The neuroendocrinology of stress in the pathophysiology of bipolar disorders

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Stress represents the major environmental element of susceptibility for mood disorders. The association between stressful life events and vulnerability to mood disorders has long been noted, since the onset of the first episode of depression was found to be preceded by a severe life event in 70-80% of cases (Brown et al., 1986; Kendler et al., 1999). The deleterious effects of exposure to environmental stressors are not restricted to unipolar depression, as there is clear evidence of a relationship between childhood trauma, particularly emotional neglect, and manifestation of bipolar disorder (BD) as well (Etain et al., 2013; Watson et al., 2013). The physiological system most specifically and significantly engaged by the response to stress in animals and humans is the hypothalamic-pituitary-adrenal (HPA) axis. As one of the most consistent findings in biological psychiatry research is the evidence of derangement of the HPA axis in patients with severe mood disorders, the mechanisms underlying the link between stress, HPA axis dysfunction, and mood dysregulation have been the focus of intense and continuous multidisciplinary research for several years. Most studies investigating alterations of HPA axis have been carried out in patients with major depressive disorder (MDD). The excessive secretion of cortisol, and lack of suppression of cortisol production in response to administration of dexamethasone (Stokes et al., 1975), a state akin to a chronic sustained stress response, was first described 40 years ago in MDD patients. Hypercortisolemia and escape from dexamethasone suppression in a significant percentage of patients with MDD constituted the most widely reported and highly replicated finding in this area. This body of evidence has stimulated research focused on the HPA axis function in BD patients as well. Advances in genetics and molecular biology have more recently led to focussing the research on the cellular elements of the stress response, particularly the glucocorticoid receptors (GRs) and other multiple cellular components involved in the complex glucocorticoid-GRs signaling. Several studies have tested the association between manifestation of BD and polymorphisms of genes encoding GRs, their chaperone proteins, and proteins involved in the regulation of the HPA axis at different levels.

Original languageEnglish
Title of host publicationBipolar Disorders
Subtitle of host publicationBasic Mechanisms and Therapeutic Implications, Third Edition
PublisherCambridge University Press
Number of pages12
ISBN (Electronic)9781107477278
ISBN (Print)9781107062719
Publication statusPublished - 1 Jan 2016


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