Exploring the Association Between COVID-19 Vaccination and Mental Disorder Risks: A Retrospective Cohort Study

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This study analyzed a large real-world dataset to examine the risk of psychiatric disorders following COVID-19 vaccination. Methods This retrospective cohort study was conducted using data from the TriNetX Research Network United States Collaboration. Patients were divided into vaccinated and nonvaccinated cohorts and matched at a 1:1 ratio using propensity scores based on age, sex, demographics, and underlying health conditions. The primary outcome was the incidence of newly diagnosed mental, behavioral, and neurodevelopmental disorders within 6 months after COVID-19 vaccination. Results The vaccinated cohort demonstrated a higher risk of mental, behavioral, and neurodevelopmental disorders (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.08–1.14). Specifically, increased risks were observed for mood disorders (HR: 1.31, 95% CI: 1.25–1.38), anxiety disorders (HR: 1.23, 95% CI: 1.18–1.28), and major depressive disorder (HR: 1.35, 95% CI: 1.28–1.42). Conversely, this group showed a lower risk of schizophrenia and related disorders (HR: 0.72, 95% CI: 0.59–0.88). Subgroup analyses revealed that these effects were more pronounced in younger individuals and female patients. Conclusion While COVID-19 vaccination remains essential for pandemic control and should be encouraged among all eligible individuals, our findings highlight the need for targeted mental health monitoring, particularly in younger individuals and women who may be more susceptible to psychological distress following vaccination. Biological sciences/Psychology Biological sciences/Immunology/Vaccines Mental disorder Behavioral disorder Neurodevelopmental disorder COVID-19 vaccination COVID-19 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The COVID-19 pandemic was an unprecedented global health crisis. As of May 2024, more than 774 million confirmed COVID-19 cases and more than 7 million COVID-19-related deaths have been reported worldwide [ 1 ]. COVID-19 can lead to life-threatening conditions, including acute respiratory distress syndrome, myocardial injury, thromboembolic events, multisystem inflammatory syndrome, septic shock, and acute kidney injury [ 2 – 4 ]. COVID-19 can also cause anosmia, encephalitis, meningitis, acute cerebrovascular disease, Guillain-Barr syndrome, cognitive decline, and mental health issues [ 5 – 8 ]. Studies have reported increased rates of anxiety, depression, post-traumatic stress disorder, psychological distress, stress, obsessive behaviors, hoarding, and paranoia during the pandemic [ 9 – 12 ]. Studies have also indicated the detrimental effects of the COVID-19 pandemic on the mental health of individuals with depression, anxiety, or obsessive-compulsive disorder [ 13 – 15 ]. A study reported increased substance use to cope with pandemic-related stress and increased rates of suicidal ideation among young adults, minority groups, and unpaid caregivers [ 16 ]. The rapid development and distribution of COVID-19 vaccines were pivotal for mitigating the effects of the COVID-19 pandemic. More than 5.1 billion individuals received at least one dose of the vaccine [ 17 ]. COVID-19 vaccination led to significant reductions in the spread of the virus, prevention of severe illness, and reduction of mortality rates [ 18 – 20 ]. However, COVID-19 vaccines may have adverse effects on mental health. Several studies have found that COVID-19 vaccination is associated with a decline in psychological distress and significant improvements in mental health [ 21 – 23 ]. By contrast, research has demonstrated that COVID-19 vaccination results in psychological complications. A major concern is the association between COVID-19 vaccine hesitancy and mental health issues. A study demonstrated that among people who received COVID-19 vaccines, vaccine hesitancy was linked to increased levels of anxiety, depression, and peritraumatic stress [ 24 ]. Another review documented the development of acute psychiatric disorders, including psychosis, mania, and severe anxiety, following vaccination [ 25 ]. A retrospective study found that vaccination was associated with the worsening of schizophrenia symptoms among older inpatients and increased anxiety, depression, and stress perception among hospitalized patients [ 26 ]. COVID-19 vaccination was essential for controlling the pandemic. Nevertheless, the mental health effects of COVID-19 vaccination must be examined. Large-scale studies are warranted to investigate the effects of COVID-19 vaccination. Understanding and mitigating these effects through targeted psychological support and effective communication strategies can improve overall mental health outcomes during and after vaccination. Using a large-scale, real-world database, this study explored the relationship between COVID-19 vaccination and the onset of psychiatric disorders and whether factors such as sex and age influence this relationship. Methods Study design and database This retrospective cohort study was conducted using data from the TriNetX Research Network, a global clinical research platform that collects real-time electronic medical data from healthcare organizations (HCOs). The TriNetX Research Network includes data from over 210 million patients sourced from more than 90 HCOs across the United States. TriNetX integrates various data types, coded using standardized classification systems: the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) for diseases; the Procedure Coding System (PCS) and Current Procedural Terminology (CPT) for procedures; the Centers for Disease Control and Prevention (CDC) Vaccine Code Set (CVX) and the Veterans Affairs (VA) National Formulary for medications; and the Logical Observation Identifiers Names and Codes (LOINC) and TriNetX Curated dataset (TNX Curated) for laboratory tests. Further information is available on their website: https://trinetx.com . In the current study, we used the US Collaborative Network of TriNetX for the period between January 1, 2022, and December 30, 2023. Due to the anonymous nature of the data, the requirement for informed consent was waived. The data used in this study were collected on January 20, 2025, and the detailed list of disease and procedure codes utilized in this study are provided in the eMethod section of the Supplementary File. Participants For this study, we selected patients aged ≥ 18 years who had at least three health-care visits and had received COVID-19 PCR tests during the study period; this step was conducted to reduce detection bias. The exclusion criteria were being diagnosed with mental, behavioral, and neurodevelopmental disorders before receiving a COVID-19 PCR test and being diagnosed with COVID-19 after receiving PCR tests. Patients were then divided into two cohorts. Patients who received COVID-19 vaccines were included in the vaccinated cohort, and patients who did not receive COVID-19 vaccines were included in the nonvaccinated cohort (Fig. 1 ). Vaccinated and nonvaccinated patients were matched at a ratio of 1:1 using propensity score matching by age, sex, and other demographic factors and by underlying diseases, psychosocial events, and laboratory measurements. Covariates Baseline characteristics were assessed before the index date. The underlying diseases explored in this study included metabolic disorders, diabetes mellitus, hypertensive diseases, ischemic heart diseases, cerebrovascular diseases, chronic rheumatic heart diseases, acute kidney failure and chronic kidney disease, chronic lower respiratory diseases, diseases of the liver, neoplasms, inflammatory polyarthropathies, systemic connective tissue disorders, degenerative diseases of the nervous system, polyneuropathies and other disorders of the peripheral nervous system, inflammatory diseases of the central nervous system, disorders of the thyroid gland, congenital malformations, deformations, and chromosomal abnormalities, episodic and paroxysmal disorders, functional dyspepsia, external causes of morbidity, tuberculosis, and long-term (current) drug therapy. Psychosocial events included problems related to housing and economic circumstances; problems related to other psychosocial circumstances; problems related to certain psychosocial circumstances; other problems related to the primary support group, including family circumstances; problems related to the social environment; problems related to employment and unemployment; and problems related to upbringing and the primary support group; medicine services and procedures. Laboratory measurements included hemoglobin, creatinine, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Additionally, body mass index (BMI) was also assessed. Outcomes The primary outcome of our study was newly diagnosed mental, behavioral, and neurodevelopmental disorders, which were identified within 6 months after the index date. These disorders included mood (affective) disorders; anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders; mental disorders due to known physiological conditions; schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders; behavioral syndromes associated with physiological disturbances and physical factors; disorders of adult personality and behavior; intellectual disabilities; pervasive and specific developmental disorders; behavioral and emotional disorders; bipolar disorder; and major depressive disorder or depressive episode. Subgroup analyses investigated whether the risks of mental, behavioral, and neurodevelopmental disorders among COVID-19 survivors differed by sex and age. Statistical analysis Statistical analysis was conducted directly within the TriNetX platform. Continuous data are reported as mean ± standard deviation (SD), and categorical data are presented as counts and percentages. To compare baseline characteristics between vaccinated and unvaccinated patients, the t test was used for analyzing continuous variables, and the chi-square test was used for examining categorical variables. Propensity score matching at a ratio of 1:1 was employed to balance baseline characteristics. Matching between vaccinated and nonvaccinated patients was achieved using the TriNetX platform's built-in function, which utilized greedy nearest neighbor matching based on variables such as age, sex, ethnicity, and ethnicity, comorbidities, psychosocial events, and laboratory data. Event-free survival curves were estimated using the Kaplan–Meier method and were assessed using the log rank test. In time-to-event analysis, hazard ratios (HRs) were calculated to quantify the relative risks of mental, behavioral, and neurodevelopmental disorders. In Cox proportional hazard models, HRs and their associated 95% confidence intervals (CIs) were estimated. The proportional hazard assumption was tested using the generalized Schoenfeld approach integrated within the TriNetX platform. For all tests, statistical significance was defined as a two-sided p value of < .05. Forest plots were generated using SRplot, a free online platform for data visualization and graphing [ 27 ]. Ethical Statement This study was conducted in accordance with the guidelines of the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) and adhered to all relevant local and international regulations and standards. The TriNetX platform complies with the US Health Insurance Portability and Accountability Act (HIPAA) and the General Data Protection Regulation (GDPR), ensuring the protection of personal health information. Data used in this study were de-identified following the standards set forth in §164.514(b)(1) of the HIPAA Privacy Rule, with formal attestation of de-identification provided. Due to the anonymized nature of the data and the retrospective study design, the requirement for informed consent was waived by the Institutional Review Board (IRB) of the Shin Kong Wu Ho-Su Memorial Hospital. Additionally, the use of TriNetX in the current study was approved by the Institutional Review Board of the Shin Kong Wu Ho-Su Memorial Hospital (Institutional Review Board Number: 20240811R). Results Baseline characteristics of study patients Initially, 157,419 patients who received COVID-19 vaccines and 1,767,831 patients who did not receive COVID-19 vaccines were identified before matching. After propensity score matching, 157,393 patients with mental, behavioral, and neurodevelopmental disorders after COVID-19 vaccination were enrolled and an equal number of controls (without COVID-19 vaccination) with mental, behavioral, and neurodevelopmental disorders were enrolled. The patient selection process is illustrated in Figure 1. The demographic characteristics, comorbidities, and laboratory measurements of both groups before and after propensity score matching is provided in Table 1. After matching, the mean age of the vaccinated cohort was 54.80 ± 20.4 years on the index date. Approximately 58.4% of the vaccinated cohort were women, and the majority were of White (55.4%) and African American (15.6%) ethnicities. The vaccinated and nonvaccinated cohorts exhibited a balanced distribution of demographics, comorbidities, psychosocial events, and laboratory data (standardized difference < 0.10). Incidence of mental, behavioral, and neurodevelopmental disorders between vaccinated and nonvaccinated cohorts We estimated the risks of mental, behavioral, and neurodevelopmental disorders in the vaccinated and nonvaccinated (control) cohorts at the 6-month follow-up (Table 2, Figure 2), detailed analyses of specific diseases were also conducted (Figure 3). Patients who received COVID-19 vaccination had higher risks of mental, behavioral, and neurodevelopmental disorders (aHR: 1.11, 95% CI: 1.08–1.14; p < .001); mood (affective) disorders (aHR: 1.31, 95% CI: 1.25–1.38; p < .001); and anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders (aHR: 1.23, 95% CI: 1.18–1.28; p < .001). They also had higher risks of behavioral syndromes associated with physiological disturbances and physical factors (aHR: 1.32, 95% CI: 1.19–1.47; p < .001), behavioral and emotional disorders (aHR: 1.63, 95% CI: 1.39–1.91; p < .001), and major depressive disorder or depressive episode (aHR: 1.35, 95% CI: 1.28–1.42; p < .001). The risks of bipolar disorder (aHR: 0.86, 95% CI: 0.70–1.07; p = 0.168) and schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (aHR: 0.72, 95% CI: 0.59–0.88; p = 0.001) were lower in vaccinated patients than in nonvaccinated patients. No significant differences were observed in the risks of mental disorders due to known physiological conditions (aHR: 1.02, 95% CI: 0.94–1.10; p = 0.068), intellectual disabilities (aHR: 0.90, 95% CI: 0.58–1.37; p = 0.644), or pervasive and specific developmental disorders (aHR: 1.47, 95% CI: 1.09–1.99; p = 0.012). Additionally, disorders of adult personality and behavior were significantly higher in the vaccinated cohort (aHR: 1.64, 95% CI: 1.21–2.23; p = 0.001). Subgroup analyses In the sex-based subgroup analysis (Figure 4, eTable 1 and eTable 2 in Supplementary file), the risks of mental, behavioral, and neurodevelopmental disorders were generally consistent between men and women in the vaccinated group, but some differences were noted. Among men, the overall risk was slightly increased and did not reach statistical significance. However, men exhibited clearly higher risks of mood (affective) disorders, anxiety disorders, and major depressive disorder. By contrast, women demonstrated a significant rise in both their overall risk of mental disorders and in these specific outcomes. Women also showed a reduced risk of schizophrenia and related psychotic disorders compared with unvaccinated women. In the age-based analysis (Figure 5, eTable 3,4,5 in Supplementary file), younger adults (18–40 years) was associated with the largest relative increase in mood (affective) disorders, anxiety disorders, and major depressive disorder, while the risk of schizophrenia and related disorders decreased in this subgroup. Adults aged 40–65 years showed only a slightly increased overall risk, which did not reach statistical significance; however, this group still had a noticeable rise in the risk of mood, anxiety, and depressive disorders compared with their nonvaccinated counterparts. In older adults (≥65 years), vaccination was linked to a modest but significant increase in the overall risk of mental, behavioral, and neurodevelopmental disorders, particularly mood, anxiety, and depressive disorders. In contrast, these older vaccinated adults experienced a lower risk of schizophrenia and related psychotic conditions compared with those who were not vaccinated. Extended analysis and sensitivity analyses To eliminate the influence of COVID-19 infection, we analyzed patients with and without COVID-19 vaccination who had no history of infection throughout lifetime and observed similar findings of increased risks for certain psychiatric disorders (Figure 6, eTable 6 in Supplementary File). Sensitivity analyses were conducted with the Global Collaborative Network on the TrinetX platform, and results were consistent with our primary data (eFigure 1, eTable 7 in Supplementary file) Discussion Key findings and implications In the current large-scale propensity score–matched study conducted using data from a multi-institutional US collaborative research network, compared with nonvaccinated patients, COVID-19-vaccinated patients had significantly higher risks of mental, behavioral, and neurodevelopmental disorders, including mood (affective) disorders, anxiety and stress-related disorders, and major depressive disorder. By contrast, vaccinated patients exhibited lower risks of schizophrenia; schizotypal, delusional, and non-mood psychotic disorders; and bipolar disorder, these findings were more pronounced among younger individuals and female patients. The results indicate that for COVID-19-vaccinated patients, comprehensive mental health screening and management strategies should be implemented to detect and address mental health disorders in the early stage, potentially improving patient outcomes. Potential mechanisms underlying psychiatric effects of COVID-19 vaccination Previous studies have suggested several mechanisms for the neurological and psychological effects of vaccination [28-30]. For example, increased levels of antibodies to myelin basic protein have been observed in patients with severe psychoneurological complications, including encephalomyelitis and transverse myelitis, after rabies vaccination; these observations suggest an underlying autoimmune mechanism for the complications [31, 32]. Vaccination can also cause increases in kynurenic acid, which may impair the function of N-methyl d-aspartate (NMDA) receptors; this impaired function leads to a chain reaction that reduces the inhibitory control of dopaminergic neurons in the ventral tegmental area and subsequently increases dopamine production, leading to psychiatric symptoms such as psychosis, anxiety, depression, and cognitive decline [33, 34]. In certain patients, COVID-19 vaccination triggered a cytokine storm, which is characterized by the elevated serum levels of IL-2, IL-6, IL-9, and tumor necrosis factor-α mediated by CD4 + T cells and which may affect the levels of monoamine neurotransmitters, leading to the altered release of dopamine, serotonin, and norepinephrine [34, 35]. Even in healthy individuals, transient increases in IL-6 following influenza vaccination have been associated with short-term changes in mood and cognitive symptoms, suggesting that low-grade inflammation may be sufficient to trigger depressive features [36]. Adjuvants and preservatives in vaccines, such as aluminum adjuvants and the thimerosal preservative, may trigger immune responses; thus, these adjuvants and preservatives are associated with neurotoxicity and psychological complications [37]. The inflammatory response triggered by the lipid nanoparticles or the antigens in vaccines, such as the spike protein and its peptide fragments, may also contribute to these adverse events (28). Additionally, stress activates the hypothalamic–pituitary–adrenal (HPA) axis, which leads to the release of cortisol. The prolonged activation of the HPA axis and consistently high cortisol levels, which may occur following vaccination, are associated with the onset of psychiatric disorders, including depression and anxiety [35, 38]. Incorrect information on COVID-19 vaccines also plays an important role in psychiatric adverse events. The development of functional neurological disorders (FND) in some COVID-19 vaccine recipients is attributed to misinformation about vaccines on social media, pandemic-related stress, and increased psychological stress [39, 40]. A previous study reported that schizophrenia patients have higher rates of vaccine hesitancy due to concerns about side effects, mistrust in the health-care system, and negative impressions of vaccination [38]. Structural barriers including transportation issues, financial constraints, and absence of consistent health-care providers also contribute to lower vaccination rates and willingness among this population [41], which may have affected the results of our study. Further studies should verify whether COVID-19 vaccination decreases the risk of schizophrenia [42]. Reevaluating the psychiatric impact of COVID-19 vaccination: a comparison with prior studies Our study results appear to contradict those of other studies [43, 44]. Walker et al. (2024) highlighted vaccination’s protective role against COVID-19-related psychiatric outcomes, particularly in reducing the risks of psychiatric disorders post-infection, especially in severe cases. In contrast, our study examines psychiatric outcomes following vaccination itself, independent of COVID-19 infection, identifying potential adverse psychiatric effects. To eliminate the influence of COVID-19 infection, we analyzed patients with and without COVID-19 vaccination who had no history of infection throughout lifetime and observed similar findings of increased risks for certain psychiatric disorders (Figure 3, eTable 8 in Supplementary file). Unlike Walker et al., who controlled prior infections, our study excluded known COVID-19 cases but not asymptomatic ones. Both studies underscore vaccination’s public health importance, while our findings emphasize the need for enhanced post-vaccination mental health monitoring to balance the protective benefits of vaccination with an awareness of potential psychiatric risks. Impact of Healthcare Access Barriers on Post-Vaccination Psychiatric Outcomes Another research in South Korea showed a rise in unmet healthcare needs during the pandemic, suggesting that disruptions in healthcare access may have played a role in worsening mental health outcomes[45]. Given our findings that vaccinated individuals, particularly women and younger adults, had an increased risk of psychiatric disorders, it is possible that barriers to mental health care further amplified these effects. Limited access to timely intervention could have prolonged symptoms or prevented early management, leading to greater long-term impact. These findings highlight the importance of integrating mental health care into vaccination programs and strengthening healthcare accessibility, particularly during public health crises. Strengths and limitations Our study has several strengths. First, we used a relatively large dataset in our study, enhancing the robustness and reliability of our findings. Second, to ensure the accuracy of our study results, we only included individuals who tested negative in a COVID-19 RNA test as controls; this approach was implemented to eliminate the effect of COVID-19 infection on patients with psychiatric disorders. Third, employing propensity score matching ensured well-balanced baseline characteristics between the vaccinated and nonvaccinated cohorts. This approach significantly enhanced the validity of the comparisons by reducing the potential impact of confounding variables. In addition, we conducted sensitivity analyses to corroborate the findings of the primary analyses as well as subgroup analyses to characterize subpopulations at high risk of mental, behavioral, and neurodevelopmental disorders for their future surveillance. Finally, COVID-19 lockdown policies in the United States significantly increased the prevalence of anxiety and depression [46, 47]. Thus, to minimize the effects of lockdown policy on the risk of mental disorders, we excluded patients diagnosed with mental disorders before 2022, when lockdown policies and social distancing were not strictly implemented [48]. This study has several limitations. First, although we evaluated vaccinated and unvaccinated patients in the United States and within the global TriNetX network, most of the HCOs from which data were obtained were located in the United States. This limits the generalizability of our conclusions to populations in other countries. Second, compared with prospective cohort studies, our use of ICD-10-CM codes for the study outcomes may introduce bias from inaccurate diagnoses. Third, although we used validated outcome definitions and propensity score matching to minimize bias, we were unable to balance the socioeconomic status and potential psychiatric factors due to the lack of relevant codes and data. Fourth, the TriNetX database was not designed to evaluate psychiatric disorders and does not contain results of psychiatric assessment tools. Therefore, we could not evaluate the severity of psychiatric disorders. Moreover, this observational study identify association, not casuality, further prospective studies targeting the psychiatric effects of COVID-19 vaccination should be conducted to verify our findings. Finally, we excluded patients with COVID-19 because such patients are at high risk of psychiatric disorders; therefore, the effect of the pandemic on the total population might have been underestimated. Public health implications and future directions Our study results emphasize the importance of strengthening mental health–related policies related to COVID-19 vaccination. The related measures include educating the public about the possibility of severe psychiatric side effects and the overall safety and benefits of COVID-19 vaccines, providing tailored educational programs that address safety concerns and prevent misinformation, and providing psychiatric consultations and behavioral interventions for individuals who experience anxiety, mood disorders, or other psychiatric symptoms post vaccination. These strategies collectively aim to protect this vulnerable population (who may develop psychiatric disorders after COVID-19 vaccination) and enhance vaccine acceptance and safety. Conclusion COVID-19 vaccination has been a cornerstone in controlling the pandemic and reducing severe disease and mortality. While increased risk of mental health issues, such as mood and anxiety disorders, has been observed in some vaccinated individuals, particularly women and younger populations, this highlights the importance of including mental health monitoring as part of post-vaccination care. Early identification and management of potential mental health concerns can help improve outcomes and reinforce the overall safety and benefits of vaccination. Declarations Authorship Contribution Statement Yu-Ting Yu : Writing-Original Draft, Conceptualization, Methodology, Formal analysis, Writing-Review & Editing, Visualization. Hsiao-Wei Wang: Writing-Review & Editing, Supervision. Shang-Wen Chang : Writing-Review & Editing, Conceptualization, Methodology, Supervision. Declaration of Competing Interest The authors declare no conflict of interest regarding the publication of this paper. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Acknowledgements The authors thank the Shin Kong Wu Ho-Su Memorial Hospital (SKH-8302-103-DR-04) for sponsoring this study. This manuscript was edited by Wallace Academic Editing. References WHO COVID-19 dashboard. ; (2024). 2024/05/15 Available from: https://data.who.int/dashboards/covid19/cases?n=c Yazdanpanah, F., Hamblin, M. R. & Rezaei, N. The immune system and COVID-19: Friend or foe? Life Sci. 256 , 117900 (2020). Clerkin, K. J. et al. COVID-19 and Cardiovascular Disease. Circulation 141 (20), 1648–1655 (2020). Kollias, A. et al. Venous thromboembolism in COVID-19: A systematic review and meta-analysis. Vasc Med. 26 (4), 415–425 (2021). Ahmed, M. U. et al. Neurological Manifestations of COVID-19 (SARS-CoV-2): A Review. Front. Neurol. 11 , 518 (2020). Ellul, M. A. et al. Neurological associations of COVID-19. Lancet Neurol. 19 (9), 767–783 (2020). Favas, T. T. et al. Neurological manifestations of COVID-19: a systematic review and meta-analysis of proportions. Neurol. Sci. 41 (12), 3437–3470 (2020). Ousseiran, Z. H., Fares, Y. & Chamoun, W. T. Neurological manifestations of COVID-19: a systematic review and detailed comprehension. Int. J. Neurosci. 133 (7), 754–769 (2023). Xiong, J. et al. Impact of COVID-19 pandemic on mental health in the general population: A systematic review. J. Affect. Disord . 277 , 55–64 (2020). Rajkumar, R. P. COVID-19 and mental health: A review of the existing literature. Asian J. Psychiatry . 52 , 102066 (2020). Dubey, S. et al. Psychosocial impact of COVID-19. Diabetes Metab. Syndr. 14 (5), 779–788 (2020). de Marques, D. et al. How is COVID-19 pandemic impacting mental health of children and adolescents? Int. J. Disaster Risk Reduct. 51 , 101845 (2020). Pan, K. Y. et al. The mental health impact of the COVID-19 pandemic on people with and without depressive, anxiety, or obsessive-compulsive disorders: a longitudinal study of three Dutch case-control cohorts. Lancet Psychiatry . 8 (2), 121–129 (2021). Hao, F. et al. Do psychiatric patients experience more psychiatric symptoms during COVID-19 pandemic and lockdown? A case-control study with service and research implications for immunopsychiatry. Brain Behav. Immun. 87 , 100–106 (2020). Zaccari, V. et al. Narrative Review of COVID-19 Impact on Obsessive-Compulsive Disorder in Child, Adolescent and Adult Clinical Populations. Front. Psychiatry . 12 , 673161 (2021). Czeisler, M. et al. Mental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic - United States, June 24–30 , MMWR Morb Mortal Wkly Rep, 2020. 69(32): pp. 1049–1057. (2020). Organization, W. H. COVID-19 vaccination, World data . COVID-19 vaccination, World data; (2024). Available from: https://data.who.int/dashboards/covid19/vaccines Huang, Y. Z. & Kuan, C. C. Vaccination to reduce severe COVID-19 and mortality in COVID-19 patients: a systematic review and meta-analysis. Eur. Rev. Med. Pharmacol. Sci. 26 5 , 1770–1776 (2022). Moghadas, S. M. et al. The Impact of Vaccination on Coronavirus Disease 2019 (COVID-19) Outbreaks in the United States. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2021. 73: pp. 2257–2264. Sezen, Y. I. et al. Risk factors and the impact of vaccination on mortality in COVID-19 patients. Bratisl. Lek. Listy . 123 6 , 440–443 (2022). Koltai, J. et al. COVID-19 Vaccination and Mental Health: A Difference-In-Difference Analysis of the Understanding America Study. Am. J. Prev. Med. 62 (5), 679–687 (2022). Perez-Arce, F. et al. COVID-19 vaccines and mental distress. PLoS One . 16 (9), e0256406 (2021). Chaudhuri, K. & Howley, P. The impact of COVID-19 vaccination for mental well-being. Eur. Econ. Rev. 150 , 104293 (2022). Palgi, Y. et al. No psychological vaccination: Vaccine hesitancy is associated with negative psychiatric outcomes among Israelis who received COVID-19 vaccination. J. Affect. Disord . 287 , 352–353 (2021). Balasubramanian, I. et al. Psychiatric adverse reactions to COVID-19 vaccines: A rapid review of published case reports. Asian J. Psychiatr . 71 , 103129 (2022). Wu, X. et al. The impact of COVID-19 vaccination on psychiatric symptoms in schizophrenia patients: A retrospective study. Med. (Baltim). 102 (23), e34016 (2023). Tang, D. et al. SRplot: A free online platform for data visualization and graphing. PLoS One . 18 (11), e0294236 (2023). Miravalle, A. A. et al. Neurological complications following vaccinations. Neurol. Res. 32 , 285–292 (2010). Tian, M. et al. Vaccine-Associated Neurological Adverse Events: A Case Report and Literature Review (Current pharmaceutical design, 2019). Carpenter, L. J. et al. The psychiatric and psychological sequelae of vaccine-induced immune thrombotic thrombocytopenia (VITT). Semin. Hematol. 59 (2), 115–119 (2022). Hemachudha, T. et al. Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination. N Engl. J. Med. 316 (7), 369–374 (1987). Hemachudha, T. et al. Immunologic studies of patients with chronic encephalitis induced by post-exposure Semple rabies vaccine. Neurology 38 , 42–42 (1988). Grover, S. et al. First episode psychosis following receipt of first dose of COVID-19 vaccine: A case report. Schizophr Res. 241 , 70–71 (2022). Lundberg-Morris, L. et al. Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study. Bmj 383 , e076990 (2023). Moncrieff, J. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol. Psychiatry . 28 (8), 3243–3256 (2023). Kuhlman, K. R. et al. Within-subject associations between inflammation and features of depression: Using the flu vaccine as a mild inflammatory stimulus. Brain, Behavior, and Immunity, 69: pp. 540–547. (2018). Shaw, C. A. & Tomljenovic, L. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity. Immunol. Res. 56 (2–3), 304–316 (2013). Jia, F. et al. Psychiatric symptoms before and after COVID-19 vaccination: A cohort study of hospitalized schizophrenia patients. Asian J. Psychiatr . 78 , 103319 (2022). Ransing, R. et al. COVID-19 anti-vaccine movement and mental health: Challenges and the way forward. Asian J. Psychiatr . 58 , 102614 (2021). Freeman, D. et al. Injection fears and COVID-19 vaccine hesitancy. Psychol. Med. 53 (4), 1185–1195 (2023). Raffard, S. et al. Attitudes towards Vaccines, Intent to Vaccinate and the Relationship with COVID-19 Vaccination Rates in Individuals with Schizophrenia . Vaccines (Basel) , 10 (8). (2022). Kim, H. J. et al. Psychiatric adverse events following COVID-19 vaccination: a population-based cohort study in Seoul, South Korea (Mol Psychiatry, 2024). Walker, V. M. et al. COVID-19 and mental illnesses in vaccinated and unvaccinated people. JAMA psychiatry . 81 (11), 1071–1080 (2024). Kim, S. et al. Short-and long-term neuropsychiatric outcomes in long COVID in South Korea and Japan. Nat. Hum. Behav. 8 (8), 1530–1544 (2024). Kim, Y. et al. National Trends in the Prevalence of Unmet Health Care and Dental Care Needs During the COVID-19 Pandemic: Longitudinal Study in South Korea, 2009–2022. JMIR Public. Health Surveill . 10 , e51481 (2024). Prati, G. & Mancini, A. D. The psychological impact of COVID-19 pandemic lockdowns: a review and meta-analysis of longitudinal studies and natural experiments . Psychol. Med. , : pp. 1–11. (2021). Chen, S. et al. The Medium-Term Impact of COVID-19 Lockdown on Referrals to Secondary Care Mental Health Services: A Controlled Interrupted Time Series Study 11 (Frontiers in Psychiatry, 2020). Boloori, A. & Saghafian, S. Health and Economic Impacts of Lockdown Policies in the Early Stage of COVID-19 in the United States. Service Sci. 15 (3), 188–211 (2023). Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.Baselinecharacteristics.docx Table2.Results.docx Supplementaryfile20250211.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 28 Apr, 2025 Submission checks completed at journal 24 Apr, 2025 First submitted to journal 19 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5145501","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":449323832,"identity":"68ecaefd-35b9-44e9-a55e-640375494fd8","order_by":0,"name":"Yu-Ting Yu","email":"","orcid":"","institution":"Shin Kong WHS Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu-Ting","middleName":"","lastName":"Yu","suffix":""},{"id":449323833,"identity":"bbf82eba-cbc7-4bd1-9424-a0ce1970cec3","order_by":1,"name":"Shang-Wen Chang","email":"data:image/png;base64,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","orcid":"","institution":"Shin Kong WHS Memorial Hospital","correspondingAuthor":true,"prefix":"","firstName":"Shang-Wen","middleName":"","lastName":"Chang","suffix":""},{"id":449323834,"identity":"75d86f15-2726-4ee1-988d-6c7e4f8855f8","order_by":2,"name":"Hsiao-Wei Wang","email":"","orcid":"","institution":"Shin Kong WHS Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hsiao-Wei","middleName":"","lastName":"Wang","suffix":""},{"id":449323835,"identity":"4c10e79b-59bd-4fa4-9752-c9d475f29031","order_by":3,"name":"Ming-Hsien Tsai","email":"","orcid":"","institution":"Shin Kong WHS Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ming-Hsien","middleName":"","lastName":"Tsai","suffix":""}],"badges":[],"createdAt":"2024-09-24 13:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5145501/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5145501/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82031896,"identity":"298d8295-3efa-48e2-8bc8-e86e0070541b","added_by":"auto","created_at":"2025-05-06 07:25:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":163738,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of cohort selection. Abbreviations: COVID-19: coronavirus disease 2019, PCR: polymerase chain reaction\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/971424e168d6884fd381e21e.jpg"},{"id":82029593,"identity":"ac0ade09-685e-4155-bd0d-18d70b263a63","added_by":"auto","created_at":"2025-05-06 07:09:09","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":105303,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of mental, behavioral, and neurodevelopmental disorders.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/62c006eb63c9b1063c172922.jpg"},{"id":82029596,"identity":"24ceb8dc-f858-4d71-83f2-efc60d40b039","added_by":"auto","created_at":"2025-05-06 07:09:09","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":116716,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of mental, behavioral, and neurodevelopmental disorders. Abbreviations: HR: hazard ratio, MBNDD: mental, behavioral, and neurodevelopmental disorders. Red dots indicate statistically significant increased HRs (HR \u0026gt; 1, P \u0026lt; 0.05). Blue dots indicate statistically significant decreased HRs (HR \u0026lt; 1, P \u0026lt; 0.05). Black dots indicate non-significant results (P ≥ 0.05).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/376d6f193da33388b2e7e18d.jpg"},{"id":82030766,"identity":"35125170-448a-4a9b-ba66-04cda8bd16f9","added_by":"auto","created_at":"2025-05-06 07:17:09","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":85697,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of outcomes stratified by sex. Abbreviations: HR: hazard ratio, MBNDD: mental, behavioral, and neurodevelopmental disorders. Red dots indicate statistically significant increased HRs (HR \u0026gt; 1, P \u0026lt; 0.05). Blue dots indicate statistically significant decreased HRs (HR \u0026lt; 1, P \u0026lt; 0.05). Black dots indicate non-significant results (P ≥ 0.05).\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/6d0f2e927db13abdfbff3e1f.jpg"},{"id":82029616,"identity":"bb42352e-2011-4ea4-8c8c-b7060ed83006","added_by":"auto","created_at":"2025-05-06 07:09:10","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":101650,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of outcomes stratified by age. Abbreviations: HR: hazard ratio, MBNDD: mental, behavioral, and neurodevelopmental disorders. Red dots indicate statistically significant increased HRs (HR \u0026gt; 1, P \u0026lt; 0.05). Blue dots indicate statistically significant decreased HRs (HR \u0026lt; 1, P \u0026lt; 0.05). Black dots indicate non-significant results (P ≥ 0.05).\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/4c48c5e7431516da2d4aeda1.jpg"},{"id":82031898,"identity":"21df65df-661d-4c43-959d-d9a8f9d260b3","added_by":"auto","created_at":"2025-05-06 07:25:09","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":122171,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of outcomes in patients without COVID-19 infection throughout lifetime\u003c/p\u003e\n\u003cp\u003eAbbreviations: HR: hazard ratio, MBNDD: mental, behavioral, and neurodevelopmental disorders. Red dots indicate statistically significant increased HRs (HR \u0026gt; 1, P \u0026lt; 0.05). Blue dots indicate statistically significant decreased HRs (HR \u0026lt; 1, P \u0026lt; 0.05). Black dots indicate non-significant results (P ≥ 0.05).\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/fabaf2ca83f3521cf3d9e413.jpg"},{"id":82033449,"identity":"2f3fadca-346e-48fc-bd4c-aeaf2d39ec18","added_by":"auto","created_at":"2025-05-06 07:41:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1515414,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/703df255-e8a9-4a37-87c5-8a185e599ee9.pdf"},{"id":82029591,"identity":"1f750673-c92a-4da7-9012-9230733efe66","added_by":"auto","created_at":"2025-05-06 07:09:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":31637,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.Baselinecharacteristics.docx","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/0eec837d755ea44d7c7dbf90.docx"},{"id":82031897,"identity":"815c9a34-1cb7-4e50-9c81-d19b2f68e08d","added_by":"auto","created_at":"2025-05-06 07:25:09","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":24756,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.Results.docx","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/0fa82861898fd57e0354247c.docx"},{"id":82030767,"identity":"bbbb289e-5f7f-4974-8a79-438646d570b9","added_by":"auto","created_at":"2025-05-06 07:17:09","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":200503,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfile20250211.docx","url":"https://assets-eu.researchsquare.com/files/rs-5145501/v1/6d217dfbc649473c957acd89.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exploring the Association Between COVID-19 Vaccination and Mental Disorder Risks: A Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe COVID-19 pandemic was an unprecedented global health crisis. As of May 2024, more than 774\u0026nbsp;million confirmed COVID-19 cases and more than 7\u0026nbsp;million COVID-19-related deaths have been reported worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCOVID-19 can lead to life-threatening conditions, including acute respiratory distress syndrome, myocardial injury, thromboembolic events, multisystem inflammatory syndrome, septic shock, and acute kidney injury [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. COVID-19 can also cause anosmia, encephalitis, meningitis, acute cerebrovascular disease, Guillain-Barr syndrome, cognitive decline, and mental health issues [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Studies have reported increased rates of anxiety, depression, post-traumatic stress disorder, psychological distress, stress, obsessive behaviors, hoarding, and paranoia during the pandemic [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Studies have also indicated the detrimental effects of the COVID-19 pandemic on the mental health of individuals with depression, anxiety, or obsessive-compulsive disorder [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A study reported increased substance use to cope with pandemic-related stress and increased rates of suicidal ideation among young adults, minority groups, and unpaid caregivers [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe rapid development and distribution of COVID-19 vaccines were pivotal for mitigating the effects of the COVID-19 pandemic. More than 5.1\u0026nbsp;billion individuals received at least one dose of the vaccine [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. COVID-19 vaccination led to significant reductions in the spread of the virus, prevention of severe illness, and reduction of mortality rates [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, COVID-19 vaccines may have adverse effects on mental health. Several studies have found that COVID-19 vaccination is associated with a decline in psychological distress and significant improvements in mental health [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. By contrast, research has demonstrated that COVID-19 vaccination results in psychological complications. A major concern is the association between COVID-19 vaccine hesitancy and mental health issues. A study demonstrated that among people who received COVID-19 vaccines, vaccine hesitancy was linked to increased levels of anxiety, depression, and peritraumatic stress [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Another review documented the development of acute psychiatric disorders, including psychosis, mania, and severe anxiety, following vaccination [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. A retrospective study found that vaccination was associated with the worsening of schizophrenia symptoms among older inpatients and increased anxiety, depression, and stress perception among hospitalized patients [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCOVID-19 vaccination was essential for controlling the pandemic. Nevertheless, the mental health effects of COVID-19 vaccination must be examined. Large-scale studies are warranted to investigate the effects of COVID-19 vaccination. Understanding and mitigating these effects through targeted psychological support and effective communication strategies can improve overall mental health outcomes during and after vaccination. Using a large-scale, real-world database, this study explored the relationship between COVID-19 vaccination and the onset of psychiatric disorders and whether factors such as sex and age influence this relationship.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and database\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study was conducted using data from the TriNetX Research Network, a global clinical research platform that collects real-time electronic medical data from healthcare organizations (HCOs). The TriNetX Research Network includes data from over 210\u0026nbsp;million patients sourced from more than 90 HCOs across the United States. TriNetX integrates various data types, coded using standardized classification systems: the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) for diseases; the Procedure Coding System (PCS) and Current Procedural Terminology (CPT) for procedures; the Centers for Disease Control and Prevention (CDC) Vaccine Code Set (CVX) and the Veterans Affairs (VA) National Formulary for medications; and the Logical Observation Identifiers Names and Codes (LOINC) and TriNetX Curated dataset (TNX Curated) for laboratory tests. Further information is available on their website: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://trinetx.com\u003c/span\u003e\u003cspan address=\"https://trinetx.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eIn the current study, we used the US Collaborative Network of TriNetX for the period between January 1, 2022, and December 30, 2023. Due to the anonymous nature of the data, the requirement for informed consent was waived. The data used in this study were collected on January 20, 2025, and the detailed list of disease and procedure codes utilized in this study are provided in the eMethod section of the Supplementary File.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003e For this study, we selected patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who had at least three health-care visits and had received COVID-19 PCR tests during the study period; this step was conducted to reduce detection bias. The exclusion criteria were being diagnosed with mental, behavioral, and neurodevelopmental disorders before receiving a COVID-19 PCR test and being diagnosed with COVID-19 after receiving PCR tests. Patients were then divided into two cohorts. Patients who received COVID-19 vaccines were included in the vaccinated cohort, and patients who did not receive COVID-19 vaccines were included in the nonvaccinated cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Vaccinated and nonvaccinated patients were matched at a ratio of 1:1 using propensity score matching by age, sex, and other demographic factors and by underlying diseases, psychosocial events, and laboratory measurements.\u003c/p\u003e\n\u003ch3\u003eCovariates\u003c/h3\u003e\n\u003cp\u003eBaseline characteristics were assessed before the index date. The underlying diseases explored in this study included metabolic disorders, diabetes mellitus, hypertensive diseases, ischemic heart diseases, cerebrovascular diseases, chronic rheumatic heart diseases, acute kidney failure and chronic kidney disease, chronic lower respiratory diseases, diseases of the liver, neoplasms, inflammatory polyarthropathies, systemic connective tissue disorders, degenerative diseases of the nervous system, polyneuropathies and other disorders of the peripheral nervous system, inflammatory diseases of the central nervous system, disorders of the thyroid gland, congenital malformations, deformations, and chromosomal abnormalities, episodic and paroxysmal disorders, functional dyspepsia, external causes of morbidity, tuberculosis, and long-term (current) drug therapy.\u003c/p\u003e \u003cp\u003ePsychosocial events included problems related to housing and economic circumstances; problems related to other psychosocial circumstances; problems related to certain psychosocial circumstances; other problems related to the primary support group, including family circumstances; problems related to the social environment; problems related to employment and unemployment; and problems related to upbringing and the primary support group; medicine services and procedures.\u003c/p\u003e \u003cp\u003eLaboratory measurements included hemoglobin, creatinine, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Additionally, body mass index (BMI) was also assessed.\u003c/p\u003e"},{"header":"Outcomes","content":"\u003cp\u003eThe primary outcome of our study was newly diagnosed mental, behavioral, and neurodevelopmental disorders, which were identified within 6 months after the index date. These disorders included mood (affective) disorders; anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders; mental disorders due to known physiological conditions; schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders; behavioral syndromes associated with physiological disturbances and physical factors; disorders of adult personality and behavior; intellectual disabilities; pervasive and specific developmental disorders; behavioral and emotional disorders; bipolar disorder; and major depressive disorder or depressive episode.\u003c/p\u003e \u003cp\u003eSubgroup analyses investigated whether the risks of mental, behavioral, and neurodevelopmental disorders among COVID-19 survivors differed by sex and age.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was conducted directly within the TriNetX platform. Continuous data are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), and categorical data are presented as counts and percentages. To compare baseline characteristics between vaccinated and unvaccinated patients, the \u003cem\u003et\u003c/em\u003e test was used for analyzing continuous variables, and the chi-square test was used for examining categorical variables. Propensity score matching at a ratio of 1:1 was employed to balance baseline characteristics. Matching between vaccinated and nonvaccinated patients was achieved using the TriNetX platform's built-in function, which utilized greedy nearest neighbor matching based on variables such as age, sex, ethnicity, and ethnicity, comorbidities, psychosocial events, and laboratory data.\u003c/p\u003e \u003cp\u003eEvent-free survival curves were estimated using the Kaplan\u0026ndash;Meier method and were assessed using the log rank test. In time-to-event analysis, hazard ratios (HRs) were calculated to quantify the relative risks of mental, behavioral, and neurodevelopmental disorders. In Cox proportional hazard models, HRs and their associated 95% confidence intervals (CIs) were estimated. The proportional hazard assumption was tested using the generalized Schoenfeld approach integrated within the TriNetX platform. For all tests, statistical significance was defined as a two-sided \u003cem\u003ep\u003c/em\u003e value of \u0026lt;\u0026thinsp;.05. Forest plots were generated using SRplot, a free online platform for data visualization and graphing [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\u003cp\u003e\u003cstrong\u003eEthical Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the guidelines of the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) and adhered to all relevant local and international regulations and standards. The TriNetX platform complies with the US Health Insurance Portability and Accountability Act (HIPAA) and the General Data Protection Regulation (GDPR), ensuring the protection of personal health information. Data used in this study were de-identified following the standards set forth in \u0026sect;164.514(b)(1) of the HIPAA Privacy Rule, with formal attestation of de-identification provided. Due to the anonymized nature of the data and the retrospective study design, the requirement for informed consent was waived by the Institutional Review Board (IRB) of the Shin Kong Wu Ho-Su Memorial Hospital. Additionally, the use of TriNetX in the current study was approved by the Institutional Review Board of the Shin Kong Wu Ho-Su Memorial Hospital (Institutional Review Board Number: 20240811R).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics of study patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInitially, 157,419 patients who received COVID-19 vaccines and 1,767,831 patients who did not receive COVID-19 vaccines were identified before matching. After propensity score matching, 157,393 patients with mental, behavioral, and neurodevelopmental disorders after COVID-19 vaccination were enrolled and an equal number of controls (without COVID-19 vaccination) with mental, behavioral, and neurodevelopmental disorders were enrolled. The patient selection process is illustrated in Figure 1. The demographic characteristics, comorbidities, and laboratory measurements of both groups before and after propensity score matching is provided in Table 1.\u003c/p\u003e\n\u003cp\u003eAfter matching, the mean age of the vaccinated cohort was 54.80 \u0026plusmn; 20.4 years on the index date. Approximately 58.4% of the vaccinated cohort were women, and the majority were of White (55.4%) and African American (15.6%) ethnicities. The vaccinated and nonvaccinated cohorts exhibited a balanced distribution of demographics, comorbidities, psychosocial events, and laboratory data (standardized difference \u0026lt; 0.10).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIncidence of mental, behavioral, and neurodevelopmental disorders between vaccinated and nonvaccinated cohorts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe estimated the risks of mental, behavioral, and neurodevelopmental disorders in the vaccinated and nonvaccinated (control) cohorts at the 6-month follow-up (Table 2, Figure 2),\u0026nbsp;\u003cbr\u003edetailed analyses of specific diseases were also conducted (Figure 3).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Patients who received COVID-19 vaccination had higher risks of mental, behavioral, and neurodevelopmental disorders (aHR: 1.11, 95% CI: 1.08\u0026ndash;1.14; p \u0026lt; .001); mood (affective) disorders (aHR: 1.31, 95% CI: 1.25\u0026ndash;1.38; p \u0026lt; .001); and anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders (aHR: 1.23, 95% CI: 1.18\u0026ndash;1.28; p \u0026lt; .001). They also had higher risks of behavioral syndromes associated with physiological disturbances and physical factors (aHR: 1.32, 95% CI: 1.19\u0026ndash;1.47; p \u0026lt; .001), behavioral and emotional disorders (aHR: 1.63, 95% CI: 1.39\u0026ndash;1.91; p \u0026lt; .001), and major depressive disorder or depressive episode (aHR: 1.35, 95% CI: 1.28\u0026ndash;1.42; p \u0026lt; .001). The risks of bipolar disorder (aHR: 0.86, 95% CI: 0.70\u0026ndash;1.07; p = 0.168) and schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (aHR: 0.72, 95% CI: 0.59\u0026ndash;0.88; p = 0.001) were lower in vaccinated patients than in nonvaccinated patients. No significant differences were observed in the risks of mental disorders due to known physiological conditions (aHR: 1.02, 95% CI: 0.94\u0026ndash;1.10; p = 0.068), intellectual disabilities (aHR: 0.90, 95% CI: 0.58\u0026ndash;1.37; p = 0.644), or pervasive and specific developmental disorders (aHR: 1.47, 95% CI: 1.09\u0026ndash;1.99; p = 0.012). Additionally, disorders of adult personality and behavior were significantly higher in the vaccinated cohort (aHR: 1.64, 95% CI: 1.21\u0026ndash;2.23; p = 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the sex-based subgroup analysis (Figure 4, eTable 1 and eTable 2 in Supplementary file), the risks of mental, behavioral, and neurodevelopmental disorders were generally consistent between men and women in the vaccinated group, but some differences were noted. Among men, the overall risk was slightly increased and did not reach statistical significance. However, men exhibited clearly higher risks of mood (affective) disorders, anxiety disorders, and major depressive disorder. By contrast, women demonstrated a significant rise in both their overall risk of mental disorders and in these specific outcomes. Women also showed a reduced\u0026nbsp;\u003cbr\u003erisk of schizophrenia and related psychotic disorders compared with unvaccinated women.\u003c/p\u003e\n\u003cp\u003eIn the age-based analysis (Figure 5, eTable 3,4,5 in Supplementary file), younger adults (18\u0026ndash;40 years) was associated with the largest relative increase in mood (affective) disorders, anxiety disorders, and major depressive disorder, while the risk of schizophrenia and related disorders decreased in this subgroup. Adults aged 40\u0026ndash;65 years showed only a slightly increased overall risk, which did not reach statistical significance; however, this group still had a noticeable rise in the risk of mood, anxiety, and depressive disorders compared with their nonvaccinated counterparts. In older adults (\u0026ge;65 years), vaccination was linked to a modest but significant increase in the overall risk of mental, behavioral, and neurodevelopmental disorders, particularly mood, anxiety, and depressive disorders. In contrast, these older vaccinated adults experienced a lower risk of schizophrenia and related psychotic conditions compared with those who were not vaccinated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended analysis and sensitivity analyses\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo eliminate the influence of COVID-19 infection, we analyzed patients with and without COVID-19 vaccination who had no history of infection throughout lifetime and observed similar findings of increased risks for certain psychiatric disorders (Figure 6, eTable 6 in Supplementary File). Sensitivity analyses were conducted with the Global Collaborative Network on the TrinetX platform, and results were consistent with our primary data (eFigure 1, eTable 7 in Supplementary file)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003eKey findings and implications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the current large-scale propensity score\u0026ndash;matched study conducted using data from a multi-institutional US collaborative research network, compared with nonvaccinated patients, COVID-19-vaccinated patients had significantly higher risks of mental, behavioral, and neurodevelopmental disorders, including mood (affective) disorders, anxiety and stress-related disorders, and major depressive disorder. By contrast, vaccinated patients exhibited lower risks of schizophrenia; schizotypal, delusional, and non-mood psychotic disorders; and bipolar disorder, these findings were more pronounced among younger individuals and female patients. The results indicate that for COVID-19-vaccinated patients, comprehensive mental health screening and management strategies should be implemented to detect and address mental health disorders in the early stage, potentially improving patient outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePotential mechanisms underlying psychiatric effects of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCOVID-19 vaccination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrevious studies have suggested several mechanisms for the neurological and psychological effects of vaccination [28-30]. For example, increased levels of antibodies to myelin basic protein have been observed in patients with severe psychoneurological complications, including encephalomyelitis and transverse myelitis, after rabies vaccination; these observations suggest an underlying autoimmune mechanism for the complications [31, 32]. Vaccination can also cause increases in kynurenic acid, which may impair the function of N-methyl d-aspartate (NMDA) receptors; this impaired function leads to a chain reaction that reduces the inhibitory control of dopaminergic neurons in the ventral tegmental area and subsequently increases dopamine production, leading to psychiatric symptoms such as psychosis, anxiety, depression, and cognitive decline [33, 34]. In certain patients, COVID-19 vaccination triggered a cytokine storm, which is characterized by the elevated serum levels of IL-2, IL-6, IL-9, and tumor necrosis factor-\u0026alpha; mediated by CD4\u003csup\u003e+\u003c/sup\u003e T cells and which may affect the levels of monoamine neurotransmitters, leading to the altered release of dopamine, serotonin, and norepinephrine [34, 35]. Even in healthy individuals, transient increases in IL-6 following influenza vaccination have been associated with short-term changes in mood and cognitive symptoms, suggesting that low-grade inflammation may be sufficient to trigger depressive features [36]. Adjuvants and preservatives in vaccines, such as aluminum adjuvants and the thimerosal preservative, may trigger immune responses; thus, these adjuvants and preservatives are associated with neurotoxicity and psychological complications [37]. The inflammatory response triggered by the lipid nanoparticles or the antigens in vaccines, such as the spike protein and its peptide fragments, may also contribute to these adverse events (28). Additionally, stress activates the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis, which leads to the release of cortisol. The prolonged activation of the HPA axis and consistently high cortisol levels, which may occur following vaccination, are associated with the onset of psychiatric disorders, including depression and anxiety [35, 38]. Incorrect information on COVID-19 vaccines also plays an important role in psychiatric adverse events. The development of functional neurological disorders (FND) in some COVID-19 vaccine recipients is attributed to misinformation about vaccines on social media, pandemic-related stress, and increased psychological stress [39, 40]. A previous study reported that schizophrenia patients have higher rates of vaccine hesitancy due to concerns about side effects, mistrust in the health-care system, and negative impressions of vaccination [38]. Structural barriers including transportation issues, financial constraints, and absence of consistent health-care providers also contribute to lower vaccination rates and willingness among this population [41], which may have affected the results of our study. Further studies should verify whether COVID-19 vaccination decreases the risk of schizophrenia [42].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReevaluating the psychiatric impact of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCOVID-19 vaccination: a comparison with prior studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study results appear to contradict those of other studies [43, 44]. Walker et al. (2024) highlighted vaccination\u0026rsquo;s protective role against COVID-19-related psychiatric outcomes, particularly in reducing the risks of psychiatric disorders post-infection, especially in severe cases. In contrast, our study examines psychiatric outcomes following vaccination itself, independent of COVID-19 infection, identifying potential adverse psychiatric effects. To eliminate the influence of COVID-19 infection, we analyzed patients with and without COVID-19 vaccination who had no history of infection throughout lifetime and observed similar findings of increased risks for certain psychiatric disorders (Figure 3, eTable 8 in Supplementary file). Unlike Walker et al., who controlled prior infections, our study excluded known COVID-19 cases but not asymptomatic ones. Both studies underscore vaccination\u0026rsquo;s public health importance, while our findings emphasize the need for enhanced post-vaccination mental health monitoring to balance the protective benefits of vaccination with an awareness of potential psychiatric risks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImpact of Healthcare Access Barriers on Post-Vaccination Psychiatric Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnother research in South Korea showed a rise in unmet healthcare needs during the pandemic, suggesting that disruptions in healthcare access may have played a role in worsening mental health outcomes[45]. Given our findings that vaccinated individuals, particularly women and younger adults, had an increased risk of psychiatric disorders, it is possible that barriers to mental health care further amplified these effects. Limited access to timely intervention could have prolonged symptoms or prevented early management, leading to greater long-term impact. These findings highlight the importance of integrating mental health care into vaccination programs and strengthening healthcare accessibility, particularly during public health crises.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study has several strengths. First, we used a relatively large dataset in our study, enhancing the robustness and reliability of our findings. Second, to ensure the accuracy of our study results, we only included individuals who tested negative in a COVID-19 RNA test as controls; this approach was implemented to eliminate the effect of COVID-19 infection on patients with psychiatric disorders. Third, employing propensity score matching ensured well-balanced baseline characteristics between the vaccinated and nonvaccinated cohorts. This approach significantly enhanced the validity of the comparisons by reducing the potential impact of confounding variables. In addition, we conducted sensitivity analyses to corroborate the findings of the primary analyses as well as subgroup analyses to characterize subpopulations at high risk of mental, behavioral, and neurodevelopmental disorders for their future surveillance. Finally, COVID-19 lockdown policies in the United States significantly increased the prevalence of anxiety and depression [46, 47]. Thus, to minimize the effects of lockdown policy on the risk of mental disorders, we excluded patients diagnosed with mental disorders before 2022, when lockdown policies and social distancing were not strictly implemented [48].\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, although we evaluated vaccinated and unvaccinated patients in the United States and within the global TriNetX network, most of the HCOs from which data were obtained were located in the United States. This limits the generalizability of our conclusions to populations in other countries. Second, compared with prospective cohort studies, our use of \u003cem\u003eICD-10-CM\u003c/em\u003e codes for the study outcomes may introduce bias from inaccurate diagnoses. Third, although we used validated outcome definitions and propensity score matching to minimize bias, we were unable to balance the socioeconomic status and potential psychiatric factors due to the lack of relevant codes and data. Fourth, the TriNetX database was not designed to evaluate psychiatric disorders and does not contain results of psychiatric assessment tools. Therefore, we could not evaluate the severity of psychiatric disorders. Moreover, this observational study identify association, not casuality, further prospective studies targeting the psychiatric effects of COVID-19 vaccination should be conducted to verify our findings. Finally, we excluded patients with COVID-19 because such patients are at high risk of psychiatric disorders; therefore, the effect of the pandemic on the total population might have been underestimated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublic health implications and future directions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study results emphasize the importance of strengthening mental health\u0026ndash;related policies related to COVID-19 vaccination. The related measures include educating the public about the possibility of severe psychiatric side effects and the overall safety and benefits of COVID-19 vaccines, providing tailored educational programs that address safety concerns and prevent misinformation, and providing psychiatric consultations and behavioral interventions for individuals who experience anxiety, mood disorders, or other psychiatric symptoms post vaccination. These strategies collectively aim to protect this vulnerable population (who may develop psychiatric disorders after COVID-19 vaccination) and enhance vaccine acceptance and safety.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCOVID-19 vaccination has been a cornerstone in controlling the pandemic and reducing severe disease and mortality. While increased risk of mental health issues, such as mood and anxiety disorders, has been observed in some vaccinated individuals, particularly women and younger populations, this highlights the importance of including mental health monitoring as part of post-vaccination care. Early identification and management of potential mental health concerns can help improve outcomes and reinforce the overall safety and benefits of vaccination.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthorship Contribution Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYu-Ting Yu\u003c/strong\u003e: Writing-Original Draft, Conceptualization, Methodology, Formal analysis, Writing-Review \u0026amp; Editing, Visualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHsiao-Wei Wang:\u0026nbsp;\u003c/strong\u003eWriting-Review \u0026amp; Editing, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShang-Wen Chang\u003c/strong\u003e: Writing-Review \u0026amp; Editing, Conceptualization, Methodology, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest regarding the publication of this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the Shin Kong Wu Ho-Su Memorial Hospital (SKH-8302-103-DR-04) for sponsoring this study. This manuscript was edited by Wallace Academic Editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWHO COVID-19 dashboard. ; (2024). 2024/05/15 Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://data.who.int/dashboards/covid19/cases?n=c\u003c/span\u003e\u003cspan address=\"https://data.who.int/dashboards/covid19/cases?n=c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYazdanpanah, F., Hamblin, M. R. \u0026amp; Rezaei, N. The immune system and COVID-19: Friend or foe? \u003cem\u003eLife Sci.\u003c/em\u003e \u003cb\u003e256\u003c/b\u003e, 117900 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClerkin, K. J. et al. COVID-19 and Cardiovascular Disease. \u003cem\u003eCirculation\u003c/em\u003e \u003cb\u003e141\u003c/b\u003e (20), 1648\u0026ndash;1655 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKollias, A. et al. Venous thromboembolism in COVID-19: A systematic review and meta-analysis. \u003cem\u003eVasc Med.\u003c/em\u003e \u003cb\u003e26\u003c/b\u003e (4), 415\u0026ndash;425 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmed, M. U. et al. Neurological Manifestations of COVID-19 (SARS-CoV-2): A Review. \u003cem\u003eFront. Neurol.\u003c/em\u003e \u003cb\u003e11\u003c/b\u003e, 518 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEllul, M. A. et al. Neurological associations of COVID-19. \u003cem\u003eLancet Neurol.\u003c/em\u003e \u003cb\u003e19\u003c/b\u003e (9), 767\u0026ndash;783 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFavas, T. T. et al. Neurological manifestations of COVID-19: a systematic review and meta-analysis of proportions. \u003cem\u003eNeurol. Sci.\u003c/em\u003e \u003cb\u003e41\u003c/b\u003e (12), 3437\u0026ndash;3470 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOusseiran, Z. H., Fares, Y. \u0026amp; Chamoun, W. T. Neurological manifestations of COVID-19: a systematic review and detailed comprehension. \u003cem\u003eInt. J. Neurosci.\u003c/em\u003e \u003cb\u003e133\u003c/b\u003e (7), 754\u0026ndash;769 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiong, J. et al. Impact of COVID-19 pandemic on mental health in the general population: A systematic review. \u003cem\u003eJ. Affect. Disord\u003c/em\u003e. \u003cb\u003e277\u003c/b\u003e, 55\u0026ndash;64 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajkumar, R. P. COVID-19 and mental health: A review of the existing literature. \u003cem\u003eAsian J. Psychiatry\u003c/em\u003e. \u003cb\u003e52\u003c/b\u003e, 102066 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDubey, S. et al. Psychosocial impact of COVID-19. \u003cem\u003eDiabetes Metab. Syndr.\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e (5), 779\u0026ndash;788 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Marques, D. et al. How is COVID-19 pandemic impacting mental health of children and adolescents? \u003cem\u003eInt. J. Disaster Risk Reduct.\u003c/em\u003e \u003cb\u003e51\u003c/b\u003e, 101845 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan, K. Y. et al. The mental health impact of the COVID-19 pandemic on people with and without depressive, anxiety, or obsessive-compulsive disorders: a longitudinal study of three Dutch case-control cohorts. \u003cem\u003eLancet Psychiatry\u003c/em\u003e. \u003cb\u003e8\u003c/b\u003e (2), 121\u0026ndash;129 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHao, F. et al. Do psychiatric patients experience more psychiatric symptoms during COVID-19 pandemic and lockdown? A case-control study with service and research implications for immunopsychiatry. \u003cem\u003eBrain Behav. Immun.\u003c/em\u003e \u003cb\u003e87\u003c/b\u003e, 100\u0026ndash;106 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZaccari, V. et al. Narrative Review of COVID-19 Impact on Obsessive-Compulsive Disorder in Child, Adolescent and Adult Clinical Populations. \u003cem\u003eFront. Psychiatry\u003c/em\u003e. \u003cb\u003e12\u003c/b\u003e, 673161 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCzeisler, M. et al. \u003cem\u003eMental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic - United States, June 24\u0026ndash;30\u003c/em\u003e, MMWR Morb Mortal Wkly Rep, 2020. 69(32): pp. 1049\u0026ndash;1057. (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrganization, W. H. \u003cem\u003eCOVID-19 vaccination, World data\u003c/em\u003e. COVID-19 vaccination, World data; (2024). Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://data.who.int/dashboards/covid19/vaccines\u003c/span\u003e\u003cspan address=\"https://data.who.int/dashboards/covid19/vaccines\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang, Y. Z. \u0026amp; Kuan, C. C. Vaccination to reduce severe COVID-19 and mortality in COVID-19 patients: a systematic review and meta-analysis. \u003cem\u003eEur. Rev. Med. Pharmacol. Sci.\u003c/em\u003e \u003cb\u003e26 5\u003c/b\u003e, 1770\u0026ndash;1776 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoghadas, S. M. et al. \u003cem\u003eThe Impact of Vaccination on Coronavirus Disease 2019 (COVID-19) Outbreaks in the United States.\u003c/em\u003e Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2021. 73: pp. 2257\u0026ndash;2264.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSezen, Y. I. et al. Risk factors and the impact of vaccination on mortality in COVID-19 patients. \u003cem\u003eBratisl. Lek. Listy\u003c/em\u003e. \u003cb\u003e123 6\u003c/b\u003e, 440\u0026ndash;443 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoltai, J. et al. COVID-19 Vaccination and Mental Health: A Difference-In-Difference Analysis of the Understanding America Study. \u003cem\u003eAm. J. Prev. Med.\u003c/em\u003e \u003cb\u003e62\u003c/b\u003e (5), 679\u0026ndash;687 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerez-Arce, F. et al. COVID-19 vaccines and mental distress. \u003cem\u003ePLoS One\u003c/em\u003e. \u003cb\u003e16\u003c/b\u003e (9), e0256406 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChaudhuri, K. \u0026amp; Howley, P. The impact of COVID-19 vaccination for mental well-being. \u003cem\u003eEur. Econ. Rev.\u003c/em\u003e \u003cb\u003e150\u003c/b\u003e, 104293 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalgi, Y. et al. No psychological vaccination: Vaccine hesitancy is associated with negative psychiatric outcomes among Israelis who received COVID-19 vaccination. \u003cem\u003eJ. Affect. Disord\u003c/em\u003e. \u003cb\u003e287\u003c/b\u003e, 352\u0026ndash;353 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBalasubramanian, I. et al. Psychiatric adverse reactions to COVID-19 vaccines: A rapid review of published case reports. \u003cem\u003eAsian J. Psychiatr\u003c/em\u003e. \u003cb\u003e71\u003c/b\u003e, 103129 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu, X. et al. The impact of COVID-19 vaccination on psychiatric symptoms in schizophrenia patients: A retrospective study. \u003cem\u003eMed. (Baltim).\u003c/em\u003e \u003cb\u003e102\u003c/b\u003e (23), e34016 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang, D. et al. SRplot: A free online platform for data visualization and graphing. \u003cem\u003ePLoS One\u003c/em\u003e. \u003cb\u003e18\u003c/b\u003e (11), e0294236 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiravalle, A. A. et al. Neurological complications following vaccinations. \u003cem\u003eNeurol. Res.\u003c/em\u003e \u003cb\u003e32\u003c/b\u003e, 285\u0026ndash;292 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTian, M. et al. \u003cem\u003eVaccine-Associated Neurological Adverse Events: A Case Report and Literature Review\u003c/em\u003e (Current pharmaceutical design, 2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarpenter, L. J. et al. The psychiatric and psychological sequelae of vaccine-induced immune thrombotic thrombocytopenia (VITT). \u003cem\u003eSemin. Hematol.\u003c/em\u003e \u003cb\u003e59\u003c/b\u003e (2), 115\u0026ndash;119 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHemachudha, T. et al. Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination. \u003cem\u003eN Engl. J. Med.\u003c/em\u003e \u003cb\u003e316\u003c/b\u003e (7), 369\u0026ndash;374 (1987).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHemachudha, T. et al. Immunologic studies of patients with chronic encephalitis induced by post-exposure Semple rabies vaccine. \u003cem\u003eNeurology\u003c/em\u003e \u003cb\u003e38\u003c/b\u003e, 42\u0026ndash;42 (1988).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrover, S. et al. First episode psychosis following receipt of first dose of COVID-19 vaccine: A case report. \u003cem\u003eSchizophr Res.\u003c/em\u003e \u003cb\u003e241\u003c/b\u003e, 70\u0026ndash;71 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLundberg-Morris, L. et al. Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study. \u003cem\u003eBmj\u003c/em\u003e \u003cb\u003e383\u003c/b\u003e, e076990 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoncrieff, J. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. \u003cem\u003eMol. Psychiatry\u003c/em\u003e. \u003cb\u003e28\u003c/b\u003e (8), 3243\u0026ndash;3256 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuhlman, K. R. et al. \u003cem\u003eWithin-subject associations between inflammation and features of depression: Using the flu vaccine as a mild inflammatory stimulus.\u003c/em\u003e Brain, Behavior, and Immunity, 69: pp. 540\u0026ndash;547. (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShaw, C. A. \u0026amp; Tomljenovic, L. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity. \u003cem\u003eImmunol. Res.\u003c/em\u003e \u003cb\u003e56\u003c/b\u003e (2\u0026ndash;3), 304\u0026ndash;316 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJia, F. et al. Psychiatric symptoms before and after COVID-19 vaccination: A cohort study of hospitalized schizophrenia patients. \u003cem\u003eAsian J. Psychiatr\u003c/em\u003e. \u003cb\u003e78\u003c/b\u003e, 103319 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRansing, R. et al. COVID-19 anti-vaccine movement and mental health: Challenges and the way forward. \u003cem\u003eAsian J. Psychiatr\u003c/em\u003e. \u003cb\u003e58\u003c/b\u003e, 102614 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFreeman, D. et al. Injection fears and COVID-19 vaccine hesitancy. \u003cem\u003ePsychol. Med.\u003c/em\u003e \u003cb\u003e53\u003c/b\u003e (4), 1185\u0026ndash;1195 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaffard, S. et al. \u003cem\u003eAttitudes towards Vaccines, Intent to Vaccinate and the Relationship with COVID-19 Vaccination Rates in Individuals with Schizophrenia\u003c/em\u003e. \u003cem\u003eVaccines (Basel)\u003c/em\u003e, \u003cb\u003e10\u003c/b\u003e(8). (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, H. J. et al. \u003cem\u003ePsychiatric adverse events following COVID-19 vaccination: a population-based cohort study in Seoul, South Korea\u003c/em\u003e (Mol Psychiatry, 2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalker, V. M. et al. COVID-19 and mental illnesses in vaccinated and unvaccinated people. \u003cem\u003eJAMA psychiatry\u003c/em\u003e. \u003cb\u003e81\u003c/b\u003e (11), 1071\u0026ndash;1080 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, S. et al. Short-and long-term neuropsychiatric outcomes in long COVID in South Korea and Japan. \u003cem\u003eNat. Hum. Behav.\u003c/em\u003e \u003cb\u003e8\u003c/b\u003e (8), 1530\u0026ndash;1544 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, Y. et al. National Trends in the Prevalence of Unmet Health Care and Dental Care Needs During the COVID-19 Pandemic: Longitudinal Study in South Korea, 2009\u0026ndash;2022. \u003cem\u003eJMIR Public. Health Surveill\u003c/em\u003e. \u003cb\u003e10\u003c/b\u003e, e51481 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrati, G. \u0026amp; Mancini, A. D. \u003cem\u003eThe psychological impact of COVID-19 pandemic lockdowns: a review and meta-analysis of longitudinal studies and natural experiments\u003c/em\u003e. \u003cem\u003ePsychol. Med.\u003c/em\u003e, : pp. 1\u0026ndash;11. (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen, S. et al. \u003cem\u003eThe Medium-Term Impact of COVID-19 Lockdown on Referrals to Secondary Care Mental Health Services: A Controlled Interrupted Time Series Study\u003c/em\u003e11 (Frontiers in Psychiatry, 2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoloori, A. \u0026amp; Saghafian, S. Health and Economic Impacts of Lockdown Policies in the Early Stage of COVID-19 in the United States. \u003cem\u003eService Sci.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e (3), 188\u0026ndash;211 (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mental disorder, Behavioral disorder, Neurodevelopmental disorder, COVID-19 vaccination, COVID-19","lastPublishedDoi":"10.21203/rs.3.rs-5145501/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5145501/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCOVID-19 vaccines significantly reduce mortality and severe complications, but potential side effects warrant careful investigation. This study analyzed a large real-world dataset to examine the risk of psychiatric disorders following COVID-19 vaccination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study was conducted using data from the TriNetX Research Network United States Collaboration. Patients were divided into vaccinated and nonvaccinated cohorts and matched at a 1:1 ratio using propensity scores based on age, sex, demographics, and underlying health conditions. The primary outcome was the incidence of newly diagnosed mental, behavioral, and neurodevelopmental disorders within 6 months after COVID-19 vaccination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe vaccinated cohort demonstrated a higher risk of mental, behavioral, and neurodevelopmental disorders (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.08–1.14). Specifically, increased risks were observed for mood disorders (HR: 1.31, 95% CI: 1.25–1.38), anxiety disorders (HR: 1.23, 95% CI: 1.18–1.28), and major depressive disorder (HR: 1.35, 95% CI: 1.28–1.42). Conversely, this group showed a lower risk of schizophrenia and related disorders (HR: 0.72, 95% CI: 0.59–0.88). Subgroup analyses revealed that these effects were more pronounced in younger individuals and female patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhile COVID-19 vaccination remains essential for pandemic control and should be encouraged among all eligible individuals, our findings highlight the need for targeted mental health monitoring, particularly in younger individuals and women who may be more susceptible to psychological distress following vaccination.\u003c/p\u003e","manuscriptTitle":"Exploring the Association Between COVID-19 Vaccination and Mental Disorder Risks: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 07:09:04","doi":"10.21203/rs.3.rs-5145501/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2025-04-28T21:07:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-24T15:21:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-04-19T08:14:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"72093b8a-e859-4cf4-b912-c0ced45a40cd","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":47815447,"name":"Biological sciences/Psychology"},{"id":47815448,"name":"Biological sciences/Immunology/Vaccines"}],"tags":[],"updatedAt":"2025-07-07T04:08:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-06 07:09:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5145501","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5145501","identity":"rs-5145501","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}