The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world’s population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19.

The aim of this sudy was to test the potential antiviral and anti-inflammatory activities of fluoxetine against SARS-CoV-2 in a K18-hACE2 mouse model of infection, and against several variants of concern in vitro, and test the hypothesis of the implication of ceramides and/or their derivatives hexosylceramides.

We evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5.

Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres (Figure 1) and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10) (Figure 2). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects (Figure 3).

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Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.

None Declared

To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19.

The main objective was two-fold: (i) to test the hypothesis that the prevalence of antidepressant use in patients hospitalized with COVID-19 would be lower than in patients with similar characteristics hospitalized without COVID-19, and (ii) to examine, among patients hospitalized with COVID-19, whether antidepressant use is associated with reduced 28-day mortality. Our secondary aim was to examine whether this potential association could only concern specific antidepressant classes or molecules, is dose-dependent, and/or only observed beyond a certain dose threshold.

We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP–HP (Assistance Publique–Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant use at admission (N = 1482) (Figure 1).

Antidepressant use was significantly less prevalent in inpatients with COVID-19 than in a matched control group of inpatients without COVID-19 (1.9% versus 4.8%; Odds Ratio (OR) = 0.38; 95%CI = 0.35–0.41, p < 0.001) (Figure 2). Antidepressant use was significantly associated with reduced 28-day mortality among COVID-19 inpatients (12.8% versus 21.2%; OR = 0.55; 95%CI = 0.41–0.72, p < 0.001), particularly at daily doses of at least 40 mg fluoxetine equivalents (Figure 3). Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations.

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Antidepressant use is associated with a reduced likelihood of hospitalization in patients infected with SARS-CoV-2 and with a reduced risk of death in patients hospitalized with COVID-19. These associations were stronger for molecules with high FIASMA activity. These findings posit that prospective interventional studies of antidepressants with the highest FIASMA activity may be appropriate to help identify variant-agnostic, affordable, and scalable interventions for outpatient and inpatient therapy of COVID-19.

None Declared

To examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalised for coronavirus disease 2019 (COVID-19).

A multicentre observational study was performed at Greater Paris University hospitals. The sample involved 14 381 patients hospitalised for COVID-19. A total of 686 (4.8%) inpatients received a BZRA at hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (standard deviation (s.d.) = 25.4). The study baseline was the date of admission, and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, medical comorbidities and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW).

Over a mean follow-up of 14.5 days (s.d. = 18.1), the primary endpoint occurred in 186 patients (27.1%) who received BZRAs and in 1134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (hazard ratio (HR) = 3.20; 95% confidence interval (CI) = 2.74–3.74; p < 0.01) and in the IPW analysis (HR = 1.61; 95% CI = 1.31–1.98, p < 0.01), with a significant dose-dependent relationship (HR = 1.55; 95% CI = 1.08–2.22; p = 0.02). This association remained significant in sensitivity analyses. Exploratory analyses indicate that most BZRAs may be associated with an increased mortality among patients hospitalised for COVID-19, except for diazepam, which may be associated with a reduced mortality compared with any other BZRA treatment.

BZRA use may be associated with an increased mortality among patients hospitalised for COVID-19, suggesting the potential benefit of decreasing dose or tapering off gradually these medications when possible.