Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV)

Abstract

Background The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activity in vitro, and observational and clinical trial evidence suggesting they prevented progression to severe disease. However, these SSRIs have not been recommended in guidelines and their antiviral activity in vivo has not been characterised. Methods PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. We recruited low-risk adult outpatients aged 18-50 with early symptomatic COVID-19 (symptoms <4 days). Patients were assigned using block randomisation to one of eleven treatment arms including oral fluoxetine (40mg/day for 7 days), or no study drug. Uniform randomisation ratios were applied across the active treatment groups while the no study drug group comprised >20% of patients at all times. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population (>2 days follow-up). The viral clearance rate was estimated under a Bayesian hierarchical linear model fitted to the log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over one week (18 measurements per patient). This ongoing trial is registered at ClinicalTrials.gov (NCT05041907). Findings Between 5 April 2022 and 8 May 2023 271 patients were concurrently randomised to either fluoxetine (n=120) or no study drug (n=151). Fluoxetine was well tolerated and accelerated the rate of viral clearance relative to the no study drug arm by 15% (95% credible interval (CrI): 2% to 34%). In a pooled meta-analysis including all unblinded patients the antiviral activity of fluoxetine was substantially less than ritonavir-boosted nirmatrelvir- 85% increase in rate of viral clearance (95% CrI: 61 to 112%); and less than remdesivir 35% (14 to 59%), molnupiravir 37% (18 to 60%), and casirivimab/imdevimab 29% (10 to 48%). Interpretation Fluoxetine has in vivo antiviral activity against SARS-CoV-2. Although the level of antiviral efficacy is substantially less than with other currently available antiviral drugs, fluoxetine might still be useful in prophylaxis where less antiviral effect is required. Funding Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.

Fluoxetine and Sertraline Potently Neutralize the Replication of Distinct SARS-CoV-2 Variants

“…Randomized clinical trials and retrospective studies have already demonstrated that treatment with antidepressants result in a milder course of COVID-19 and a reduced mortality rate [ 20 , 23 , 47 , 48 , 49 , 50 ]. Furthermore, there was a lower infection rate among patients using antidepressants, indicating that fluoxetine and sertraline may have a protective effect against SARS-CoV-2 infections [ 51 ].…”