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Stress, Sex Hormones, Inflammation, and Major Depressive Disorder Psychopharmacology (2019) 236:3063–3079 https://doi.org/10.1007/s00213-019-05326-9 REVIEW Stress, sex hormones, inflammation, and major depressive disorder: Extending Social Signal Transduction Theory of Depression to account for sex differences in mood disorders George M. Slavich1 & Julia Sacher2 Received: 10 October 2018 /Accepted: 8 July 2019 /Published online: 29 July 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Social Signal Transduction Theory of Depression is a biologically plausible, multi-level theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental adversity with internal biological processes that drive depression pathogenesis, maintenance, and recurrence. Central to this theory is the hypothesis that interpersonal stressors involving social threat (e.g., social conflict, evaluation, rejection, isolation, and exclusion) upregulate inflammatory processes that can induce several depressive symptoms, including sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. The original article describing this formulation (Psychol Bull 140:774–815, 2014) addressed critical questions involving depression onset and recurrence, as well as why depression is strongly predicted by early life stress and comorbid with anxiety disorders and certain physical disease conditions, such as asthma, rheumatoid arthritis, chronic pain, and cardiovascular disease. Here, we extend the theory to help explain sex differences in depression prevalence, which is a defining feature of this disorder. Central to this extension is research demonstrating that ovarian hormone fluctuations modulate women’s susceptibility to stress, brain structure and function, and inflammatory activity and reactivity. These effects are evident at multiple levels and are highly context- dependent, varying as a function of several factors including sex, age, reproductive state, endogenous versus exogenous hormones, and hormone administration mode and dose. Together, these effects help explain why women are at greater risk for developing inflammation-related depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders during the reproductive years, especially for those already at heightened risk for depression or in the midst of a hormonal transition period. Keywords Life stress . Social threat . Cytokines . Inflammation . Sex differences . Sex hormones . Neuroinflammation . Risk . Depression . Disease Introduction economic impact on society that exceeds $200 billion per year in the USA alone (Greenberg et al. 2015). Nearly Depression is a serious psychiatric condition that often 17% of all men and 25% of all women experience a major emerges early in life and exerts a substantial social and depressive episode during their lifetime (Kessler et al. 2010), and although not all individuals develop multiple This article belongs to a Special Issue on Neuroimmune Signaling in episodes, recurrence is common with up to 60% of people Psychiatric Disease. experiencing more than one lifetime depressive episode (Monroe et al. 2014b). This impact is further compounded * George M. Slavich by the fact that depression is associated with increased [email protected] risk for several somatic health conditions that have an immunologic basis and can greatly affect wellbeing, in- 1 Cousins Center for Psychoneuroimmunology and Department of cluding asthma, rheumatoid arthritis, chronic pain, cardio- Psychiatry and Biobehavioral Sciences, University of California, vascular disease, certain cancers, and neurodegenerative Los Angeles, UCLA Medical Plaza 300, Room 3156, Los Angeles, CA 90095-7076, USA disorders (Slavich in press). Given the serious implications of depression for overall 2 Emotion NeuroimaGinG (EGG)-Lab and Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, health, one might expect that researchers have long pos- Stephanstrasse 1a, 04103 Leipzig, Germany sessed biologically plausible theories of major depressive 3064 Psychopharmacology (2019) 236:3063–3079 disorder (MDD) that could be used to develop effective Social Signal Transduction Theory treatments. Progress on this front has been slow, though, of Depression due in part to the high cost historically associated with assessing neural, immunologic, genetic, and genomic pro- Several contemporary theories have attempted to explain how cesses underlying depression in humans. However, these life stress increases risk for depression by affecting social- methods have become considerably more affordable in re- environmental (e.g., Brown and Harris 1978), psychodynamic cent years, leading to a proliferation of exciting new data (e.g., Blatt 2004), and cognitive (e.g., Beck 1967)processes. revealing how social-environmental adversity influences Although these formulations have served as invaluable blue- biological processes that promote risk for depression and prints for studying factors that contribute to and affect depres- related diseases. sion, their ability to provide a complete biopsychosocial pic- One of the most recent and important insights from this ture of the disorder has been limited by three main issues. work has involved the realization that psychological stress First, these theories have accounted for some symptoms and can strongly upregulate components of the immune system features of MDD—particularly those involving social, psy- involved in inflammation (Segerstrom and Miller 2004; chological, and cognitive processes—but they have not pro- Steptoe et al. 2007). Inflammation, in turn, is known to induce vided satisfactory explanations for somatic or neurovegetative depression-like behavior in animals and several symptoms of aspects of the disorder. Second, they have not typically includ- depression in many (although not all) individuals (Dantzer ed biological data and, consequently, have not described et al. 2008;Milleret al. 2009 ). Inflammatory mediators, par- mechanisms that are most proximally responsible for generat- ticularly pro-inflammatory cytokines, can also promote anxi- ing depressive symptoms, let alone the full clinical and biobe- ety symptoms and increase risk for the types of physical health havioral phenotype. Finally, these theories have generally problems that frequently co-occur with MDD (O’Donovan characterized depression at one major level of analysis (e.g., et al. 2013), thus making a focus on inflammation critically cognition) but have not drawn convincing links with other up- important for developing a more complete understanding of or down-stream processes that are implicated in this disorder. the full range of clinical symptoms and somatic ailments that Social Signal Transduction Theory of Depression ad- frequently accompany this disorder. dresses these issues by spanning several major levels of anal- Although studies on stress and inflammation, and ysis to generate a biologically plausible explanation for both inflammation and depression, have largely represented cognitive and somatic symptoms of MDD, as well as several distinct lines of enquiry, Slavich and Irwin (2014) recently other clinical phenomena that are frequently experienced by integrated these literatures to describe how experiences of many depressed individuals (e.g., anxiety, chronic pain) but life stress influence neural, physiologic, molecular, and ge- not presently regarded as symptoms of the disorder. The the- nomic processes that drive depression pathogenesis, main- ory is grounded in the basic understanding that the primary tenance, and recurrence. The resulting Social Signal purpose of the human brain and immune system is to keep the Transduction Theory of Depression represents the first bio- body safe from physical and biological threats that could logically plausible, multi-level theory of MDD. In the orig- cause illness or death if left unaddressed (Slavich in press; inal article describing this formulation, the authors ad- Slavich and Auerbach 2018). To accomplish this task, the dressed several important questions in depression research, brain continually surveys the social environment for threats including how depression develops, why it frequently re- that historically increased an individual’sriskofphysicalharm curs, why it is strongly predicted by early life stress, and or wounding. These social-environmental stressors, which in- why it often co-occurs with symptoms of anxiety and with clude things like social conflict, isolation, rejection, and ex- certain physical disease conditions. In the present paper, we clusion, get represented in brain regions that play a role in extend this discussion to help explain one of the most strik- processing experiences of social and physical threat, pain, ing features of depression—namely, the dramatic increase and interoceptive cues. These brain regions in turn project to in risk for MDD in women relative to men following the lower-level regions that upregulate systemic inflammatory ac- pubertal transition in adolescence. To accomplish this goal, tivity via several non-mutually exclusive pathways, including we first summarize Social Signal Transduction Theory of the sympathetic nervous system (SNS), hypothalamic- Depression and existing research supporting this theory. pituitary-adrenal (HPA) axis, vagus nerve, and meningeal Second, we describe known sex differences in depression lymphatic vessels (Irwin and Cole 2011; Slavich and Cole and inflammation, and how sex hormones influence
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