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. 2022 Oct 5;11(19):5882.
doi: 10.3390/jcm11195882.

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

Nicolas Hoertel  1   2 , Marina Sánchez-Rico  2   3 , Johannes Kornhuber  4 , Erich Gulbins  5 , Angela M Reiersen  6 , Eric J Lenze  6 , Bradley A Fritz  7 , Farid Jalali  8 , Edward J Mills  9 , Céline Cougoule  10 , Alexander Carpinteiro  5   11 , Christiane Mühle  4 , Katrin Anne Becker  5 , David R Boulware  12 , Carlos Blanco  13 , Jesús M Alvarado  3 , Nathalie Strub-Wourgaft  14 , Cédric Lemogne  1   15 , Frédéric Limosin  1   2 , On Behalf Of Ap-Hp/Université Paris Cité/Inserm Covid-Research Collaboration Ap-Hp Covid Cdr Initiative And Entrepôt de Données de Santé Ap-Hp Consortium
Affiliations

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

Nicolas Hoertel et al. J Clin Med. .

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.

Keywords: COVID-19; FIASMA; SARS-CoV-2; antidepressant; ceramide; fluoxetine; fluvoxamine; mortality; sigma-1 receptor; sphingomyelinase.

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Conflict of interest statement

N.H., M.S.R., J.K., E.G., A.C., C.M. and F.L. are inventors on a patent application related to methods of treating COVID-19, filled by Assistance Publique—Hopitaux de Paris in France. N.H. has received personal fees and non-financial support from Lundbeck, outside the submitted work. C.L. has received personal fees and non-financial support from Lundbeck and Otsuka Pharmaceutical, outside the submitted work. E.L. has received grant support (non-federal) from COVID Early Treatment Fund, Mercatus Center Emergent Ventures, the Skoll Foundation, the Taylor Family Institute for Innovative Psychiatric Research, the Center for Brain Research in Mood Disorders, the Patient-Centered Outcomes Research Institute, Janssen, and the Barnes Jewish Foundation, and has received consulting fees from Janssen and Jazz Pharmaceuticals. A.R. has received grant or research support from the McDonnell Center for Systems Neuroscience, the McDonnell Center for Cellular and Molecular Neurobiology, and the Taylor Family Institute for Innovative Psychiatric Research. A.R. and E.L. are inventors on a patent application related to methods of treating COVID-19, which was filed by Washington University in St. Louis. Other authors declare no conflict of interest related to this work.

Figures

Figure 1
Figure 1
Study cohort. α Matched for age, sex, hospital, period of hospitalization, and number of medical conditions. β Matched for age, sex, hospital, period of hospitalization, number of medical conditions, any current diagnosis of psychiatric disorders, use of other psychotropic medications (benzodiazepines or Z-drugs, antipsychotic medications, mood stabilizers) or any medication prescribed according to compassionate use or as part of a clinical trial, and clinical and biological markers of COVID-19 severity.
Figure 2
Figure 2
Prevalence of antidepressant use in inpatients hospitalized with and without COVID-19 (N = 82,586). (A) prevalence of antidepressant use in a matched analytic sample of inpatients with and without COVID-19, based on age, sex, hospital, period of hospitalization, and number of medical conditions; (B) association between antidepressant use and SARS-CoV-2 infection in a matched analytic sample of inpatients with and without COVID-19, stratified by age, sex, period of hospitalization, and any current diagnosis of psychiatric disorder; (C) comparison of antidepressant use with statin use, and fluoxetine or fluvoxamine use with atorvastatin use, in a matched analytic sample of inpatients with and without COVID-19; (D) associations across antidepressant classes.
Figure 3
Figure 3
Antidepressant use and 28-day all-cause mortality in a matched analytic sample of patients hospitalized with COVID-19 (N = 1482). (A) Mortality rates in COVID-19 inpatients with and without an antidepressant at baseline in a matched analytic sample based on age, sex, hospital, period of hospitalization, number of medical conditions, any current diagnosis of psychiatric disorders, use of other psychotropic medications (benzodiazepines or Z-drugs, antipsychotic medications, mood stabilizers) or any medication prescribed according to compassionate use or as part of a clinical trial, and clinical and biological markers of COVID-19 severity; (B) associations between antidepressant use at baseline and 28-day mortality, stratified by age, sex, and period of hospitalization; (C) comparison of baseline use of antidepressants, fluoxetine, and fluoxetine or fluvoxamine with baseline use of dexamethasone and tocilizumab; (D) associations across antidepressant classes; abbreviations: ns, not significant.
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