It is logical for us to consider that stress may precipitate depressive episodes, but how? 

​Stress plays a significant role in our everyday life, naturally it is beneficial for us as it protects us from dangerous situations. However, in excessive amounts it can be significantly damaging to our well being, and the HPA axis hypothesis  demonstrates the relationship betwen stress and depression.

 

Stressful life events including events in childhood, such as the loss of the parent / child physical or sexual abuse, increases the vulnerability of affective disorders and anxiety

 

These events then may further cause “biological wounds” e.g. long lasting alterations in neurons containing corticotropin-releasing factor, again increasing the individual’s vulnerability to stressors later on in life

In particular chronic stress and stressful events have been linked to the onset of depression and its severity

 

HPA axis 

The HPA axis is the second part of the stress response, which is slower and exerts effects for a longer duration 

 

How does the stress response work? 

• The hypothalamic-pituitary-adrenal (HPA) axis mediates the neuroendocrine response to stressors

• The response is initiated in the CNS releasing Corticotropin releasing hormone (CRH)  from the hypothalamus. CRH inhibits the enzyme tyrosine hydroxylase which allows the synthesis of noradrenaline. This is the link between the neuroendocrine theory and monaomine theory 

• This release activates the pituitary gland to release the hormone ACTH

• In turn this leads to the adrenal cortex/glands  secreting stress hormone CORTISOL into the bloodstream 

• After this, mineralcorticoid and glucocorticoid receptors act as part of a negative feedback mechanism to prevent the release of CRH from the hypothalamus, dampening down the stress response.This allows the  body to return to normal until another stress response is initiated 

 

What is thought to happen in depression? 

 

There have been many studies indicating that an impaired HPA axis induces depression. There are two possible reasons for HPA overactivity in depressed individuals : 

1. Hypercortisolaemia or excess cortisol may affect the NUMBER or FUNCTION of glucocorticoid receptors.This aleration in glucocorticoid and mineralcorticoid recpetors may contribute to the pathophysiology of depression 

2. Loss/impaired negative feedback: the loss of the negaive feedback mechanism result in: 

• MORE CRH release which inhibits tyrosine hydroxylase 

• Noradrenaline synthesis is therefore inhibited  

 

 

Evidence for such theories

• Hypercholesterolaemia 

• Increase of messenger RNA in CNS of hypothalamus in depressed patients 

• Decrease in number of CRF binding sites in the prefrontal cortex in suicide symptoms threfore maybe a downregulation 

• Increased central levels of CRF 

 

Potential targets therefore :

• Glucocorticoid antagonists 

• Cortisol synthesis inhiboitors which include metyrapone, ketoconazole, aminogluthamide