- One positive to come out of the Covid-19 pandemic has been the scientific community coming together to combat the virus.
- While new vaccine production was a technological tour-de-force, a dusty off-the-shelf antidepressant, fluvoxamine, may also prove useful.
- This and other antidepressants may lead to future therapeutic innovations harnessing novel anti-inflammatory (anti-cytokine) properties.
Recently, an antidepressant called fluvoxamine (Luvox) has made headlines as a possible low-cost treatment for Covid. How does that work?
Fluvoxamine belongs to a common class of antidepressants called selective serotonin reuptake inhibitors (SSRIs). Other medications in this group include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). In the Brazilian study that made headlines, only fluvoxamine was tested for the ability to reduce complications from Covid-19. And it seems to have worked: Patients taking fluvoxamine were significantly less likely to require hospitalization for Covid-19 infection than those who did not.1 Is there something special about fluvoxamine that makes it good against Covid, or is this true for other antidepressants as well?
All SSRIs (and many other antidepressants) modulate a chemical signal called serotonin in the brain. But there’s a lot we don’t understand about how these medications work. For one thing, although virtually all antidepressants affect serotonin in some way, different antidepressants, including different SSRIs, have distinct “side properties.” These side properties likely cause specific side effects in some people; they also may be why some patients respond better to some antidepressants than others.
The recent study in Brazil was inspired by one of the side properties of fluvoxamine. Not only is fluvoxamine a potent modulator of serotonin, but it also activates a protein inside cells called the Sigma 1 Receptor (S1R). S1R has many functions, and one of them is to regulate inflammatory responses mediated by chemicals called cytokines.
Cytokines are a kind of ancient “alarm system” for your body. A subset of “first responder” cells, which are widely distributed throughout your body, release cytokines to warn the immune system when nearby tissues have become infected. Your body’s response is to mobilize resources to combat the infection at its source — this includes increasing blood flow to the area and facilitating the invasion of disease-combatting immune cells to kill infected tissue and clean up debris. This is what we observe as inflammation.
Some types of severe infection are marked by an over-release of cytokines called a “cytokine storm.” In a cytokine storm, so much cytokine is released that the body’s inflammatory response is too strong. The resultant tissue destruction is more deadly than the infection itself. One type of disease marked by cytokine storm is sepsis — a potentially lethal condition in which bacteria infect the bloodstream and quickly spread throughout the body — another such condition is Covid-19. Early on in the pandemic, the medical community recognized that at least some of the severest symptoms of Covid-19 infection, including the respiratory distress that landed patients in the ICU and often killed them, were caused by cytokine storm in the lungs and other critical organs.
Less than a year prior to the Covid-19 pandemic, researchers showed that fluvoxamine could reduce cytokine storm in an animal model of sepsis.2 When the pandemic hit, some astute clinicians put “two and two together” and realized that if fluvoxamine could help reduce cytokine storm in lab animals, then perhaps it could do the same thing in humans with Covid-19. The study in Brazil, and a similar smaller one published about a year earlier,3 is the outcome - and while results should be viewed with sensible caution, they are based on a solid scientific hypothesis, strong pre-clinical evidence, and appear promising in real-world human populations.
But there’s more to this story than “fluvoxamine has anti-inflammatory properties that may help Covid patients.” As it turns out, other antidepressants may be useful too. In fact, fluoxetine (Prozac), the grand-daddy of all SSRIs that is much more widely used, is also an activator of S1R. In a separate study conducted in Europe, hospitalized Covid-19 patients taking fluoxetine or several other antidepressants including paroxetine, escitalopram, and the non-SSRIs mirtazapine (Remeron) and venlafaxine (Effexor), all had a significantly lower incidence of severe respiratory distress and death than those who were not taking these medications.4
It is possible that by improving patients' mood, energy levels, and motivation, the antidepressant actions of these medications contribute to more positive Covid outcomes, but it seems unlikely that this alone explains their observed benefits.
An alternative is that the benefits in Covid-19 infection are mediated by neither antidepressant action nor by S1R activation, but by a totally different side property of these drugs, all of which are strong inhibitors of an enzyme called acid sphingomyelinase. This is a normal cellular component used by Covid-19 (and similar viruses) to enter cells. In fact, the SSRIs fluoxetine, escitalopram, sertraline, as well as the older antidepressants amitriptyline, imipramine, and maprotiline — all of which are potent inhibitors of acid sphingomyelinase — can inhibit Covid-19 infection in a lab dish (and amitriptyline works in actual humans too).5
As if that weren’t enough, there is strong evidence that fluoxetine, and possibly other SSRIs, can help calm down mast cells - one of the main cytokine-producing cells in the lungs of Covid-19 patients - by inhibiting yet another receptor, for ATP.6
Finally, the core serotonin-modulatory activity of antidepressant medications may be important for warding off some of the severe consequences of Covid-19 in the body. Another hallmark of Covid-19 infection is a hypercoagulable state in which clots form spontaneously to cause infarcts — killing healthy tissue by choking off small blood vessels. Platelets, the cell fragments in serum responsible for clotting, release serotonin to activate each other and form clots. But platelets don’t make their own serotonin, they rely on an enzyme to take it up from serum, and this is the same enzyme inhibited by SSRIs. Chronic SSRI treatment may decrease blood clotting by reducing platelet serotonin stores,7 a potential benefit in Covid-19 infection.
The bottom line is that several antidepressants, not just fluvoxamine, may improve Covid infection outcomes by modulating inflammatory and other physiological responses outside the brain. They do this by affecting serotonin, but also through other mechanisms that are usually not considered part of their main mechanism of action. But this is actually not too different from how these medications work for depression and anxiety — which we are still learning about, and which is certainly not simply by correcting a “serotonin deficit” in the brain.8
1. Reis et al, The Lancet, October 2021. https://www.sciencedirect.com/science/article/pii/S2214109X21004484?via…
2. Rosen et al, Science Transl Medicine, February 2019. https://www.science.org/doi/10.1126/scitranslmed.aau5266
3. Lenze et al, JAMA, November 2020. https://jamanetwork.com/journals/jama/fullarticle/2773108
4. Hoertel, Molecular Psychiatry, February 2021. https://www.nature.com/articles/s41380-021-01021-4
5. Carpinteiro et al, Cell Reports Medicine, November 2020. https://pubmed.ncbi.nlm.nih.gov/33163980/
6. Hoque et Ryan, The Journal of Immunology, May 2019. https://www.jimmunol.org/content/202/1_Supplement/54.11
7. Halperin et Reber, Dialogues Clin Neurosci. March 2007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181838/
8. See: Healthy Prescriptions, What's New in Treatment for Depression?