Evidence for the Role of Hypothalamic–Pituitary–Adrenal Axis Dysfunction in the Pathogenesis of Mood Disorders

Laura Maclachlan, Stuart Watson
European Psychiatric Review, 2010;3(1):54-57
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Abstract

Mood disorders are an important cause of disability worldwide. They manifest as biological, cognitive and psychological symptoms, and can seriously impair quality of life. In isolation, the monoamine theory of depression has not offered a satisfactory explanation for the pathophysiology of mood disorders. There is increasing clinical and experimental evidence to suggest that hypothalamic–pituitary–axis (HPA) dysfunction has a significant pathophysiological role in mood disorders. This article reviews the evidence for HPA axis dysfunction in major depression and bipolar disorder and explores the therapeutic potential for targeting this dysfunction in the management of these disorders.
Keywords
Bipolar disorder, mood disorder, corticotrophin, cortisol, depression, hypothalamic–pituitary–adrenal axis, neuropsychological
Disclosure The authors have no conflicts of interest to declare.
Received: October 26, 2009 Accepted January 14, 2010
Correspondence: Stuart Watson, Institute of Neurosciences, Leazes Wing, Royal Victoria Infirmary, Newcastle, NE1 4LP, UK. E: stuart.watson@ncl.ac.uk
Hypothalamic–Pituitary–Adrenal Axis Anatomy and Physiology

The hypothalamic–pituitary–adrenal (HPA) axis is a regulatory system for reactions to stress, immune system responses, mood and emotions, neuronal survival, neurogenesis and energy storage and expenditure. The HPA axis functions on both a neuronal and an endocrine level and is mediated via regulatory inputs releasing factors and hormones. It has central and peripheral actions, mediates the co-ordination of circadian events such as the sleep/wake cycle and food intake, helps with the ability to cope with, adapt to and recover from stress and promotes learning and memory processes.

Within the hypothalamus, paraventricular nuclei (PVN) cells secrete corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP). This stimulates the release of adrenocorticotrophic hormone (ACTH) from the anterior lobe of the pituitary into the systemic circulation. ACTH promotes the release of the glucocorticoid cortisol from the adrenal cortex, which is released in a diurnal pattern.1

The effects of cortisol are mediated by specialised intracellular steroid receptor family subtypes, two of which include the high-affinity type I mineralocorticoid receptor (MR) and the low-affinity type II glucocorticoid receptor (GR).2 Cortisol diffuses through the cellular membrane, binds to these receptors and promotes their translocation to the nucleus. Once within the nucleus, the activated receptors interact with other transcription factors or bind to specific DNA to promote expression of various genes.

The HPA axis is highly regulated. On a neuronal level secretory cells in the PVN receive inputs from several regions in the brain, including the amygdala, hippocampus and nuclei of the midbrain. The axis is also regulated via a process of homeostatic negative feedback control via GR and MR activation in the hippocampus, hypothalamus and pituitary.

Hypothalamic–Pituitary–Adrenal Axis Dysregulation in Mood-disordered Patients

HPA axis dysregulation has been shown to be associated with mood disorders. An increased number of CRH and AVP neurons in the PVN,3v hypersecretion of CRH and AVP, increased cortisol levels in plasma, urine, cerebrospinal fluid and saliva, exaggerated cortisol responses to ACTH and enlarged hypothalamus, pituitary and adrenal glands have been demonstrated in individuals with severe mood disorders.4,5

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Evidence for the Role of Hypothalamic–Pituitary–Adrenal Axis Dysfunction in the Pathogenesis of Mood Disorders

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