SSRI use during acute COVID-19 and risk of long COVID among patients with depression

Background: Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a poorly understood condition with symptoms across a range of biological domains that often have debilitating consequences. Some have recently suggested that lingering SARS-CoV-2 virus particles in the gut may impede serotonin production and that low serotonin may drive many Long COVID symptoms across a range of biological systems. Therefore, selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability, may be used to prevent or treat Long COVID. SSRIs are commonly prescribed for depression, therefore restricting a study sample to only include patients with depression can reduce the concern of confounding by indication. Methods: In an observational sample of electronic health records from patients in the National COVID Cohort Collaborative (N3C) with a COVID-19 diagnosis between September 1, 2021, and December 1, 2022, and a comorbid depressive disorder, the leading indication for SSRI use, we evaluated the relationship between SSRI use during acute COVID-19 and subsequent 12-month risk of Long COVID (defined by ICD-10 code U09.9). We defined SSRI use as a prescription for SSRI medication beginning at least 30 days before acute COVID-19 and not ending before SARS-CoV-2 infection. To minimize bias, we estimated relationships using nonparametric targeted maximum likelihood estimation to aggressively adjust for high-dimensional covariates. Results: We analyzed a sample (n = 302,626) of patients with a diagnosis of a depressive condition before COVID-19 diagnosis, where 100,803 (33%) were using an SSRI. We found that SSRI users had a significantly lower risk of Long COVID compared to nonusers (adjusted causal relative risk 0.92, 95% CI (0.86, 0.99)) and we found a similar relationship comparing new SSRI users (first SSRI prescription 1 to 4 months before acute COVID-19 with no prior history of SSRI use) to nonusers (adjusted causal relative risk 0.89, 95% CI (0.80, 0.98)). Conclusions: These findings suggest that SSRI use during acute COVID-19 may be protective against Long COVID, supporting the hypothesis that serotonin may be a key mechanistic biomarker of Long COVID.

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UNC Libraries
Published
2024-11-05
DOI
https://doi.org/10.17615/qzk6-0023
Primary Topic
Long-Term Effects of COVID-19
Type
article
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article

SSRI use during acute COVID-19 and risk of long COVID among patients with depression

Andrew N. Mertens, Eugene S. Hurwitz, John M. Colford, Jeremy Coyle et al.
UNC Libraries
Long-Term Effects of COVID-19
article

SSRI use during acute COVID-19 and risk of long COVID among patients with depression

Andrew N. Mertens, Eugene S. Hurwitz, John M. Colford, Jeremy Coyle, Sanjeev Deshpande, Zachary Butzin-Dozier, Jianxin Shi, Ji Y, Painter Rebecca C., Hubbard A.E., van der Laan M.J
article en

Abstract

Background: Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a poorly understood condition with symptoms across a range of biological domains that often have debilitating consequences. Some have recently suggested that lingering SARS-CoV-2 virus particles in the gut may impede serotonin production and that low serotonin may drive many Long COVID symptoms across a range of biological systems. Therefore, selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability, may be used to prevent or treat Long COVID. SSRIs are commonly prescribed for depression, therefore restricting a study sample to only include patients with depression can reduce the concern of confounding by indication. Methods: In an observational sample of electronic health records from patients in the National COVID Cohort Collaborative (N3C) with a COVID-19 diagnosis between September 1, 2021, and December 1, 2022, and a comorbid depressive disorder, the leading indication for SSRI use, we evaluated the relationship between SSRI use during acute COVID-19 and subsequent 12-month risk of Long COVID (defined by ICD-10 code U09.9). We defined SSRI use as a prescription for SSRI medication beginning at least 30 days before acute COVID-19 and not ending before SARS-CoV-2 infection. To minimize bias, we estimated relationships using nonparametric targeted maximum likelihood estimation to aggressively adjust for high-dimensional covariates. Results: We analyzed a sample (n = 302,626) of patients with a diagnosis of a depressive condition before COVID-19 diagnosis, where 100,803 (33%) were using an SSRI. We found that SSRI users had a significantly lower risk of Long COVID compared to nonusers (adjusted causal relative risk 0.92, 95% CI (0.86, 0.99)) and we found a similar relationship comparing new SSRI users (first SSRI prescription 1 to 4 months before acute COVID-19 with no prior history of SSRI use) to nonusers (adjusted causal relative risk 0.89, 95% CI (0.80, 0.98)). Conclusions: These findings suggest that SSRI use during acute COVID-19 may be protective against Long COVID, supporting the hypothesis that serotonin may be a key mechanistic biomarker of Long COVID.

UNC Libraries
University of North Carolina at Chapel Hill (US)
Bill and Melinda Gates Foundation, Yale University, University of Southern California, Children's Hospital of Philadelphia, University of Nebraska Medical Center, Vanderbilt University, University of Miami, University of Pennsylvania, Ohio State University, Emory University, Tufts Medical Center, NYU Langone Medical Center, University of Wisconsin-Madison, Northwestern University, George Washington University, Wake Forest University, Cincinnati Children's Hospital Medical Center, Vanderbilt Institute for Clinical and Translational Research, University of Chicago, University of Minnesota, University of Michigan, Harvard Catalyst, Loyola University Chicago, University of Utah, University of Washington, University of Texas Medical Branch, Tulane University, Johns Hopkins University, University of Oklahoma, Institute for Translational Medicine and Therapeutics, Institute of Clinical and Translational Sciences, University of Rochester, University of Cincinnati, Pennsylvania State University, Rush University, University of South Carolina, Virginia Commonwealth University, Southern California Clinical and Translational Science Institute, West Virginia University, Montana State University, Rutgers, The State University of New Jersey, MedStar Health Research Institute, Georgetown-Howard Universities Center for Clinical and Translational Science, University of Texas Health Science Center at Houston, NorthShore University HealthSystem, Vanderbilt University Medical Center, Institute of Translational Health Sciences, Penn State Clinical and Translational Science Institute, Louisiana Clinical and Translational Science Center, Ochsner Health, West Virginia Clinical and Translational Science Institute, Stony Brook University, National Institutes of Health, University of Illinois at Urbana-Champaign, Institute for Clinical and Translational Research, University of Wisconsin, Madison, University of California, Los Angeles, Weill Cornell Medical College, University of California, Davis, Oregon Clinical and Translational Research Institute, University of California, San Diego, University of Oklahoma Health Sciences Center, University of California, San Francisco, Michigan Institute for Clinical and Health Research, University of Texas Health Science Center at San Antonio, University of California, Irvine, Leonard M. Miller School of Medicine, Center for Clinical and Translational Research, University of Colorado Denver, Center for Clinical and Translational Science, University of Massachusetts, Center for Clinical and Translational Science, Mayo Clinic, Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Irving Medical Center, Columbia University, Translational Research Institute, University of Arkansas for Medical Sciences, South Carolina Clinical and Translational Research Institute, Medical University of South Carolina, Clinical and Translational Science Institute, University of Florida, Clinical and Translational Science Center, University of New Mexico, National Center for Advancing Translational Sciences, Institute for Integration of Medicine and Science, Colorado Clinical and Translational Sciences Institute, Yale Center for Clinical Investigation, Yale School of Medicine, Institute for Clinical and Translational Science, University of California, Irvine, Wake Forest Clinical and Translational Science Institute, Wake Forest School of Medicine, Accelerated Innovation Research Initiative Turning Top Science and Ideas into High-Impact Values
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