Molecular pathway in the brain may explain why some patients suffering from inflammatory diseases develop depression

Feeling sick can be "all in the head" for people with inflammatory disorders or for those receiving immunotherapy, say Robert Dantzer and Keith Kelley, professors in the department of animal sciences at the University of Illinois at Urbana-Champaign.

"For the first time, we have evidence of a strong relationship between a molecular event and the development of psychopathology," Dantzer said.

The two scientists, who have collaborated for 25 years, have identified how a molecular pathway in the brain may explain why some patients suffering from inflammatory diseases develop depression. "The goal of our research is to understand the mechanisms that are responsible for causing depression in patients with inflammatory diseases," Dantzer said.

Depressive disorders occur in 12 to 30 percent of patients who suffer from various diseases with an inflammatory component, including coronary heart disease and autoimmune diseases such as rheumatoid arthritis and inflammatory bowels. These mood disorders usually are attributed to psychological problems encountered by patients having to deal with the suffering and disability brought about by their diseases.

However, Dantzer and Kelley explained, research on patients whose immune systems are boosted by immunotherapy challenge this view and suggest that depression may originate in the immune system.

Immunotherapy is used to treat patients who suffer either from kidney cancer or melanoma with metastasis, or from viral infections such as hepatitis C and AIDS.

"A few thousand cancer patients and several hundreds of thousands of hepatitis C patients are treated each year with immunotherapy," Dantzer said.

Immunotherapy involves the injections of cytokines, which are chemicals normally made by immune cells that boost the immune system to fight infectious pathogens and kill cancer cells. Unfortunately, immunotherapy also causes depression in 33 percent of patients, as reported by Dantzer in 2002.

Symptoms of depression begin within days to weeks of beginning treatment and vanish once it ends. "The occurrence of depression in cytokine-treated patients indicates that treatment must be discontinued since depressed patients can commit suicide," he said.

For about 30 years, depression has been linked to low levels of serotonin, a brain chemical that regulates mood. Drugs called selective serotonin reuptake inhibitors (SSRIs) such as Prozac ease depression by elevating serotonin levels.

"Although SSRIs can be used to treat immunotherapy-induced depression, they are not 100 percent effective and will not prevent suicide in patients with suicidal thoughts," Dantzer said. "Clinical studies are investigating whether SSRI treatment could be used in a preventative manner if it were possible to identify in advance those vulnerable patients."

Since the 1980s, medical professionals have observed that patients treated with cytokines experience a greater occurrence of depression. Until recently, the mechanisms of depression during cytokine therapy have remained unclear. By exploring potential mechanisms, Dantzer and Kelley hope to help patients avoid depression while benefiting from the immune boosting effects of cytokine treatments.

This summer, they started a series of experiments on mice, whose immune responses are similar to those in humans, to show how cytokine treatment causes serotonin depletion. The work is funded by a newly awarded $1.7 million five-year grant from the National Institute of Mental Health.

Dantzer and Kelley hypothesize that cytokines suppress serotonin by activating an enzyme called indoleamine-2,3-dioxygenase (IDO) that catabolizes tryptophan, an essential amino acid provided by ingested food. In the brain, IDO prevents tryptophan from being turned into serotonin, which causes decreased levels of serotonin and leads to the symptoms of depression.

Dantzer and Kelley will seek to identify specific brain areas where cytokines activate IDO and where serotonin levels differ. They theorize that the same brain areas related to depression will show increased IDO activation and decreased serotonin levels.

They also will evaluate potential treatments that may ease cytokine-caused depression. Oxidizing agents and free radicals activate IDO. Antioxidants will be used in an effort to decrease the free radicals, which may decrease the IDO activation.

By suppressing the IDO activity, tryptophan should be available to be converted to serotonin, the researchers believe. If antioxidant treatment proves effective in the mice, then human patients eventually may benefit from the approach.

A research technician, a postdoctoral fellow and two graduate students will perform the experiments during the next five years. Undergraduate students also will be given opportunities to help in the lab work.

"One of the best ways to expand this field is to encourage undergraduates to participate," Kelley said. "Experience in our lab opens doors of veterinary, medical and graduate schools. It’s one thing to have a great grade-point average and solid test scores, but to also have your name on a paper published in a peer-reviewed journal is remarkable."

Recent work by Dantzer and Kelley was sparked by the observation by Dr. Andrew Miler, a psychiatrist at Emory University, that Prozac lessens the level of depression in patients receiving immunotherapy.

In 2002, Dantzer, in a paper published in the journal Molecular Psychiatry, reported why cytokines cause depression. He found that cancer patients treated with cytokines had decreased blood levels of tryptophan. As tryptophan levels decreased, the severity of depression increased. That finding compelled Dantzer and Kelley to study how cytokines induce depression.

"We have always known that behavioral changes accompany sickness," Kelley said. "For example, sickness will cause a person to sleep and eat less. Over the past 25 years, Robert and I have studied why sickness causes those behavioral changes."

The work by Dantzer and Kelley is part of a growing trend of laboratory research that is melding the fields of immunology, psychology, neuroscience and biochemistry. They hope to expand the immunology field at Illinois by developing a program for integrative immunology and behavior.

"Right now at the University of Illinois, there are seven professors and research associates with nearly $12 million in grants in the area of integrative immunology and behavior," Kelley said. "We plan to use that financial base as a foundation to write a program project grant proposal that will fund graduate students and postdocs to study integrative immunology and behavior."

Since they first met in 1979, Dantzer and Kelley have combined their training in veterinary medicine, psychology, immunology, physiology and biochemistry to produce 95 published papers. They often build upon their complementary strengths. "Robert will dream of such ideas as how hope affects healing, and I will think of how to test those ideas," Kelley said.

In a landmark study published in 1992, Dantzer and Kelley were the first researchers to observe that mice develop a fever and display sickness-related behavior when cytokines are administered directly to the brain. "Previously, it was believed that sickness only occurs below the neck and the brain had nothing to do with it," Kelley said.

In another study in mice, Dantzer and Kelley found that when one of the neuronal pathways from the body to the brain is severed, cytokines do not cause sickness behavior.

"Signals from the immune system that indicate sickness do not reach the brain, so the brain does not know that it should show behavioral symptoms of sickness," Kelley said.

A growing number of scientists consider the immune system a sixth sense. "We can’t touch, smell, taste, see or hear a virus," Kelley said, "but we have an organ that senses and responds to infectious pathogens, and transmit this information to the brain. That organ is our immune system."

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