Reduced risk of severe COVID-19 with lithium use: a large-scale comparison with valproate users and other COVID-19 patients

Background: Lithium, a commonly used mood stabilizer with immunomodulatory and antiviral properties, has been hypothesized to lessen the severity of COVID-19, but population-level evidence remains limited. Methods: In this retrospective cohort study, we examined electronic health records from over 1.49 million adults with confirmed COVID-19 in Israel between March 2020 and November 2021. Individuals were categorized based on sustained use of lithium (n=857), valproate (n=5,302), or no exposure to either medication. Severe COVID-19 was defined as hospitalization, respiratory support, extracorporeal membrane oxygenation, or death. To account for baseline differences, we applied inverse probability weighting and logistic regression with correction for rare events. Results: Lithium use was associated with significantly lower odds of severe COVID-19, even though users were older and had more medical comorbidities. In contrast, valproate use was linked to increased risk. Conclusion: These findings suggest that lithium may provide a protective effect against severe COVID-19 outcomes, independent of underlying vulnerability, and support further investigation into the broader health implications of psychotropic medications.