Medications Modulating the Acid Sphingomyelinase/Ceramide System and 28-Day Mortality among Patients with SARS-CoV-2: An Observational Study
Nicolas Hoertel, Katayoun Rezaei, Marina Sánchez-Rico, Alfonso Delgado-Álvarez, Johannes Kornhuber, Erich Gulbins, Mark Olfson, Charles Ouazana-Vedrines, Alexander Carpinteiro, Céline Cougoule, Katrin Anne Becker, Jesús M Alvarado, Frédéric Limosin
Pharmaceuticals, doi:10.3390/ph16081107
Prior evidence indicates the potential central role of the acid sphingomyelinase (ASM)/ ceramide system in the infection of cells with SARS-CoV-2. We conducted a multicenter retrospective observational study including 72,105 adult patients with laboratory-confirmed SARS-CoV-2 infection who were admitted to 36 AP-HP (Assistance Publique-Hôpitaux de Paris) hospitals from 2 May 2020 to 31 August 2022. We examined the association between the ongoing use of medications functionally inhibiting acid sphingomyelinase (FIASMA), which reduces the infection of cells with SARS-CoV-2 in vitro, upon hospital admission with 28-day all-cause mortality in a 1:1 ratio matched analytic sample based on clinical characteristics, disease severity and other medications (N = 9714). The univariate Cox regression model of the matched analytic sample showed that FIASMA medication use at admission was associated with significantly lower risks of 28-day mortality (HR = 0.80; 95% CI = 0.72-0.88; p < 0.001). In this multicenter observational study, the use of FIASMA medications was significantly and substantially associated with reduced 28-day mortality among adult patients hospitalized with COVID-19. These findings support the continuation of these medications during the treatment of SARS-CoV-2 infections. Randomized clinical trials (RCTs) are needed to confirm these results, starting with the molecules with the greatest effect size in the study, e.g., fluoxetine, escitalopram, and amlodipine.
References
Austin, Using the Standardized Difference to Compare the Prevalence of a Binary Variable between Two Groups in Observational Research, Commun. Stat. Simul. Comput,
doi:10.1080/03610910902859574Brunotte, Zheng, Mecate-Zambrano, Tang, Ludwig et al., Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro, Pharmaceutics,
doi:10.3390/pharmaceutics13091400Butler, Hobbs, Gbinigie, Rahman, Hayward et al., Molnupiravir plus Usual Care versus Usual Care Alone as Early Treatment for Adults with COVID-19 at Increased Risk of Adverse Outcomes (PANORAMIC): An Open-Label, Platform-Adaptive Randomised Controlled Trial, Lancet,
doi:10.1016/S0140-6736(22)02597-1Calusic, Marcec, Luksa, Jurkovic, Kovac et al., Safety and Efficacy of Fluvoxamine in COVID-19 ICU Patients: An Open Label, Prospective Cohort Trial with Matched Controls, Br. J. Clin. Pharmacol,
doi:10.1111/bcp.15126Carpinteiro, Edwards, Hoffmann, Kochs, Gripp et al., Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells, Cell Rep. Med,
doi:10.1016/j.xcrm.2020.100142Carpinteiro, Gripp, Hoffmann, Pöhlmann, Hoertel et al., Inhibition of Acid Sphingomyelinase by Ambroxol Prevents SARS-CoV-2 Entry into Epithelial Cells, J. Biol. Chem,
doi:10.1016/j.jbc.2021.100701Chen, Wu, Chen, Zhan, Wu et al., Sertraline Is an Effective SARS-CoV-2 Entry Inhibitor Targeting the Spike Protein, J. Virol,
doi:10.1128/jvi.01245-22Chevance, Gourion, Hoertel, Llorca, Thomas et al., Ensuring Mental Health Care during the SARS-CoV-2 Epidemic in France: A Narrative Review, L'Encephale,
doi:10.1016/j.encep.2020.04.005Cipriani, Furukawa, Salanti, Chaimani, Atkinson et al., Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults with Major Depressive Disorder: A Systematic Review and Network Meta-Analysis, Lancet,
doi:10.1016/S0140-6736(17)32802-7Clelland, Ramiah, Steinberg, Clelland, Analysis of the Impact of Antidepressants and Other Medications on COVID-19 Infection Risk in a Chronic Psychiatric in-Patient Cohort,
doi:10.1192/bjo.2021.1053Darquennes, Le Corre, Le Moine, Loas, Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study, Pharmaceuticals,
doi:10.3390/ph14030226Dei Cas, Ottolenghi, Morano, Rinaldo, Roda et al., Link between Serum Lipid Signature and Prognostic Factors in COVID-19 Patients, Sci. Rep,
doi:10.1038/s41598-021-00755-zDeng, Rayner, Ramaraju, Abbas, Garcia et al., Efficacy and Safety of Selective Serotonin Reuptake Inhibitors in COVID-19 Management: A Systematic Review and Meta-Analysis, Clin. Microbiol. Infect,
doi:10.1016/j.cmi.2023.01.010Elm, Altman, Egger, Pocock, Gøtzsche et al., The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies, Ann. Intern. Med,
doi:10.7326/0003-4819-147-8-200710160-00010Fred, Kuivanen, Ugurlu, Casarotto, Levanov et al., Antidepressant and Antipsychotic Drugs Reduce Viral Infection by SARS-CoV-2 and Fluoxetine Shows Antiviral Activity Against the Novel Variants in Vitro, Front. Pharmacol,
doi:10.3389/fphar.2021.755600Fritz, Hoertel, Lenze, Jalali, Reiersen, Association between Antidepressant Use and ED or Hospital Visits in Outpatients with SARS-CoV-2. Transl, Psychiatry,
doi:10.1038/s41398-022-02109-3Gulbins, Palmada, Reichel, Lüth, Böhmer et al., Acid Sphingomyelinase-Ceramide System Mediates Effects of Antidepressant Drugs, Nat. Med
Ho, Imai, King, Stuart, Matchit, Nonparametric Preprocessing for Parametric Causal Inference, J. Stat. Softw,
doi:10.18637/jss.v042.i08Hoertel, Blachier, Blanco, Olfson, Massetti et al., A Stochastic Agent-Based Model of the SARS-CoV-2 Epidemic in France, Nat. Med,
doi:10.1038/s41591-020-1001-6Hoertel, Blachier, Sánchez-Rico, Limosin, Leleu, Impact of the Timing and Adherence to Face Mask Use on the Course of the COVID-19 Epidemic in France, J. Travel Med,
doi:10.1093/jtm/taab016Hoertel, Boulware, Sánchez-Rico, Burgun, Limosin, Prevalence of Contraindications to Nirmatrelvir-Ritonavir among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease, JAMA Netw. Open
Hoertel, Chevance, Limosin, Inclusion and Exclusion Criteria and Psychological Research
Hoertel, Do the Selective Serotonin Reuptake Inhibitor Antidepressants Fluoxetine and Fluvoxamine Reduce Mortality Among Patients With COVID-19?, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2021.36510Hoertel, Rico, Vernet, Beeker, Jannot et al., Association between SSRI Antidepressant Use and Reduced Risk of Intubation or Death in Hospitalized Patients with Coronavirus Disease 2019: A Multicenter Retrospective Observational Study,
doi:10.1101/2020.07.09.20143339Hoertel, Sánchez-Rico, Cougoule, Gulbins, Kornhuber et al., Repurposing Antidepressants Inhibiting the Sphingomyelinase Acid/Ceramide System against COVID-19: Current Evidence and Potential Mechanisms, Mol. Psychiatry,
doi:10.1038/s41380-021-01254-3Hoertel, Sánchez-Rico, De La Muela, Abellán, Blanco et al., Risk of Death in Individuals Hospitalized for COVID-19 With and Without Psychiatric Disorders: An Observational Multicenter Study in France, Biol. Psychiatry Glob. Open Sci,
doi:10.1016/j.bpsgos.2021.12.007Hoertel, Sánchez-Rico, Gulbins, Kornhuber, Carpinteiro et al., Association Between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: An Observational Multicenter Study, Clin. Pharmacol. Ther,
doi:10.1002/cpt.2317Hoertel, Sánchez-Rico, Gulbins, Kornhuber, Carpinteiro et al., Association between FIASMA Psychotropic Medications and Reduced Risk of Intubation or Death in Individuals with Psychiatric Disorders Hospitalized for Severe COVID-19: An Observational Multicenter Study, Transl. Psychiatry
Hoertel, Sánchez-Rico, Gulbins, Kornhuber, Vernet et al., Association between Benzodiazepine Receptor Agonist Use and Mortality in Patients Hospitalised for COVID-19: A Multicentre Observational Study, Epidemiol. Psychiatr. Sci,
doi:10.1017/S2045796021000743Hoertel, Sánchez-Rico, Herrera-Morueco, De La Muela, Gulbins et al., Comorbid Medical Conditions Are a Key Factor to Understand the Relationship between Psychiatric Disorders and COVID-19-Related Mortality: Results from 49,089 COVID-19 Inpatients, Mol. Psychiatry,
doi:10.1038/s41380-021-01393-7Hoertel, Sánchez-Rico, Kornhuber, Gulbins, Reiersen et al., Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19, J. Clin. Med,
doi:10.3390/jcm11195882Hoertel, Sánchez-Rico, Vernet, Beeker, Jannot et al., Association between Antidepressant Use and Reduced Risk of Intubation or Death in Hospitalized Patients with COVID-19: Results from an Observational Study, Mol. Psychiatry,
doi:10.1038/s41380-021-01021-4Hoertel, Sánchez-Rico, Vernet, Beeker, Neuraz et al., Dexamethasone Use and Mortality in Hospitalized Patients with Coronavirus Disease 2019: A Multicentre Retrospective Observational Study, Br. J. Clin. Pharmacol,
doi:10.1111/bcp.14784Hoertel, Sánchez-Rico, Vernet, Jannot, Neuraz et al., Observational Study of Chlorpromazine in Hospitalized Patients with COVID-19, Clin. Drug Investig,
doi:10.1007/s40261-021-01001-0Hoertel, Sánchez-Rico, Vernet, Jannot, Neuraz et al., Observational Study of Haloperidol in Hospitalized Patients with COVID-19, PLoS ONE,
doi:10.1371/journal.pone.0247122Khater, El-Khouly, Abdel-Bar, Al-Mahallawi, Ghorab, Fluoxetine Hydrochloride Loaded Lipid Polymer Hybrid Nanoparticles Showed Possible Efficiency against SARS-CoV-2 Infection, Int. J. Pharm,
doi:10.1016/j.ijpharm.2021.121023Kirenga, Mugenyi, Sánchez-Rico, Kyobe, Muttamba et al., Association of Fluvoxamine with Mortality and Symptom Resolution among Inpatients with COVID-19 in Uganda: A Prospective Interventional Open-Label Cohort Study, Mol. Psychiatry,
doi:10.1038/s41380-023-02004-3Kornhuber, Muehlbacher, Trapp, Pechmann, Friedl et al., Identification of Novel Functional Inhibitors of Acid Sphingomyelinase, PLoS ONE,
doi:10.1371/journal.pone.0023852Kornhuber, Tripal, Reichel, Mühle, Rhein et al., Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): A Novel Pharmacological Group of Drugs with Broad Clinical Applications, Cell. Physiol. Biochem,
doi:10.1159/000315101Kornhuber, Tripal, Reichel, Terfloth, Bleich et al., Identification of New Functional Inhibitors of Acid Sphingomyelinase Using a Structure-Property-Activity Relation Model, J. Med. Chem,
doi:10.1021/jm070524aLagunas-Rangel, Neutrophil-to-Lymphocyte Ratio and Lymphocyte-to-C-Reactive Protein Ratio in Patients with Severe Coronavirus Disease 2019 (COVID-19): A Meta-Analysis, J. Med. Virol,
doi:10.1002/jmv.25819Lenze, Mattar, Zorumski, Stevens, Schweiger et al., Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2020.22760Lenze, Reiersen, Santosh, Repurposing Fluvoxamine, and Other Psychiatric Medications, for COVID-19 and Other Conditions, World Psychiatry,
doi:10.1002/wps.20983Lim, Tignanelli, Hoertel, Boulware, Usher, Prevalence of Medical Contraindications to Nirmatrelvir/Ritonavir in a Cohort of Hospitalized and Nonhospitalized Patients With COVID-19, Open Forum Infect. Dis,
doi:10.1093/ofid/ofac389Loas, Van De Borne, Darquennes, Le Corre, Association of Amlodipine with the Risk of In-Hospital Death in Patients with COVID-19 and Hypertension: A Reanalysis on 184 COVID-19 Patients with Hypertension, Pharmaceuticals,
doi:10.3390/ph15030380Marín-Corral, Rodríguez-Morató, Gomez-Gomez, Pascual-Guardia, Muñoz-Bermúdez et al., Metabolic Signatures Associated with Severity in Hospitalized COVID-19 Patients, Int. J. Mol. Sci,
doi:10.3390/ijms22094794Matta, Wiernik, Robineau, Carrat, Touvier et al., Association of Self-Reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic, JAMA Intern. Med,
doi:10.1001/jamainternmed.2021.6454Mühle, Kremer, Vetter, Schmid, Achenbach et al., COVID-19 and Its Clinical Severity Are Associated with Alterations of Plasma Sphingolipids and Enzyme Activities of Sphingomyelinase and Ceramidase,
doi:10.1101/2022.01.19.22269391Naz, Asif, Alwutayd, Sarfaraz, Abbasi et al., Repurposing FIASMAs against Acid Sphingomyelinase for COVID-19: A Computational Molecular Docking and Dynamic Simulation Approach, Molecules,
doi:10.3390/molecules28072989Neuraz, Lerner, Digan, Paris, Tsopra et al., Natural Language Processing for Rapid Response to Emergent Diseases: Case Study of Calcium Channel Blockers and Hypertension in the COVID-19 Pandemic, J. Med. Internet Res,
doi:10.2196/20773Németh, Sz Űcs, Vitrai, Juhász, Németh et al., Fluoxetine Use Is Associated with Improved Survival of Patients with COVID-19 Pneumonia: A Retrospective Case-Control Study, Ideggyógy. Szle,
doi:10.18071/isz.74.0389Oskotsky, Marić, Tang, Oskotsky, Wong et al., Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants, JAMA Netw. Open
Petrache, Pujadas, Ganju, Serban, Borowiec et al., Marked Elevations in Lung and Plasma Ceramide in COVID-19 Linked to Microvascular Injury,
doi:10.1172/jci.insight.156104Péricat, Leon-Icaza, Sanchez Rico, Mühle, Zoicas et al., Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model, Int. J. Mol. Sci,
doi:10.3390/ijms232113623Reis, Dos, Moreira-Silva, Silva, Thabane et al., Effect of Early Treatment with Fluvoxamine on Risk of Emergency Care and Hospitalisation among Patients with COVID-19: The TOGETHER Randomised, Platform Clinical Trial, Lancet Glob. Health,
doi:10.1016/S2214-109X(21)00448-4Schloer, Brunotte, Goretzko, Mecate-Zambrano, Korthals et al., Targeting the Endolysosomal Host-SARS-CoV-2 Interface by Clinically Licensed Functional Inhibitors of Acid Sphingomyelinase (FIASMA) Including the Antidepressant Fluoxetine, Emerg. Microbes Infect,
doi:10.1080/22221751.2020.1829082Schloer, Brunotte, Mecate-Zambrano, Zheng, Tang et al., Drug Synergy of Combinatory Treatment with Remdesivir and the Repurposed Drugs Fluoxetine and Itraconazole Effectively Impairs SARS-CoV-2 Infection in Vitro, Br. J. Pharmacol,
doi:10.1111/bph.15418Seftel, Boulware, Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19, Open Forum Infect. Dis,
doi:10.1093/ofid/ofab050Solaimanzadeh, Nifedipine and Amlodipine Are Associated with Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19, Cureus,
doi:10.7759/cureus.8069Sonawane, Barale, Dhanavade, Waghmare, Nadaf et al., Structural Insights and Inhibition Mechanism of TMPRSS2 by Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2: A Molecular Modeling Approach, Inform. Med. Unlocked,
doi:10.1016/j.imu.2021.100597Stuart, Lee, Leacy, Prognostic Score-Based Balance Measures Can Be a Useful Diagnostic for Propensity Score Methods in Comparative Effectiveness Research, J. Clin. Epidemiol,
doi:10.1016/j.jclinepi.2013.01.013Sukhatme, Reiersen, Vayttaden, Sukhatme, Fluvoxamine, A Review of Its Mechanism of Action and Its Role in COVID-19, Front. Pharmacol,
doi:10.3389/fphar.2021.652688Sánchez-Rico, De La Muela, Herrera-Morueco, Geoffroy, Limosin et al., AP-HP/Université de Paris/INSERM COVID-19 Research Collaboration/AP-HP COVID CDR Initiative/Entrepôt de Données de Santé AP-HP Consortium. Melatonin Does Not Reduce Mortality in Adult Hospitalized Patients with COVID-19: A Multicenter Retrospective Observational Study, J. Travel Med,
doi:10.1093/jtm/taab195Sánchez-Rico, Limosin, Vernet, Beeker, Neuraz et al., Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study, J. Clin. Med,
doi:10.3390/jcm10245891Sánchez-Rico, Rezaei, Delgado-Álvarez, Limosin, Hoertel et al., Comorbidity Patterns and Mortality Among Hospitalized Patients with Psychiatric Disorders and COVID-19, Rev. Bras. Psiquiatr,
doi:10.47626/1516-4446-2023-3076Terry, Grambsch, Modeling Survival Data: Extending the Cox Model
Tham, Jonsson, Andersson, Söderlund, Allard et al., Efficacy and Tolerability of Antidepressants in People Aged 65 Years or Older with Major Depressive Disorder-A Systematic Review and a Meta-Analysis, J. Affect. Disord,
doi:10.1016/j.jad.2016.06.013Torretta, Garziano, Poliseno, Capitanio, Biasin et al., Severity of COVID-19 Patients Predicted by Serum Sphingolipids Signature, Int. J. Mol. Sci,
doi:10.3390/ijms221910198Zimniak, Kirschner, Hilpert, Geiger, Danov et al., The Serotonin Reuptake Inhibitor Fluoxetine Inhibits SARS-CoV-2 in Human Lung Tissue. Sci,
doi:10.1038/s41598-021-85049-0
