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The latest drugs off the shelf to show potential beneficial properties in regards to covid are fluoxetine and fluvoxamine. Retrospective cohort studies have shown a significant risk reduction for hospitalizations and intubation or death in covid patients who are on antidepressants. This has led to short-term use of both as yet another affordable potential therapeutic that has been here the whole time.
These two drugs in particular are known as SSRIs (Serotonin Selective Reuptake Inhibitors) Prozac and Luvox their respective brand names. Like many drugs they have multiple effects across the body, they are also inhibitors of ASM (acid sphingomyelinase) an enzyme that cleaves sphingomyelinase into two parts resulting in a ceramide and phosphorylcholine.
During infection, the virus will activate this ASM enzyme causing excess ceramide production which results in clustering of the ACE2 enzyme on the cell membrane. In vitro removing ceramide will stop the infection and restoring it results in the infection returning. This makes ceramide production a ripe target for pharmacotherapy via ASM inhibition or AC (acid ceramidase) upregulation which metabolizes ceramide.
Functional inhibitors of acid sphingomyelinase (FIASMA) include many drugs across the spectrum, not just antidepressants. Amlodipine is a calcium channel blocker that retrospective studies have also shown to reduce the covid fatality rate. Benztropine an anticholinergic drug for Parkinson’s and Attention Deficit Hyperactivity Disorder inhibits ASM and is a Sigma 1 receptor ligand another theoretical mechanism of action that may contribute to its antiviral properties. Clomiphene, a selective estrogen receptor modulator (SERM) blocks both covid and Ebola virus in the lab. Hydroxyzine, a common antihistamine was shown in a study to have a significant association with reduced mortality.
Fluvoxamine though of all these has generated the most buzz due to two recently published studies. The first, an actual randomized placebo-controlled study had eighty patients receive 100-300 mg of fluvoxamine daily for fourteen days. Seventy-two patients received placebo and six would go on to have worsening symptoms defined as hospitalization, shortness of breath, or oxygen saturation less than 92%. In the treatment group, zero patients would meet the criteria for worsening symptoms.
The next study looked at an even lower dose of 50mg of fluvoxamine twice daily in sixty-five patients none of which were hospitalized and at a fourteen-day follow up no patients reported any residual symptoms. The placebo group of forty-eight volunteers resulted in six hospitalizations and twenty-nine patients reported having residual symptoms at the follow up. Fluvoxamine like benztropine is also a Sigma 1 receptor agonist; perhaps this dual mechanism of action explains the positive results.
Jacob Hyatt Pharm D.
Father of three, Pharmacist, Realtor, Landlord, Independent Health and Medicine Reporter
Further Reading and References
Kornhuber J, Hoertel N, Gulbins E. The acid sphingomyelinase/ceramide system in COVID-19 [published online ahead of print, 2021 Oct 4]. Mol Psychiatry. 2021;1-8. doi:10.1038/s41380-021-01309-5
Han L, Shan G, Chu B, et al. Accelerating drug repurposing for COVID-19 treatment by modeling mechanisms of action using cell image features and machine learning [published online ahead of print, 2021 Nov 5]. Cogn Neurodyn. 2021;1-9. doi:10.1007/s11571-021-09727-5
Williams TL, Colzani MT, Macrae RGC, et al. Human embryonic stem cell-derived cardiomyocyte platform screens inhibitors of SARS-CoV-2 infection. Commun Biol. 2021;4(1):926. Published 2021 Jul 29. doi:10.1038/s42003-021-02453-y
Kornhuber J, Tripal P, Reichel M, Mühle C, Rhein C, Muehlbacher M, Groemer T, W, Gulbins E: Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): A Novel Pharmacological Group of Drugs with Broad Clinical Applications. Cell Physiol Biochem 2010;26:9-20. doi: 10.1159/000315101
Hoertel N, Sánchez-Rico M, Cougoule C, et al. Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms [published online ahead of print, 2021 Aug 12]. Mol Psychiatry. 2021;1-2. doi:10.1038/s41380-021-01254-3
Hoertel N. Do the Selective Serotonin Reuptake Inhibitor Antidepressants Fluoxetine and Fluvoxamine Reduce Mortality Among Patients With COVID-19? JAMA Netw Open. 2021;4(11):e2136510. doi:10.1001/jamanetworkopen.2021.36510
Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(22):2292-2300. doi:10.1001/jama.2020.22760
Seftel D, Boulware DR. Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19. Open Forum Infect Dis. 2021 Feb 1;8(2):ofab050. doi: 10.1093/ofid/ofab050. PMID: 33623808; PMCID: PMC7888564.Published in