Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial | Critical Care Medicine | JAMA | JAMA Network
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    9 Comments for this article
    EXPAND ALL
    One More Drug, One More Hope
    Sarosh Ahmed Khan, MBBS; MD; FACP; FRCP Edin | Naseem Medical Center, Baghe Mehtab, Srinagar, Kashmir, India
    After most drugs have failed to show improvement in patients with COVID-19 especially for reducing mortality, now a common drug used in psychiatry has been tried. It only shows our desperation at finding a solution to this pandemic.

    In this study, of the 1337 screened, only 13.53% (181 patients) were included and only 140 (10.47%) completed the study. As the exclusion criteria strictly excluded "real symptomatic patients," we can safely infer that the participants were practically asymptomatic. And most asymptomatic patients improve without any treatment.

    Now we also know that the psychological impact in COVID-19 pandemic
    is enormous. It has caused a parallel epidemic of fear, anxiety, and depression. This issue of mental health disorders was highlighted early in the pandemic. Also the emotional responses brought on by the COVID-19 pandemic, resulting in relapses or worsening of an already existing mental health condition, has also been previously stressed (1). The scare of COVID-19 is high and a drug like fluvoxamine is quite likely to help. A recent study published in The Lancet Psychiatry points towards a bidirectional association between COVID-19 and psychiatric disorders (2). Almost 1 in 5 COVID-19 patients had a diagnosis of anxiety, depression, insomnia etc. and this number was higher than those diagnosed with influenza, kidney stones or even a major bone fracture during this year. The authors even suggest that a diagnosis of mental illness might be an independent risk factor (2).
    The vulnerability to a potential threat especially in patients who suffer from obsessive compulsive disorder is well recognized (3). Fluvoxamine is an established drug used to treat anxiety disorders and OCD.

    Reading too much into the results would be premature and unwise.

    References:
    1. Yao H, Chen J-H, Xu Y-F. Patients with mental health disorders in the COVID-19 epidemic. The Lancet Psychiatry; Correspondence 7(4): E21, APRIL 01, 2020. DOI:https://doi.org/10.1016/S2215-0366(20)30090-0
    2. Taquet M, Luciano S, Geddes JR and Harrison PJ. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. The Lancet Psychiatry; November 09, 2020 DOI:https://doi.org/10.1016/S2215-0366(20)30462-4
    3. Nissen JB, D.R.M.A. Højgaard DRMA and Thomsen PH. The immediate effect of COVID-19 pandemic on children and adolescents with obsessive compulsive disorder. BMC Psychiatry, 20; Article number: 511. 20 October 2020.
    CONFLICT OF INTEREST: None Reported
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    Fluvoxamine's liver metabolism
    Jakub Grabowski, MD, PhD | Department of Developmental Psychiatry, Psychotic and Old Age Disorders, Faculty of Medicine, Medical University of Gdansk, Poland
    Lenze et al describe potential benefits from the use of fluvoxamine in the treatment of COVID-19 infection (1). While certain limitations of the study were pointed out, we feel that the matter of fluvoxamine impact on liver metabolism needs more elaboration.

    As mentioned in the text, fluvoxamine is an inhibitor of CYP450 1A2. What needs underlining is that it is one of the strongest inhibitors identified with a potential to increase serum concentration of other medications up to tenfold (2).

    Naproxen, a non-steroidal anti-inflammatory drug (NSAID) used widely in symptomatic treatment of viral infections is one
    of the medications metabolized by CYP1A2 with its O-demethylation decreased by 38% (R-naproxen) and 28% (S-naproxen) after use of furafylline, a much less potent CYP1A2 inhibitor than fluvoxamine) (3).

    Current evidence suggest naproxen’s potential in management of COVID-19 infection (4) and with its known cytokine regulation mechanism coming in line with this of fluvoxamine’s immunomodulatory activity (5) we definitely need clear information on the possible use of naproxen throughout the study. As there is no data on concomitant medications in Lenze et al's article we may only presume that with its easy accessibility and wide use ($323.6 million sales worth of the OTC formulation in 2019 only), at least some of the patients took naproxen for symptoms of COVID-19 infection simultaneously with fluvoxamine. Therefore, the suggested potential beneficial effect of fluvoxamine may also be a result of increased naproxen serum concentration and could as well be achieved by up-titrating NSAID’s dose. This, of course, requires future studies.

    As for Khan’s comment on the article, we can practically exclude any beneficial effect of fluvoxamine on mental health due to the very short (15 days) exposure to the drug in this study. SSRIs typically start giving effects after 3-6 weeks.

    REFERENCES

    1. 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. Published online November 12, 2020. doi:10.1001/jama.2020.22760
    2. Koponen HJ, Leinonen E, Lepola U. Fluvoxamine increases the clozapine serum levels significantly. Eur Neuropsychopharmacol. 1996;6(1):69-71.
    3. Miners JO, Coulter S, Tukey RH, Veronese ME, Birkett DJ. Cytochromes P450, 1A2, and 2C9 are responsible for the human hepatic O’demethylation of R- and S-naproxen. Biochem Pharmacol. 1996;51(8):1003-1008.
    4. Yousefifard M, Zali A, Zarghi A, Madani Neishaboori A, Hosseini M, Safari S. Non-steroidal anti-inflammatory drugs in management of COVID-19; A systematic review on current evidence. Int J Clin Pract. 2020;74(9).
    5. Sacerdote P, Carrabba M, Galante A, Pisati R, Manfredi B, Panerai AE. Plasma and synovial fluid interleukin-1, interleukin-6 and substance P concentrations in rheumatoid arthritis patients: Effect of the nonsteroidal anti inflammatory drugs indomethacin, diclofenac and naproxen. Inflamm Res. 1995;44(11):486-490.
    CONFLICT OF INTEREST: None Reported
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    Interesting
    Deborah Sharp, BM BCh FRCGP PhD | University of Bristol, UK
    I was fascinated to see this report. I worked in Holland as this drug was entering phase 3 trials and helped with the final studies' analyses and dossier writing. It was rapidly superseded as an antidepressant but really rather pleased to read that it may have another and possibly more useful role going forward. I look forward to seeing some mechanistic studies.
    CONFLICT OF INTEREST: I worked for Duphar BV and brought Fluvoxamine to the market in the UK and Europe in the early 80s
    Fluvoxamine-How does it work ?
    Friedrich Bock, MD | Indepenedent
    In summer 2020 two German study groups reported that fluoxetine (AKA Prozac) might inhibit replication of SARS-CoV-2 (1), perhaps through inhibition of the acid sphingomeyelinase.

    There are also studies which postulate that the application of fluvoxamine resulted in higher levels of melatonin and cortisol (eg 2).

    The authors of this study explain the effect of fluvoxamine with its ability to act as an SIR-agonist.

    If the effect of these substances are not correlated to the SSRI-mechanism could it make sense to combine them ?

    References

    1. Emerg Microbes Infect. 2020 Dec;9(1):2245-2255. doi: 10.1080/22221751.2020.1829082

    2. Clin
    Pharmacol Ther. 2000 Jan;67(1):1-6. doi: 10.1067/mcp.2000.104071.
    CONFLICT OF INTEREST: None Reported
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    Off-Label Multi-threat Medical Countermeasures (MTMC) Drugs
    Fred Cowan, BS Microbiology | Uppsala Inc
    This work has a rational basis and implications not just for COVID-19 but for other inflammatory pathologies with limited treatment options. I previously proposed the use of off-label drugs with secondary anti-inflammatory pharmacology and potential synergy with other multi-threat medical countermeasures (MTMCs)  to treat inflammatory pathology (1).

    List of dozens of such off-label MTMC drugs have been expanded to include some statins, colchicine, metformin and, particularly promising  fluvoxamine as described in this study that has prevented COVID-19- associated pathology.

    These drugs and compounds can be used in synergy and in vitro screening methods to identify such drugs and
    determine their potential synergy are available.

    References

    1. Cowan FM, Broomfield CA, Stojiljkovic MP and Smith WJ. A Review of Multi-Threat Medical Countermeasures Against Chemical Warfare and Terrorism. Military Medicine 169, 850-855, 2004.
    https://www.researchgate.net/publication/8123980_A_Review_of_Multi-Threat_Medical_Countermeasures_against_Chemical_Warfare_and_Terrorism
    2. Patent Filed 
    3. Patent
    CONFLICT OF INTEREST: Filed patent on related technology. Published PCT patent application: COMPOSITIONS AND METHODS FOR PREVENTION AND TREATMENT OF IMMUNE COMPLEX DISEASE This application claims benefit of U.S. Serial No. 62/656,084 filed April 11, 2018 https://patentscope.wipo.int/search/docs2/pct/WO2019199918/pdf/IWF_AUv6tYHBZWclQhjLQa-VLGZtg50aP1UGa23muYniJnUYDIf9Wft0sBiQuT_XMOh9R_ZdJpFcQwI-rg8A18pOfACZdnwbXbS_2kdAkNjvK_hYgJGmwFs5YLm2K7if?docId=id00000050813524 PCT application abandon, US application filed. in press
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    Interesting study With an Unlikely Conclusion
    Moutasim Al-Shaer, MD, FACP | Saint Francis Hospital
    In this study, the authors relied exclusively on subjective patient reported data to determine the outcomes. One can only conclude that subjective symptoms of worsening were less reported in patient taking a medication that is indicated to treat anxiety. Furthermore, the dosing pattern of intervention was similar to its use in treating social anxiety.

    I believe that this preliminary study should be interpreted as 'fluvoxamine lessens anxiety and improves psychological well being in patients suffering this disease associated with significant anxie,' rather than assuming that the medication has a direct biochemical effect on the severity of the illness. In
    this study I think fluvoxamine likely treated the anxiety component associated with the disease rather than modified the body immune response to the disease

    Coronavirus disease 2019 (SARS-CoV-2) infection is an infection associated with significant psychological stress on those affected and the treating team. Personally, I have seen many patients experiencing significant symptoms even after recovery from the disease that can only be interpreted after extensive workup as psychological in nature rather than organic.

    I believe that one common poorly recognized complication of (SARS-CoV-2) infection is posttraumatic stress disorder ( PTSD).
    CONFLICT OF INTEREST: None Reported
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    Author Response: Fluvoxamine's Liver Metabolism
    Angela Reiersen, MD, MPE | Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO
    Dr. Jakub Grabowski’s comment suggests that fluvoxamine’s drug interaction with naproxen could have had a beneficial effect by increasing the level of this NSAID. Five study participants took naproxen during the clinical trial (three in the fluvoxamine group, two in the placebo group). Another stopped naproxen due to having COVID-19. None of these individuals had adverse events or experienced clinical deterioration as defined by the study. With so few participants taking naproxen, it seems very unlikely that this had much if any effect on the study results. However, it is still important to consider drug interactions as possible contributors to fluvoxamine’s apparent benefit in COVID-19. For example, fluvoxamine increases melatonin levels through inhibition of CYP1A2, whether the melatonin is endogenously produced or taken as a supplement (1). The SARS-CoV-2 virus may activate the NLRP3 inflammasome (2), which may contribute to cytokine storm (3). Melatonin may reduce inflammation through its inhibition of the NLRP3 pathway (4,5).

    References

    1. Härtter S, Wang X, Weigmann H, Friedberg T, Arand M, Oesch F, Hiemke C. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. J Clin Psychopharmacol. 2001 Apr;21(2):167-74.

    2. van den Berg DF, Te Velde AA. Severe COVID-19: NLRP3 Inflammasome Dysregulated. Front Immunol. 2020 Jun 26;11:1580.

    3. Ratajczak MZ, Kucia M. SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells. Leukemia. 2020 Jul;34(7):1726-1729.

    4. García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, Acuña-Castroviejo D. Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J. 2015 Sep;29(9):3863-75.

    5. Volt H, García JA, Doerrier C, Díaz-Casado ME, Guerra-Librero A, López LC, Escames G, Tresguerres JA, Acuña-Castroviejo D. Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. J Pineal Res. 2016 Mar;60(2):193-205.
    CONFLICT OF INTEREST: None Reported
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    A Missing Link in the COVID-19 and Fluvoxamine Story
    Lanfranco Ranieri Paolo Troncone, PhD | Instituto Butantan - São Paulo - Brazil
    This comment is intended to bring to the knowledge of the authors a possible missing link in the rationale for the effectiveness of fluvoxamine against COVID-19. The interaction of this antidepressant with Sigma-1 receptors is quite important as it modulates IRE-1 and the cytokine storm cascade, as reported by Rosen and colleagues (cited by the authors). What went overlooked is that one of the proteins encoded by the SARS-COV-2 virus also interacts with Sigma-1 receptors and is called NSP-6. I presented a brief letter on this argument (1). This document was offered to JAMA and several other journals without success in May and June. It is also interesting to note that the antidepressant effects of Fluvoxamine are of late onset and therefore it should not be confused with reported feelings of improvement that could confuse the interpretation of the data in this interesting clinical trial.

    Congratulations.

    Reference
    1. Lanfranco R. Troncone. COVID-19, cytokine storm and sigma-1 receptors: potential treatments at hand?. Authorea. July 23, 2020. DOI: 10.22541/au.159335613.31156244/v2
    CONFLICT OF INTEREST: None Reported
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    Melatonin and Fluvoxamine
    Harold Pupko, M.D. | Private Practice
    Fluvoxamine is being touted as a drug with potential to be repurposed for treating COVID. Its mechanism of action may include the fact that it can increase melatonin levels (1).

    My Medical Society in December hosted an international symposium on the use of melatonin to treat COVID (2), which addressed theoretical possibilities raised last year by researchers that melatonin may have a role in treating COVID (3, 4).

    References

    1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779245/
    2. https://www.youtube.com/watch?v=p_4JeOj1JLc 
    3. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000970
    4. https://www.sciencedirect.com/science/article/abs/pii/S0024320520303313?via%3Dihub
    CONFLICT OF INTEREST: None Reported
    Preliminary Communication
    November 12, 2020

    Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of Psychiatry, School of Medicine, Washington University in St Louis, St Louis, Missouri
    • 2Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, Washington University in St Louis, St Louis, Missouri
    • 3Division of Biostatistics, Informatics Institute, School of Medicine, Washington University in St Louis, St Louis, Missouri
    • 4Department of Anesthesiology, School of Medicine, Washington University in St Louis, St Louis, Missouri
    JAMA. 2020;324(22):2292-2300. doi:10.1001/jama.2020.22760
    Key Points

    Question  Does fluvoxamine, a selective serotonin reuptake inhibitor and σ-1 receptor agonist, prevent clinical deterioration in outpatients with acute coronavirus disease 2019 (COVID-19)?

    Findings  In this randomized trial that included 152 adult outpatients with confirmed COVID-19 and symptom onset within 7 days, clinical deterioration occurred in 0 patients treated with fluvoxamine vs 6 (8.3%) patients treated with placebo over 15 days, a difference that was statistically significant.

    Meaning  In this preliminary study, adult outpatients with symptomatic COVID-19 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days; however, determination of clinical efficacy would require larger randomized trials with more definitive outcome measures.

    Abstract

    Importance  Coronavirus disease 2019 (COVID-19) may lead to serious illness as a result of an excessive immune response. Fluvoxamine may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production.

    Objective  To determine whether fluvoxamine, given during mild COVID-19 illness, prevents clinical deterioration and decreases the severity of disease.

    Design, Setting, and Participants  Double-blind, randomized, fully remote (contactless) clinical trial of fluvoxamine vs placebo. Participants were community-living, nonhospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 infection, with COVID-19 symptom onset within 7 days and oxygen saturation of 92% or greater. One hundred fifty-two participants were enrolled from the St Louis metropolitan area (Missouri and Illinois) from April 10, 2020, to August 5, 2020. The final date of follow-up was September 19, 2020.

    Interventions  Participants were randomly assigned to receive 100 mg of fluvoxamine (n = 80) or placebo (n = 72) 3 times daily for 15 days.

    Main Outcomes and Measures  The primary outcome was clinical deterioration within 15 days of randomization defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater.

    Results  Of 152 patients who were randomized (mean [SD] age, 46 [13] years; 109 [72%] women), 115 (76%) completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (absolute difference, 8.7% [95% CI, 1.8%-16.4%] from survival analysis; log-rank P = .009). The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events.

    Conclusions and Relevance  In this preliminary study of adult outpatients with symptomatic COVID-19, patients treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. However, the study is limited by a small sample size and short follow-up duration, and determination of clinical efficacy would require larger randomized trials with more definitive outcome measures.

    Trial Registration  ClinicalTrials.gov Identifier: NCT04342663

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