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In a nutshell
- Scientists discovered that fluoxetine (Prozac) protects against deadly infections in two ways: by directly fighting bacteria and by helping organs resist damage during severe infections – effects completely unrelated to its antidepressant properties
- The protection works independently of serotonin, the brain chemical typically targeted by antidepressants, suggesting this common medication has previously unknown mechanisms for fighting infection
- While the research was conducted in mice and requires human trials, the findings are particularly promising because fluoxetine is already FDA-approved and has a well-established safety record spanning three decades
LA JOLLA, Calif. — A medication best known for treating depression may be a powerful new weapon against severe infections. Scientists at the Salk Institute have discovered that fluoxetine, commonly sold as Prozac, not only helps fight bacterial infections but also protects vital organs from the collateral damage of severe infection in a mouse model of sepsis. This dual action could have significant implications for future treatments.
While doctors have long struggled to treat sepsis effectively, this research, published in Science Advances,points to a possible new approach using a drug that’s been safely prescribed for over 30 years.
“When treating an infection, the optimal treatment strategy would be one that kills the bacteria or virus while also protecting our tissues and organs,” says Professor Janelle Ayres, holder of the Salk Institute Legacy Chair and Howard Hughes Medical Institute Investigator, in a statement. “Most medications we have in our toolbox kill pathogens, but we were thrilled to find that fluoxetine can protect tissues and organs, too. It’s essentially playing offense and defense, which is ideal, and especially exciting to see in a drug that we already know is safe to use in humans.”
The timing is particularly relevant given recent findings that SSRI users experienced less severe COVID-19 infections and were less likely to develop long COVID. This broader protective effect against different types of infections suggests these drugs might help enhance global preparedness for future pandemics.
Sepsis develops when an infection triggers an overwhelming response from the body’s immune system. This excessive reaction can quickly spiral out of control, damaging vital organs and often leading to death. Current treatments mainly focus on fighting the infection with antibiotics, but suppressing the immune response can backfire by making patients more vulnerable to their initial infection or susceptible to new ones.
The research team, led by Robert Gallant, a former graduate student researcher in Ayres’ lab, found that mice treated with fluoxetine before developing sepsis had much better survival rates than untreated mice. Eight hours after infection, treated mice showed lower bacterial levels, indicating the drug helped control the infection directly. But what really caught the scientists’ attention was how the drug provided additional protection beyond just fighting bacteria.
Fluoxetine boosted levels of an anti-inflammatory molecule called IL-10, which prevented dangerous accumulations of fatty substances in the blood, a condition called hypertriglyceridemia. This helped the heart maintain proper function during infection. Importantly, these protective effects worked independently of the drug’s bacteria-fighting properties, demonstrating true dual-purpose potential.
Perhaps most surprisingly, these benefits had nothing to do with serotonin, the brain chemical typically targeted by fluoxetine when used as an antidepressant. Mice without circulating serotonin still experienced the same infection-fighting benefits from the drug.
“That was really unexpected, but also really exciting,” says study first author Robert Gallant, a former graduate student researcher in Ayres’ lab. “Knowing fluoxetine can regulate the immune response, protect the body from infection, and have an antimicrobial effect—all entirely independent from circulating serotonin—is a huge step toward developing new solutions for life-threatening infections and illnesses. It also really goes to show how much more there is to learn about SSRIs.”
During the experiments, treated mice maintained better organ function across the board. Their hearts worked more efficiently, their livers showed less damage, and their immune systems achieved a better balance between fighting infection and preventing self-inflicted damage.
“Fluoxetine, one of the most prescribed drugs in the United States, is promoting cooperation between host and pathogen to defend against infection-induced disease and mortality,” says Ayres, who also heads the Molecular and Systems Physiology Laboratories at Salk. “Finding dual protective and defensive effects in a repurposed drug is really exciting.”
However, there’s still much work to be done before fluoxetine could be used to treat sepsis in humans. The study only looked at mice, and the strongest benefits appeared when the drug was given before infection — something that wouldn’t typically happen in real-world cases. The research team is now exploring appropriate dosing regimens for patients who already have sepsis and investigating whether other SSRIs might have similar protective effects.
Paper Summary
Methodology
The research team studied female mice around 3 months old, dividing them into groups that either received daily fluoxetine treatments or a placebo for one week. They then introduced bacteria known to cause sepsis and monitored multiple health indicators, including survival rates, organ function, and various biological markers. To understand how fluoxetine worked, they conducted additional experiments with mice lacking circulating serotonin and measured levels of different inflammatory molecules and bacteria in various organs.
Results
Mice receiving fluoxetine before infection showed significantly better outcomes across several measures. They had lower bacterial levels in their organs, better heart and liver function, and improved survival rates. The drug worked through two separate mechanisms: directly fighting bacteria and helping the body maintain better control over inflammation and metabolism during infection. Importantly, these benefits occurred even in mice lacking serotonin, showing the effects were independent of the drug’s antidepressant action.
Limitations
The study focused only on female mice, so results might differ in males or humans. The protective effects were strongest when fluoxetine was given preventively, which isn’t typical in clinical situations. While the research examined specific bacterial infections, the benefits might not extend to all types of infections or sepsis cases.
Discussion and Takeaways
This research reveals fluoxetine’s unexpected dual role in fighting infection – both attacking bacteria directly and helping the body protect itself from damage during severe infections. This common antidepressant appears to work through previously unknown mechanisms unrelated to its effects on serotonin and mood. These findings could lead to new treatment strategies for sepsis and other serious infections.
Funding Sources
The research received support from multiple National Institutes of Health grants (DPI AI144249, R01 AI14929, F31 AI169988, T32 GM007240-43, T32 GM133351, NCI CCSG: P30CA014195) and the NOMIS Foundation. The authors declared no competing interests.
Publication Details
The study, “Fluoxetine promotes IL-10–dependent metabolic defenses to protect from sepsis-induced lethality,” was published in Science Advances on February 14, 2025. The research represents collaborative work from scientists at the Salk Institute and the University of Washington.
