Cognitive correlates of hypothalamic – pituitary – adrenal axis in major depression

www.expert-reviews.com ISSN 1744-6651 © 2011 Expert Reviews Ltd 10.1586/EEM.10.79 Alterations in hypothalamic–pituitary–adrenal (HPA) axis function, such as hypercortisolism and reduced feedback sensitivity, have been a prominent finding in neuroendocrine investigations of major depressive disorder (MDD). Cognitive impairments, particularly those concerning attention, memory and executive function have also consistently been reported in MDD. However, the causes of these cognitive deficits remain unclear. Several studies have investigated the relationship between HPA axis dysfunction and neuropsychological impairment in MDD. After a brief introduction to HPA axis function, we will provide an overview of the evidence of HPA axis dysfunction on the one hand and cognitive impairment on the other hand in MDD. Following a summary of glucocorticoid (GC) action on cognitive function in healthy human participants, we will then present a review of the findings investigating relationships between HPA axis dysfunction and neuropsychological impairment in patients with MDD. Finally, we will selectively describe psychopharmacological and psychotherapeutic intervention studies addressing HPA axis regulation and associated cognitive function in MDD. HPA axis function In response to a physical or psychological stressor, the HPA system becomes activated, resulting in a ‘cascade’ of hormone release. Corticotropin-releasing hormone (CRH) and arginine vasopressine (AVP) are secreted from neurons in the paraventricular nucleus (PVN) of the hypothalamus which in turn stimulate the synthesis and release of adrenocorticotropic hormone (ACTH), also known as corticotropin, in the anterior pituitary. ACTH then promotes the release of GCs (mainly corticosterone in rodents, and cortisol in humans and primates) from the adrenal cortex. Cortisol exerts negative feedback on the hypothalamus and pituitary to inhibit the synthesis and secretion of CRH and ACTH, respectively, in order to maintain a homeostasis of circulating GCs. In addition, the hippocampus exerts negative feedback on the PVN, thereby reducing HPA axis activity. Cortisol binds to two subtypes of intracellular corticosteroid receptors, the mineralocorticoid receptor (MR), also referred to as the type I receptor, and the GC receptor (GR) or type II receptor. Recently, membrane-bound GRs and MRs have also been identified [1,2]. GRs are widely distributed throughout the Nicole Schlosser1, Oliver T Wolf†2 and Katja Wingenfeld3