Major depression is undoubtedly one of the major healthcare issues in the 21st century According to the latest WHO report on 23 February 2017, depression is now ranked as the single largest contributor of years lived with disability worldwide, and the major contributor to the global burden of disease. (WHO, 2017) Stress response system abnormalities in Depression The most robust and consistent finding in major depression so far has been its link to the abnormalities of the stress response system. The stress response system is a complex, multilevel mechanism largely dependent on feedback regulation. It relies on two main elements – the autonomic stress response which exerts immediate effects when the organism is faced with physiological or psychological stressors; and the impact on the hypothalamo-pituitary-adrenal (HPA) axis. A detailed account of the structure and physiology of both components of the stress response system is thoroughly given by Ulrich-Lai & Herman (2009) and is outside the scope of this review. However, to understand the nature of the abnormalities which will be discussed further, it is essential to highlight the key characteristics of the HPA-axis. In response to stressful stimuli, the suppression of the subgenual prefrontal cortex and the activation of amygdala lead to the stimulation of the autonomic sympatheti axis, and the HPA axis (Dioro et al. 1993; Phelps and LeDoux, 2015; Gold, 2015). The autonomic sympathetic axis is responsible for the most rapid response, and acts via the secretion of epinephrine by the adrenal glands; the HPA axis is activated minutes after the epinephrine surge, and represents a cascade of events starting with the secretion of the corticotropin releasing factor (CRF, also known as corticotropinreleasing hormone, or CRH) from the paraventricular nucleus of the hypothalamus into the portal circulation, which stimulates the synthesis and release of adrenocorticotropic hormone (ACTH) by the pituitary. The ACTH further stimulates the synthesis and release of the glucocorticoid hormone cortisol by the adrenal cortex. Glucocorticoids are known to exert a range of functions, such as promoting gluconeogenesis, catabolic and antianabolic activity, suppression of innate immunity in immune organs, insulin resistance and a prothrombotic state. The key role of glucocorticoids consists in maintaining homoeostasis in response to stress (Juruena, 2014).