In a recent study posted to the medRxiv* preprint server, researchers investigated if non-psychiatric PASC-AMs [post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-associated manifestations] increase the risk of new-onset psychiatric illness diagnosis.

Study: Manifestations Associated with Post Acute Sequelae of SARS-CoV2 Infection (PASC) Predict Diagnosis of New-Onset Psychiatric Disease: Findings from the NIH N3C and RECOVER Studies. Image Credit: Africa Studio/Shutterstock


PASC refers to persistent or new clinical manifestations involving several organs following acute coronavirus disease 2019 (COVID-19) infections. Previous studies have reported a higher risk of new-onset psychiatric illness in the initial 21 to 120 days of acute SARS-CoV-2 infections. However, it is not clear whether PASC-AMs increase the risk of new-onset psychiatric illness following SARS-CoV-2 infections.

About the study

In the present observational study, researchers examined the association between PASC-AMs and the diagnosis of new-onset psychiatric illness after acute SARS-CoV-2 infections.

Data were retrospectively obtained from electronic health records (EHR) of several clinical organizations (n=65) in the United States (US), which are a part of the national institute of health (NIH) national COVID cohort collaborative (N3C) enclave. A total of 3,937,101 records of SARS-CoV-2-infected patients frozen on 12 May 2022 were analyzed, comprising data on demographics, laboratory results, medications, comorbidities, clinical outcomes, and the status of SARS-CoV-2 infection and psychiatric illness diagnoses.

Data included>6.5 billion laboratory test reports, 622 million procedures, and 2.2 billion drug exposures from 754 million health encounters. EHRs were harmonized by using the OMOP (observational medical outcomes partnership) model. Non-psychiatric PASC-AMs were recorded 21 to 120 days post-COVID-19 diagnosis and before the diagnosis of new-onset psychiatric illness.

The analysis included patients with COVID-19 diagnosis confirmed by antigen tests or polymerase chain reaction (PCR) test post 1 January 2020. Patients were excluded if they had a history of psychiatric illnesses before 21 days of testing SARS-CoV-2-positive and those without health records before >1 year and after 120 days of being diagnosed with COVID-19.

OMOP model codes were mapped to 178 terminologies of human phenotype ontology (HPO) representing PASC-AMs. Logistic regression models were used for the analysis based on sex, age, comorbidities, and race, and the odds ratios (ORs) were calculated. HPO terminologies were recorded between 21 days of acute COVID-19 onset and either diagnosis of new-onset psychiatric illness or 120 days if no new-onset psychiatric illness was reported. In addition, sensitivity analyses were performed to compensate for missing body mass index (BMI) data and to assess if the results were consistent between outpatients and inpatients.


A total of 1,135,973 acute COVID-19 patients were considered for the final analysis, whose average age was 40.5 years, and most of them (56%) were women. A substantial association was observed for seven of 11 HPO categories (OR values ranged between 1.1 and 2.3) with new-onset psychiatric illness, most prominently for cardiovascular (OR 1.8) and neurological (OR 2.3) PASC-AMs.

For anxiety, HPO categories were substantially associated, with OR values of 2.06 and 2.14 for cardiovascular and neurological categories, respectively. Similar results were observed in the sensitivity analyses. The team observed that 2.4% of patients were diagnosed with psychiatric illness in the post-acute COVID-19 phase (between day 21 and day 120 days of SARS-CoV-2 infection diagnosis). Neurological and constitutional PASC-AMs were most commonly reported and occurred in 4.3% and 4.9% of patients.

In the analysis, 95 out of 154 HPO-encoded phenotype features substantially differed among patients with psychiatric disorders such as anxiety, dementia, psychosis, and mood disorders. Pulmonary, neurological, gastrointestinal, cardiovascular, endocrine, ear, nose, and throat (ENT)-associated and constitutional PASC-AMs were associated with increased risks of new-onset psychiatric illness.

The association between HPO categories varied between anxiety and mood disorders. Cardiovascular manifestations were associated with increased anxiety risks to a larger extent than mood disorders. On the other hand, endocrinal manifestations increased the risk of mood disorders but did not substantially increase anxiety risks.

Patients with neurological manifestations were found to be at a substantially increased risk of dementia and psychosis, and cardiovascular and constitutional manifestations increased the risk of dementia. However, PASC patients with respiratory manifestations showed a reduced likelihood of dementia.


Overall, the study findings showed that PASC-AMs influence the risk of developing a new-onset psychiatric illness, and the observation underpins the need for psychiatric screening among PASC patients. Further research must be conducted to assess the association between COVID-19 severity and risk of new-onset psychiatric illness with prospective studies since the retrospective design of the study does not enable the determination of pathophysiological mechanisms underlying the psychiatric sequelae of COVID-19.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.


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