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PrEPPEP |
Oskotsky et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.33090 (Peer Reviewed) |
death, ↑57.9%, p=0.62 |
Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants |
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Retrospective database analysis of 83,584 patients in the USA, showing lower mortality with existing fluoxetine use in PSM analysis. There were 11 fluvoxamine patients, showing non-statistically significant higher mortality. |
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Prophylaxis study
Prophylaxis study
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| Oskotsky et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.33090 (Peer Reviewed) |
| Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants |
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Retrospective database analysis of 83,584 patients in the USA, showing lower mortality with existing fluoxetine use in PSM analysis. There were 11 fluvoxamine patients, showing non-statistically significant higher mortality.
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risk of death, 57.9% higher, RR 1.58, p = 0.62, treatment 2 of 11 (18.2%), control 19 of 165 (11.5%), fluvoxamine.
risk of death, 26.0% lower, RR 0.74, p = 0.04, treatment 48 of 481 (10.0%), control 956 of 7,215 (13.3%), fluoxetine.
Oskotsky et al., 11/15/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 8 authors.
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Late |
Calusic et al., British Journal of Clinical Pharmacology, doi:10.1111/bcp.15126 (Peer Reviewed) |
death, ↓42.0%, p=0.03 |
Safety and efficacy of fluvoxamine in COVID-19 ICU patients: an open label, prospective cohort trial with matched controls |
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Prospective PSM study of 51 COVID-19 ICU patients in Croatia and 51 matched controls, showing significantly lower mortality with treatment. |
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Late treatment study
Late treatment study
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| Calusic et al., British Journal of Clinical Pharmacology, doi:10.1111/bcp.15126 (Peer Reviewed) |
| Safety and efficacy of fluvoxamine in COVID-19 ICU patients: an open label, prospective cohort trial with matched controls |
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Prospective PSM study of 51 COVID-19 ICU patients in Croatia and 51 matched controls, showing significantly lower mortality with treatment.
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risk of death, 42.0% lower, RR 0.58, p = 0.03, treatment 30 of 51 (58.8%), control 39 of 51 (76.5%), adjusted, propensity score matching.
Calusic et al., 11/1/2021, prospective, propensity score matching, Croatia, Europe, peer-reviewed, 7 authors.
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PrEPPEP |
Rauchman et al., medRxiv, doi:10.1101/2021.10.25.21265218 (Preprint) |
death, ↓2.0%, p=0.83 |
Ongoing use of SSRIs and the hospital course of COVID-19 patients: a retrospective outcome analysis |
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Retrospective 9,043 COVID-19+ patients in the USA, 832 with existing SSRI use, showing no significant difference in mortality. None of the patients were on fluvoxamine. Authors note that specific SSRIs such as fluvoxamine may be effective.. |
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Prophylaxis study
Prophylaxis study
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| Rauchman et al., medRxiv, doi:10.1101/2021.10.25.21265218 (Preprint) |
| Ongoing use of SSRIs and the hospital course of COVID-19 patients: a retrospective outcome analysis |
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Retrospective 9,043 COVID-19+ patients in the USA, 832 with existing SSRI use, showing no significant difference in mortality. None of the patients were on fluvoxamine. Authors note that specific SSRIs such as fluvoxamine may be effective, and that fluvoxamine is a sigma-1 receptor (S1R) agonist and has the strongest binding affinity to S1R of all SSRIs.
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risk of death, 2.0% lower, RR 0.98, p = 0.83, RR approximated with OR.
Rauchman et al., 10/26/2021, retrospective, USA, North America, preprint, 6 authors.
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Review |
Hashimoto et al., European Archives of Psychiatry and Clinical Neuroscience, doi:10.1007/s00406-021-01326-z (Review) (Peer Reviewed) |
review |
Old drug fluvoxamine, new hope for COVID-19
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Review of research supporting the use of fluvoxamine for COVID-19. Authors note the favorable safety profiles, widespread availability, very low cost, and oral administration. |
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Review
Review
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| Hashimoto et al., European Archives of Psychiatry and Clinical Neuroscience, doi:10.1007/s00406-021-01326-z (Review) (Peer Reviewed) |
| Old drug fluvoxamine, new hope for COVID-19
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Review of research supporting the use of fluvoxamine for COVID-19. Authors note the favorable safety profiles, widespread availability, very low cost, and oral administration.
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Hashimoto et al., 9/2/2021, peer-reviewed, 3 authors.
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Late |
Reis et al., The Lancet Global Health, doi:10.1016/S2214-109X(21)00448-4 (preprint 8/23/2021) (Peer Reviewed) |
death, ↓30.3%, p=0.24 |
Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial |
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Together Trial showing significantly lower hospitalization/extended ER visits with fluvoxamine treatment. Adherence was only 73.2%. Symptom onset was unspecified or >= 4 days for 57% of patients. The schedule of study activities specifies.. |
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Late treatment study
Late treatment study
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| Reis et al., The Lancet Global Health, doi:10.1016/S2214-109X(21)00448-4 (preprint 8/23/2021) (Peer Reviewed) |
| Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial |
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Together Trial showing significantly lower hospitalization/extended ER visits with fluvoxamine treatment. Adherence was only 73.2%. Symptom onset was unspecified or >= 4 days for 57% of patients. The schedule of study activities specifies treatment administration only one day after randomization, adding an additional day delay. Overall mortality is high for the patient population. Results may be impacted by late treatment, poor SOC, and may be specific to local variants [1, 2]. Per-protocol analysis shows significantly improved results in this trial. Authors note that ITT analysis provides more real-world evidence, however RCTs do not provide real-world evidence. For a drug like fluvoxamine, which is widely available, and a condition like COVID-19, which has a significant risk of death and must be treated immediately for best results, RCTs are biased toward participants that do not need help to recover, or do not believe that the drug will help. (Because patients can decline participation and take the drug). Notably, the remaining patients that choose to participate are less likely to believe adherence is important. In real-world use, including patients that decline RCT participation, and with patients informed of the benefit, adherence is likely to be much better. Note that per-protocol analysis could affect randomization.The primary outcome changed in the March 21 clinicaltrials.gov update (observation >12hrs changed to >6hrs). This is not explained or mentioned in the paper.Authors state "this study is only the second study to show an important treatment benefit for a repurposed drug in the early treatment population", however the actual number is at least 66 based on our database at the time of publication, using a conservative definition of at least 10% benefit (with statistical significance).The total dose used is less than half of that in Lenze et al. There is an unusual amount of missing data - age is unknown for 6.5% of patients according to the sub-group analysis. Both age <=50 and >50 show better results on the primary outcome than the overall result. The number of placebo patients changed significantly between the preprint and journal version. The number of treatment patients with viral clearance results reduced significantly between the preprint and journal version. Also see [3]. NCT04727424.For other issues with this trial see: [4, 5].
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risk of death, 30.3% lower, RR 0.70, p = 0.24, treatment 17 of 741 (2.3%), control 25 of 756 (3.3%), OR converted to RR, ITT.
risk of death, 90.8% lower, RR 0.09, p = 0.02, treatment 1 of 548 (0.2%), control 12 of 618 (1.9%), OR converted to RR, per protocol.
risk of mechanical ventilation, 22.2% lower, RR 0.78, p = 0.33, treatment 26 of 741 (3.5%), control 34 of 756 (4.5%), OR converted to RR, ITT.
risk of hospitalization, 21.6% lower, RR 0.78, p = 0.10, treatment 75 of 741 (10.1%), control 97 of 756 (12.8%), OR converted to RR, ITT.
extended ER observation or hospitalization, 66.0% lower, RR 0.34, p < 0.001, treatment 541, control 609, per protocol.
extended ER observation or hospitalization, 32.0% lower, RR 0.68, p = 0.004, treatment 79 of 741 (10.7%), control 119 of 756 (15.7%), ITT.
extended ER observation or hospitalization, 31.0% lower, RR 0.69, p = 0.006, treatment 78 of 740 (10.5%), control 115 of 752 (15.3%), mITT.
risk of no virological cure, 49.3% higher, RR 1.49, p = 0.09, treatment 167 of 207 (80.7%), control 163 of 221 (73.8%), adjusted.
Reis et al., 8/23/2021, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 27 authors.
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Late |
Németh et al., SSRN, doi:10.2139/ssrn.3896539 (Preprint) |
death, ↓67.0%, p=0.003 |
Fluoxetine May Improve Survival of Patients with COVID-19 Pneumonia: A Retrospective Case-Control Study |
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Retrospective 269 hospitalized patients in Hungary, 110 treated with fluoxetine, showing lower mortality with treatment. |
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Late treatment study
Late treatment study
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| Németh et al., SSRN, doi:10.2139/ssrn.3896539 (Preprint) |
| Fluoxetine May Improve Survival of Patients with COVID-19 Pneumonia: A Retrospective Case-Control Study |
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Retrospective 269 hospitalized patients in Hungary, 110 treated with fluoxetine, showing lower mortality with treatment.
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risk of death, 67.0% lower, RR 0.33, p = 0.003, treatment 15 of 110 (13.6%), control 49 of 159 (30.8%), adjusted, OR converted to RR, multivariable logistic regression.
Németh et al., 8/12/2021, retrospective, Hungary, Europe, preprint, 6 authors.
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Review |
Hoertel et al., Molecular Psychiatry, doi:10.1038/s41380-021-01254-3 (Review) (Peer Reviewed) |
review |
Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms |
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Review of the mechanisms of action and clinical studies for the treatment of COVID-19 with FIASMA antidepressants such as fluoxetine, fluvoxamine, paroxetine, escitalopram, or amitriptyline. |
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Review
Review
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| Hoertel et al., Molecular Psychiatry, doi:10.1038/s41380-021-01254-3 (Review) (Peer Reviewed) |
| Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms |
Review of the mechanisms of action and clinical studies for the treatment of COVID-19 with FIASMA antidepressants such as fluoxetine, fluvoxamine, paroxetine, escitalopram, or amitriptyline.
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Hoertel et al., 8/12/2021, peer-reviewed, 12 authors.
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PrEPPEP |
Assanovich et al., Psychiatry, Psychotherapy and Clinical Psychology, doi:10.34883/PI.2021.12.2.007 (Peer Reviewed) |
Fluvoxamine in the Treatment of Patients with COVID-19 |
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Report on the use of fluvoxamine for COVID-19 noting that "patients with COVID-19 taking fluvoxamine did not report clinical complications of coronavirus infection". Only the abstract is currently available. |
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Prophylaxis study
Prophylaxis study
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| Assanovich et al., Psychiatry, Psychotherapy and Clinical Psychology, doi:10.34883/PI.2021.12.2.007 (Peer Reviewed) |
| Fluvoxamine in the Treatment of Patients with COVID-19 |
Report on the use of fluvoxamine for COVID-19 noting that "patients with COVID-19 taking fluvoxamine did not report clinical complications of coronavirus infection". Only the abstract is currently available.
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Assanovich et al., 6/29/2021, peer-reviewed, 1 author.
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Review |
Sukhatme et al., Front. Pharmacol., doi:10.3389/fphar.2021.652688 (Review) (Peer Reviewed) |
review |
Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19 |
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Review of mechanisms of action of fluvoxamine and other SSRIs that could be beneficial for COVID-19 treatment, including lower platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking, reg.. |
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Review
Review
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| Sukhatme et al., Front. Pharmacol., doi:10.3389/fphar.2021.652688 (Review) (Peer Reviewed) |
| Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19 |
Review of mechanisms of action of fluvoxamine and other SSRIs that could be beneficial for COVID-19 treatment, including lower platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking, regulation of inositol-requiring enzyme 1α-driven inflammation, and increased melatonin levels.
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Sukhatme et al., 4/20/2021, peer-reviewed, 4 authors.
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Review |
Kirsch, S. (Review) (Preprint) |
review |
COVID FAQ |
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COVID FAQ from the founder of the COVID-19 Early Treatment Fund [1], including an extensive analysis of the fluvoxamine trials and other supporting evidence. |
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Review
Review
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| Kirsch, S. (Review) (Preprint) |
| COVID FAQ |
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COVID FAQ from the founder of the COVID-19 Early Treatment Fund [1], including an extensive analysis of the fluvoxamine trials and other supporting evidence.
Kirsch et al., 3/6/2021, preprint, 1 author.
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PrEPPEP |
Darquennes et al., Pharmaceuticals, doi:10.3390/ph14030226 (Peer Reviewed) |
death, ↓41.3%, p=0.06 |
Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study |
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Retrospective 350 COVID-19 hospitalized patients in Belgium, showing lower mortality with existing long-term FIASMA treatment, not quite reaching statistical significance for all FIASMA medications, but reaching statistical significance f.. |
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Prophylaxis study
Prophylaxis study
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| Darquennes et al., Pharmaceuticals, doi:10.3390/ph14030226 (Peer Reviewed) |
| Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study |
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Retrospective 350 COVID-19 hospitalized patients in Belgium, showing lower mortality with existing long-term FIASMA treatment, not quite reaching statistical significance for all FIASMA medications, but reaching statistical significance for amlodipine.
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risk of death, 41.3% lower, RR 0.59, p = 0.06, treatment 93, control 257, OR converted to RR, multivariable logistic regression, control prevalance approximated with overall prevalence.
Darquennes et al., 3/7/2021, retrospective, Belgium, Europe, peer-reviewed, 4 authors.
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Early |
Seftel et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab050 (Peer Reviewed) |
death/ICU, ↓83.9%, p=0.15 |
Prospective cohort of fluvoxamine for early treatment of COVID-19 |
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Details
Prospective quasi-randomized (patient choice) study with 125 outpatients, 77 treated with fluvoxamine, showing lower death/ICU admission (0 of 77 vs. 2 of 48), lower hospitalization (0 of 77 vs. 6 of 48), and faster recovery with treatmen.. |
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Early treatment study
Early treatment study
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| Seftel et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab050 (Peer Reviewed) |
| Prospective cohort of fluvoxamine for early treatment of COVID-19 |
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Prospective quasi-randomized (patient choice) study with 125 outpatients, 77 treated with fluvoxamine, showing lower death/ICU admission (0 of 77 vs. 2 of 48), lower hospitalization (0 of 77 vs. 6 of 48), and faster recovery with treatment. Note that 12 treatment patients were added but are not reflected in the table in the paper (because the numbers had been previously published and the IRB did not allow updating the table).
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risk of death/ICU, 83.9% lower, RR 0.16, p = 0.15, treatment 0 of 77 (0.0%), control 2 of 48 (4.2%), relative risk is not 0 because of continuity correction due to zero events.
risk of hospitalization, 94.0% lower, RR 0.06, p = 0.003, treatment 0 of 77 (0.0%), control 6 of 48 (12.5%), relative risk is not 0 because of continuity correction due to zero events.
risk of no recovery, 98.7% lower, RR 0.01, p < 0.001, treatment 0 of 77 (0.0%), control 29 of 48 (60.4%), relative risk is not 0 because of continuity correction due to zero events.
Seftel et al., 2/1/2021, prospective quasi-randomized (patient choice), USA, North America, peer-reviewed, 2 authors.
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Early |
Lenze et al., JAMA, doi:10.1001/jama.2020.22760 (Peer Reviewed) |
progression, ↓92.7%, p=0.009 |
Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial |
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RCT 152 outpatients, 80 treated with fluvoxamine showing lower progression with treatment (0 of 80 versus 6 of 72 control). |
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Early treatment study
Early treatment study
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| Lenze et al., JAMA, doi:10.1001/jama.2020.22760 (Peer Reviewed) |
| Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial |
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RCT 152 outpatients, 80 treated with fluvoxamine showing lower progression with treatment (0 of 80 versus 6 of 72 control).
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risk of disease progression, 92.7% lower, RR 0.07, p = 0.009, treatment 0 of 80 (0.0%), control 6 of 72 (8.3%), relative risk is not 0 because of continuity correction due to zero events, clinical deterioration over 15 days.
risk of hospitalization, 82.0% lower, RR 0.18, p = 0.009, treatment 1 of 80 (1.2%), control 5 of 72 (6.9%), COVID-19 hospitalization within 15 days, see supplemental appendix for details.
Lenze et al., 11/12/2020, Double Blind Randomized Controlled Trial, USA, North America, peer-reviewed, 11 authors.
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Late |
Hoertel et al., Molecular Psychiatry, doi:10.1038/s41380-021-01021-4 (Peer Reviewed) |
Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study |
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Retrospective 7,230 hospitalized COVID-19 patients in France, 345 receiving an antidepressant medication within 48 hours of admission. There was a significant association between antidepressant use and reduced risk of intubation or death .. |
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Late treatment study
Late treatment study
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| Hoertel et al., Molecular Psychiatry, doi:10.1038/s41380-021-01021-4 (Peer Reviewed) |
| Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study |
Retrospective 7,230 hospitalized COVID-19 patients in France, 345 receiving an antidepressant medication within 48 hours of admission. There was a significant association between antidepressant use and reduced risk of intubation or death (HR 0.56, p < 0.001). Fluvoxamine is not included because there was only one person taking it in this study.
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Hoertel et al., 8/17/2020, peer-reviewed, 17 authors.
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