Posted by SLS on February 3, 2003, at 20:47:15
In reply to Re: Mifepristole (RU-486) lowers cortisol? » SLS, posted by Pfinstegg on February 3, 2003, at 18:36:32
Hi Pfinstegg.
> My understanding of how mefipristone works is somewhat different from yours.I am quite sure that it exerts its antiglucocorticoid activity via receptor antagonism.
> In the original study at Stanford, in which the patients had psychotic depressions and elevated 24-hour cortisols prior to treatment, the results, in about 60% of the patients, was a lowering of the cortisol levels to normal after 7 days of treatment- this was accompanied by a dramatic improvement in depressive symptoms.
I would like to see this study. Where might I find it?
> Mefipristone is thought to block the cortisol from continuing to damage the hippocampus; thus, while you may have more intercellular cortisol in the brain during the week of treatment, you are also allowing the hippocampus to physically recover- regaining normal size and blood flow, and increasing the number of receptors.
Has this increase in tissue volume or blood-flow been observed and measured directly through imaging in those subjects for whom mifepristone was introduced? Which came first: increased blood-flow or increased tissue volume? I find that measuring blood-flow to infer cause-and-effect is a "Catch-22". Does an area of the brain become more active because of increased blood-flow or is increased blood-flow the consequence of an increase in brain activity? As an example, I think the researchers at the NIMH got it wrong several years ago when they purported that the mood-stabilizing effects of nimodipine, which are modest at best, were derived from the increase in blood-flow seen with its use.
When it comes to the brain, I can't help but to be guarded when evaluating what the investigators of a particular study have measured (data), what cause-and-effect they think they have demonstrated (associations), and what their exercise in logic - which usually relies upon the data and interpretations supplied previously by others - determines to be the mechanistic explanation of their observations (hypothesis), and thus to be extrapolated and used to predict the consequences inferred by their explanations (speculation).
Lithium and valproate are also capable of protecting from destruction and facilitating growth of hippocampal tissue. In addition, antidepressants also foster a return to normal of the size of the hippocampus, but only if one responds to them robustly. (This seems to me to be a reversal of an atrophy that these structures might experience during extended periods of greatly reduced cortical activity attendant to extended periods of severe depression). I tried to take a low dose of lithium (300mg) for its putative neuroprotective and neurotrophic properties. I figured that it might remain in the background so as to prevent further damage until I find the right treatment for my depression. Unfortunately, I found it depressogenic and cognitively impairing.
> Then, according to my understanding, the mefipristone is stopped; patients who have been successfully treated are now able to re-establish a normal feed-back loop, so that the hippocampal receptors for cortisol can carry out normal uptake, and shut down the over-production of CRH by the hypothalamus- thus re-establishing HPA regulation.
It sounds do-able. I would like to try something to re-regulate my HPA. My circulating cortisol is high and I am a dexamethasone challenge non-suppressor.
> Mefipristone is meant to be a brief treatment, allowing the hippocampus to regain more normal functioning. The thought is that after that, on-going treatment with ADs will be more effective- more, and more normal, receptors to deal with!Wow. That's a compelling idea. It definitely deserved your "!" It sounds like so much wholesome an approach to coaxing the system to begin regulating itself more properly. Thanks for this. I had never heard this before.
- Scott
poster:SLS
thread:139015
URL: http://www.dr-bob.org/babble/20030130/msgs/139207.html