Antidepressant could stop deadly sepsis

An antidepressant drug used to treat obsessive-compulsive disorder could save people from deadly sepsis, new research suggests.

Sepsis is a significant cause of death around the world. The federal Centers for Disease Control and Infection calls it "the body's extreme response to an infection." Essentially, the body's immune response spirals out of control, and the normally beneficial inflammation becomes harmful. The result can be tissue damage, organ failure or even death.

"Sepsis is very dangerous. In the U.S., 1.7 million get it every year, and 270,000 people die," said the senior author. "Once you get diagnosed, you have a high chance of mortality. And there is no good treatment. Basically, we will try to keep you alive and monitor you as much as we can. So clearly there is a critical need for treatment."

The authors identify the ER-resident protein sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sublethal challenge in two models of acute inflammation.

Mechanistically, authors find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression but does not inhibit the classical inflammatory signaling pathways.

The team has identified a drug that could offer that treatment - and previous safety testing of the drug could fast-track it into use in hospitals around the country. The researchers were looking at a little-studied biological process inside our cells when they determined it has an important role in regulating inflammation. They began studying it partly because there are already drugs that can affect players in the process.

To evaluate the potential of one drug, the antidepressant fluvoxamine, to stop sepsis, the team tested it in a mouse model of the disease. The drug worked very effectively, they found. Fluvoxamine protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes.

While the drug will need to be tested in people to determine its effectiveness at battling human sepsis, previous testing to determine its safety should accelerate that process.

The senior hypothesizes that the same biological process could be targeted to generate beneficial inflammation when needed, such as in immunocompromised people. "By inhibiting the receptor, we could activate inflammation in conditions where patient don't have a proper inflammatory response," the senior author said.