The hypothalamic–pituitary–adrenal axis

The hypothalamus–pituitary–adrenal (HPA) axis appears to be crucial in the development of the symptoms of depression.¹ Patients with depression frequently have high circulating levels of cortisol,⁸ the hormone released from the adrenal cortex.⁵ Providing evidence for the connection from the other direction, patients with Cushing’s syndrome (characterised by a long-term increase in the levels of glucocorticoids, including cortisol)⁹ often show symptoms of depression, symptoms which are relieved when the cortisol overactivity is treated.⁸

Long term HPA overactivity has neurotoxic effects, particularly on the hippocampus.² One proposed mechanism for the neurotoxic effects of cortisol is via the molecule BDNF (brain-derived neurotrophic factor), which normally sustains the viability of neurones.^2,5 Chronic elevated cortisol reduces BDNF levels, which can lead to loss of neurones in the brain, particularly the hippocampus.^2,3,5 Interestingly, treatment with antidepressants appears to restore the monoamine depletion seen as a result of chronic stress; this restoration can increase BDNF levels (and other trophic factors) and, potentially, restore some of the changes to the brain seen in depression.^3,5

References:

1. Brites D, Fernandes A. Neuroinflammation and depression: microglia activation, extracellular microvesicles and microRNA dysregulation. Front Cell Neurosci 2015; 9: 476.
2. Lam RW, Mok H. Depression. Oxford University Press. 2008.
3. Boku S, Nakagawa S, Toda H, Hishimoto A. Neural basis of major depressive disorder: beyond monoamine hypothesis. Psychiatry Clin Neurosci 2018; 72 (1): 3–12.
4. Marx W, Penninx BWJH, Solmi M, et al. Major depressive disorder. Nat Rev Dis Primers 2023; 9 (1): 44.
5. Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 5th Edition. © Cambridge University Press, 2021.
6. Penner-Goeke S, Bothe M, Rek N, et al. High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders. Proc Natl Acad Sci USA 2023; 120 (49): e2305773120.
7. Arloth J, Bogdan R, Weber P, et al.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium PGC. Genetic differences in the immediate transcriptome response to stress predict risk-related brain function and psychiatric disorders. Neuron 2015; 86 (5): 1189–1202.
8. Murphy BE. Steroids and depression. J Steroid Biochem Mol Biol 1991; 38 (5): 537–559.
9. National Institute for Health and Care Excellence. Cushing’s syndrome. December 2024.