Reviving an old antidepressant for the fight against COVID-19

Reviving an old antidepressant for the fight against COVID-19

With the publication of results from the TOGETHER trial in the medical journal The Lancet, there is buzz surrounding the treatment of COVID-19 with the (old-as-dirt) antidepressant fluvoxamine. No, that wasn’t a typo; I said treatment of COVID-19 with an antidepressant. This post will explain why it might not be as far fetched as it seems at first glance.

What is fluvoxamine?

Fluvoxamine (also known as Luvox) is a selective serotonin reuptake inhibitor (SSRI) that has been available since the early 1980s. For more information on SSRIs, check out my other article here. As with other SSRIs, it can be used to treat mental illnesses such as: anxiety, depression, and obsessive-compulsive disorder (OCD). However, it fell out of favor with the development of other SSRI agents that had easier administration schedules (fluvoxamine needs to be taken twice a day, whereas most popular agents are just once daily) and the fact that fluvoxamine can also affect how the body processes certain other medications (i.e. drug interactions).

Why is fluvoxamine even being studied in the treatment of COVID-19?

Early on in the pandemic, the scientific community was collectively grasping at any straws that could potentially help. A major initiative was undertaken to try to identify any existing drugs that could be repurposed in order to work in COVID-19. Many of these, such as hydroxychloroquine and lopinavir/ritonavir, were unfortunately complete flops. As with many things in science, the potential use of fluvoxamine in COVID-19 is due to a series of unrelated events lining up in just the right way by accident.

The background

Dr. Angela Reiersen, a child psychiatrist in St. Louis with an added special interests in genetic and neurodevelopmental diseases, had recently observed something interesting in patients with a rare genetic disease called Wolfram syndrome. She noticed that some of these patients responded poorly to a specific antidepressant (sertraline; Zoloft), yet responded better to other antidepressants (fluvoxamine was one of them).

*Knowledge break*

Before I go any further, I’m going to answer a question that I’m frequently asked: “How do drugs know where to go?” (e.g. “how does the ibuprofen know to help my headache?“)

The answer is that they don’t. Medications will literally go any and everywhere that they can physically reach in your body.

Think of a molecule of medication in your body like a tiny Roomba that just bounces around aimlessly until it gets to where it can fit.

The next point that’s important to know is that medications are not necessarily like a key that can just fit into one lock. Some medications, like fluvoxamine, can have effects in many different parts of the body.

*Back to our regularly scheduled program*

So, realizing that this could be a sign of fluvoxamine must be doing something different than sertraline, Dr. Reiersen looked into it further and discovered there was some information pointing to the fact that fluvoxamine, on top of its SSRI activity, also activated a specific receptor that sertraline inactivated. This receptor, the sigma-1 receptor (S1R), is not very well known, but we’ll get to why it’s potentially important next:

An unrelated group of researchers in Virginia, which included Dorian Rosen and Alban Gaultier, had recently published an article in 2019 detailing how this same sigma-1 receptor seemed to be involved in the inflammatory cascade that can be seen in severe infections like sepsis. In their research, they identified that activating this receptor could potentially help reduce the runaway inflammatory response that can happen with sepsis (their research was in mice, so very preliminary).

Why all of this was important is because severe COVID-19 is primarily caused by an out-of-control immune response that causes tons of inflammation (also known as a “cytokine storm“). This is why some of the main treatments of severe COVID-19 are anti-inflammatory drugs like steroids, and not antivirals. So, the theory was that if fluvoxamine is potentially able to offer a reduction in this inflammatory response, then maybe it could be useful if started early on in the course of the illness.

Results from a small study

In the early days of the COVID-19 pandemic a group of researchers led by two psychiatrists (Dr. Eric Lenze & the previously mentioned Dr. Angela Reiersen) began enrolling patients into a study that would serve as a first preliminary assessment of fluvoxamine. What this small study observed was that the participants who received fluvoxamine (when compared to those who received placebo) were less likely to have a severe illness that would require hospitalization. The only catch was that this study was very small; they only had a total of 152 participants (80 received fluvoxamine and 72 received a placebo sugar pill). Also, only 6 participants needed hospitalization (all in the placebo group); so it makes it hard to draw a firm conclusion based on the small number of participants and hospitalizations.

In other words, the level of certainty that the results weren’t just a statistical fluke was not very high.

How was fluvoxamine studied in the TOGETHER trial?

After the results from the initial smaller study were published, other groups decided to begin studies to confirm the preliminary results. One of these studies was the TOGETHER trial. You may recognize the name of the study from my other article on ivermectin, since this study evaluated many different types of treatments in different groups of people simultaneously.

Study design

The TOGETHER trial was a randomized (double-blind) placebo controlled trial. For a more detailed explanation of what a randomized controlled trial (RCT) is, please see the relevant section of this article. For those who don’t want the long-winded version, an RCT is the gold-standard way to study a new treatment.

The study, which occurred in different areas in Brazil, randomly allocated either fluvoxamine or placebo to people with COVID-19. The treatment was given to people early on in the course of the illness, and they wanted to see if the same impact on hospitalization rates would be observed (one small variation was that, on top of hospital admissions, they also looked at emergency room visits where the patient was kept under observation).

What they found

This trial was much larger, enrolling almost 1500 participants (741 received fluvoxamine and 750 received placebo). What they observed:

Fluvoxamine GroupPlacebo Group
11% (79 of 741)
required hospitalization*
16% (119 of 756)
required hospitalization
*
*Most (87%) of these were hospital admissions;
13% were ER visits where patients were kept under observation

As you can see in the table above, fluvoxamine was again shown to decrease the rates of hospitalizations (5% reduction). For those that want a more practical way to visualize the results:

In order to prevent 1 person from requiring hospitalization for COVID-19, you would need to treat 20 people with fluvoxamine.

Other findings from TOGETHER

Unfortunately, it wasn’t all rainbows and butterflies for fluvoxamine in this study:

  • It’s unclear in the article if they counted wait times as part of the “emergency visit for greater than 6 hours under observation”. One part of the article says that they don’t, but then another says that they do.
  • Because we are using a decently high dose of an antidepressant without gradually building up to it, there were more side effects in the fluvoxamine group than in the placebo group; which led to more people stopping fluvoxamine early. Luckily, there was no difference in the rates of serious side effects with the drug compared to placebo.

Other studies

While the 2 studies I already mentioned are the best quality evidence that we currently have, there are other studies that have looked at fluvoxamine as well. While these don’t equate to the same level of proof, they can still help inform us.

Observational study

The first study is an observational study from France looking at people that were admitted to hospitals. An observational study is essentially when we go back into health records and look at data from patients that were already admitted. While these studies offer an excellent “real-world” look, they also have one glaring problem: they don’t have randomization. Because of this, there can often be differences between the study groups that can skew results.

In this observational study, they saw that people who were already taking SSRI antidepressants when they were admitted to the hospital were less likely to require intubation and were less likely to die while in hospital.

Open-label non-randomized trial

Another study, this one from Croatia, did something called a cohort trial. This one has quite a few holes in it as far as “best practices” for good trial quality. They didn’t randomize people (literally everyone admitted to the ICU within a specific timeframe got fluvoxamine), and then they compared these people to historical data from prior patients. While this may sound reasonable, it can lead to some biases making it into the study. This is how some of the original studies on hydroxychloroquine were done, so I tend to not put too much weight to the results of this trial.

So, while they did find that fluvoxamine decreased the likelihood of dying, it’s hard to put much faith in this result on its own. Taking into account all the other studies, it’s possible that the results are legitimate; but, it’s best to be objective and not jump to conclusions too quickly with this specific study.

Coming soon

There are currently a few other studies underway to study fluvoxamine; so, I am hoping that these can bring clarity and potentially confirm what was observed in the studies to date.

Obviously, they could also show the complete opposite and bring us right back to where we started…But we can’t really worry about that until the results are published. We can only use the data that we have access to right now.


What does this mean for fluvoxamine in the treatment of COVID-19?

Taken together, all this seems to point to fluvoxamine being the most promising repurposed drug to give in early COVID-19.

This seems less and less likely to become the next hydroxychloroquine or ivermectin (i.e. failed hypotheses to date). Everything seems to be pointing in the same direction, and it’s based on much higher quality studies as well.

Are we certain that it will help? I don’t think I would be confident enough to say with certainty.

But, I think it could be considered by some physicians on a case-by-case basis for certain high risk people after a discussion of the risks and benefits, particularly if the patient can’t access treatments like monoclonal antibodies, molnupiravir, or nirmatrelvir/ritonavir.

I think it’s important to recognize that, at the end of the day, even if it does work as advertised in the TOGETHER trial it’s still not a miracle drug.

The current best way to help reduce infections, prevent hospitalizations and deaths is still vaccination (by a very wide margin).


The Bottom Line

This article details all the random events that had to line up for fluvoxamine to even be studied in the first place. While the data is still growing, the signal seems to be pretty consistent that it *could* have a role to play in COVID-19 management.

Does it become a legitimate treatment option for COVID-19; or does it gets relegated to the scrapheap with our other failed attempts at repurposing drugs? Future studies will help decide the ultimate fate of fluvoxamine.

Is this a “game-changer”? Probably not; but, it’s one of the first repurposed treatments that seems to offer some hope for treatment outside the hospital setting. When you consider that a 10-day course probably wouldn’t cost more than $4 to $20, it makes it very appealing for lower-resource settings.

*Disclaimer, a lot of this information is best guesses (particularly the proposed mechanism that fluvoxamine could help). However, it’s always been a big belief of mine that you are likely to understand something better when you know the why behind it…so that’s why I included the theoretical mechanism.

Dan Landry

Daniel (Dan) Landry, founder of Rxplanation.com, is an infectious diseases pharmacist at the Dr-Georges-L.-Dumont University Hospital Centre in Moncton, NB, Canada.

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