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The HPA (hypothalamic-pituitary-adrenal) axis matters because it is the body's central stress-hormone pathway. Its dysfunction is one of the most consistent biological findings in depression. It is a three-step hormonal cascade, the hypothalamusA small brain structure that controls basic functions like hunger, temperature, sleep and hormone release.Read more →, pituitary gland, and adrenal glands, that together produce the stress hormone cortisol. For example, imagine two people facing the same stressful exam: one shows a normal cortisol rise and recovery, while the other, with depression, shows persistently raised cortisol that fails to switch off properly. In practice, this abnormal cortisol regulation is measurable and is used as a research tool in depression.

The hypothalamusA small brain structure that controls basic functions like hunger, temperature, sleep and hormone release.Read more → releases CRH (corticotropin-releasing hormone), which stimulates the pituitary gland to release ACTH (adrenocorticotropic hormone), which in turn stimulates the adrenal glands to release cortisol. Cortisol then normally suppresses further CRH and ACTH release, a negative feedback loop that keeps the whole system in balance. In depression, this feedback loop is often impaired, producing chronically raised cortisol levels. The dexamethasone suppression test exploits this: dexamethasone (a synthetic steroid) should normally suppress cortisol release via this same feedback loop, but many patients with depression show reduced or failed suppression, called non-suppression. Chronic stress, and the chronically raised cortisol it produces, can also damage the hippocampusA brain structure central to forming new memories.Read more → (a brain structure very sensitive to cortisol). This is one proposed mechanism linking prolonged stress to memory and mood problems. Take a patient with severe, longstanding depression whose dexamethasone suppression test shows non-suppression: this is consistent with the impaired negative feedback typical of the condition. In practice, the test is now used mainly for research rather than routine diagnosis, but it demonstrates the underlying HPA axis abnormality clearly.

• When is cortisol normally at its highest during the day?
• From which hypothalamic nucleus is corticotropin-releasing hormone secreted?
• Which psychiatric presentation is most characteristic of prolonged cortisol excess?

• CRH, released by the hypothalamusA small brain structure that controls basic functions like hunger, temperature, sleep and hormone release.Read more → first in the cascade, unlike ACTH which is released downstream by the pituitary.
• Cortisol non-suppression, seen on the dexamethasone suppression test in depression, whereas normal feedback fully suppresses cortisol in health.
• Chronic stress, damages the hippocampusA brain structure central to forming new memories.Read more → via prolonged high cortisol, rather than causing the acute, adaptive cortisol rise of a single stressful event.
• HPA axis dysfunction, a research marker of depression, unlike a routine diagnostic test used in everyday clinical practice.

• Midnight is the normal nadir rather than the peak.
• CatatoniaA syndrome of abnormal movement and behaviour, ranging from being frozen and unresponsive to being excessively agitated.Read more → is not the characteristic presentation.
• Cortisol falls to its lowest around sleep onset and midnight.
• Levels are declining through the afternoon.
• Evening levels are well below the morning peak.

• Localise the clue to the relevant anatomical level, cell type, pathway or molecular process.
• Map that structure or process to its normal function.
• Predict the deficit or clinical sign produced when it is disrupted.
• Reject options that belong to a neighbouring structure, pathway or level of explanation.