Early Life Stress in Depressive Patients: Role of Glucocorticoid and Mineralocorticoid Receptors and of Hypothalamic-Pituitary-Adrenal Axis Activity (original) (raw)
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Early life stress, HPA axis, and depression
Considerable evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology, especially depression. The most recent studies reviewed herein suggest that early life stressors are associated with an increased risk for mood disorders in adulthood. This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and depression and the role of early life stress as an important risk factor for HPA axis dysregulation. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during antidepressant treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in major depression, but few studies have assessed the activity of mineralocorticoid receptors in depression. Thus, more studies are needed to elucidate this issue.
Update on stress and depression: the role of the hypothalamic-pituitary-adrenal (HPA) axis
Revista Brasileira De Psiquiatria, 2003
Over the past 50 years, relationships between stress and the neurobiological changes seen in psychiatric disorders have been well-documented. A major focus of investigations in this area has been the role of the hypothalamic-pituitary-adrenal (HPA) axis, both as a marker of stress response and as a mediator of additional downstream pathophysiologic changes. This review examines the emerging literature concerning the relationship between stress, HPA axis function, and depression, as well as the role of early life stress as an important risk factor for HPA axis dysregulation. The more recent studies reviewed suggest that the prominence of HPA axis hyperactivity in adults with depressive and anxiety disorders may constitute a link between the occurrence of adversity in childhood and the development of adult psychopathology
Early-life stress and HPA axis trigger recurrent adulthood depression
Epilepsy & behavior : E&B, 2013
It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. During acute stress, adaptive physiological responses occur, which include hyperactivity of the HPA axis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or 'allostasis'. It is correct to state that at the same time that our experiences change our brain and thoughts, namely, changing our mind, we are changing our neurobiology. Increased adrenocortical secretion of hormones, primarily cortisol in major depression, is one of the most consistent findings in neuropsychiatry. A significant percentage of patients with major depression have been shown to exhibit increased concentrations of cortisol, an exaggerated cortisol response to adrenocorticotropic hormone, and an enlargement of both the pituitary and adrenal glands. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood. These abnormalities appear to be related to changes in the ability of hormones to bind to GR and MR receptors. First episodes may begin with an environmental stressor, but if the cycles continue or occur unchecked, the brain becomes kindled or sensitized, and future episodes of depression, hypomania, or mania will occur independently of an outside stimulus, with greater frequency and intensity. Generally, HPA axis changes appear in chronic depressive and more severe episodes. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA dysfunction has been associated with higher rates of relapse and chronicity.
Early life stress in depressive patients: HPA axis response to GR and MR agonist
Background: Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients. Methods: We included 30 subjects, 20 patients with current major depression (HAM-D 21 ≥ 17). Patients were recruited into two groups according to ELS history assessed by the Childhood Trauma Questionnaire (CTQ). The cortisol measures in the saliva and plasma were evaluated after using (at 10:00 p.m.) placebo, fludrocortisone (MR agonist), or dexamethasone (GR agonist). Results: Depressed patients showed a significantly lower salivary cortisol upon waking after placebo compared with controls. Moreover, cortisol awakening responses (CAR) after MR agonist were found to be lower in depressed patients than in controls.With CTQ scores, HAM-D 21 , body mass index and CAR after placebo, GR agonist, MR agonist we found in a Linear Regression model that depressive patients with ELS (p = 0.028) show differences between placebo vs. MR agonist (R = 0.51; p < 0.05) but not after GR agonist; in depres-sive patients, without ELS the data show differences between placebo vs. MR agonist (R = 0.69; p < 0.05); but now as well placebo vs. GR agonist (R = 0.53; p < 0.05). Conclusion: Our findings indicate that MR activity is impaired in depressed patients compared with controls. Furthermore, in spite of the previous limitations described, in depressed patients with ELS, there was suppression by MR agonist, indicating that patients with ELS are sensitive to MR agonists. In contrast with depressed patients without ELS, we find suppression after both MR and GR agonist. These data suggested that in ELS an imbalance exists between MR and GR with MR dysfunction.
Reduced glucocorticoid receptors: consequence or cause of depression?
Trends in Endocrinology & Metabolism, 2006
Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is common in patients with major depression. A recent study demonstrates that reduced expression of the glucocorticoid receptor in mice causes depression-like behaviors and HPA axis dysfunction following stressor exposure. This model offers a novel system for the study of the pathophysiology that underlies depression-like behaviors. It also adds to the growing evidence that implicates glucocorticoid receptor dysfunction in depression.
2020
Early-life stress (ELS) is associated with a higher risk of psychopathologies in adulthood, such as depression, which may be related to persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate the effects of ELS on the functioning of the HPA axis in clinical and experimental situations. Clinically, patients with current depressive episodes, with and without ELS, and healthy controls, composed the sample. Subjects took a capsule containing placebo, fludrocortisone, prednisolone, dexamethasone or spironolactone followed by an assessment of plasma cortisol the morning after. Experimentally, male Wistar rats were submitted to ELS protocol based on variable, unpredictable stressors from postnatal day (PND)1 to PND21. On PND65 animals were behaviorally evaluated through the forced-swimming test (FST). At PND68, pharmacological challenges started, using mifepristone, dexamethasone, spironolactone, or fludrocortisone, and corticosterone levels were d...
The Journal of neuropsychiatry and clinical neurosciences, 2015
The role of stress in the origin and development of depression may be conceived as the result of multiple converging factors, including the chronic effect of environmental stressors and the long-lasting effects of stressful experiences during childhood, all of which may induce persistent hyperactivity of the hypothalamic-pituitary-adrenal axis. These changes, including increased availability of corticotropin-releasing factor and cortisol, are also associated with hyperactivity of the amygdala, hypoactivity of the hippocampus, and decreased serotonergic neurotransmission, which together result in increased vulnerability to stress. The role of other monoaminergic neurotransmitters, genetic polymorphisms, epigenetic mechanisms, inflammatory processes, and altered cognitive processing has also been considered in the development of a comprehensive model of the interactions between different factors of vulnerability. Further understanding of the underlying mechanisms that link these facto...
Psychoneuroendocrinological links between chronic stress and depression
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2003
Objective: The goal of this report is to develop a comprehensive model, which integrates psychosocial and neurobiological aspects, for better understanding the link between chronic stress and mood disorders. Method: A selective review of the relevant bibliography was conducted. The significant data were integrated with clinical and preclinical findings, particularly focusing on the effect of the hypothalamopituitary-adrenal (HPA) activity on the serotonergic neurotransmission in the CNS. Results: The reviewed data shows that chronic application of stress responses may lead to alterations in the regulation of the HPA system, and the resulting hypercortisolism may be reflected in various psychoneuroendocrinological processes, such as the observed in the serotonergic system, which was implicated in the origin and development of depression. Conclusions: The analysis of the interactions between the different components of this process, suggests that normalization of the HPA system, either directly through psychopharmacologic strategies, or indirectly through psychotherapeutic approaches oriented to improve the cognitive appraisal of stressful situations, may provide us with more effective diagnostic, preventive, and therapeutic methods in the treatment of widespread anxiety and mood disorders.
Neuronal actions of glucocorticoids: Focus on depression
The Journal of Steroid Biochemistry and Molecular Biology, 2008
Stress, acting through glucocorticoids (GC), has profound effects on brain physiology and pathology and is causally implicated in depressive illness. Here, we consider the information derived from genetic models generated to probe the role of the hypothalamo-pituitary-adrenal axis in depression. This essay also briefly reviews the status of knowledge regarding GC actions on neuronal birth, survival and death from the perspective of the importance of these phenomena in depression.