Can my antidepressant help prevent severe Covid?


Recently, an antidepressant called fluvoxamine (Luvox) made headlines as a possible low-cost treatment for Covid. How? ‘Or’ What this job?

Fluvoxamine belongs to a common class of antidepressants called selective serotonin reuptake inhibitors (SSRIs). Other drugs 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 its 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 effective against Covid, or is this also true for other antidepressants?

All SSRIs (and many other antidepressants) modulate a chemical signal called serotonin in the brain. But there is a lot that we don’t understand about how these drugs work. On the one hand, although virtually all antidepressants affect serotonin in one way or another, different antidepressants, including different SSRIs, have different “side properties”. These side properties are likely to cause specific side effects in some people; they may also explain why some patients respond better to certain antidepressants than others.

The recent study in Brazil was inspired by one of the secondary properties of fluvoxamine. Not only is fluvoxamine a potent modulator of serotonin, 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 old “alarm system” for your body. A subset of “first responder” cells, which are widely distributed throughout your body, release cytokines to alert the immune system when nearby tissues are infected. Your body’s response is to mobilize resources to fight infection at its source – this includes increasing blood flow to the area, making it easier for disease-fighting immune cells to invade to kill infected tissue and clean up debris. . The combined effect of all of this is what we observe as inflammation.

Certain types of serious infections are marked by an excessive release of cytokines called a “cytokine storm”. In a cytokine storm, so many cytokines are released that the body’s inflammatory response is too strong. The resulting tissue destruction is more deadly than the infection itself. One type of disease marked by the cytokine storm is sepsis – a potentially fatal condition in which bacteria infect the bloodstream and spread rapidly throughout the body – another such condition is Covid-19. At the onset of the pandemic, the medical community recognized that at least some of the more serious symptoms of Covid-19 infection, including respiratory distress that landed patients in intensive care and often killed them , were caused by a cytokine storm in the lungs and other organs.

A brilliant drug!

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Less than a year before the Covid-19 pandemic, researchers showed that fluvoxamine could reduce the cytokine storm in an animal model of sepsis.2 When the pandemic struck, some astute clinicians put ‘two and two together’ and realized that if fluvoxamine could help reduce the cytokine storm in lab animals, maybe it could do the same in humans. with Covid-19. The study in Brazil, and a similar smaller study published about a year earlier,3 is the result – and while the results should be viewed with reasonable caution, they are based on solid scientific hypothesis, strong preclinical evidence, and appear promising in real-world human populations.

But there is more to this story than “fluvoxamine has anti-inflammatory properties that may help Covid patients.” It turns out that other antidepressants can also help. In fact, fluoxetine (Prozac), the grandfather of all SSRIs that is much more widely used, is also an activator of S1R. In a separate study 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 did not take these drugs.4

One possibility is that these effects are not mediated by activation of S1R, but by an entirely different “side property” of these drugs, all of which are potent inhibitors of an enzyme called acid sphingomyelinase. This is a normal cellular component that is 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 acid sphingomyelinase inhibitors – can inhibit Covid-19 infection in a lab dish (and amitriptyline actually works in humans too).5

As if that weren’t enough, there is strong evidence that fluoxetine, and possibly other SSRIs, can inhibit the activation of mast cells – one of the major cytokine-producing cells in the lungs of Covid-19 patients. – by inhibiting yet another receptor, for ATP.6

Finally, the main serotonin modulating activity of antidepressant drugs may itself be important in warding off some of the serious consequences of Covid-19. Another hallmark of Covid-19 infection is a hypercoagulable state in which clots spontaneously form to cause heart attacks – killing healthy tissue by suffocating small blood vessels. Platelets, the cell fragments of serum responsible for clotting, release serotonin to activate each other and form clots. But platelets don’t make their own serotonin, they depend on an enzyme to absorb it into the serum, and it’s the same enzyme inhibited by SSRIs. In fact, a side effect of chronic SSRI treatment is decreased blood clotting, which may be beneficial in Covid-19 infection.

The bottom line is that several antidepressants, not just fluvoxamine, can improve Covid infection outcomes by modulating inflammatory and other physiological responses outside of the brain. They do this by affecting serotonin, but also via other mechanisms that are generally not considered to be part of their primary mechanism of action. But it’s actually not much different from the way these drugs work for depression and anxiety – which we’re still learning about, and which certainly is. not by simply correcting a “serotonin deficiency” in the brain.7


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