Depression: An Evolutionary Byproduct of Immune System? --- Emory University research

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http://www.sciencedaily.com/releases/2012/03/120301103756.htmScienceDaily (Mar. 1, 2012) — Depression is common enough -- afflicting one in ten adults in the United States -- that it seems the possibility of depression must be "hard-wired" into our brains. This has led biologists to propose several theories to account for how depression, or behaviors linked to it, can somehow offer an evolutionary advantageSome previous proposals for the role of depression in evolution have focused on how it affects behavior in a social context. A pair of psychiatrists addresses this puzzle in a different way, tying together depression and resistance to infection. They propose that genetic variations that promote depression arose during evolution because they helped our ancestors fight infection.An outline of their proposal appears online in the journal Molecular Psychiatry.The co-authors are , MD, P. Timmie professor of psychiatry and behavioral sciences at Emory and director of psychiatric oncology at Winship Cancer Institute, and Raison, MD, previously at Emory and now at the University of Arizona.For several years, researchers have seen links between depression and inflammation, or over-activation of the immune system. People with depression tend to have higher levels of inflammation, even if they're not fighting an infection."Most of the genetic variations that have been linked to depression turn out to affect the function of the immune system," says. "This led us to rethink why depression seems to stay embedded in the genome.""The basic idea is that depression and the genes that promote it were very adaptive for helping people -- especially young children -- not die of infection in the ancestral environment, even if those same behaviors are not helpful in our relationships with other people," Raison says.Infection was the major cause of death in humans' early history, so surviving infection was a key determinant in whether someone was able to pass on his or her genes. The authors propose that evolution and genetics have bound together depressive symptoms and physiological responses that were selected on the basis of reducing mortality from infection. Fever, fatigue/inactivity, social avoidance and anorexia can all be seen as adaptive behaviors in light of the need to contain infection, they write.The theory provides a new explanation for why stress is a risk factor for depression. The link between stress and depression can be seen as the byproduct of a process that preactivates the immune system in anticipation of a wound, they write.Similarly, a disruption of sleep patterns can be seen in both mood disorders and when the immune system is activated. This may come from our ancestors' need to stay on alert to fend off predators after injury, says. and Raison's theory could also guide future research on depression. In particular, the presence of biomarkers for inflammation may be able to predict whether someone will respond to various treatments for depression. and Raison are involved in ongoing research on whether certain medications, which are normally used to treat auto-immune diseases, can be effective with treatment-resistant depression.Further infoA Study of Infliximab for Treatment Resistant Major Depressionhttp://clinicaltrials.gov/ct2/show/NCT00463580#miller%20infliximab%20depressionMajor depression is increasingly recognized to be a chronic and highly recurrent condition, which results in significantly increased health problems. One possible mechanism that may contribute to treatment resistance is increased production and release of chemicals called proinflammatory cytokines in patients with major depression. These chemicals mediate the body's response to infectious agents like bacteria and have been shown to be increased by psychological stress. They produce the symptoms that we associate with being sick, including fever, malaise and changes in sleep and appetite. Several lines of evidence indicate that proinflammatory cytokines may contribute to the development of major depression and may thus represent a novel target for the pharmacological treatment of the disorder.The TNF-alpha antagonist, Infliximab(Remicade®), is an infusion style drug approved by the FDA for the treatment of inflammatory conditions like Crohns disease and rheumatoid arthritis. We are conducting a study to see if the infliximab (Remicade®) is more effective than placebo in acutely reducing symptoms of depression in patients who have elevated proinflammatory markers and have not responded to, or been unable to tolerate, at least two previous treatments in the current depressive episode. Proinflammatory markers are measured by a simple blood test for C-Reactive Protein(CRP)levels in the body.After appropriate screening to determine eligibility, 64 subjects with treatment resistant depression will be randomized to receive three infusions of either infliximab(Remicade®)or placebo(salt water) in the Emory Infliximab Infusion Center in the Division of Digestive Diseases, Emory University School of Medicine. Subjects will be followed for 12 weeks with evaluations at weeks 0 (baseline), 1, 2, 3, 4, 6, 8, 10 and 12. The first infliximab(Remicade®)infusion will occur at the first (Baseline) visit. The second infusion will occur at Study Week 2 (the third visit). The third infusion will occur at Study Week 6 (Visit 6). The choice of three infusions, and the infusion schedule, is based on current recommendations for the use of infliximab(Remicade®)in conditions for which it has received FDA approval. Subjects will be evaluated for twelve weeks by trained clinicians for changes in depression symptoms and improvements in quality of life. In addition, a physician will evaluate subjects each visit to make sure they are remaining healthy. Blood will be withdrawn at baseline prior to infusion and all subsequent visits to check labs for safety but also to evaluate potential relationships between changes in inflammatory activity and therapeutic response. After Study Week 12, participants will be monitored by phone, every 4 weeks during the 22-Week Post Study Follow-up Phase to assess physical and psychiatric symptoms in the period following the final infusion. At the baseline and Week 8 visits, subjects will be admitted to the Atlanta Clinical Translational Science Institute(ACTSI),a research unit in the Emory Hospital, for an extended evaluation. The purpose of coming to the ACTSI will be for researchers to evaluate whether treatment with infliximab improves endocrine function, inflammation, sleep and thinking abilities in people who are depressed. For all other visits (Week 1, 2, 4, 6, 10 and 12), participants will come for an office visit in the Winship Cancer Institute.