While effective COVID-19 vaccines continue to be approved and distributed worldwide, these injections are only one step of a multistep process to control the devastation caused by the pandemic. Even with millions of people receiving COVID-19 vaccines, the virus will continue to spread, and viral mutations will keep testing the efficacy of available vaccines. Many public health experts say that identifying medications that can prevent people from developing severe COVID-19 illness is also important—particularly treatments that are inexpensive and widely available.
Some recent data show that antidepressants—especially the selective serotonin reuptake inhibitor (SSRI) fluvoxamine—might fit the bill. In late 2020, JAMA published a report describing how adults with COVID-19 who were given fluvoxamine for 15 days were much less likely to have worsening symptoms and require hospitalization than those given placebo. In fact, of the 80 participants who received fluvoxamine, none experienced clinical worsening (compared with 8% of patients who received placebo).
Lead study author Eric Lenze, M.D., the Wallace and Lucille K. Renard Professor of Psychiatry at Washington University School of Medicine in St. Louis, cautioned that larger trials with longer follow-up periods are needed. But he said that he was encouraged by the strong preliminary data that seemed to suggest the medication was well tolerated by the patients. He and colleagues in the United States and Canada are now conducting a larger trial involving about 1,100 patients.
Why Fluvoxamine?
The seeds of this potential COVID-19 breakthrough began last spring, as researchers noticed that severe COVID-19 illness was precipitated by a rapid release of inflammatory molecules called cytokines.
Angela Reiersen, M.D., M.P.E., an associate professor of child psychiatry at Washington University, read about these “cytokine storms” and recalled some of her clinical work with people with Wolfram syndrome—a rare inherited disorder characterized by childhood-onset diabetes; vision loss; and neuropsychiatric problems, including anxiety and depression.
Reiersen had found that some antidepressants seemed less effective at treating depression in patients with this disorder. She hypothesized that the reason might be due to the medications’ targeting of a protein called sigma-1 receptor (S1R), which regulates an important cellular stress response to infection that is dysregulated in Wolfram syndrome. Antidepressants that turned this receptor on seemed to reduce depressive symptoms in patients with Wolfram syndrome, while those that inhibited S1R did not. Also, a study from the University of Virginia had shown that activating S1R could reduce cytokine production and the severity of sepsis (excess inflammation in response to bacterial infection) in mice, and Reiersen surmised that S1R-activating antidepressants might be able to prevent COVID-induced inflammation and subsequent clinical worsening.
She connected with Lenze, who was looking to repurpose psychiatric medications as potential COVID-19 therapeutics, and the two wrote a protocol in 24 hours for a clinical trial.
Lenze and Reiersen picked fluvoxamine since it offered many advantages: the drug has a strong affinity for S1R; is highly fat soluble, which enables higher concentrations to reach organs like the lungs or the brain; and has a lower risk of cardiac side effects compared with other SSRIs.
Evidence Other SSRIs Work
Fluvoxamine may not be the only antidepressant that can help patients with COVID-19.
Nicolas Hoertel, M.D., Ph.D., M.P.H., an associate professor of psychiatry at the University of Paris, noticed early in the pandemic that patients in the geriatric psychiatry clinic where he worked did not seem to be getting as severely ill from COVID-19 as others in the city. This was despite the patients’ being at a higher risk of a poor COVID-19 prognosis given their older age and medical comorbidities.
Like Lenze and Reiersen, Hoertel reasoned that antidepressants might be reducing inflammation in these patients. He and colleagues tested this hypothesis by examining the medical records from over 7,200 adults who were admitted with COVID-19 to one of the 39 hospitals in Paris’ public hospital system.
The analysis, which was published in Molecular Psychiatry, showed that hospitalized COVID-19 patients who took antidepressants at the time of their admission were about 40% less likely to die or require intubation than other hospitalized COVID-19 patients. Several SSRIs seemed to offer the strongest protection, particularly fluvoxamine’s close relative fluoxetine, which reduced intubation or death by 70%. (Fluvoxamine is rarely used in Europe so Hoertel had no data for that drug.)
Not every antidepressant was effective against COVID-19, however, and Hoertel’s team could not find an underlying connection to point to why this might be. For example, mirtazapine—a potent S1R activator—seemed to offer no benefit, whereas sertraline—an S1R inhibitor—did.
A few months after Hoertel released his preliminary findings, Erich Gulbins, M.D., Ph.D., director of the Institute for Molecular Biology at the University of Duisburg-Essen in Germany, reached out.
“He told me that all the antidepressants that worked were strong inhibitors of an enzyme called acid sphingomyelinase,” he said. Basically, this enzyme breaks down some of the fatty molecules on cell surfaces, which makes them more permeable; the COVID-19 virus exploits this enzyme to facilitate its invasion of cells. “The antidepressants were effectively blocking the virus from gaining entry,” Hoertel said.
Factors for Prescribers to Consider
Joshua Rosenblatt, M.D., a consultation-liaison psychiatrist and assistant professor of psychiatry at the University of Toronto, finds the theory that antidepressants are keeping COVID-19 from entering cells intriguing, though he thinks anti-inflammatory mechanisms are a main source of effect.
“Another theory that has been raised is that antidepressants reduce sickness behavior,” he said. “When people start to develop COVID-19 symptoms, they may find it harder to get out of bed or eat enough, which can make the illness worse.” Antidepressants may reduce feelings of fatigue and encourage people with mild illness to be more active.
Regardless of the mechanism behind why patients given antidepressants have a less severe response to COVID-19, the clinical potential could be tremendous, Lenze noted. “None of these mechanisms directly target the virus,” he said. “Therefore, viral mutations should not reduce the effectiveness of antidepressants.”
Rosenblatt, whose research focuses on mood disorder pharmacology, thinks antidepressants could be useful to mitigate the damage of large COVID-19 outbreaks, as these medications are cheap and readily available. Such a scenario unfolded last Thanksgiving at the Golden Gate horse race track in Berkeley, Calif. After more than 100 staff got infected in a super-spreader event, the track physician, David Seftel, M.D., offered fluvoxamine to infected workers; of the 65 who accepted, none required hospitalization.
“The earlier someone with COVID-19 symptoms receives these drugs, the better,” Hoertel said. “However, I would not suggest people take antidepressants solely as a prophylactic.”
Lenze also recommended against psychiatrists and other physicians shifting patients who are stable on other antidepressants to the antidepressants that appear to reduce the severity of COVID-19. “I’ve had some colleagues ask whether they should switch their patients to fluvoxamine since it might offer COVID-19 protection, and my response is if patients are responding to their current treatment, there is no need to switch,” he said.
Reiersen added that there might be a rationale for psychiatrists to prescribe luvoxamine to patients who have been infected with COVID-19, since the virus has been linked with lingering health problems related to inflammation. However, there are still many biological questions about the relationship between antidepressants and COVID-19. “Much of modern psychopharmacology owes itself to infectious medicine,” Lenze said, noting that the tuberculosis drug iproniazid was the forebear of modern antidepressants. “It’s time we returned the favor.” ■
“Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial” is posted
here.
“Association Between Antidepressant Use and Reduced Risk of Intubation or Death in Hospitalized Patients With COVID-19: Results From an Observational Study” is posted
here.