Treatments and Their Effects The Role of Inflammation in the Pathophysiology of Depression : Different

Compelling evidence suggests that inflammation contributes to the development of depression. Many depressed individuals have higher levels of proinflammatory mediators, which appear to interact with many of the pathophysiological domains of depression, including neuroendocrine function, neurotransmitter metabolism, and synaptic plasticity. This is further supported by observation that therapeutic administration of interferon-α (IFN-α) leads to depression in a significant proportion of patients. These findings suggest that targeting proinflammatory cytokines and their signaling pathways may represent a unique therapeutic opportunity to treat depression and related conditions, such as labile anger, irritability, and fatigue. (J Rheumatol 2011;38 Suppl 88:48–54; doi:10.3899/ jrheum.110903) Key Indexing Terms: INFLAMMATION DEPRESSION INTERFERON From the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; University of Manitoba, Winnipeg, Manitoba; The University of Western Ontario, London, Ontario, Canada; and Sanford Burnham Medical Research Institute, La Jolla, California, USA. Supported by an unrestricted grant from Abbott Canada. Dr. Lotricht is supported by NIMH and NARSAD. Dr. Guenther has acted as consultant for Abbott Laboratories, Amgen Canada, Galderma Canada, LEO Pharma, Janssen, Schering-Plough Canada, and Wyeth; and has received investigator-initiated study support from Astellas Pharma Canada; and contract research support from Abbott Laboratories, Amgen Canada, Astellas Pharma Canada, Celgene Corporation, Centocor Ortho Biotech, EMD Serono Canada, Galderma Canada, Isotechnika, Janssen-Ortho, LEO Pharma, Novartis Pharmaceuticals Canada, Pfizer, Schering-Plough Canada, and Stiefel Laboratories. F.E. Lotrich, MD, PhD, Assistant Professor, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine; H. El-Gabalawy, MD, FRCPC, Professor of Medicine and Immunology, University of Manitoba; L.C. Guenther, MD, FRCPC, Professor and Chair, Division of Dermatology, The University of Western Ontario; C.F. Ware, PhD, Director, Infectious and Inflammatory Diseases Center, and Professor, Laboratory of Molecular Immunology, Sanford Burnham Medical Research Institute. Address correspondence to Dr. F.E. Lotrich, University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, 3811 Ohara Street, Pittsburgh, PA 15123, USA; E-mail: lotrichfe@upmc.edu. Major depression, according to the World Health Organization, is a leading cause of disability worldwide1. With an annual prevalence of approximately 7% and lifetime prevalence of 16%, depression carries a significant burden to patients and society2,3. Depression is also associated with an increased risk of premature mortality4,5. While many depressed patients (up to 1% of women and 7% of men) eventually commit suicide6, the condition is also highly comorbid with medical disorders that are associated with increased mortality, such as cancer and some cardiovascular and autoimmune diseases7,8,9. Although current antidepressants lead to some response in many cases, most patients are partially or completely unresponsive to treatment10. This is partly because the pathophysiology of depression has not been elucidated and currently available treatments do not effectively target all the pathological processes that are responsible for the major symptoms of depression. Thus, there is an urgent need to identify novel pathological pathways relevant to depression upon which new conceptual frameworks and targets to improve treatment outcomes can be built. In recent years, significant attention has been directed at the relationship between the brain and peripheral organs. One promising development in this area is the emergence of inflammation and an activated immune system as common underlying mechanisms in the development of many neuropsychiatric diseases, including major depression. The aim of this article is to provide an overview of recent evidence in support of this hypothesis. EVIDENCE FOR INCREASED INFLAMMATION IN DEPRESSION: THE ROLE OF PROINFLAMMATORY CYTOKINES Patients with major depression, with or without other medical illness, have been found to have activated inflammatory pathways11. This includes elevations in relevant proinflammatory cytokines and acute-phase proteins, as well as increased expression of their biomarkers, including chemokines and adhesion molecules12. It is important to note that inflammatory markers have been found in the peripheral blood circulation and in the cerebrospinal fluid (CSF), suggesting that the brain is directly influenced by peripherally derived mediators12,13. The effect of cytokines from the periphery on the brain is somewhat surprising due to the lack of specific transporters for larger peptides and proteins, such as cytokines at the blood-brain barrier. However, recent experimental evidence suggests at least 3 possible pathways by which such molecules could access the brain13,14,15. The first pathway is a Rheumatology The Journal of on May 29, 2014 Published by www.jrheum. org Downloaded from 49 Lotrich, et al: Inflammation and depression in IMID leaky blood-brain barrier that occurs in major depression. The second pathway involves activation of the endothelial cells that line the cerebral vasculature and produce cytokines inside the blood-brain barrier. Finally, inflammatory mediators can bind to receptors associated with the vagus nerve and thereby signal inflammatory changes in the brain. Once in the brain, proinflammatory cytokines activate both neuronal and non-neuronal cells, similar to their activity in the peripheral inflammatory response16. According to a recent metaanalysis by Howren, et al17, increased serum and/or plasma concentrations of interleukin 6 (IL-6) and C-reactive protein (CRP) are the most frequently observed inflammatory markers in depressed patients. Other cytokines implicated in depression include IL-1ß and tumor necrosis factor-α (TNF-α)18,19,20,21. Recent literature suggests that functional variants of the IL-1ß and TNF-α genes may increase risk for depression and reduce response to antidepressant therapy22,23. Further, according to a prospective study by van den Biggelaar, et al24, elevated levels of CRP and an increased capacity of leukocytes to produce IL-1 predicted later onset of depression in elderly individuals without a history of depression. This suggests that inflammation precedes and potentially leads to depression. Several studies have also reported positive correlations between severity of depressive symptoms and plasma concentrations of various inflammatory mediators21,25,26. In addition to data that link inflammatory mediators with depressive symptoms, it has also been shown that both acute and chronic administration of cytokines or cytokine inducers [i.e., lipopolysaccharide (LPS) or vaccination] can cause behavioral symptoms that are similar to those found in people who suffer from major depression27,28. For example, individuals injected with LPS displayed short-term increases in symptoms of depression and anxiety27, and those given a Salmonella typhi vaccine exhibited depressed mood, fatigue, mental confusion, and psychomotor slowing28. Severity of symptoms, in both cases, correlated with the rise in inflammatory mediators in peripheral blood. MECHANISMS OF CYTOKINE-INDUCED