The COVID-19 pandemic significantly impacted global healthcare systems, notably increasing the risk of mental health problems due to lockdowns, social distancing, and uncertainty. While COVID-19 vaccines have been crucial in mitigating the pandemic's severity and mortality, concerns remain regarding post-COVID-19 sequelae and vaccine-related adverse events, particularly psychiatric AEs. Previous research on the correlation between mental health and COVID-19 breakthrough infections exists, but studies specifically examining post-vaccination psychiatric AEs have been limited, primarily consisting of case reports and case series. This study aimed to address this gap by investigating the association between COVID-19 vaccination and various psychiatric AEs using a large population-based cohort in Seoul, South Korea, leveraging the Korean National Health Insurance Service (KNHIS) claims database. The researchers sought to quantify the incidence and risk of specific psychiatric disorders following vaccination, providing valuable data for informing vaccination strategies and clinical management.

Existing literature suggests a link between viral infections, including COVID-19, and an increased risk of psychiatric manifestations. However, evidence regarding psychiatric AEs following COVID-19 vaccination was scarce prior to this study. While some studies indicated a possible alleviation of psychological distress after vaccination, others reported cases of psychiatric reactions, including psychosis, depression, anxiety, and other disorders. The lack of robust population-level data underscored the need for this study to provide a more comprehensive understanding of the relationship between COVID-19 vaccination and psychiatric outcomes.

This retrospective cohort study utilized data from the KNHIS claims database, encompassing a randomly selected 50% of the Seoul population (n=4,348,412) as of January 1, 2021. Individuals under 20 years of age were excluded. The study population was divided into vaccinated (received two doses by October 1, 2021) and unvaccinated groups. The primary outcome measure was the cumulative incidence of psychiatric AEs per 10,000 population at one week, two weeks, one month, and three months post-vaccination. Secondary outcome measures included the risks of psychiatric AEs using odds ratios (ORs) and hazard ratios (HRs). The study controlled for confounding factors such as age, gender, insurance level, Charlson's comorbidity index (CCI), presence of diabetes mellitus (DM), hypertension (HTN), hyperlipidemia, COPD, and prior COVID-19 infection. Statistical analyses were performed using SAS Enterprise Guide, including the Kolmogorov-Smirnov test for normality, Student's t-test and chi-square test for comparing baseline characteristics, and multiple logistic regression and Cox proportional hazards regression to assess the association between vaccination and psychiatric AEs. The study adhered to STROBE guidelines.

A total of 2,027,353 individuals were included in the analysis (1,718,999 vaccinated, 308,354 unvaccinated). At three months post-vaccination, the vaccinated group showed significantly higher cumulative incidences of depression, anxiety, dissociative, stress-related, and somatoform disorders, sleep disorders, and sexual disorders compared to the unvaccinated group. Conversely, the cumulative incidences of schizophrenia and bipolar disorder were significantly lower in the vaccinated group. Cox proportional hazards regression revealed that COVID-19 vaccination significantly increased the risks of depression, anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders, while significantly reducing the risks of schizophrenia and bipolar disorder. Subgroup analyses revealed that the risk of schizophrenia increased with age, while the risks of depression, bipolar disorder, and anxiety disorders decreased with age. Higher CCI scores were associated with increased risks of depression, anxiety, and sleep disorders. Heterologous vaccination was associated with the highest risk of depression and anxiety disorders, while cDNA-only vaccination showed the lowest risk of bipolar disorder. The study also provided detailed cumulative incidence rates for each psychiatric disorder at various time points and stratified by vaccine type (mRNA-only, cDNA-only, heterologous).

This study provides robust evidence of the differential impact of COVID-19 vaccination on various psychiatric disorders. The increased risk of several anxiety and mood disorders in the vaccinated group, coupled with the decreased risk of schizophrenia and bipolar disorder, highlights the complex relationship between vaccination and mental health. The observed findings may be partly explained by the impact of COVID-19 and vaccines on the immune system and inflammatory processes, potentially affecting neurotransmitter systems involved in mood regulation and psychosis. The elevated risk associated with heterologous vaccination suggests that vaccine type may play a role in the manifestation of psychiatric AEs. These findings underscore the need for clinicians to be aware of potential mental health consequences following COVID-19 vaccination, particularly in vulnerable populations.

This large-scale population-based study demonstrates that COVID-19 vaccination differentially affects the incidence and risk of various psychiatric disorders. While increasing the risk of several anxiety and mood disorders, it concomitantly reduces the risk of schizophrenia and bipolar disorder. These findings highlight the complexity of the relationship between COVID-19 vaccination and mental health and emphasize the need for ongoing monitoring and careful consideration of potential psychiatric AEs, particularly in individuals with pre-existing vulnerabilities. Future research should investigate the underlying mechanisms and potential long-term effects.

This study has limitations inherent to retrospective cohort studies using claims data. ICD-10 coding may lead to misclassification biases. The study excluded individuals under 20 years of age, limiting the generalizability to the entire population. The follow-up period was limited to three months, precluding an assessment of long-term effects. Finally, the study's focus on Seoul, South Korea, may limit the generalizability to other populations and geographic regions. Future prospective studies with longer follow-up periods are needed to confirm these findings and investigate potential long-term impacts.