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Review 2: "Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute Sequelae of COVID-19"

This preprint discusses the importance of SSRIs and their effect on long-COVID.. Reviewers find this study to be potentially informative and strong, highlighting the study’s contribution to new treatments for PASC.

Published onJan 05, 2023
Review 2: "Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute Sequelae of COVID-19"
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Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute Sequelae of COVID-19

AbstractImportancePost-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 may be postulated to be of benefit in patients with PASC, although clinical trial data are lacking.ObjectivesThe 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.DesignRetrospective 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.SettingPopulation-based study at US medical centers.ParticipantsAdults (≥ 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.ExposuresExposure 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 MeasurementDevelopment of PASC based on a previously validated XGBoost-trained algorithm. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed.ResultsA 26% reduction in the RR of PASC (0.74 [95% CI, 0.63-0.88]; P = 5 × 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 RelevanceSSRIs 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.Key pointsQuestionDo Selective Serotonin Reuptake Inhibitors with and without agonist activity at the sigma-1 receptor (S1R) prevent Post-Acute Sequelae of COVID-19?FindingsIn this retrospective study leveraging real-world clinical data that included 17 933 patients, a 28% reduction in risk of PASC was observed for S1R agonist SSRIs and a 25% reduction in risk of PASC was observed for non-S1R agonist SSRIs, both versus controls, using a computable phenotype to define PASC.MeaningSSRIs may play a role in managing the long term disease burden of COVID-19. Future prospective studies are warranted to confirm these findings and evaluate potential mechanisms of action.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



The use of Selective Serotonin Reuptake Inhibitors (SSRIs) has been widely examined in cohort studies and randomized trials for the treatment of acute COVID symptoms and recovery. Specifically, fluvoxamine has been examined in several randomized trials and demonstrated treatment benefits for both prevention of clinical progression and time to recovery. Observational studies have examined whether patients already on SSRIs had a greater risk of hospitalization or death and have found protective effects. It should come as only logical then, to examine whether these drugs have a role in long COVID. For that reason, this study is very timely and potentially important. 

The methods are sound and use a typical nested case-control approach. There is a sufficient number of patients that if they detect a treatment effect, it is likely sufficiently powered. The effect size detected also appears to be in line with the therapeutic studies of SSRIs in acute COVID. 

Some of the text is overly long; for example the introduction and some of the reporting of results are inconsistent. There is no reason, for example, to report a p-value as P = 5 x 10-4. I am not convinced that the mechanism of action is understood about antidepressants in COVID and it is entirely speculative that they may have antiviral or anti-inflammatory properties. The study is interesting and will probably lead to a lot of off-label prescribing and use by a population of patients that otherwise have nothing else. However, we ultimately need a large randomized trial to inform whether this is an agent that can be widely recommended.

Abhishek Kumar:

Jubilant Biosys is a global CRO/CDMO that provides comprehensive drug discovery, contract research, and manufacturing services in partnership with leading worldwide pharmaceutical and healthcare companies.

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