SSRIs should be considered for off-label use in high-risk covid patients, even though their exact way of working against the virus isn’t yet known.
It’s a little-known fact that one of the first antidepressants actually started out as a treatment for tuberculosis.
The monoamine oxidase inhibitor iproniazid led to improvements in wellbeing in patients with tuberculosis, and only later were its antidepressant effects explored and marketed.
Now another class of antidepressants is showing promise as anti-infectives in another pandemic. There’s growing observational and clinical trial evidence suggesting people with severe covid who are taking certain SSRI antidepressants – in particular, fluvoxamine and fluoxetine – appear to have better covid outcomes. But it’s not yet understood why.
The earliest evidence came from a randomised placebo-controlled trial involving 152 adults with symptomatic covid infection who weren’t hospitalised and also didn’t have major risk factors for severe disease. This study, which took place in 2020, found none of the patients given 15 days’ treatment with fluvoxamine deteriorated, while 8.3% of those in the placebo group did.
Not long after that study was published, an observational study among 7320 adults hospitalised with covid found a 44% reduction in the risk of intubation or death among patients who were given any antidepressant within 48 hours of admission. Since then, several other observational and interventional trials have found reduced risk of hospitalisation, intubation, and mortality from covid in patients treated with or taking SSRI antidepressants – in particular, fluoxetine and fluvoxamine.
One of the most recent studies – the TOGETHER multi-platform randomised placebo-controlled trial in nearly 1500 adults – showed a 91% reduction in covid mortality and 32% reduction in the risk of remaining in emergency for more than six hours or being transferred to a tertiary hospital.
While it’s tempting to think that antidepressants might be achieving better covid outcomes simply by improving patients’ mental health, there are actually several independent – and much faster-acting – mechanisms by which these drugs may be directly interacting with SARS-CoV-2 and altering its impact.
“The reason why we looked at fluvoxamine in the first place was because it’s a strong sigma-one receptor agonist and that gives it strong anti-inflammatory effects,” says Professor Angela Reiersen, associate professor of psychiatry at the Washington University School of Medicine in St Louise, United States. There have also been mouse studies suggesting the drug could reduce sepsis mortality through targeting this receptor.
Fluvoxamine isn’t the only SSRI that interacts with the sigma-one receptor, but it’s the most potent agonist, Professor Reiersen says, closely followed by fluoxetine. Fluvoxamine is also relatively unique in inhibiting the metabolism of melatonin, thereby increasing the levels of this anti-inflammatory compound.
SSRIs generally may also be reducing the hypercoagulation seen in patients with severe covid by inhibiting platelet function and decreasing mast cell activation, both of which contribution to coagulation.
A third mechanism involves the enzyme acid sphingomyelinase and has a direct effect on the virus rather than the disease it causes. “Drugs that reduce the activity of this particular enzyme decrease the production of ceramide, which is a molecule that tends to be in the outer membrane of cells, and if there’s more ceramide there, it makes it easier for the virus to get into the cell,” Professor Reiersen says.
Professor Edward Mills, from the Department of Health Research Methods, Evidence and Impact at McMaster University in Canada – who was involved with TOGETHER trial – said even though the study was blinded, it was clear that some patients in trial were responding better than others.
With the subgroup analysis of the study finding no clear signal that any one type of patient was more likely to benefit from fluvoxamine than any other, the question was how fluvoxamine might be used, particularly with drugs such as Paxlovid (nirmatrelvir-ritonavir) now available.
“The whole thing of repurposed medicines … is they’re useful until you’ve got a direct-acting drug,” Professor Mills told The Medical Republic. “Paxlovid is a very powerful drug, and in many ways, fluvoxamine isn’t that relevant in the era of Paxlovid.”
However, he said fluvoxamine was probably a better covid treatment than molnupiravir, and could also be vital in regions where an expensive drug such as Paxlovid was not yet widely available.
There are further trials under way – for example, combining fluvoxamine with an inhaled steroid – and Professor Mills argues that drugs that act as “broad-spectrum” anti-inflammatories, as is speculated for SSRIs such as fluvoxamine, could be useful in dealing with future infectious disease outbreaks where inflammation is a major component of severe disease.
Fluvoxamine and other SSRIs are not yet officially approved or indicated for use in treating covid. Professor Reiersen and colleagues have submitted an application for emergency use authorisation for fluvoxamine in the US, and are also planning further randomised controlled trials, including one for treatment of long covid.
But given the drug’s safety – particularly for such a short course – and its availability, Professor Reiersen would like more clinicians to consider it as an off-label option for high-risk patients in the early stages of covid infection: “There’s no reason why, just because it’s a psychiatric drug, that that it shouldn’t be used for other purposes.”
