Biological Psychiatry - Vol. 2

By Hugo D'Haenen; J.A. Den Boer et al. | Go to book overview

Neuroendocrinology of Mood Disorders

Dorothy K.Y. Sit and Anthony J. Rothschild


The major mood disorders are associated with specific, highly reproducible neuroendocrine alterations, and conversely, certain endocrine disorders (e.g. hypothyroidism and Cushing's disease) are associated with higher than expected rates of mood disturbances. Neuroendocrine abnormalities have been thought to provide a 'window on the brain', revealing clues regarding the pathophysiology of central nervous system dysfunction. This neuroendocrine strategy is based on extensive research which indicates that the secretion of peripheral endocrine hormones is largely controlled by the respective pituitary trophic hormone. The pituitary hormones are in turn regulated by hypothalamic release and release-inhibiting hormones. Mood disorders are associated with multiple alterations, specifically of the hypothalamic–pituitary–adrenal (HPA), hypothalamic–pituitary–thyroid (HPT) and growth hormone axes. In this chapter, we review the research on the alterations of these axes and also discuss the roles of melatonin, dehydroepiandrosterone, parathyroid hormone and gonadal hormones in the pathophysiology of mood disorders.



Hypercortisolism has been prevailingly linked to the hormonal stress response found in patients experiencing affective disorders, especially in depression. Stressful life events may trigger a psychiatric condition in susceptible individuals, perhaps indicating a response of the HPA axis. Current research, however, is now aimed at understanding the mechanism by which the HPA axis may be causally linked to the pathophysiology of mood disorders. A growing body of preclinical and clinical research continues to provide information on the close ties between abnormalities in the HPA axis and various regions of the brain, with their subsequent influence to alter function of crucial neurotransmitters (and their receptors), relevant to the development of affective disorders.

HPA Axis Function

Corticosteroids and Mood Effects

Cortisol and the HPA axis play a crucial role in the stress response system, acting as an important interface between the central nervous system and the peripheral endocrine response system (Holsboer, 2001). Each hormone in the HPA axis cascade, as well as the other neuropeptides, possesses important effects not only on behaviour and emotions, but have significant roles in modulating the immune, endocrine and autonomic nervous systems. Cortisol enhances the availability of glucose, the main nutrient for all cells, including those found in the brain. Hypercortisolism, as a reflection of a hyperactive HPA axis state, now is postulated to be causally linked to the pathophysiology of depression.

Patients with depression and documented hypercortisolism often present with vegetative changes, such as sleep disturbance and energy reduction, decreased attention and cognition, psychosis, suicidally, anxiety, psychomotor disturbances or decreased libido (Wolkowitz, 1994). More recent literature hypothesizes that current antidepressants stimulate corticosteroid receptor expression, causing enhanced negative feedback on the HPA axis restoring appropriate corticotropin-releasing hormone (CRH) and Cortisol levels. By reducing the levels of circulating Cortisol, mood and vegetative symptoms may improve.

Historically, medically ill patients who were prescribed steroids such as prednisone, dexamethasone, cortisone and other synthetic corticosteroids for various medical conditions reportedly developed behavioural and emotional changes, such as mood lability, depression, hypomania, memory and attention changes, or psychosis. Those treated with exogenous corticosteroids seem to present with hypomania, while those with an underlying condition that produces increased endogenous steroids present with depression (Plihal et al., 1996). Patients with Cushing's syndrome (non-adrenocorticotropic hormone [ACTH] related) and disease (increased ACTH) develop depression at similar incidence rates, even though the disease origins are different, implying that Cortisol contributes to the development of psychiatric symptoms (Murphy, 1991).

Of note, patients with Addison's disease, an immune-related disorder leading to adrenocortical insufficiency, may also develop depression which responds to Cortisol and other hormone replacement therapy (Leigh and Kramer, 1984). DeBattista et al. (2000) reported on 22 patients with non-psychotic depression who were randomly assigned to a one-day treatment with either ovine CRH, hydrocortisone or saline. Depression rating scales given immediately prior to treatment and the day following treatment demonstrated a rapid and robust reduction in depressive symptoms. Arana et al. (1995) and Dinan et al. (1997) described brief open-label trials using high-dose dexamethasone for the treatment of depression, reporting significant symptom improvement. On the otherhand, Wolkowitz et al. (1996) found the contrary, albeit in a very small sample size of five patients. Wolkowitz and Reus, (1999) postulated that bom anti-glucocorticoid treatment and brief high-dose steroid treatment may have similar effects on the HPA axis, such as lowering of Cortisol levels through upregulation of brain corticosteroid receptors; altering levels of the other adrenal steroid hormones; and increase in ACTH levels (after dexamethasone's initial inhibitory effect on ACTH production is worn off).

The HPA Axis, Serotonin, and Hippocampal Pathophysiology

It appears that corticosteroids influence brain function through the modulation of gene expression, and direct cell membrane effects


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