Are SSRIs a New Weapon in the COVID Fight?

F. Perry Wilson, MD, MSCE


November 16, 2021

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.

The hope that existing medications would prove to be effective treatments for COVID springs eternal, and a host of promising agents have come and, after rigorous study, gone.

These include classics like hydroxychloroquine and ivermectin, and slightly less-celebrated agents like melatonin.

There has even been one undeniable hit — dexamethasone — which in multiple randomized trials now has demonstrated its ability to reduce mortality in individuals with severe COVID.

Over the past year, support for one additional agent, fluvoxamine, has been quietly building on the backs of several small studies until, in September, we got data from the large TOGETHER trial, which found that the use of fluvoxamine in early COVID-19 was associated with a significant reduction in the risk for prolonged ED visit or hospitalization.


There were numerically fewer deaths in the fluvoxamine arm as well.

Fluvoxamine is cheap and widely available, but, let's be honest — it does not get prescribed a lot compared with other SSRIs. So the results of the TOGETHER trial prompted a straightforward question: Is the fluvoxamine effect a class effect? In other words, would any SSRI, with their class-level antithrombotic and anti-inflammatory effects, work?

The first answers are now trickling in, with the largest study to date examining this question appearing in JAMA Network Open.

Now, this is not a randomized trial; it's a propensity score–matched cohort study. But it's big, representing data from 87 healthcare centers across the US. Here's how it worked.

Researchers collected data from the electronic health record on 83,584 individuals with COVID-19 from January to September of 2020. So just to orient ourselves, this is the pre-vaccine era and really a time before SSRIs were on the radar as a treatment. The cohort included hospitals, emergency rooms, and urgent care, but this was a pretty sick group: The overall mortality rate was 8.6%.

About 4% of the cohort was receiving SSRIs on or around the time they were diagnosed. And I'll pause there to note that is quite a bit lower than expected. Around 13% of adults in the US take SSRIs.

Does that mean SSRIs are protective even against COVID infection? The study was not designed to answer that question, but it's certainly an intriguing possibility.

What the study was designed to answer was whether, among people infected with COVID-19, the SSRIs were beneficial. The raw numbers don't look good for the antidepressants. The mortality rate was 14.6% among those taking SSRIs compared with 8.4% among those not taking SSRIs.

But don't close the book on them just yet. People who take SSRIs are different from those who don't. In this cohort, those on SSRIs were twice as likely to have coronary vascular disease and COPD, and, unsurprisingly, three times as likely to have a mood disorder. Seventy-four percent of those on SSRIs were hospitalized when they entered the cohort compared with just 44% of those not on SSRIs.


Propensity-score matching tries to compare apples to oranges by finding oranges that look a lot like apples. You build a multivariable statistical model predicting SSRI use. Depression would be a major predictor, for example. You then predict the probability of SSRI use for everyone in the cohort — whether they truly used them or not. You then match those that used them to people who don't but have a similar propensity score for use. Propensity score–matching evangelists would say this is like a clinical trial: Everything about the patients is basically the same after matching, except one person got the drug and one didn't.

It's not really a randomized trial, but it is better than looking at the raw data. And, after propensity score–matching, we find that, overall, SSRI use in general was associated with a reduction in mortality — by a modest, but statistically significant, 8%.


What about fluvoxamine? Who knows; only 11 out of the 3401 patients on SSRIs were taking that particular SSRI.

But a strong beneficial effect was seen with fluoxetine, which is sold under the brand name Prozac, with a 9.8% mortality rate compared with 13.3% among propensity-matched controls. The authors don't break down the other SSRIs individually, but as a group they didn't do great. Mortality rate was 15.4% compared with 17% in propensity-matched controls.

So, do SSRIs work for COVID-19? Do some work? Does only fluvoxamine work? There seems to be some promise here, but not at the breakthrough level.

And, of course, the field upon which we judge these drugs is changing. If Pfizer's protease inhibitor proves to be as effective as their press release suggests it is, 30% mortality reductions from SSRIs may seem quaint. Still, it's nice to have some more potential arrows in our quiver, and it's encouraging to see the search continue for cheap, effective, and widely available COVID treatments.

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

Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.