disorders (1.59, 1.34-1.90), sleep disorders (1.95, 1.60-2.39); and prescriptions for antipsychotics (3.78, 2.74-5.21), antidepressants (1.55, 1.29-1.87), benzodiazepines (1.82, 1.58-2.11), and opioids (1.40, 1.26-1.55). Overall, the risk of any mental health outcome was increased with a HR of 1.58, 95% CI 1.47-1.70; and difference in incidence rate of 32.04, 25.76-38.81 per 1000 person-years. These results were consistent when comparing to a historical control cohort. Additionally, mental health risks were increased even further in participants who tested positive in hospital settings. Finally, participants who were fully vaccinated had a lower risk of mental health outcomes compared to those infected when unvaccinated or partially vaccinated. All observed risks of mental health outcomes were attenuated or even lower after SARS-CoV-2 infection compared with those with other respiratory infections, or with participants in the test-negative control cohort. In this prospective cohort study, people who survived COVID-19 were at increased risk of psychiatric outcomes and related psychotropic medications. These risks were higher in those with more severe disease, treated in hospital settings, and were significantly reduced in fully vaccinated people. Of note, compared to participants with other respiratory infections or with only negative testing results, those infected with SARS-CoV-2 had an even lower risk of mental health outcomes, warranting further research into causation. The early identification and treatment of psychiatric disorders among survivors of COVID-19 should be a priority in the long-term management of COVID-19. Particular attention might be needed for those with severe (hospitalized) disease and those who were not fully vaccinated at the time of infection.