Understanding depression and anxiety
◄Previous: 2.1 The operation and control of the HPA axis

# 2.2 Relating stress and depression biologically

Evidence from studies on humans suggests that dysregulation (the breakdown of regulation) of the HPA axis due to chronic activation of the axis is linked to depression.

For instance, high levels of cortisol are found in the urine, blood and cerebrospinal fluid (CSF) (the fluid that bathes the brain and spinal cord) of many untreated depressed patients compared to controls who are not depressed.

What do high levels of cortisol suggest?

## Answer

They suggest hyperactivity in the HPA axis of those who are depressed, as cortisol levels are high and uncontrolled.

Do these results tell us if high levels of cortisol cause depression?

## Answer

No – they tell us there is a correlation. The depression might have led to high cortisol levels, rather than vice versa.

However some evidence that high levels of glucocorticoids such as cortisol can actually cause low mood in people is provided by Cushing’s disease. This disease is sometimes caused by a tumour in the pituitary gland, which consequently secretes extra ACTH, which then stimulates the adrenal cortex to secrete more cortisol. If the level of cortisol is reduced (for instance by using drug treatment), the depression lifts.

Why does this suggest a causal role for high levels of cortisol in depression?

## Answer

In Cushing’s disease the direction of causation is fairly certain: high levels of cortisol lead to depression. The fact that reducing cortisol levels lifts depression strengthens the case that cortisol plays a causal role.

As well as high cortisol levels, CRF concentrations in the cerebrospinal fluid of depressed patients are also high, compared to those who do not have depression.

Where is CRF produced?

## Answer

CRF is produced by neurons in the hypothalamus, and also in the amygdala; both are involved in the activating the stress response in the HPA axis.

This fits in with the finding from post-mortem studies that the brains of people with depression have more CRF-producing neurons in the hypothalamus compared to controls. Moreover, if CRF is injected into the brains of rats, these animals show some behaviours characteristic of depression such as insomnia, decreased appetite, decreased interest in sex, and increased anxiety (Arborelius et al., 1999). All these findings lend weight to the idea that hyperactivity in the HPA axis plays a causal role in depression and anxiety.

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