Do SSRIs lower the risk of long COVID?

In a recent study posted to the medRxiv* preprint server, researchers conducted a retrospective study to determine whether selective serotonin reuptake inhibitors (SSRI) with immunomodulatory and antiplatelet properties can decrease the risk of post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC).

Background

Emerging data suggest that approximately one-third of the patients who recover from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections may experience PASC or long COVID symptoms.

Various symptoms, including persistent fatigue, shortness of breath, muscle and joint pain, fever, cognitive impairments, inability to exercise, loss of taste and smell, and other complications of the cardiovascular, nervous, digestive, and renal systems have been reported by PASC patients.

While the pathophysiology remains unclear, hypothesized mechanisms include immune dysfunction, viral reservoirs, hormone dysregulation, and the formation of microclots.

Studies with animal models and in vitro and clinical experiments suggest that SSRIs have immunosuppressive and immunomodulatory properties that might reduce the clinical outcomes of COVID-19 and the risk of PASC. The binding of SSRIs to the sigma-1 receptor (S1R) in the endoplasmic reticulum is thought to reduce the activation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα) and interleukin-6 (IL-6).

Controlled trials with fluvoxamine, an SSRI, have shown evidence of protection against the cytokine storm elicited during severe COVID-19. Therefore, the potential of SSRIs to reduce the risk of PASC through down-regulating pro-inflammatory responses needs to be examined further.

About the study

In the present study, the researchers used anonymized electronic health records from the National COVID Cohort Collaborative (N3C) repository consisting of information on diagnoses, procedures, medications, lab tests, and demographic factors.

Individuals aged 18 years or above with a positive reverse transcription polymerase chain reaction (RT-PCR) or antigen test or an International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code of U07.1 for COVID-19 were included in the study. Only patients with an index date between October 1, 2021, and April 7, 2022, were considered for the study.

Two exposure groups were defined based on baseline exposure to a minimum of one SSRI with and without agonist activity at S1R. The third group was the control group with no baseline exposure to either type of SSRI. The measured primary outcome was the diagnosis of PASC using a learning algorithm trained on patients with diagnosed PASC.

Statistical analyses compared patients receiving SSRI treatment with and without S1R agonism to patients without exposure to any SSRIs. Furthermore, the individual exposure propensity scores were evaluated separately for various factors such as demographic factors, body mass index, a wide range of comorbidities, previous SARS-CoV-2 infections, immunotherapy for COVID-19, exposures to other S1R binding ligands or baseline serotonin and norepinephrine reuptake inhibitors (SNRIs), baseline antidepressant, benzodiazepine, or antipsychotic medication, and COVID-19 vaccinations.

Results

The results reported a 26% reduction in the relative risk of PASC among patients receiving baseline SSRIs with S1R agonism compared to the control group receiving no SSRI treatment. The relative risk of PASC among patients receiving non-S1R agonist SSRI treatment also showed a 25% reduction compared to the control group.

Furthermore, when the patients receiving S1R agonist and S1R non-agonist baseline SSRI treatments were compared, no significant change in relative risk was observed, indicating that the protective effects of SSRI against long COVID symptoms might not be related to S1R agonism. The authors speculated that the mechanism through which SSRIs reduce the risk of PASC could be related to their immunomodulatory properties or their antiplatelet activity, which could impact the microclots that contribute to PASC pathology.

The study also indicated a reduced risk of severe clinical outcomes and hospitalization among patients who were administered fluvoxamine or other SSRIs in the early stages of COVID-19.

Conclusions

To summarize, the study investigated the impact of SSRIs on the relative risk of PASC by conducting a retrospective analysis of data from patients who received S1R agonist and S1R non-agonist baseline SSRI therapy.

Overall, the results reported a 26% and 25% reduction in the relative risk of PASC among patients who received baseline SSRI treatment with and without S1R agonist activity, respectively. The findings suggested that the mechanism through which SSRIs reduce PASC symptoms and risk is not related to S1R agonism but could be associated with the antiplatelet and immunomodulatory properties of SSRIs. The results highlight the need for more clinical trials to explore the use of SSRIs in COVID-19 treatment to reduce the development of PASC.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.