In a preliminary randomised clinical trial of COVID-19 patients with mild-to-moderate disease who were attempting to recover in their homes, researchers found that fluvoxamine seems to prevent some of the most serious complications of the illness and make hospitalisation and the need for supplemental oxygen less likely, according to a study in the Journal of the American Medical Association.
The study, a collaboration between the Washington University School of Medicine in St. Louis Department of Psychiatry and Division of Infectious Diseases, involved 152 patients infected with SARS-CoV-2, the virus that causes COVID-19. Researchers compared the outcomes of those treated with fluvoxamine to the outcomes of those given an inactive placebo. After 15 days, none of the 80 patients who had received the drug experienced serious clinical deterioration. Meanwhile, six of the 72 patients given placebo (8.3%) became seriously ill, with four requiring hospitalisation.
“The patients who took fluvoxamine did not develop serious breathing difficulties or require hospitalisation for problems with lung function,” said the paper’s first author, Dr Eric J Lenze, the Wallace and Lucille Renard Professor of Psychiatry. “Most investigational treatments for COVID-19 have been aimed at the very sickest patients, but it’s also important to find therapies that prevent patients from getting sick enough to require supplemental oxygen or to have to go to the hospital. Our study suggests fluvoxamine may help fill that niche.”
Fluvoxamine is used commonly to treat obsessive-compulsive disorder (OCD), social anxiety disorder and depression. It is in a class of drugs known as selective serotonin-reuptake inhibitors (SSRIs), but unlike other SSRIs, fluvoxamine interacts strongly with a protein called the sigma-1 receptor. That receptor also helps regulate the body’s inflammatory response.
“There are several ways this drug might work to help COVID-19 patients, but we think it most likely may be interacting with the sigma-1 receptor to reduce the production of inflammatory molecules,” said senior author Dr Angela M Reiersen, an associate professor of psychiatry. “Past research has demonstrated that fluvoxamine can reduce inflammation in animal models of sepsis, and it may be doing something similar in our patients.”
Reiersen said the drug’s effects on inflammation could prevent the immune system from mounting an overwhelming response, which is thought to occur in some COVID-19 patients who seem to improve after a few days of illness and then worsen. Many of those patients end up hospitalised, and some die.
In an innovative twist to research during the pandemic, the study was conducted remotely. When a symptomatic patient tested positive and enrolled in the study, research staff delivered the medication or inactive placebo to them, along with thermometers, automatic blood pressure monitors and fingertip oxygen sensors.
“Our goal is to help patients who are initially well enough to be at home and to prevent them from getting sick enough to be hospitalised,” said Dr Caline Mattar, an assistant professor of medicine in the Division of Infectious Diseases. “What we’ve seen so far suggests that fluvoxamine may be an important tool in achieving that goal.”
For two weeks, subjects took either the antidepressant drug or placebo sugar pills while having daily interactions with members of the research team — via phone or computer. That allowed patients to report on their symptoms, oxygen levels and other vital signs. If patients suffered shortness of breath or were hospitalised for pneumonia, or their oxygen saturation levels fell below 92%, their conditions were considered to have deteriorated.
“The good news is that not a single person taking the active medication experienced deterioration,” Reiersen said. “We believe this drug may be the reason, but we need to study more patients to make sure.”
The researchers will begin a larger study in the next few weeks. Lenze, the director of the Healthy Mind Lab at the School of Medicine, is an expert in using mobile and internet technology to conduct clinical trials. He said that although this initial study involved patients in the St. Louis region, the next phase of the research will involve patients from throughout the country.
“We bring the study to the patients, giving them tools to monitor their health at home,” Lenze said. “Our hope is that we can keep these patients healthy enough to avoid hospitalisation.”
This work was supported by the Taylor Family Institute for Innovative Psychiatric Research, the Bantly Foundation, the Center for Brain Research in Mood Disorders at Washington University and the COVID-19 Early Treatment Fund. Additional support from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Grant number UL1 TR002345.
Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19
A Randomized Clinical Trial
Eric J. Lenze, MD; Caline Mattar, MD; Charles F. Zorumski, MD; et al Angela Stevens, BA; Julie Schweiger; Ginger E. Nicol, MD; J. Philip Miller, AB; Lei Yang, MPH, MSIS; Michael Yingling, MS; Michael S. Avidan, MBBCh4; Angela M. Reiersen, MD, MPE1
JAMA. Published online November 12, 2020. doi:10.1001/jama.2020.22760
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.
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.
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.
Of 152 patients who were randomized (mean [SD] age, 46  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.
Full Journal of the American Medical Association study (Open access) report