Emerging evidence suggests that selective serotonin reuptake inhibitors (SSRIs) are remarkably effective in treating acute COVID and preventing long-haul COVID; depressed and anxious patients could be well protected
Early on during the coronavirus pandemic, there was much talk of how repurposing of existing drugs would 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. In early 2020, researchers quickly set about identifying potential candidates for repurposing – antivirals seemed obvious but as more aspects of the behaviour of the virus emerged, the list widened to include less obvious agents. Ivermectin was quickly established as an effective treatment for COVID-19, supported by numerous trials and several systematic reviews.
It still remains largely ignored in the West and, incomprehensibly, is dismissed and even briefed-against by influential health organisations.
A practical problem with the repurposing approach was that attention was predominantly 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. As our understanding of the virus grows, new treatment options are beginning to emerge
One of the drugs that has emerged is fluvoxamine – a drug that has been shown to be remarkably effective in treating early COVID-19 and in preventing COVID long-haul effects. Fluvoxamine is an inexpensive drug that has been in use for 37 years and has been used by an estimated 10 million people. This article describes the evidence that supports fluvoxamine.
This story starts way back in 2019 with the observation that fluvoxamine worked in sepsis to reduce damaging aspects of the inflammatory response during sepsis through the S1R-IRE1 pathway, and decreased shock in murine sepsis models.
Fluvoxamine has a number of actions that could be helpful in COVID-19. It is a selective serotonin reuptake inhibitor and reduces reuptake of serotonin by platelets. Release of serotonin from platelets is implicated in the acute respiratory distress syndrome of COVID-19. However, fluvoxamine also has a number of other actions that could contribute to reduced inflammatory effects; they are1:
- 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
- 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 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 started at the University of Washington in which outpatients with confirmed, mild COVID-19 were randomly assigned to receive either fluvoxamine 100mg three-times a day or placebo for 15 days.2 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.
Perhaps the most telling evidence comes from a real-world study in the US.3 In this study people who were diagnosed with COVID-19 were offered fluvoxamine or ‘no treatment’. (The US has a similar policy to the UK; that is, 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 neighbours, more decided to switch. It is noteworthy that there were no hospitalisations and no long-hauler symptoms in the fluvoxamine group, although the fluvoxamine group contained more people with comorbidities (notably, more diabetes). 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 systematic bias.
The findings 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. 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.
A Phase III RCT (Stop Covid 2) is now underway in the US and plans to recruit 880 patients.5
Where do we go from here?
A question that is often raised is, “how long can we afford to wait for Phase
III 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 offer fluvoxamine for COVID-19. It is perhaps fortunate that those patients who have become severely depressed because of interminable lockdowns, loss of livelihood and loneliness, might 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 III 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 – that is, adopt the rational, ethical approach.
References
- Sukhatme VP et al. Fluvoxamine: A review of its mechanism of action and its role in COVID-19. Front Pharmacol 2021;12:652688.
- Lenze E J et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial. JAMA 2020;324:2292–300.
- Seftel S, Boulware DR. Prospective cohort of fluvoxamine for early treatment of COVID-19. Open Forum Infect Dis 2021;8.
- 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. Mol Psychiatry 2021. https://doi.org/10.1038/s41380-021-01021-.
- https://clinicaltrials.gov/ct2/show/NCT04668950 (accessed May 2021).
