Neuroendocrine-immune Interactions in Major Depressive Disorder: Glucocorticoids and Glucocorticoid Receptors

Frances Isabella Weston*, Luca Sforzini, Annamaria Cattaneo, Carmine Maria Pariante

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review


Major depressive disorder is a leading cause of disability worldwide; therefore, effective treatment options are crucial. However, due to the highly heterogeneous nature of depression, a comprehensive understanding of the disease is lacking and treatment options are limited. Whilst the pathology of depression is complex, neuroendocrine–immune interactions have consistently been linked to the disease. Hypothalamic–pituitary–adrenal (HPA) axis dysfunction has been identified as one of the main contributing factors, impacting 50–80% of patients with depression. The ‘glucocorticoid resistance model’ provided the first explanations of this dysfunction, suggesting reduced function of the glucocorticoid receptor; thus, glucocorticoid resistance, seen in some MDD patients, allows pro-inflammatory pathways to evade normal feedback inhibition by glucocorticoids. However, recent research has suggested alternative mechanisms, which identify cortisol as a pro-inflammatory mediator of stress reactions. Additional research into glucocorticoid dysfunction in MDD has also found single nucleotide polymorphisms in FKBP5, a key regulator of glucocorticoid receptor function, to play a role in HPA axis dysfunction and thus confer risk of depression. These effects are mediated by gene–environment interactions, specifically adverse early-life events. Whilst the underlying epigenetic mechanisms are not fully understood, increased FKBP5 mRNA expression and altered FKBP5 methylation are thought to play a role in impaired HPA axis function. An increased understanding of the interactions involving FKBP5 may in turn increase understanding of the pathophysiology of depression. This will allow identification of high-risk individuals who have past adverse early-life experiences. In turn, this may also impact the course of future antidepressant treatment and development.

Original languageEnglish
Title of host publicationMasterclass in Neuroendocrinology
PublisherSpringer Nature
Number of pages23
Publication statusPublished - 2023

Publication series

NameMasterclass in Neuroendocrinology
ISSN (Print)2662-2068
ISSN (Electronic)2662-2076


  • FKBP5
  • Glucocorticoid resistance
  • Glucocorticoids
  • Hypothalamic–pituitary–adrenal axis
  • Inflammation
  • Major depressive disorder
  • Neuroendocrine immunology


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