Article by Christine Clark.
Evidence from trials and real world experience shows that selective serotonin reuptake inhibitors (SSRIs) are effective in treating acute covid and preventing long-haul covid.
Experts agree that repurposing of existing drugs should be the quickest way to find effective treatments. Repurposing of drugs that are already approved for other indications should, theoretically, overcome some regulatory hurdles. Moreover, safety and tolerability are well known for existing drugs and so all that is needed is trials to show the size of positive effect. Many potential candidates for repurposing have been identified – and one of these is fluvoxamine.
A practical problem with the repurposing approach is that attention was originally focused on the late effects of covid-19 – patients who were seriously ill with hypoxaemia and multi-organ failure. What was needed was effective early treatment to prevent serious illness and the need for hospitalisation. There is still a need for effective early treatment to shorten the course of the disease and to minimise the numbers of people who require hospital treatment – and this is the stage at which fluvoxamine can be most useful.
Fluvoxamine is an inexpensive drug that has been in use for 37 years and has been used by an estimated 10 million people. It is currently approved for treatment of depression and obsessive compulsive disorder (OCD).
The story started in 2019 with the observation that fluvoxamine works in sepsis where it reduces damaging aspects of the inflammatory response through the Sigma-1 receptor – inositol requiring enzyme (S1R-IRE1) pathway. Fluvoxamine decreased shock in murine sepsis models. The S1R-IRE1 pathway is involved in cytokine production and S1R controls the production of inflammatory cytokines by inhibiting IRE1.1
Fluvoxamine has a number of actions that could be helpful in covid-19.2
- Selective serotonin reuptake inhibitor (SSRI) – reduces reuptake of serotonin by platelets. Release of serotonin from platelets is implicated in the acute respiratory distress syndrome of covid-19
- Reduced histamine release from mast cells
- Interference with lysosomal trafficking of virus –effectively preventing release of virus particles from lysosomes
- Interference with lysosomal membrane binding of acid sphingomyelinase (ASM)
- Sigma-1 receptor agonism and effects of IRE1-mediated inflammation – reducing inflammatory cytokines
- Increased melatonin levels
In early 2020, when it was realised that the rapid deterioration seen in some covid-19 patients was associated with a cytokine storm, researchers asked the question, ‘Could fluvoxamine, a selective serotonin reuptake inhibitor and sigma-1 receptor agonist, prevent clinical deterioration in outpatients with acute coronavirus disease 2019 (covid-19)?’. Prevention of platelet uptake of serotonin and sigma-1 receptor agonism were thought likely to be the most important mechanisms of action in covid-19. A trial was funded by the Covid-19 Early Treatment Fund (CETF) to answer the question.
Outpatients with confirmed, mild covid-19 were randomly assigned to receive either fluvoxamine 100mg three times a day or placebo for 15 days.3 The results showed that clinical deterioration leading to hospitalisation 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 = 0.009). At the time the results were largely dismissed because they came from a “small study”. Arguably, the study had, in fact, answered the question very clearly.
Real world evidence
Real world evidence is provided by a study in the US in which people who were diagnosed with covid-19 were offered fluvoxamine or ‘no treatment’. (The US has similar policy to the UK – no active treatment is offered until patients become severely ill). Initially, only about one third of patients opted for fluvoxamine but later as they saw the effects in their friends and colleagues many decided to switch. There were more patients with comorbidities (notably – more diabetes) in the fluvoxamine group – more healthy people opted for ‘no treatment’. There were no hospitalisations and no long-hauler symptoms in the fluvoxamine group, despite the higher frequency of comorbidities. In the ‘no treatment’ group 12.5% were hospitalised, one died, 60% had long-haul symptoms after two weeks and 29% had more than four symptoms. Although not a double-blind, randomised trial, the results are important because the differences were so stark. Moreover, it is difficult to see how they could have occurred by chance or through bias.
The results from these two trials are corroborated by findings in psychiatric hospitals. Following early observations that staff were experiencing a higher prevalence of symptomatic and severe covid-19 than the patients, a large study was undertaken in France. The records of more than 7000 adults hospitalised for covid-19 were examined.4 Of these, 345 patients received an antidepressant within 48 hours of admission. The results showed a significant association between antidepressant use and reduced risk of intubation or death (Hazard ratio, 0.56; 95% CI, 0.43–0.73, p < 0.001). The authors were cautious in their interpretation and called for double-blind randomised controlled trials of antidepressants in covid-19.
Two other pieces of evidence also help to confirm the picture:
A retrospective cohort study was conducted in Germany to investigate the impact of concomitant long-term medication—with a focus on ACE inhibitors and oral anticoagulation—on clinical outcomes in patients hospitalized with coronavirus disease 2019. In total 6637 patients in 853 German hospitals were included and multivariable logistic regression model was used to identify independent predictors for mortality or need for ventilation. What stood out clearly was that four factors were actually protective (reduced risk) – Vitamin K antagonists, DOACs (direct-acting oral anticoagulants), female gender and depression. The authors noted that antidepressants had been suggested as potential therapy to prevent neurologic complications of covid and that a trial had been started to investigate fluoxetine in this setting (NCT04377308).6
Another interesting finding is that researchers reviewing medical billing data for nearly 740,000 COVID-19 patients in the US showed patients on antipsychotic drugs targeting S1R were half as likely as those on other types of antipsychotic drugs to require mechanical ventilation.7
Finally, there is real world evidence from the experience of doctors who have used fluvoxamine in the treatment protocols. In a recent interview for medical Update Online, Steve Kirsch reported that doctors commonly say (of fluvoxamine), “This is the most powerful drug in my arsenal. I will never, ever give up this drug – it is unethical”.
Where do we go from here?
A phase 3 RCT (Stop Covid 2 – NCT04668950 ) in the US has recently been halted and further information is expected soon.
A question that is often raised is, “how long can we afford to wait for phase 3 trial results when the evidence already available suggests powerful, life-saving effects?” Moreover, in the case of fluvoxamine, the drug appears to exert a pronounced effect on long-haul covid – a condition estimated to affect at least 10% of those who have had covid-19.
Another argument that is often advanced is that if a drug does no harm and the alternative is ‘no treatment’, then the only ethically justifiable option is to offer the drug.
Many doctors decline to prescribe drugs that are not covered by official guidelines and so would not prescribe fluvoxamine for covid-19. It is perhaps fortunate that those patients who have become severely depressed as a result of interminable lockdowns, loss of livelihood and loneliness might actually find that they have been prescribed a drug that affords them very good protection against covid-19.
Increasingly academics, philanthropists and concerned observers are beginning to argue that there is no time for large phase 3 trials during a pandemic because while such trials proceed people continue to suffer and die. Deciding not to act also has a cost. There is a need to evaluate the available evidence for promising interventions, such as fluvoxamine, and look for the options that reduce deaths and the need for hospitalisation – this is the rational, ethical approach
- Rosen D et al. Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Science Translational Medicine 2019:11: eaau5266. DOI: 10.1126/scitranslmed.aau5266
- Sukhatme VP, Reiersen AM, Vayttaden SJ and Sukhatme VV Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19. Front. Pharmacol. 2021;12:652688. doi: 10.3389/fphar.2021.652688
- Lenze E J et al Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial JAMA. 2020;324:2292-2300. doi:10.1001/jama.2020.22760. Published online November 12, 2020.
- Seftel S & Boulware DR. Prospective cohort of fluvoxamine for early treatment of COVID-19. Open Forum Infect Dis 2021;8: ofab050. doi:10.1093/ ofid/ofab050
- Hoertel N et al. Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study. Molecular Psychiatry. 2021 https://doi.org/10.1038/s41380-021-01021
- Frohlich GM et al. Impact of oral anticoagulation on clinical outcomes of COVID-19: a nationwide cohort study of hospitalized patients in Germany. Clin Res Cardiol (2021). https://doi.org/10.1007/s00392-020-01783-x
- Gordon DE et al. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. J Science 2020 370 (6521), eabe9403. doi:10.1126/science.abe9403-