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Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19

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Importance  Neuropsychiatric symptoms have been reported as a prominent feature of postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC.

Observations  Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric symptom has been reported in as many as 90% of patients 6 months after COVID-19 hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors.

Conclusions and Relevance  Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors. By enrolling large patient samples and conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery (RECOVER), a multicenter research initiative funded by the National Institutes of Health, will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention.

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Article Information

Accepted for Publication: May 2, 2022.

Published Online: June 29, 2022. doi:10.1001/jamapsychiatry.2022.1616

Corresponding Author: Naomi M. Simon, MD, MSc, Department of Psychiatry, NYU Grossman School of Medicine, One Park Avenue, 8th Floor, New York, NY 10016 (

Author Contributions: Drs Frontera and Simon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Both authors.

Acquisition, analysis, or interpretation of data: Both authors.

Drafting of the manuscript: Both authors.

Critical revision of the manuscript for important intellectual content: Both authors.

Administrative, technical, or material support: Frontera.

Conflict of Interest Disclosures: Dr Frontera reported grants from the National Institutes of Health (NIH), consulting support from FirstKind and Braincool, publishing fees from Thieme, and speaking fees from Physician Education Resource (PER) outside the submitted work. Dr Simon reported grants from the NIH during the conduct of the study; grants from the NIH, Patient-Centered Outcomes Research Institute, Department of Defense, American Foundation for Suicide Prevention, Cohen Veterans Network, and Vanda Pharmaceuticals; consulting fees from Vanda Pharmaceuticals, Bionomics Limited, BehavR LLC, Praxis Therapeutics, Cerevel, Genomind, and Engrail Therapeutics; spousal equity in G1 Therapeutics and Zentalis; and royalties or fees from APA Publishing, Wolters Kluwer (UpToDate), and Wiley (Deputy Editor, Depression and Anxiety) outside the submitted work. No other disclosures were reported.

Funding/Support: Both authors receive funding as co-investigators/faculty at the NYU Grossman School of Medicine for the RECOVER initiative (OTA-21-015A Post-Acute Sequelae of SARS-CoV-2 Infection Initiative: NYU Langone Health Clinical Science Core). Dr Frontera receives funding for the following COVID-19–related grants from these NIH institutes: National Institute of Neurological Disorders and Stroke (3U24NS11384401S1), National Heart, Lung, and Blood Institute (1OT2HL161847-01), and National Institute on Aging (3P30AG066512-01).

Role of the Funder/Sponsor: The funding organization had no role in the preparation, review, or approval of the manuscript or decision to submit the manuscript for publication.

Additional Information: There was no original data collection or analyses for this Special Communication.

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