Innovative Approaches for the Treatment of Depression: Targeting the HPA Axis

Abstract

Altered activity of the hypothalamic pituitary adrenal (HPA) axis is one of the most commonly observed neuroendocrine abnormalities in patients suffering from major depressive disorder (MDD). Altered cortisol secretion can be found in as many as 80% of depressed patients. This observation has led to intensive clinical and preclinical research aiming to better understand the molecular mechanisms which underlie the alteration of the HPA axis responsiveness in depressive illness. Dysfunctional glucocorticoid receptor (GR) mediated negative feedback regulation of cortisol levels and changes in arginine vasopressin (AVP)/vasopressin V1b receptor and corticotrophin-releasing factor/CRF1 receptor regulation of adrenocotricotrophin (ACTH) release have all been implicated in over-activity of the HPA axis. Agents that intervene with the mechanisms involved in (dys)regulation of cortisol synthesis and release are under investigation as possible therapeutic agents. The current status of some of these approaches is described in this review.

Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder

“…For instance, there is considerable evidence that CRF and vasopressin work in concert to coordinate the neuroendocrine stress response, with both playing important roles in coordinating behavioral emotions of anxiety. [27,28] Indeed, redundancy within such an important homeostatic system would seem likely.…”

Psychosis and Adhesion Molecules

“…CRH triggers the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH subsequently stimulates the release of cortisol or corticosterone in humans and rodents, respectively (Thomson and Craighead, 2008;Pariante and Lightman, 2008). However, the molecular pathway in the brain affected by excess levels of plasma corticosteroids is not known.…”

“…Among many environmental factors, repeated stressful events are associated with the onset of depression, and stress activates the hypothalamic-pituitary-adrenocortical (HPA) system (Gold et al, 1988a, b;Post, 1992;Bartanusz et al, 1993;Herman et al, 1995;Aguilera and Rabadan-Diehl, 2000;McEwen, 2004;Sala et al, 2004;Alfonso et al, 2005;Dallman et al, 2006). The negative feedback of corticosteroids on the HPA system occurs at the level of the hypothalamus and the anterior pituitary via the glucocorticoid receptors (Thomson and Craighead, 2008;Pariante and Lightman, 2008). Dysregulation of this negative feedback mechanism is reported in patients with major depressive disease, which results in hyperactivity of the HPA system and higher basal levels of serum corticosterone (Carroll et al, 1976;Holsboer et al, 1984;Nemeroff et al, 1984;Halbreich et al, 1985a, b;Schatzberg et al, 1985;Gold et al, 1986a;Young et al, 1993).…”

The HPA axis and GABA-Glutamate Systems as Potential Antidepressant Targets in Prostate Cancer

“…Chronic stress can therefore lead to elevated levels of cortisol, which also contributes to an elevated risk of depression [58]. Higher levels of its trophic precedents CRH and ACTH, plus cortisol itself, are consistently seen within depressed patients [59,60], with some data [61] indicating that up to 80% of depressed patients have elevated cortisol levels. Gold, Drevets and Charney [62] described several pathways between elevated cortisol and depression, including alteration of prefrontal cortex function, amygdala and hypothalamus hyperactivity and reductions in volume and function of the hippocampus.…”