Latest understanding of Depression and Stress

An original article appeared this month in the psychiatric literature which reviewed our current understanding of the stress response system (the HPA:  hypothalamic pituitary axis).  The research group was looking for genetic variations in the HPA to see if there was a link to depression.

The brain has widely distributed receptors for a hormone called CRH (corticotropin-releasing hormone); it has two receptor types, Type 1 and Type 2.  CRH is released after stress:  release of noradrenaline and serotoinin and neuropeptide Y by a stressed brain leads to CRH release.  CRH binds to the Type 1 and Type 2 receptors and this leads to the cognitive and behavioural aspects of the stress response: fight or flight (amygdala), appetite changes (hypothalamus), cognitive fear (cortex), and finally ACTH release (from the hypothalamus to the pituitary) which leads to the production and release of cortisol from the adrenal gland.

The cortisol released from the adrenal binds to its own receptors throughout the body to mediate the stress response, and it regulates metabolic, immune, neurologic functioning; promotes cell differentiation; and, importantly feeds back to the brain to slow release of CRH and stop the response.  Mineralocorticoids are also released to regulation blood pressure and counterbalances cortisol to slow stress response in body.

The literature is inconclusive on whether antidepressants affect the HPA with the suggestion being they do—they appear to decrease HPA activity and lower circulating corticosteroids.  I have heard that tricyclic antidepressants have a larger impact than SSRIs.

Genetic variation of the receptors within the HPA are known; few are conclusively linked to psychiatric illness, but there are many suggested correlations in the published literature.  There are studies linking psychotic depression to the cortisol receptor; CRH receptors Type 1and 2 are linked to PTSD, panic disorder, MS, major depression after early childhood abuse, and predicted response to antidepressants.

Novel antidepressants for the treatment of depression which are anti-glucocorticoid (they slow the stress response) are in the pipeline.  One surprising agent, mifiprestone (aka. RU486) treats psychotic depression and suppresses CRH.

I think the jury is still out on what we can do in psychiatry to manipulate the HPA to treat and prevent depression.





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