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Epilepsy Behav. 2014 Sep;38:148-59. doi: 10.1016/j.yebeh.2013.10.020. Epub 2013 Nov 20.

Early-life stress and HPA axis trigger recurrent adulthood depression.

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Stress and Affective Disorders (SAD) Programme, Department of Neurosciences and Behavior, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil; Dept. of Psychological Medicine, Institute of Psychiatry, King's College London, UK. Electronic address:


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.


Cortisol; Early-life stress; Glucocorticoid Receptor (GR) and mineralocorticoid; Hypothalamic–pituitary–adrenal (HPA) axis; Kindling; Receptor (MR) Depression

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