From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression

Psychological Bulletin (Impact Factor: 14.76). 01/2014; 140(3). DOI: 10.1037/a0035302
Source: PubMed


Major life stressors, especially those involving interpersonal stress and social rejection, are among the strongest proximal risk factors for depression. In this review, we propose a biologically plausible, multilevel theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental stress with internal biological processes that drive depression pathogenesis. Central to this social signal transduction theory of depression is the hypothesis that experiences of social threat and adversity up-regulate components of the immune system involved in inflammation. The key mediators of this response, called proinflammatory cytokines, can in turn elicit profound changes in behavior, which include the initiation of depressive symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. This highly conserved biological response to adversity is critical for survival during times of actual physical threat or injury. However, this response can also be activated by modern-day social, symbolic, or imagined threats, leading to an increasingly proinflammatory phenotype that may be a key phenomenon driving depression pathogenesis and recurrence, as well as the overlap of depression with several somatic conditions including asthma, rheumatoid arthritis, chronic pain, metabolic syndrome, cardiovascular disease, obesity, and neurodegeneration. Insights from this theory may thus shed light on several important questions including how depression develops, why it frequently recurs, why it is strongly predicted by early life stress, and why it often co-occurs with symptoms of anxiety and with certain physical disease conditions. This work may also suggest new opportunities for preventing and treating depression by targeting inflammation. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

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Available from: Michael R Irwin, Mar 27, 2014
    • "A potential reason for therapeutic failure is that dysfunction in MDD is not restricted to the brain. MDD is a systemic illness with central and peripheral inflammatory changes at the core of MDD pathology (Erdem et al., 2011;Lisi et al., 2013;Noto et al., 2014;Powell et al., 2014;Setiawan et al., 2015;Shimizu et al., 1996;Slavich and Irwin, 2014). Patients with inflammatory diseases have a higher incidence of MDD than the general population (Dickens et al., 2002;Graff et al., 2009;Krishnadas et al., 2011;Lo Fermo et al., 2010), and 20-82% of patients treated with pro-inflammatory cytokines like interferon develop MDD (Capuron et al., 2002;Krishnadas et al., 2011;Musselman et al., 2001;Reichenberg et al., 2005). "
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    ABSTRACT: Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of anti-depressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated pro-inflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1β, TNFα, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients.
    No preview · Article · Jan 2016 · Neurobiology of Disease
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    • "Keywords: social stress, social behavior, immune system, transgenerational effects, Inflammation, BDNF, progesterone, cytokines INTRODUCTION A social signal transduction theory of depression has been proposed that states that exposure to social adversity, especially during early life, alters immune responses, and these changes mediate depression symptoms such as anhedonia and impaired social behavior (Slavich and Irwin, 2014). Cytokine mediated effects have been specifically implicated in depression and anxiety associated alterations in social behavior (Dantzer et al., 2008). "
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    • "Depression is primarily characterized by anhedonia and dysphoric mood (American Psychiatric Association [APA], 2013), referring at a cerebral level to hypo-activity of the reward system and hyperactivity of the punishment system, respectively (e.g., Pryce et al., 2011). Depression has been causally related to both acute and chronic stress (Alloy, Abramson, Walshaw, & Neeren, 2006; Pizzagalli, 2014; Slavich & Irwin, 2014; Tennant, 2001). Individual dispositions such as dysfunctional attitudes—e.g., pathological perfectionism and need for approval—, ruminative responses—repetitive and passive focus on the causes and consequences of one's symptoms of distress without engagement in active coping or problem solving to alleviate dysphoric mood—, and pessimistic attributions—the tendency to ascribe negative life events to internal (self-dependent), stable (unlikely to change), and global (likely to affect all areas of life) causes—have been identified as depressogenic factors (Alloy et al., 2006; Joorman, 2009; Michl, McLaughlin, Shepherd, & Nolen-Hoeksema, 2013; Mor & Winquist, 2002). "
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