. 2025 Jul 24;16(1):6829.

doi: 10.1038/s41467-025-61961-1.

Risk of neuropsychiatric and related conditions associated with SARS-CoV-2 infection: a difference-in-differences analysis

Yiwen Lu^#^{1

2}, Jiayi Tong^#^{1

3

4}, Dazheng Zhang^#^{1

3}, Jiajie Chen^{1

3}, Lu Li^{1

2}, Yuqing Lei^{1

3}, Ting Zhou^{1

3}, Leyna V Aragon^{5

6}, Michael J Becich⁷, Saul Blecker⁸, Nathan J Blum⁹, Dimitri A Christakis¹⁰, Mady Hornig^{5

11}, Maxwell M Hornig-Rohan⁵, Ravi Jhaveri¹², W Schuyler Jones¹³, Amber Brown Keebler¹⁴, Kelly Kelleher¹⁵, Susan Kim¹⁶, Abu Saleh Mohammad Mosa^{17

18}, Kathleen Pajer¹⁹, Jonathan Platt²⁰, Hayden T Schwenk²¹, Bradley W Taylor²², Levon H Utidjian²³, David A Williams²⁴, Raghuram Prasad²⁵, Josephine Elia²⁶, Christopher B Forrest²³, Yong Chen^{27

28

29

30

31

32}

Affiliations

¹ Center for Health AI and Synthesis of Evidence (CHASE), Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵ RECOVER Patient, Caregiver, or Community Advocate Representative, New York, NY, USA.
⁶ University of New Mexico, Health Sciences Center, Albuquerque, NM, USA.
⁷ Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸ Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
⁹ Division of Developmental and Behavioral Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Center for Child Health, Behavior and Development, Seattle Children's Research Institute, Seattle, WA, USA.
¹¹ Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
¹² Division of Infectious Diseases, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
¹³ Duke Clinical Research Institute, Duke University Health System, Durham, NC, USA.
¹⁴ Division of General Internal Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁵ The Research Institute, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
¹⁶ University of California, San Francisco, Division of Rheumatology, Benioff Children's Hospital, San Francisco, CA, USA.
¹⁷ Department of Biomedical Informatics, Biostatistics, and Medical Epidemiology, University of Missouri School of Medicine, Columbia, MO, USA.
¹⁸ Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁹ University of Ottawa Department of Psychiatry, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
²⁰ Department of Epidemiology, The University of Iowa College of Public Health, Iowa City, IA, USA.
²¹ Stanford School of Medicine, Division of Pediatric Infectious Diseases, Stanford, CA, USA.
²² Clinical and Translational Science Institute, The Medical College of Wisconsin, Milwaukee, WI, USA.
²³ Applied Clinical Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁴ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
²⁵ Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Department of Pediatrics, Nemours Children's Health Delaware, Sydney Kimmel School of Medicine, Philadelphia, PA, USA.
²⁷ Center for Health AI and Synthesis of Evidence (CHASE), Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ychen123@upenn.edu.
²⁸ The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. ychen123@upenn.edu.
²⁹ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ychen123@upenn.edu.
³⁰ Leonard Davis Institute of Health Economics, Philadelphia, PA, USA. ychen123@upenn.edu.
³¹ Penn Medicine Center for Evidence-based Practice (CEP), Philadelphia, PA, USA. ychen123@upenn.edu.
³² Penn Institute for Biomedical Informatics (IBI), Philadelphia, PA, USA. ychen123@upenn.edu.

^# Contributed equally.

PMID: 40707478
PMCID: PMC12290120
DOI: 10.1038/s41467-025-61961-1

Risk of neuropsychiatric and related conditions associated with SARS-CoV-2 infection: a difference-in-differences analysis

Yiwen Lu et al. Nat Commun. 2025.

. 2025 Jul 24;16(1):6829.

doi: 10.1038/s41467-025-61961-1.

Authors

Affiliations

¹ Center for Health AI and Synthesis of Evidence (CHASE), Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵ RECOVER Patient, Caregiver, or Community Advocate Representative, New York, NY, USA.
⁶ University of New Mexico, Health Sciences Center, Albuquerque, NM, USA.
⁷ Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸ Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
⁹ Division of Developmental and Behavioral Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Center for Child Health, Behavior and Development, Seattle Children's Research Institute, Seattle, WA, USA.
¹¹ Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
¹² Division of Infectious Diseases, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
¹³ Duke Clinical Research Institute, Duke University Health System, Durham, NC, USA.
¹⁴ Division of General Internal Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁵ The Research Institute, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
¹⁶ University of California, San Francisco, Division of Rheumatology, Benioff Children's Hospital, San Francisco, CA, USA.
¹⁷ Department of Biomedical Informatics, Biostatistics, and Medical Epidemiology, University of Missouri School of Medicine, Columbia, MO, USA.
¹⁸ Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁹ University of Ottawa Department of Psychiatry, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
²⁰ Department of Epidemiology, The University of Iowa College of Public Health, Iowa City, IA, USA.
²¹ Stanford School of Medicine, Division of Pediatric Infectious Diseases, Stanford, CA, USA.
²² Clinical and Translational Science Institute, The Medical College of Wisconsin, Milwaukee, WI, USA.
²³ Applied Clinical Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁴ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
²⁵ Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Department of Pediatrics, Nemours Children's Health Delaware, Sydney Kimmel School of Medicine, Philadelphia, PA, USA.
²⁷ Center for Health AI and Synthesis of Evidence (CHASE), Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ychen123@upenn.edu.
²⁸ The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. ychen123@upenn.edu.
²⁹ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ychen123@upenn.edu.
³⁰ Leonard Davis Institute of Health Economics, Philadelphia, PA, USA. ychen123@upenn.edu.
³¹ Penn Medicine Center for Evidence-based Practice (CEP), Philadelphia, PA, USA. ychen123@upenn.edu.
³² Penn Institute for Biomedical Informatics (IBI), Philadelphia, PA, USA. ychen123@upenn.edu.

^# Contributed equally.

PMID: 40707478
PMCID: PMC12290120
DOI: 10.1038/s41467-025-61961-1

Abstract

The COVID-19 pandemic has been associated with increased neuropsychiatric conditions in children and youths, with evidence suggesting that SARS-CoV-2 infection may contribute additional risks beyond pandemic stressors. This study aims to assess the full spectrum of neuropsychiatric conditions in COVID-19 positive children (ages 5-12) and youths (ages 12-20) compared to a matched COVID-19 negative cohort, accounting for factors influencing infection risk. Using EHR data from 25 institutions in the RECOVER program, we conduct a retrospective analysis of 326,074 COVID-19 positive and 887,314 negative participants matched for risk factors and stratified by age. Neuropsychiatric outcomes are examined 28 to 179 days post-infection or negative test between March 2020 and December 2022. SARS-CoV-2 positivity is confirmed via PCR, serology, or antigen tests, while negativity requires negative test results and no related diagnoses. Risk differences reveal higher frequencies of neuropsychiatric conditions in the COVID-19 positive cohort. Children face increased risks for anxiety, OCD, ADHD, autism, and other conditions, while youths exhibit elevated risks for anxiety, suicidality, depression, and related symptoms. These findings highlight SARS-CoV-2 infection as a potential contributor to neuropsychiatric risks, emphasizing the importance of research into tailored treatments and preventive strategies for affected individuals.

PubMed Disclaimer

Conflict of interest statement

Competing interests: R.J. is a consultant for AstraZeneca, Seqirus, Dynavax, receives an editorial stipend from Elsevier and Pediatric Infectious Diseases Society and royalties from Up To Date/Wolters Kluwer. The remaining authors declare no competing interests.

Figures

**Fig. 1**
Selection of participants for both COVID-19-positive and COVID-19-negative patients, stratified by age (children and youths).

**Fig. 2. Risk difference of post-acute COVID-19 neuropsychiatric and related conditions in children aged 5–11, compared to the COVID-19-negative cohort.**
Outcomes include cluster-level conditions across adverse childhood experiences, anxiety disorders, disruptive behavior disorders, eating and feeding disorders, elimination disorders, gender dysphoria/sexual dysfunction, intentional self-harm/suicidality, mood disorders, neurocognitive disorders, neurodevelopmental disorders, personality disorders, psychotic disorders, sleep-wake disorders, standalone symptoms, substance use and dependence, and tic disorders. The composite outcome refers to the occurrence of any listed neuropsychiatric or related condition. The sample size was 141,349 for the COVID-19 positive group and 441,790 for the COVID-19 negative group. Risk differences and 95% confidence intervals are shown. Red lines indicate statistically significant differences (p < 0.05), while gray lines indicate non-significant findings. P-values were calculated using two-sided t-tests; no adjustments were made for multiple comparisons.

**Fig. 3. Risk difference of post-acute COVID-19 neuropsychiatric and related conditions in youths aged 12 to 20, compared to the COVID-19-negative cohort.**
Outcomes include cluster-level conditions across adverse childhood experiences, anxiety disorders, disruptive behavior disorders, eating and feeding disorders, elimination disorders, gender dysphoria/sexual dysfunction, intentional self-harm/suicidality, mood disorders, neurocognitive disorders, neurodevelopmental disorders, personality disorders, psychotic disorders, sleep-wake disorders, standalone symptoms, substance use and dependence, and tic disorders. The composite outcome refers to the occurrence of any listed neuropsychiatric or related condition. The sample size was 184,725 for the COVID-19 positive group and 445,524 for the COVID-19 negative group. Risk differences and 95% confidence intervals are shown. Red lines indicate statistically significant differences (p < 0.05), while gray lines indicate non-significant findings. P values were calculated using two-sided t tests; no adjustments were made for multiple comparisons.

See this image and copyright information in PMC

Update of

Does SARS-CoV-2 Infection Increase Risk of Neuropsychiatric and Related Conditions? Findings from Difference-in-Differences Analyses.
Chen Y, Lu Y, Tong J, Zhang D, Chen J, Li L, Lei Y, Zhou T, Aragon L, Becich M, Blecker S, Blum N, Christakis D, Hornig M, Hornig-Rohan M, Jhaveri R, Jones W, Keebler A, Kelleher K, Kim S, Mosa A, Pajer K, Platt J, Schwenk H, Taylor B, Utidjian L, Williams D, Prasad R, Elia J, Forrest C. Chen Y, et al. Res Sq [Preprint]. 2025 Jan 8:rs.3.rs-5621095. doi: 10.21203/rs.3.rs-5621095/v1. Res Sq. 2025. Update in: Nat Commun. 2025 Jul 24;16(1):6829. doi: 10.1038/s41467-025-61961-1. PMID: 39866876 Free PMC article. Updated. Preprint.

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Risk of neuropsychiatric and related conditions associated with SARS-CoV-2 infection: a difference-in-differences analysis

Affiliations

Risk of neuropsychiatric and related conditions associated with SARS-CoV-2 infection: a difference-in-differences analysis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

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LinkOut - more resources

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