04. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19

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Fluvoxamine for COVID-19 infection? Where did that idea come from? Ah, the sigma-1 receptor.

Hi! Jim Phelps here for the Psychopharmacology Institute. Not only is fluvoxamine for COVID an interesting idea with an interesting potential biochemical mechanism behind it, but here’s a randomized trial in the Journal of the American Medical Association showing that fluvoxamine prevents clinical deterioration in patients already symptomatically infected. Because of study limitations, the investigators regard this as a preliminary trial, but it’s impressive. Among 150 patients, 8% of those receiving placebo had a marked worsening of their illness, vs zero of those receiving fluvoxamine.

Let’s first examine the biochemical mechanism that makes fluvoxamine a candidate treatment for a viral illness, and then we’ll come back and look at who these patients were and how their course was evaluated. As you know, lung damage from an excessive inflammatory response has prompted the use of multiple immunomodulatory drugs in COVID-19 infection—from fancy stuff like an interleukin-6 receptor blocker, such as tocilizumab, which is now approved for use in COVID-19, to basics, like steroids. Steroids can worsen COVID-associated lung injury, but they can help when hyperinflammation is part of the problem, as is common in COVID-19 infection.

Indeed, a 2020 Lancet review suggested screening COVID-19 patients for hyperinflammation marked by things like increasing ferritin or decreasing platelets and using steroids, tocilizumab, or other anti-inflammatory measures to address this.

So, can fluvoxamine dampen hyperinflammation? In 2019, a team from Virginia published mouse data showing that fluvoxamine affects not just the serotonin reuptake protein but also the sigma-1 receptor. In a review titled “What were You Doing Before the War? Repurposing Psychiatry During the Pandemic,” Dr. Ginger Nicol and colleagues explained that sigma-1 receptor activation restricts cytokine expression without inhibiting classical inflammatory signaling pathways. So, it’s a useful property. Several SRIs actually have anti-inflammatory effects, but because fluvoxamine is a potent sigma-1 receptor agonist, it was chosen for this randomized trial for patients with COVID-19.

The study details are fascinating, as this was done during a period of high infection rates in outpatients using a simple remote method, which was a package left at the participant’s doorstep. The box contained a fingertip oxygen saturation sensor, a thermometer, and the study medication, either fluvoxamine or placebo. Everything else was handled by email and phone—recruitment, consent, instructions, and twice-daily symptom surveys. Fluvoxamine was increased from 50 to 100 twice daily, then 100 mg 3 times daily over 3 days, was continued at the highest tolerable dose, and then stopped after 2 weeks without taper.

Clinical deterioration, the primary endpoint, was defined as the development of significant dyspnea or an oxygen saturation less than 92%. Pulmonary deterioration occurred in zero of 80 fluvoxamine patients vs 6 of 72 placebo patients. That’s 8%. As for adverse events, 1 person in the fluvoxamine group and 5 in the placebo group had nausea or vomiting, with no other significant differences.

The authors suggest that their study not be regarded as a definitive demonstration of efficacy because of multiple limitations, especially the small sample size. Although they met prespecified power requirements, they lost 20% of participants along the way. Replication is needed. The authors also remind us that although fluvoxamine does not prolong QT intervals, it does have drug interactions via inhibition of CYP1A2 and 2C19.

What does this mean for psychiatrists? Well, if you are called to consult on a patient with COVID-19 and thought an SRI was indicated, you might consider fluvoxamine more than usual. At minimum, this paper serves to bring us closer to our medical colleagues through recognition that our medications have multiple mechanisms, some worth considering in other battles.

Although screening and follow-up required an estimated 4500 person hours, this study was mounted very quickly, and the remote approach is quite novel. For more on this, look at the study methods. Bravo to the investigators!

Abstract

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

Eric J. Lenze, Caline Mattar, Charles F Zorumski, Angela Stevens, Julie Schweiger, Ginger E. Nicol, J Philip Miller, Lei Yang, Michael Yingling, Michael S. Avidan, Angela Reiersen

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 requre larger randomized trials with more definitive outcome measures.

Reference

Lenze, E. J., Mattar, C., Zorumski, C. F., Stevens, A., Schweiger, J., Nicol, G. E., … & Reiersen, A. M. (2020). Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA, 324(22), 2292-2300.

Related References

• Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., Manson, J. J., & HLH Across Speciality Collaboration, UK (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet, 395(10229), 1033–1034. 
• Nicol, G. E., Karp, J. F., Reiersen, A. M., Zorumski, C. F., & Lenze, E. J. (2020). “What were you before the war?” Repurposing psychiatry during the COVID-19 pandemic. The Journal of Clinical Psychiatry, 81(3), 20com13373. 
• Rosen, D. A., Seki, S. M., Fernández-Castañeda, A., Beiter, R. M., Eccles, J. D., Woodfolk, J. A., & Gaultier, A. (2019). Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Science Translational Medicine, 11(478), eaau5266. 
• Shajib, M. S., & Khan, W. I. (2015). The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiologica, 213(3), 561-574.