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Re: Cortisol

Posted by jrbecker on April 8, 2003, at 0:39:06

In reply to Re: Cortisol and DHEA Balance jrbecker, posted by Ron Hill on April 7, 2003, at 16:59:52

> So is it your belief that atypical depression (i.e.; low motivation, anhedonia, anergy, hypersomnia, etc) is not correlated with elevated levels of cortisol?
> -- Ron


good question. It seems very likely based on the research that excessive cortisol plays a fairly direct role in causing the onset of depression. Although I think the issue is somewhat more complicated in atypical cases than in melancholic types. George Chrousos and Philip Gold of NIMH as well as Charles Nemeroff of Emory are some advocates for the role of the CRH pathway in terms of its more direct role [than monoamine metabolites] in the cause of depression.

A good read that might be a knowledgeable summary for those unfamiliar with this might be:

Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. PW Gold 1 and GP Chrousos 2. Molecular Psychiatry 2002, Volume 7, Number 3, Pages 254-275

To give a basic synopsis, it is hypothesized that in melancholic depression, the CRH pathway is being chronically stimulated, which simplifies to Corticotropin-releasing hormone --> ACTH --> Cortisol and NE release. This leads to the "typical" symptoms of depression due to chronic stress activation: low appetite, little sleep, anxiety, fearfulness of what the future holds, etc.

In atypical depression, the stress system has pretty much fallen into disrepair. Whether it's because all atypicals were once melancholic in nature whose stress systems' have now crashed... well this is unknown. What is known is that atypical and melancholics have been found to be genetically distinct based on twin studies. Accordingly, many experts are beginning to think of the two types as completely different illnesses altogether. It's been shown that people with lower cortisol are more prone to PTSD, so perhaps there is a difference in predisposition that separates melancholics from atypicals as well.

Back to the stress system. It is believed that CRH is down-regulated in atypical sufferers (possibly due partly to feedback inhibtion from cortisol itself). Secondly, it is unclear whether cortisol itself is lower as well (there have been both studies that have measured high levels of cortisol as well as some that measured low levels of cortisol). Either way, it points to a problem of dysregulation of the stress system.

Another monkey wrench to throw into this theorizing is the idea of atypical depression as an offshoot of bipolar depression. There seems to be some good evidence of this when looking at the overlap of biplar II sufferers who have very comparable atypical features. If this is indedd the case, it might even suggest that atypical depression and that of bipolar illness have totally other mechanisms at fault besides the stress system.

In many ways, CRH and cortisol have been branded as conditionally "bad." However, this is in cases where it is being chronically overstimulated. CRH in the brain has been shown to be sort of like an endogenous cocaine. It increases dopamine and norepinpehrine release and has been related to all forms of primal drive and motivation. So, at normal levels it's a pretty good thing. Ron, this is where I actually answer your question specifically. Is excessive cortisol at fault for anhedonia? Yes seems to be the simple answer. Excessive cortisol is known to damage hippocampal regions of the brain as well as play a feedback stopgap to further CRH output. It is well known that this is what is occuring overtime in melancholic brains. Is this happening in atypical brains? My guess would be yes, but not to the same extent. Hippocampal damage(manifestation of atypical features) as well as low CRH (a major role in anhedonic symptoms) are major players in the illnesses' dabilitating effects. Whether anhedonic symptoms is due to ~current~ excessive cortisol is not clear. Unfortunately, a backwards way to correct this problem in atypical cases would be the introduction of a CRH potentiator to rejump the pathway. Who knows if this is the end-to-all-answers solution though.

What I do know is that stimulants, cocaine, exercise, selegiline, testosterone-replacement, and nicotine have all temporarily lifted my anhedonia. So obviously it's a Dopamine/NE connection, but it seems CRH is the more likely direct candidate at fault.

As for why I take the pregnenolone over the DHEA. I really can't say why. I don't know if in the end it's actually interefering somehow with my antidepressive treatment. But my belief is that it seems to have a more direct increase of dopamine through modulation of GABA than does DHEA. So maybe that's why I might be seeing more benefits in comparison to DHEA at equal doses. At the same time, it can also cause more anxiety. Either way, both supplements are somewhat similar in the end. As I mentioned before, the safer bet may be the DHEA.





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