Associations of selective serotonin reuptake inhibitors and long COVID risk in patients with depression: a retrospective cohort study.

Purpose: To evaluate the potential of selective serotonin reuptake inhibitors (SSRIs) in reducing the risk of long COVID in patients with depression.

Methods: This retrospective cohort study analyzed U.S. electronic health records from TriNetX platform to compare the risk of long COVID among adults with depression who were prescribed SSRIs versus non-SSRI antidepressants between March 2020 and December 2022. The main outcome was the long COVID diagnosis. As a sensitivity analysis, CDC-defined long COVID symptoms were used as alternative outcomes. Cox proportional hazards models were used to assess outcomes occurring 3-6 and 3-12 months after the index SARS-CoV-2 infection, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated.

Results: After propensity score matching, the study included 31,264 patients, and the risk of long COVID diagnosis was significantly lower in the SSRI cohort compared to the matched non-SSRI antidepressant cohort, with hazard ratios of 0.57 (95% CI: 0.44-0.73) for the 3-6-month period and 0.59 (95% CI: 0.49-0.72) for the 3-12-month period. Sensitivity analyses in matched cohorts of 17,100 patients showed that SSRI use was associated with a significantly reduced risk of long COVID symptoms, consistent across symptom categories and pandemic periods.

Conclusions: In adult patients with depression, SSRIs compared with non-SSRI antidepressants were associated with a lower risk of long COVID. These results offer preliminary evidence that SSRIs may help prevent long COVID in high‑risk populations and warrant further preclinical and clinical investigation.