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This transcript has been edited for clarity.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson of the Yale School of Medicine.
By virtually all metrics, vaccine development for COVID-19 has been an astonishing success. But when it comes to therapeutics, the picture is much more mixed. This means the tip of the spear of the battle against coronavirus is and will remain vaccination. But, as you know, not everyone is getting vaccinated; we need therapeutics.
For nearly 2 years, the search for existing molecules with activity against COVID-19 has proceeded apace, but the process has been haphazard and colored by political bias and misinformation. Melatonin, hydroxychloroquine, azithromycin, and, most recently, ivermectin showed some initial promise — only for rigorous randomized trials to shoot them down.
The idea that some existing drug would be a miracle cure for COVID-19 is basically fantasy. As Dr. Matsumoto said in the 1990 post-apocalyptic action film Robot Jox, "That kind of luck does not exist."
But the idea that some existing molecule might have some efficacy, some moderate ability to curb the disease process, is much more likely. See dexamethasone, a drug that costs about $1 a pill, for an example of this. Does it save every life? No. But it has clearly moved the needle on COVID-19 care.
And an old drug may be joining our COVID arsenal. A new, large clinical trial suggests that fluvoxamine — yes, the antidepressant fluvoxamine — might substantially reduce the severity of COVID-19 illness.
But before we dig into the clinical results, it’s important to consider whether there is even biologic plausibility here. Why should fluvoxamine work against COVID?
This is the molecule itself.
It's a potent binder of the serotonin transporter, leading to its antidepressant effects, but this doesn't explain any anti-COVID activity.
The off-target effects of fluvoxamine are more interesting. Of all the SSRIs, fluvoxamine has the strongest affinity for the sigma-1 receptor, which might lend it some of its anxiolytic effects. But that receptor has many effects. This 2019 Science Translational Medicine article suggests that the receptor may have a substantial role in cytokine release, which is, of course, a mechanism by which COVID-19 lands people in the hospital.
SSRIs also have well-described platelet-inhibiting properties, and the prothrombotic nature of COVID-19 is equally well described.
So, there is some potential there. But as I've said over and over again in this space, biologic plausibility is the start of medical research, not the end.
You need real, randomized data to move from "interesting drug" to "new treatment for COVID."
In November 2020, the first such data came out in JAMA. One hundred and fifty-two outpatients with COVID-19 were randomized to 100 mg of fluvoxamine three times a day for 15 days, or placebo.
None of the patients in the fluvoxamine group had clinical deterioration, compared with six in the placebo group. A significant difference, but the small numbers here leave plenty of room for interpretation.
Now we have a much more definitive trial, thanks to the TOGETHER consortium, which uses an adaptive design with a standardized protocol to rapidly evaluate potential new therapies. This is the same group that recently poured cold water on ivermectin, as their data showed no statistical difference in outcomes among individuals randomized to ivermectin vs placebo.
But swap out ivermectin with fluvoxamine, and the results were different. Now, these data have not yet been peer reviewed, but this appears to be a high-quality study, with a preregistered endpoint and a decent sample size of 1472 outpatients with COVID-19. Half of them were randomized to receive 100 mg of fluvoxamine twice daily for 10 days; the rest got placebo.
The primary outcome was a composite of hospitalization or an ED visit for observation that lasted longer than 6 hours.
The medication did indeed reduce the risk for that primary endpoint, something none of the other candidates in the TOGETHER trials have done yet, with 10.4% of the fluvoxamine group compared with 14.7% of the placebo group getting hospitalized or spending time in the ED.
That means you'd need to treat around 23 patients with fluvoxamine to avoid one patient clinically decompensating. At about fifty cents a pill, or $10 for a course of this therapy, that's not a bad deal. Regeneron's monoclonal antibody cocktail is about $1000 for a dose.
Harder endpoints didn't differ significantly between the groups; 2.3% of the fluvoxamine group died compared with 3.3% of the placebo group, but that difference, while encouraging, is consistent with a chance finding.
Indeed, the success of the drug was driven primarily by the fact that fewer fluvoxamine patients had a prolonged stay in the ED. The difference in hospitalization full stop was not as profound.
Other limitations: The study was conducted entirely in Brazil, where vaccination rates are low, and largely before the dominance of the Delta variant — so interpret these results with caution.
Also, I feel obliged to remind everyone that fluvoxamine is not an entirely benign drug. Like all SSRIs, side effects include gastrointestinal problems, weight gain, and sexual dysfunction.
Still, this is how this stuff is supposed to work. You start with some biologic plausibility, do some proof-of-concept studies, and confirm with a large randomized trial. Ideally, you follow that up with a validation trial. You don't just pick a drug with biologic plausibility and start selling it off-label online and promoting it on YouTube and Twitter. This is a case-study for why. It muddies the waters. There is a process to vet potential therapies — and fluvoxamine shows us how the process should work.
Is fluvoxamine a game changer? No. As I said at the beginning, we are incredibly unlikely to find a medication off-the-shelf that just so happens to cure COVID-19. But it may provide some real benefit at a reasonable cost. So, let's keep going down this road, evaluate the effect of this drug in a broader population, in the face of Delta, and even in hospitalized patients, and use our most rigorous standards to figure out the truth.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com.
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Image 1: Wikimedia Commons
Image 2: Lenze EJ, et al. JAMA. 2020;324:2292-2300. doi:10.1001/jama.2020.22760
Image 3: F. Perry Wilson, MD, MSCE
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Cite this: F. Perry Wilson. Could Fluvoxamine Work as COVID Treatment? - Medscape - Sep 08, 2021.