Nearly a third of patients with an inflammatory disease may develop depression, which until recently has been attributed to their inability to cope with the disease. However, research on patients who are aided via immunotherapy has challenged this theory. Robert Dantzer, DVM, PhD, and Keith Kelley, PhD, believe that they have found strong evidence of a relationship between a molecular pathway in the brain and development of psychopathology.

“Depression is a risk factor for a bad outcome,” said Dr. Dantzer in an interview with Neuropsychiatry Reviews. “What our research is showing is that you have to put everything in a different perspective. The idea is that the depression is linked biologically to the disease. It is not just the way that the molecules are involved in the disease process but [that] the physiology of the disease acts on the brain and is responsible for depression. Actually, the severity of the disease will result in a higher risk for depression. So it’s a mirror image of the usual interpretation that people give of the association between depression and disease.” Dr. Dantzer is an Adjunct Professor of Psychoneuroimmunology in the Department of Animal Sciences, University of Illinois at Urbana–Champaign and Director of the Laboratory of Integrative Neurobiology at the University of Bordeaux, France.

The prevalence of depression in the general population is about 3% to 5%. In patients with chronic inflammation—such as occurs with coronary heart disease or type 2 diabetes mellitus—the prevalence of depression increases to between 12% and 30%. Immunotherapy, which involves the injection of cytokines, also causes depression in about a third of patients, noted Dr. Dantzer. Symptoms of depression begin within days to weeks of treatment and disappear when the treatment ends. Thus, Dr. Dantzer wanted to help patients avoid depression while they still benefited from the immune-boosting effects of cytokine treatments.

TRYPTOPHAN, CYTOKINES, AND DEPRESSION

Drs. Dantzer and Kelley conducted a series of experiments on mice to show how cytokine treatment causes serotonin depletion. They hypothesized that cytokines suppress serotonin by activating the enzyme indoleamine-2,3-dioxygenase (IDO) that catabolizes tryptophan. Dr. Dantzer explained that in the brain, IDO prevents tryptophan from being turned into serotonin, which causes decreased levels of serotonin and leads to the symptoms of depression.

“From clinical studies, we have learned that depressed patients either suffering from chronic inflammatory disorders or who are treated with cytokines have decreased plasma levels of tryptophan,” he said. “Second, we have observed that the enzyme responsible for that is induced not only at the periphery but in the brain.”

Dr. Dantzer pointed out that his current research is built on a concept that he had ignored a few years ago, which is the fact that the brain is representing what is going on in the body—“what we already knew for quite a long time, but in terms of inflammation, and it is doing that with the same molecules as the ones that are promoting inflammation at the periphery. If you have an inflammatory response in your body, it will be represented in the brain with exactly the same molecules that in your body are responsible for inflammation. This normally is responsible for what we call sickness behavior—why you feel sick and behave in a sick way when you are ill.”

ON TARGET FOR NEW TREATMENTS

Dr. Dantzer said that if his hunches are correct, then logical targets for decreasing the risk of depression in patients with inflammatory disorders are the cytokine system or the IDO enzyme to avoid both the decrease in serotonin and the generation of neuroactive compounds derived from tryptophan. For example, he said, antioxidants may be used in an effort to decrease free radicals, which may enhance the IDO activation. By suppressing the IDO activity, more tryptophan should be available to be converted to serotonin, he theorized. If antioxidant treatment proves effective in the mice, then humans eventually may benefit from the approach. “The main potential of clinical application is the discovery of new targets for drugs aiming at decreasing the risk of developing mood disorders when you are sick,” he said.

Treating all patients who will undergo interferon therapy with an antidepressant is not necessarily the right preventive solution, stressed Dr. Dantzer. It is not yet known whether antidepressant treatment will affect interferon treatment for the disease, he said—“in this case, the immune cells of the body and their ability to kill tumor cells. You are preventing the occurrence of depression with an antidepressant treatment, but at the same time this antidepressant treatment could also act on immune cells so that they are less able to do what they are supposed to do. My own advice would be to tell the clinician to try to identify those patients who are at risk for developing depression. We know that patients who are at risk for developing depression are already high in terms of depressed moods.”

—Colby Stong

Suggested Reading
Capuron L, Neurauter G, Musselman DL, et al. Interferon-alpha-induced changes in tryptophan metabolism: relationship to depression and paroxetine treatment. Biol Psychiatry. 2003;54:906-914.
Capuron L, Ravaud A, Miller AH, Dantzer R. Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy. Brain Behav Immun. 2004;18:205-213.

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