The Corticosteroid Receptor Hypothesis of Depression

Abstract

Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

Blockade of the Mineralocorticoid Receptor in Healthy Men: Effects on Experimentally Induced Panic Symptoms, Stress Hormones, and Cognition

“…Thus, it is possible that the positive effects of antidepressants on cognitive function in depressed patients are mediated by a rise of hippocampal MR. This is also consistent with findings that the MR antagonist spironolactone hampered antidepressive effects of an antidepressant in humans (Holsboer, 2000) and that substances that upregulate MR enhance the effects of antidepressants (Jahn et al, 2004).…”

“…However, in patients with Addison's disease it was recently shown that MR are needed for encoding learned material (Tytherleigh et al, 2004). Furthermore, MR function is altered in major depression that is associated with cognitive deficits (Buckley, 2006;Holsboer, 2000;Young et al, 2003).…”

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

“…For instance, changes in CRH or CRH receptor function may contribute to this phenomenon. Patients with major depression usually have a blunted ACTH response to the administration of CRH, which is believed to be secondary to desensitized CRH receptors (Holsboer, 2000). Treatment of depressed patients with pyrazolopyrimidine (CRH receptor antagonist) have shown reductions in clinician and patient-reported depression and anxiety scores (Zobel et al, 2000), suggesting not only therapeutic potential, but also implying that normalization of HPA axis function and subsequent treatment of mood and anxiety disorders are dependent on CRH and CRH receptor function.…”

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

“…Antidepressants normalize the hormonal stress response in patients with major depression, but the molecular mechanisms underlying this effect are still unknown (Holsboer, 2000;Pariante et al, 2004b;Neigh and Nemeroff, 2006;Pariante, 2006). Patients with major depression have a hyperactivity of the main hormonal stress response system, the hypothalamic-pituitary-adrenal (HPA) axis, as shown by increased levels of corticotropin-releasing factor (CRF) in the brain, and of the endogenous glucocorticoid hormone, cortisol, in the plasma (Holsboer, 2000;Pariante et al, 2004b;Neigh and Nemeroff, 2006;Pariante, 2006).…”

“…Patients with major depression have a hyperactivity of the main hormonal stress response system, the hypothalamic-pituitary-adrenal (HPA) axis, as shown by increased levels of corticotropin-releasing factor (CRF) in the brain, and of the endogenous glucocorticoid hormone, cortisol, in the plasma (Holsboer, 2000;Pariante et al, 2004b;Neigh and Nemeroff, 2006;Pariante, 2006). Moreover, several lines of evidence indicate that these HPA axis abnormalities contribute to the development of the depressive symptoms.…”