Depression May Be Caused By 'Allergy' to Stress

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An over-excited immune system may explain why some people are susceptible to depression, according to new research on mice.

Mice whose immune systems responded to stress by overproducing an inflammatory compound called Interleukin-6 were more likely to become the mousy versions of depressed than mice with non-overactive immune systems, the research found. This same compound is elevated in depressed humans, said study researcher Georgia Hodes, suggesting hope for new depression treatments.

"There's probably a subset of people with depression who have this over-sensitive inflammatory response to stress and that this is leading to the symptoms of depression," Hodes, a postdoctoral researcher at the Mount Sinai Medical Center in New York, told LiveScience.

Hodes added that stress could be thought of as an allergen, like pet dander, with the over-reactive immune system making you depressed rather than giving you runny nose.

"In some ways, it is an analogy to an allergy," Hodes said. "You have something that is not really dangerous, but your body thinks it is, so you have this massive immune response. In this case, the stressor is what they're having this massive immune response to."

Some of the symptoms of depression — lack of energy, loss of appetite — mirror the body's response to physical illness, Hodes noted.

The immune system and depression

Interleukin-6, or IL-6, is a cytokin, a molecule used for cell-to-cell communication that is important in immune response. Researchers have found elevated levels of this cytokin in the blood of people with depression, but it hasn't been clear whether IL-6 is the result of the disorder or one of the causes. [Top 10 Controversial Psychiatric Disorders]

Hodes and her colleagues investigated the question by exposing mice to larger, meaner and older male mice. They first measured the younger mice's IL-6 levels right after an initial meeting — which was usually quite stressful, and often involved the younger mouse getting pinned down or bitten by the older.

The researchers continued exposing the young mouse to the older mouse for 10 days, a process called repeated social defeat stress. After 10 days, the young mouse was put in an open space with an empty cage. The researchers timed how long the animal investigated the empty cage, and then put a new, aggressive mouse in the cage and timed how long the younger mouse investigated him.

Healthy mice will explore a caged comrade, Hodes said, but most mice exposed to repeated social defeat will steer clear, a type of social withdrawal that can indicate "depression" for mice. The researchers also measured how much sugar water the stressed mice drank. Healthy mice love sweet liquids, but depressed ones don't seek it out, just as depressed people may fail to find joy in the things that usually make them happy.

Treating stress susceptibility

The stressed-out mice showed different responses to the caged aggressor in the final test. Some cowered far from the cage, while others investigated the caged mouse. This behavior was linked to IL-6, the researchers found: The mice that had shown a major spike in IL-6 during their first encounter with an aggressor were the ones cowering in a corner. The mice with less-severe immune responses initially acted normal.

Next, the researchers blocked the action of IL-6 with a drug that prevents the cytokin from traveling from the body to the brain. They found that the drug made stress-susceptible mice act normal.

"We were able to show that those animals became resilient and didn't show susceptibility to the stressor," Hodes said.

Finally, the researchers wanted to be certain the effects they were seeing could be traced to the immune system and the immune system alone. So they irradiated the bone marrow of non-susceptible mice and gave them bone marrow transplants from the susceptible rodents. Because the bone marrow is where new immune cells are built, this had the effect of giving otherwise normal mice a stress-susceptible immune system.

Sure enough, the transplanted mice started acting just like their depression-prone counterparts. The researchers will report their results Tuesday (Oct. 16) at the annual meeting of the Society for Neuroscience in New Orleans.

Some of the drugs used in the study to dampen that immune response are already on the market to treat rheumatoid arthritis in humans, she said. That means they could easily be tested for use in depression. The researchers are now working with mice genetically altered not to produce IL-6 to investigate whether those animals can be used as bone marrow donors to cure stress-susceptible mice.

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