TY - CHAP
T1 - Neuroendocrine-immune Interactions in Major Depressive Disorder
T2 - Glucocorticoids and Glucocorticoid Receptors
AU - Weston, Frances Isabella
AU - Sforzini, Luca
AU - Cattaneo, Annamaria
AU - Pariante, Carmine Maria
N1 - Funding Information:
Acknowledgments and Disclosures Dr. Pariante is supported by the Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium (104025), which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer; by the NARSAD grant RE14032; by the U.K. Medical Research Council (MR/N015746/1); and by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King‘s College London.
Funding Information:
Dr. Sforzini and Prof. Pariante have received research funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966–2, as part of the EU-PEARL project. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Publisher Copyright:
© 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - FKBP5
KW - Glucocorticoid resistance
KW - Glucocorticoids
KW - Hypothalamic–pituitary–adrenal axis
KW - Inflammation
KW - Major depressive disorder
KW - Neuroendocrine immunology
UR - http://www.scopus.com/inward/record.url?scp=85149924107&partnerID=8YFLogxK
U2 - 10.1007/978-3-031-21358-8_6
DO - 10.1007/978-3-031-21358-8_6
M3 - Chapter
AN - SCOPUS:85149924107
T3 - Masterclass in Neuroendocrinology
SP - 135
EP - 157
BT - Masterclass in Neuroendocrinology
PB - Springer Nature
ER -