Trends in Neurosciences
Volume 31, Issue 9, September 2008, Pages 464-468
Journal home page for Trends in Neurosciences

Review
The HPA axis in major depression: classical theories and new developments

https://doi.org/10.1016/j.tins.2008.06.006Get rights and content

Studies over the last 40 years have demonstrated that hyperactivity of the hypothalamic-pituitary-adrenal axis is one of the most consistent biological findings in major depression psychiatry, but the mechanisms underlying this abnormality are still unclear.

Introduction

Hypothalamic-pituitary-adrenal (HPA) axis activity is governed by the secretion of adrenocorticotrophic hormone-releasing factor (CRF) and vasopressin (AVP) from the hypothalamus, which in turn activate the secretion of adrenocorticotrophic hormone (ACTH) from the pituitary, which finally stimulates the secretion of the glucocorticoids (cortisol in humans and corticosterone in rodents) from the adrenal cortex. Glucocorticoids then interact with their receptors in multiple target tissues including the HPA axis, where they are responsible for feedback inhibition both on CRF and AVP from the hypothalamus and directly on secretion of ACTH from pituitary corticotropes (see below). The activated HPA axis not only regulates body peripheral functions such metabolism and immunity but also has profound effects on the brain. For example, glucocorticoids regulate neuronal survival, neurogenesis, the sizes of complex anatomical structures such as the hippocampus, the acquisition of new memories and the emotional appraisal of events (reviewed in Ref. [1]). Considering its role at the interface between stress and brain functioning, it is perhaps not surprising that the HPA axis has been found abnormal in psychiatric disorders, and in particular in major depression. For example, a significant percentage of depressed patients have increased levels of cortisol in the saliva, plasma and urine, and increased size (as well as activity) of the pituitary and adrenal glands (reviewed in Ref. [2]).

This increased activity of the HPA axis is thought to be related, at least in part, to reduced feedback inhibition by endogenous glucocorticoids. Through binding to their cognate receptors in the HPA axis—the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR)—endogenous glucocorticoids serve as potent negative regulators of HPA axis activity, in particular the synthesis and release of CRF in the paraventricular nucleus and proopiomelanocortin/ACTH in the pituitary. Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in major depression come from a multitude of studies demonstrating that the HPA axis is not suppressed by pharmacological stimulation of the GR with an oral dose of the synthetic glucocorticoid dexamethasone; by contrast, even a small dose of dexamethasone induces a potent feedback inhibition of the HPA axis in healthy subjects, leading to reduced cortisol levels for up to 24 h. Reduced glucocorticoid receptor function in peripheral tissues, such as in peripheral blood mononuclear cells and skin cells, has also been described in depressed patients. Interestingly, successful antidepressant treatment is associated with resolution of the impairment in the negative feedback on the HPA axis by glucocorticoids (reviewed in Ref. [3]).

With this background in mind, covering the main findings from the last decades, this review will concentrate on the most recent advances and the newest and most promising translational developments in this research area. Specifically, we will present data supporting the hypothesis that HPA axis hyperactivity is not a simple consequence or an epiphenomenon of depression, but on the contrary that it is a risk factor predisposing to the development of depression, brought about by early life experiences programming molecular changes as well as by genetic liability.

Section snippets

HPA axis hyperactivity: chicken rather than egg?

One of the most striking developments in this field has been the discovery over the last few years that the increased activity of the HPA axis (and of CRF-containing circuits) might reflect a susceptibility that can be programmed through early life events. Indeed, laboratory animal studies have demonstrated that separating neonatal rodents and non-human primates from their mothers for long periods elicits HPA axis changes that persist into adulthood and that resemble those present in depressed

Glucocorticoid receptor: the weakest link?

As we have described above, the increased activity of the HPA axis is thought to be related, at least in part, to altered feedback inhibition by endogenous glucocorticoids, which is mediated by binding to the MR and the GR. This mechanism is explained in Figure 1. Basically, circulating glucocorticoids (cortisol in humans) bind to the GR outside the brain (such as in the pituitary) or inside the brain (hippocampus and hypothalamus). The activated GR, in turn, induces a feedback inhibition

HPA axis and depression: what now?

Several methods and approaches have recently been developed to assess novel aspects of HPA axis activity or to add a new level of sophistication to our understanding, and some of these have been tested in depression.

There has been increasing awareness of the importance of MR in regulation of HPA activity. MR is abundant in limbic areas of the brain and has a high affinity for cortisol and corticosterone. This would suggest that it is actively occupied at most times of the day. Two lines of

Acknowledgements

C.M.P.'s research is funded by the UK Medical Research Council (MRC), the American Psychiatric Institute for Research and Education (APIRE), the British Academy, the Guy's and St. Thomas’ Charitable Trust, the King's Development Trust, the NARSAD Mental Health Research Association, and the NIHR South London and Maudsley NHS Trust and Institute of Psychiatry (King's College London) Biomedical Research Centre. S.L.L.'s research is funded by the Biotechnology and Biological Sciences Research

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