Pharmacotherapy Options for COVID-19: Does Fluvoxamine Have a Place in Therapy?

Availability of COVID-19 vaccinations has been an issue for many regions of the world effected by the pandemic.¹ Barriers to access and concerns over the vaccination continue to enable the development of viral mutations, whereas overall rates of vaccination have continued to stall.¹ The need for safe and effective treatment against the various strains of COVID-19 increase, and investigators continue to assess various pharmacologic options. Antivirals and immunologic therapies that had shown efficacy in trials have continued to diminish in efficacy as mutations emerge.² Other pharmacologic options studied have failed to show any clinical benefit for patients.³ Finding medications that have clinical efficacy continues to be of the highest importance.

Reis and colleagues evaluated the clinical efficacy of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) and a σ-1 receptor agonist, at reducing the progression of COVID-19 to hospitalization.^4,5 The appeal of medications in these classes include the widespread availability and affordability of these agents, alongside the well-documented safety profile.⁴ It is hypothesized that fluvoxamine could prove efficacious because of its anti-inflammatory and possible antiviral effects.^4,5 A smaller, randomized, placebo-controlled trial found that higher-dosed fluvoxamine reduced hospitalizations and requirements in supplemental oxygen among mildly symptomatic, outpatient adults.⁶

The TOGETHER trial (NCT04727424) evaluated several repurposed pharmacologic therapies against COVID-19 in a multiarm, 1-to-1, placebo-controlled, double-blinded, randomized clinical trial among 11 sites in Brazil. Patients met criteria for inclusion if they were older than 18 years of age, had a positive SARS-CoV-2 diagnostic test at screening or within the previous 7 days, and had presented to an outpatient care clinic for COVID-19 symptoms, beginning within the previous 7 days. Patients were required to be unvaccinated and have a high-risk condition, including diabetes, hypertension requiring medication, cardiovascular disease, certain respiratory conditions (including asthma and smoking), a body mass index greater than 30 kg/m2, stage 4 or 5 chronic kidney disease, immunosuppression, or current or recent cancer. Patients were excluded if they required hospitalization for COVID-19, had an illness caused by other viral pathogens, had an inability to use SSRIs, or had dyspnea attributed to another acute or chronic lung disease, such as decompensated chronic obstructive pulmonary disease.⁴

Patients were randomly assigned to start fluvoxamine 100 mg twice a day for 10 days or matching placebo, along with standard-of-care therapies for symptom management in both arms. The primary outcome of interest was a composite end point of medical admission to a hospital setting for COVID-19, defined as an observation period lasting 6 or more hours in the emergency department or any referral for hospitalization within 28 days of randomization. Secondary end points of interest included associated times of disease progression or resolution, safety and tolerability of the trial medication, and clinical monitoring of disease severity.⁴

A total of 1497 participants were recruited and randomized to fluvoxamine (n = 741) or placebo (n = 756). Patients were randomized, on average, at 3.8 days of symptoms (standard deviation, 1.87). The study’s intention-to-treat analysis found a significant reduction in the primary composite end point, attributed to the need for retention in the emergency setting for at least 6 hours (Table). The calculated number needed to treat (NNT) was 20 patients. All other secondary end points were unchanged compared with placebo. Rates of treatment-emergent adverse events did not differ significantly between fluvoxamine and placebo.⁴

The authors concluded that fluvoxamine may have a place in therapy for the management of outpatient, unvaccinated adults with COVID-19 infection to reduce the progression to hospitalization.⁴ The authors also call on subsequent research to establish whether these effects are a SSRI-class effect or related to fluvoxamine alone.⁴ Although fluvoxamine shows some statistical significance in reducing hospital setting visits, it appears this clinical benefit is limited to unvaccinated patients requiring extended stays in the emergency department, not those admitted to the hospital. Rates of hospitalization and death did not differ in the intention-to-treat population, although there was a statistical decrease in death in the per-protocol population.⁴ Some retrospective reviews have found reduction in mortality, but the benefit appears modest in this analysis.⁷ A recent commentary on outpatient therapeutics estimated that at a 5% risk of hospitalization, fluvoxamine had the lowest NNT at 80 patients and lowest total drug cost of $1122.⁸ There are also differences in the prescribing patterns of antidepressants in different parts of the world that would influence the generalizability of this trial.^9,10 SSRIs continue to show promise for partial management of COVID-19, and ongoing clinical trials will help identify its place in therapy.¹¹

References

1. Wang Y, Liu Y. Multilevel determinants of COVID-19 vaccination hesitancy in the United States: a rapid systematic review. Prev Med Rep. 2021;25:101673. doi:10.1016/j.pmedr.2021.101673
2. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of antibodies and antiviral drugs against Covid-19 Omicron variant. N Engl J Med. 2022;386(10):995-998. doi:10.1056/NEJMc2119407
3. Bartoli A, Gabrielli F, Alicandro T, Nascimbeni F, Andreone P. COVID-19 treatment options: a difficult journey between failed attempts and experimental drugs. Intern Emerg Med. 2021;16(2):281-308. doi:10.1007/s11739-020-02569-9
4. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2022;10(1):e42-e51. Published correction appears in Lancet Glob Health. 2022 Apr;10(4):e481
5. Sukhatme VP, Reiersen AM, Vayttaden SJ, 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
6. 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
7. Oskotsky T, Maric I, Tang A, et al. Mortality risk among patients with COVID-19 prescribed selective serotonin reuptake inhibitor antidepressants. JAMA Netw Open. 2021;4(11):e2133090. doi:10.1001/jamanetworkopen.2021.33090
8. Lee TC, Morris AM, Grover SA, Murthy S, McDonald EG. Outpatient therapies for COVID-19: how do we choose? Open Forum Infect Dis. 2022;9(3):ofac008. doi:10.1093/ofid/ofac008
9. Brody DJ, Gu Q. Antidepressant use among adults: United States, 2015-2018. NCHS Data Brief. 2020;(377):1-8.
10. Alcantara GC, Coutinho ESF, Faerstein E. Pattern evolution of antidepressants and benzodiazepines use in a cohort. Rev Saude Publica. 2020;54:40. doi:10.11606/s1518-8787.2020054001887
11. Fluvoxamine for early treatment of Covid-19 (stop Covid 2). ClinicalTrials.gov. Updated January 13, 2022. Accessed March 20, 2022. https://clinicaltrials.gov/ct2/show/NCT04668950.