Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute Sequelae of COVID-19

{ 'institution': [{'name': 'medRxiv'}], 'indexed': { 'date-parts': [[2022, 11, 11]], 'date-time': '2022-11-11T05:52:47Z', 'timestamp': 1668145967576}, 'posted': {'date-parts': [[2022, 11, 10]]}, 'group-title': 'Infectious Diseases (except HIV/AIDS)', 'reference-count': 0, 'publisher': 'Cold Spring Harbor Laboratory', 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'accepted': {'date-parts': [[2022, 11, 10]]}, 'abstract': '<jats:p>Importance: Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, ' 'prompting evaluation of interventions that might lower risk. Selective serotonin reuptake ' 'inhibitors (SSRIs) potentially could modulate risk of PASC via their central hypothesized ' 'immunomodulatory, and/or antiplatelet properties and therefore have been hypothesized to be ' 'of potential benefit in patients with PASC, although clinical data are lacking. Objectives: ' 'The main objective was to evaluate whether SSRIs with agonist activity at the sigma-1 ' 'receptor lower the risk of PASC, since agonism at this receptor may serve as a mechanism by ' 'which SSRIs attenuate an inflammatory response. A secondary objective was to determine ' 'whether potential benefit could be traced to sigma-1 agonism by evaluating the risk of PASC ' 'among recipients of SSRIs that are not S1R agonists. Design: Retrospective study leveraging ' 'real-world clinical data within the National COVID Cohort Collaborative (N3C), a large ' 'centralized multi-institutional de-identified EHR database. Presumed PASC was defined based ' 'on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code to more ' 'comprehensively identify patients likely to have the condition, since the ICD code has come ' 'into wide-spread use only recently. Setting: Population-based study at US medical centers. ' 'Participants: Adults (≥ 18 years of age) with a confirmed COVID-19 diagnosis date between ' 'October 1, 2021 and April 7, 2022 and at least one follow up visit 45 days post-diagnosis. Of ' 'the 17 933 patients identified, 2021 were exposed at baseline to a S1R agonist SSRI, 1328 to ' 'a non-S1R agonist SSRI, and 14 584 to neither. Exposures: Exposure at baseline (at or prior ' 'to COVID-19 diagnosis) to an SSRI with documented or presumed agonist activity at the S1R ' '(fluvoxamine, fluoxetine, escitalopram, or citalopram), an SSRI without agonist activity at ' 'S1R (sertraline, an antagonist, or paroxetine, which does not appreciably bind to the S1R), ' 'or none of these agents. Main Outcome and Measurement: Development of PASC based on a ' 'previously validated XGBoost-trained algorithm. Using inverse probability weighting and ' 'Poisson regression, relative risk (RR) of PASC was assessed. Results: A 26% reduction in the ' 'RR of PASC (0.74 [95% CI, 0.63-0.88]; P = 5 x 10-4) was seen among patients who received an ' 'S1R agonist SSRI compared to SSRI unexposed patients and a 25% reduction in the RR of PASC ' 'was seen among those receiving an SSRI without S1R agonist activity (0.75 [95% CI, 0.62 - ' '0.90]; P = 0.003) compared to SSRI unexposed patients. Conclusions and Relevance: SSRIs with ' 'and without reported agonist activity at the S1R were associated with a significant decrease ' 'in the risk of PASC. Future prospective studies are warranted.</jats:p>', 'DOI': '10.1101/2022.11.09.22282142', 'type': 'posted-content', 'created': { 'date-parts': [[2022, 11, 10]], 'date-time': '2022-11-10T23:20:15Z', 'timestamp': 1668122415000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute ' 'Sequelae of COVID-19', 'prefix': '10.1101', 'author': [ { 'ORCID': 'http://orcid.org/0000-0003-3532-4809', 'authenticated-orcid': False, 'given': 'Hythem', 'family': 'Sidky', 'sequence': 'first', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-4616-1171', 'authenticated-orcid': False, 'given': 'David K', 'family': 'Sahner', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-2031-9209', 'authenticated-orcid': False, 'given': 'Andrew T', 'family': 'Girvin', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-8423-6464', 'authenticated-orcid': False, 'given': 'Nathan', 'family': 'Hotaling', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sam G', 'family': 'Michael', 'sequence': 'additional', 'affiliation': []}, {'given': 'Michael G', 'family': 'Kurilla', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ken', 'family': 'Gersing', 'sequence': 'additional', 'affiliation': []}, {'name': 'The N3C consortium', 'sequence': 'additional', 'affiliation': []}], 'member': '246', 'container-title': [], 'original-title': [], 'link': [ { 'URL': 'https://syndication.highwire.org/content/doi/10.1101/2022.11.09.22282142', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 11, 10]], 'date-time': '2022-11-10T23:20:16Z', 'timestamp': 1668122416000}, 'score': 1, 'resource': {'primary': {'URL': 'http://medrxiv.org/lookup/doi/10.1101/2022.11.09.22282142'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 11, 10]]}, 'references-count': 0, 'URL': 'http://dx.doi.org/10.1101/2022.11.09.22282142', 'relation': {}, 'published': {'date-parts': [[2022, 11, 10]]}, 'subtype': 'preprint'}