Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19

Abstract

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. 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). 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). 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. Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations. These treatments may reduce SARS-CoV-2 infections and COVID-19-related mortality in inpatients, and may be appropriate for prophylaxis and/or COVID-19 therapy for outpatients or inpatients.

Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model

“…These findings support prior preclinical studies that showed an in vitro efficacy of fluoxetine against SARS-CoV-2 in different host cells (i.e., Vero E6, Calu-1, Calu-3, HEK293T-ACE2-TMPRSS2 cells) and human lung epithelial cells [ 12 , 17 , 18 ]. They are also in line with results of observational studies showing significant associations between fluoxetine use and reduced COVID-19-related mortality or mechanical ventilation [ 20 , 22 , 24 , 25 ] and laboratory-detectable SARS-CoV-2 infection [ 24 , 26 ], and extend them by indicating that fluoxetine effects could be observed quickly when administrated after the start of the infection. Furthermore, they are consistent with results from animal models of septic shock and allergic asthma showing that fluoxetine markedly reduces the inflammatory reaction [ 42 ].…”

“…Nevertheless, these findings are consistent with preclinical data indicating that the inhibition of the ASM/ceramide system by fluoxetine prevents infection of Vero E6 cells with pp-VSV-SARSCoV-2 spike [ 12 ] and that the reconstitution of ceramides in cells treated with fluoxetine restores the infection [ 12 ]. They are also in line with observational study results suggesting the utility of medications with high FIASMA activity against COVID-19 disease progression [ 23 , 24 , 36 ]. The modification of the metabolic ratio hexosylceramide/ceramide by fluoxetine is a novel finding of this study that might explain its observed antiviral and anti-inflammatory effects, as this ratio has been shown to correlate with clinical disease severity and inflammation markers in patients with COVID-19 [ 55 ].…”

“…Finally, a prospective cohort study [ 33 ] of patients admitted to intensive care unit for COVID-19 reported a significant association between the 15-day use of fluvoxamine prescribed at 300 mg/d and reduced mortality. Taken together, these findings support that certain antidepressants, and particularly fluoxetine or fluvoxamine, could be efficient when prescribed at doses of at least 20–40 mg fluoxetine equivalents [ 24 , 25 ] in limiting clinical deterioration of patients infected with SARS-CoV-2 in both ambulatory and acute-care settings.…”

“…First, several preclinical studies demonstrated the in vitro efficacy of fluoxetine against different variants of SARS-CoV-2 in human and non-human (i.e., Vero E6, Calu-1, Calu-3, HEK293T-ACE2-TMPRSS2) cells [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Second, five retrospective observational cohort studies [ 20 , 21 , 22 , 23 , 24 ] of patients with COVID-19 in the acute-care setting reported reduced death or mechanical ventilation in those prescribed with SSRIs prior to hospitalization—particularly fluoxetine. Another observational study [ 25 ] also found that exposure to antidepressants, especially those with functional inhibition of acid sphingomyelinase (FIASMA) properties such as fluoxetine, was associated with reduced incidence of emergency department visitation or hospital admission among SARS-CoV-2 positive outpatients, in a dose-dependent manner and from daily doses of at least 20 mg fluoxetine equivalents.…”

“…Another observational study [ 25 ] also found that exposure to antidepressants, especially those with functional inhibition of acid sphingomyelinase (FIASMA) properties such as fluoxetine, was associated with reduced incidence of emergency department visitation or hospital admission among SARS-CoV-2 positive outpatients, in a dose-dependent manner and from daily doses of at least 20 mg fluoxetine equivalents. Moreover, a retrospective cohort study conducted in an adult psychiatric facility suggested a significant negative association of prior antidepressant use—particularly fluoxetine—with laboratory-detectable SARS-CoV-2 infection [ 26 ], a finding that has been recently replicated in another observational study [ 24 ]. Third, in the ambulatory setting, two prospective randomized, placebo-controlled trials [ 27 , 28 , 29 ] and one non-randomized open-label clinical study [ 30 ], as well as a meta-analysis [ 31 ], found a significant association between the short-term use (10–15 days) of fluvoxamine prescribed at a dose between 100 and 300 mg/d within 7 days of symptom onset and reduced risk of clinical deterioration.…”