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HPA Axis and Depression - Way Too Long

Posted by Cam W. on April 28, 2000, at 21:36:15

In reply to Re: Investigational drug assay and specific receptors., posted by Scott L. Schofield on April 28, 2000, at 9:33:56

> Hi Cam.
> I know you have recently performed a ton of research into HPA stuff. What sorts of things have persuaded these researchers to consider anomalies in these systems to be causes of depressive disorders rather than the consequences of them?
> - Scott

Scott - To do justice to why I believe that a dysregulated HPA axis is the 'cause of the depressive symptoms' of depression I will need at least three studies that I have in my files at work. I think depression is 'caused' by physical or psychological trauma(s) which result in a dysregulation of the HPA axis, sustaining the depressive symptoms. I have already written myself a note to pick these up Monday. (I really need my files at home, but to duplicate them would unnecessarily kill a couple extra trees). I will muddle through with an overview of how I understand this concept and, if necessary give a more complete hypothesis in Monday's posting. Tell me if you would like a further explanation than the following (it does get a little more involved, but is way cool). The following is from notes that I made from a Charles Nemeroff article (didn't write down the reference) and supplemented by a subsequent readings that I think I remember.

The hypothalamus is the controller of hormone secretion in the brain (and body). Peptides secreted by the hypothalamus stimulate or inhibit the pituitary's release of various hormones [eg thyroid stimulating hormone (TSH); growth hormone (GH); adrenocorticotropic hormone (ACTH)]. These hormones control the release of other hormones from various glands throughout the body (outside of the nervous system) and also control their own release, via negative feedback by attaching to inhibitory receptors in the hypothalamus and pituitary (keeping TSH, GH, and ATCH levels from becoming excessive).

The release of TSH and GH (by a number of stimulators) is blunted in people with depession. Lowered levels of TSH (thyroid insufficiency) causes a depression that is non-responsive to antidepressants (as Noa has pointed out on a number of occasions).

The HPA axis (hypothalamus-pituitary-adrenal axis) controls the body's response to stress (the fight-or-flight reaction to physical or psychological stress). To prepare this response to stressful situations, the hypothalamus increases the production and secretion of corticotropin releasing hormone (CRH) which, via the portal blood vessels, and with the help of vasopressin, induces the pituitary to release ACTH and -endorphins.

ACTH is released into the body's circulatory system, which attaches to receptors on the adrenal gland (located on top of the kidneys) and causes the adrenal gland to dump cortisol into the bloodstream.

CRH instructs the body to slow the activity in certain bodily areas (eg raphe - leading to a decrease in sleep response; digestion - decreased appetite; and decreased sexual desire - leading to a 'limp willy') while corisol increases the activity of other areas of the body involved in self-preservation (eg increase in blood flow to muscles - leading to restlessness; and more alertness - heightened senses).

Chronic activation of the HPA axis reduces the ability of cortisol to shut off the release of CRH and ACTH (a breakdown of the negative feedback system) and leads to the syndrome we call depression. Unmedicated depressed individuals show chronically increased HPA axis activity (as seen by increased cortisol levels in the CSF, urine and blood).

Researchers have also shown that the pituitary and adrenal glands are enlarged in depressed people, probably due to increased production (and thus release) of ACTH and cortisol, respectively. These chronic hypersecretions are probably due to uncontrolled or aberrant CRH activity in the hypothalamus. It is thought that the dysregulated hypothalamus is the main cause of HPA axis hyperactivity and thus the development of depressive symptoms (eg lowered libido, anxiety, insomnia, etc.). Depressed people also show a blunted response by the adrenal glands to ACTH, but still the adrenals pump out excess cortisol. This blunted response could be the body trying to curb cortisol release.

One thing that all ADs have in common (be they SRIs, NRI, TCAs, MAOIs, NDRIs, ECT, etc.) is that they all decrease CRH levels. An eloquent article by Frank Hoebester (sp?) explains this in detail (I have cited this article earlier this year as a must read, but I can't remember in which thread - this was the article that I said was not bathroom reading). This is one of the articles that I have in my files at work.

Everyone has a different level of stress needed to induce depression. It is sort of like everyone has a bar set at a different level from everyone else. The level of this bar is determined by genetics and early life environmental factors (eg physical or emotional abuse as a child). After a certain level of stress is surpassed, the HPA axis uncouples and depression ensues. It is thought that similar levels of a bar are seen in people predisposed to schizophrenia or bipolar disorder. If a certain level of stress or 'trigger' (emotional, physical, drug-induced, etc.) is surpassed the disorder is manifested. I believe this is called the stress-diathesis model (diasthesis = environment, I think). Both Nemeroff from Emory (for depression) and Ming Tsuang from Harvard (for schizophrenia) champion this theory.

Also, as I mentioned in my last post, that decreasing serotonin (and to a lesser extent norepinephrine) in someone without depression will not cause depression; but adding these neurotransmitters (by SRI or NRI) does resolve depressive symptoms.

It is interesting to note that the downregulation of -adrenoceptors caused by most antidepressants (which incidentally takes 2 to 4 weeks - the time it takes for AD effect to kick in) causes a decrease in the expression of the CRH gene in the hypothalamus (thus decresed CRH production).

Also, CRH-receptor antagonists resolve depression and anxiety immediately (like downregulating -adrenoceptors, but with immediate action). The CRH-receptor antagonists currently being tested for relief of anxiety seem only to work for a short period of time and the increased CRH gene expression returns. There are also some side effect problems with these agents.

Also, another study that I have implicates glucocorticoid receptor (GR) function in depression. GRs are the receptors for cortisol that shut off the flow of CRH from the hypothalamus and ACTH from the pituitary. Basically, they are the negative feedback receptors that breakdown in the dysregulation of the HPA axis.

I hope that I have made this sort of clear, as this is why I think the HPA axis is linked to depression, but like you say, HPA axis dysregulation could be a consequence of depression. Although the evidence against this seems fairly strong (but not conclusive).

Thanks for putting me throught this mental work-out. I think that I now have a clearer picture in my mind of what I have been talking about. This is such an excellent forum to think out loud.

Your companion in curiosity - Cam W.




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