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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 15 of 15. This is the beginning of the thread.
Posted by Ame Sans Vie on February 2, 2003, at 21:04:29
I just thought I'd ask what everyone else had heard about this, as I just saw it mentioned in the magazine 'Psychology Today' as I was perusing it in Barnes & Noble. It was listed in a long chart of anti-depressant drugs and seemed oddly out of place (an abortifacient being psychologyically useful...?), until I read that it was known to lower cortisol? Could this be an option for anxiety/depression? Anybody?
Artemisia absinthium the Hoerte mara fond growan maciant,
Michael
Posted by Pfinstegg on February 3, 2003, at 10:25:11
In reply to Mifepristole (RU-486) lowers cortisol?, posted by Ame Sans Vie on February 2, 2003, at 21:04:29
Yes, it does. There are presently studies going on at NIH and Stanford on both bipolar and unipolar depression, including patients with elevated 24-hour urinary cortisols and psychotic features. The first study, done at Stanford, on psychotically depressed patients, showed dramatic remissions with 7-10 days of mefipristone treatment, so the two present studies have been widened to include less ill patients. It is the only AD which has been promising enough to be "fast-tracked" by the FDA- they did that last August. People who are interested can join the large study now going on at NIH; as of December, 2002, they were still recruiting new patients.
Pfinstegg
Posted by SLS on February 3, 2003, at 15:04:47
In reply to Re: Mifepristole (RU-486) lowers cortisol? » Ame Sans Vie, posted by Pfinstegg on February 3, 2003, at 10:25:11
> > I just thought I'd ask what everyone else had heard about this, as I just saw it mentioned in the magazine 'Psychology Today' as I was perusing it in Barnes & Noble. It was listed in a long chart of anti-depressant drugs and seemed oddly out of place (an abortifacient being psychologyically useful...?), until I read that it was known to lower cortisol? Could this be an option for anxiety/depression? Anybody?
> Yes, it is.
Hi.
Actually, mifepristone causes the body to secrete huge amounts of cortisol!
To be accurate, mifepristone reduces cortisol *activity* in the body by blocking cortisol receptors. However, by blinding regulatory cells from seeing cortisol, they ask the body to produce more to compensate for a perceived deficit. This type of systemic regulation is known as a negative-feedback loop.
I am very excited to see so such much focus on developing anticortisol drugs to treat depression. However, I am more than a bit nervous to flood my whole body with cortisol on a permanent basis. For example, perhaps there are subtypes of the cortisol receptor that mifepristone cannot not block. Tissues containing such a receptor would manifest the effects of hypercortisolemia. I don't know. I'd just like to see this issue addressed thoroughly.
You might want to take a quick look at the use of the "antifungal" drug, ketoconazole. It too opposes the activity of cortisol and has shown some value in depression. However, I don't recall through what mechanism(s). I think it actually influences the adrenal glands directly to reduce their production of cortisol. If you research it, will you please post what you find?
Thanks.
- Scott
Posted by Jack Smith on February 3, 2003, at 16:07:51
In reply to Re: Mifepristole (RU-486) lowers cortisol? » Ame Sans Vie, posted by Pfinstegg on February 3, 2003, at 10:25:11
> It is the only AD which has been promising enough to be "fast-tracked" by the FDA- they did that last August.
To expand on this, it is the only drug for mental health that has EVER been put on fast track by the FDA. This is quite shocking for two reasons. . . .
1. The pill is controversial as is, with the whole abortion debate--and this is a Republican administration.
2. The FDA is usually really slow with approving AD and other psychopharmocological drugs (e.g. reboxetine, moclobemide, selegeline patch)
These two things can mean one of two things--either this drug is really incredible or the drug company that makes it has a hell of a lot of political power.
Jack
Posted by Ame Sans Vie on February 3, 2003, at 17:41:25
In reply to Re: Mifepristole (RU-486) lowers cortisol?, posted by SLS on February 3, 2003, at 15:04:47
Hi, thanks for the info. This is all I've found so far on ketoconazole:
"BACKGROUND: Hypercortisolemia is frequently observed in major depression but its pathophysiologic significance is unknown. In patients in whom hypercortisolism contributes to depressive symptomatology, antiglucocorticoid agents should have antidepressant effects. METHODS: Twenty medication-free depressed patients (eight of whom were hypercortisolemic and twelve of whom were not) received either the cortisol biosynthesis inhibitor, ketoconazole (400-800 mg/d p.o.) or placebo for 4 weeks in a double-blind manner, and behavioral ratings were performed weekly. RESULTS: Ketoconazole, compared to placebo, was associated with improvements in depression ratings in the hypercortisolemic, but not in the non-hypercortisolemic patients. The hormonal changes seen (decreased dehydroepiandrosterone and testosterone levels and increased pregnenolone and pregnenolone-sulfate levels) are consistent with enzymatic blockade of C17,20-lyase, 11-hydroxylase, and 17-hydroxylase. Ketoconazole was generally well tolerated with no occurrence of significant side effects or laboratory abnormalities. CONCLUSIONS: This small-scale double-blind study suggests that antiglucocorticoids have antidepressant activity in hypercortisolemic depressed patients. The data are consistent with a causal role of adrenocortical dysfunction in some depressed patients and suggest the need for larger-scale trials." http://www.biopsychiatry.com/ketoconazole.htm
I'll post more as I find it!
--Michael
Posted by Pfinstegg on February 3, 2003, at 18:36:32
In reply to Re: Mifepristole (RU-486) lowers cortisol?, posted by SLS on February 3, 2003, at 15:04:47
My understanding of how mefipristone works is somewhat different from yours. 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. 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.
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.
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!
Pfinstegg
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
Posted by Pfinstegg on February 4, 2003, at 0:15:46
In reply to Re: Mifepristole (RU-486) lowers cortisol?, posted by SLS on February 3, 2003, at 20:47:15
Hi Scott..The Stanford study is now in Phase 11a, and the only report I have been able to find is a news release:
http://mednews.stanford.edu/news-releases-html/2002/augreleases/mifep
It has become so striking to me how many clear biological and neuro-endocrine markers there are for major depression, and how under-utilized they are in the treatment plans we get. I'm not sure that any of us even get anything resembling a "plan"! One article which showed how recovery from a 24-year bipolar disorder was followed by a gradual normalization of the DST, thyroid and hypofrontality emphasized the importance of biological follow-up, but it's a Japanese study!
"Recovery from neuroendocrinological abnormalities and frontal hypoperfusion after remission in a case of rapid cycling bipolar disorder" Psychiatry Clin Neurosci 1997 Aug; 51(4):207-12
A study that caught my attention was one from Tasmania (!), showing that about half the patients treated with TMS reverted to DST suppressor status. I was told by the doctor who administered TMS to me that the same rough figures apply to ECT- as well as to a wide range of medications, as you say. The study is:
"DST reversal in rTMS-treated depression" Aust NZ J Psychiatry. 1999 Apr:33 (2): 274-7
Over the past 5 months I became convinced that I wanted to search for treatment for myself which addressed the basic biological abnormalities- and all the knowledge and information on PB was a tremendous help with that. The things I have done: TMS, T3, T4, low dose estrogen, fish oil and tianeptine (a great hippocampus-protector in baby tree shrews, whose brains are very similiar to ours)- well, it is all working! There are more and more relevant articles flooding onto Medline, and I want to keep up with them, as I feel confident that excellent treatments aimed at the basic brain abnormalities are only a few years away.
Having a high 24-hour cortisol, and being a DST non-suppressor, have you considered TMS and mifepristone? If you can spare the time, and put up with all the hassles, you can get both at NIH. They do an incredibly thorough work-up, and that could set the standard for your follow-up care.
Take care- I wish you the very best
Pfinstegg
Posted by Kari on February 4, 2003, at 11:37:55
In reply to Mifepristole (RU-486) lowers cortisol?, posted by Ame Sans Vie on February 2, 2003, at 21:04:29
Does anyone know if there is a recognized problem which causes a constant adrenaline excess eventually leading to something similar to adrenal insufficiency which involves adrenaline rather than cortisol? Or is there no such thing :)? I am not referring to anxiety or depression, BTW...
Thanks,
Kari.
Posted by bozeman on February 6, 2003, at 21:48:44
In reply to question, posted by Kari on February 4, 2003, at 11:37:55
> Does anyone know if there is a recognized problem which causes a constant adrenaline excess eventually leading to something similar to adrenal insufficiency which involves adrenaline rather than cortisol? Or is there no such thing :)? I am not referring to anxiety or depression, BTW...
> Thanks,
> Kari.Kari --
I thought that was "adrenal exhaustion" brought on from being at full-tilt stress for too long. Some of the symptoms resemble depression but it's an endocrine depletion condition. Or are you talking about something else?
bozeman
Posted by Kari on February 7, 2003, at 14:40:52
In reply to Re: question, posted by bozeman on February 6, 2003, at 21:48:44
Thanks, bozeman.
I was referring to adrenal exhaustion but I thought that usually involves cortisol and I am sure that adrenaline was the main problem in my case...
Posted by lvrlife111 on January 26, 2004, at 4:40:37
In reply to Mifepristole (RU-486) lowers cortisol?, posted by Ame Sans Vie on February 2, 2003, at 21:04:29
> I just thought I'd ask what everyone else had heard about this, as I just saw it mentioned in the magazine 'Psychology Today' as I was perusing it in Barnes & Noble. It was listed in a long chart of anti-depressant drugs and seemed oddly out of place (an abortifacient being psychologyically useful...?)
> MichaelHi Michael et al,
I have had lifelong chronic depression with no treatment. It became worse after a 10-month heightened stress period. Debilitating! Soon thereafter
I had the unfortunate occasion to have to take RU-486 for a condom breakage; however within the first 6 hours of taking it I had a body-wide feeling of peace I hadn't known in I don't know how many years.I assumed then that my depression must be due to hormone imbalance, since mifepristole is a hormone.
I am fascinated and shocked to read this topic on your posting board after doing a search on how to lower cortisol in the brain.I am convinced reducing or flushing cortisol from my brain is partially the answer to the malaise. Therefore I would like to find out more.
Sincerely,
leslie(Scott's comment however seemed worrisome.. that it may cause greater systemic release of cortisol as a result of blocking the hippocampus' cortisol receptors.)
Posted by poop'd-out on August 26, 2004, at 14:30:00
In reply to Re: Mifepristole (RU-486) lowers cortisol?, posted by lvrlife111 on January 26, 2004, at 4:40:37
> I have had lifelong chronic depression with no treatment. It became worse after a 10-month heightened stress period. Debilitating! Soon thereafter
> I had the unfortunate occasion to have to take RU-486 for a condom breakage; however within the first 6 hours of taking it I had a body-wide feeling of peace I hadn't known in I don't know how many years.
>
> I assumed then that my depression must be due to hormone imbalance, since mifepristole is a hormone.
> I am fascinated and shocked to read this topic on your posting board after doing a search on how to lower cortisol in the brain.
>
> I am convinced reducing or flushing cortisol from my brain is partially the answer to the malaise. Therefore I would like to find out more.
>
> Sincerely,
> leslie
>
> (Scott's comment however seemed worrisome.. that it may cause greater systemic release of cortisol as a result of blocking the hippocampus' cortisol receptors.)
>
>
I don't know if you are still following this thread but I was curious as to how long you felt good for after taking mifepristone. Was it just for that day, or was it sustained for a week or so?Thanks,
Beth
Posted by jrbecker on August 30, 2004, at 9:37:26
In reply to Re: Mifepristole (RU-486) lowers cortisol? » lvrlife111, posted by poop'd-out on August 26, 2004, at 14:30:00
http://biz.yahoo.com/prnews/040830/nym048_1.html
Press Release Source: Corcept Therapeutics Incorporated
Corcept Therapeutics Receives Special Protocol Assessment from FDA for Two Pivotal Phase III Trials of CORLUX(TM)
Monday August 30, 6:00 am ET
MENLO PARK, Calif., Aug. 30 /PRNewswire-FirstCall/ -- Corcept Therapeutics Incorporated (Nasdaq: CORT - News) today announced that it has reached a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA) for the design of two pivotal Phase III clinical trials evaluating CORLUX(TM) (mifepristone) for the treatment of the psychotic features of psychotic major depression (PMD). The Company plans on initiating the first of these trials immediately and expects the second to commence in the fourth quarter of 2004. Corcept anticipates having initial results from these studies available in the first half of 2006. CORLUX has been granted Fast Track designation for this indication.
ADVERTISEMENT
"We are pleased to have reached agreement with the FDA on the design of these two pivotal trials and are excited to begin," said Dr. Joseph K. Belanoff, Corcept's chief executive officer. "PMD is a disorder that affects approximately three million people in the United States each year and for which there are no FDA-approved treatments. We look forward to determining the efficacy and safety of CORLUX. Through these studies, we will investigate whether CORLUX will provide rapid and sustained relief from the psychotic symptoms of this crippling illness."Clinical Trial Design
The primary endpoint for the two randomized, double-blind, placebo- controlled Phase III clinical trials of CORLUX is the proportion of patients with at least a 50% improvement in the Brief Psychiatric Rating Scale Positive Symptom Subscale (BPRS PSS) at both Day 7 and Day 56, otherwise known as a categorical improvement. The BPRS is an 18-item rating instrument used to assess psychopathology and the PSS includes the four items in the BPRS that specifically measure psychosis. Patients must have at least mild psychotic symptoms (BPRS PSS greater than or equal to 12) to enter the studies and will be hospitalized if clinically necessary. BPRS PSS assessments will also be made at Days 14, 28 and 42.
"In our interactions with the FDA, we have discussed various potential primary endpoints to demonstrate that CORLUX provides a rapid and sustained response. In our previously completed Corcept 03 trial, we measured responses at Day 7 sustained to Day 28 and continued to measure symptom scores for about one-third of the patients through Day 56. There was a statistically significant difference between the CORLUX and placebo groups on the BPRS PSS at Day 56. Therefore, we reached agreement with the FDA to have the primary endpoint for these pivotal trials be a substantial reduction in psychotic symptoms at both Day 7 and Day 56, which will demonstrate rapid and sustained relief," commented Dr. Belanoff.
The first of these trials, Corcept 07, which will begin immediately, is similar in design to the Corcept 03 trial, and will enroll up to 280 patients at approximately 20 sites in the U.S. with a randomized one-to-one distribution into either a treatment or a placebo arm. Patients in the treatment arm will receive 600 mg of CORLUX once daily for a period of seven days. All patients are to be off any antidepressant and antipsychotic medication for at least one week before beginning the seven day treatment period. After the seven days of CORLUX treatment, all patients will receive antidepressant therapy through Day 56. Treatment with antipsychotic medications or electroconvulsive therapy will not be allowed at any time during the study.
The second clinical trial, Corcept 06, will enroll approximately 440 patients at about 30 sites in the U.S. These patients will be evenly distributed among three active dose groups (300 mg, 600 mg and 1200 mg) or a placebo group with patients receiving once daily dosing for a period of seven days. The three dosing levels fulfill the FDA's request to supplement data on a range of potential doses beyond that provided by our 33 patient dose ranging study completed in 2001. All patients in the study must be off any antidepressant and antipsychotic medication for at least one week before the seven day treatment period and will receive antidepressant therapy starting on Day 1 through Day 56. As with Corcept 07, treatment with antipsychotic medications or electroconvulsive therapy will not be allowed at any time during this study.
Previously Completed Trials
The Company has completed four studies of CORLUX for the treatment of psychotic features of PMD. In January 2001, a dose finding clinical trial evaluating the efficacy, tolerability and dose response of CORLUX showed that after one week of treatment, approximately two-thirds of the patients in the two higher dosage groups (600 mg and 1200 mg) experienced clinically meaningful reductions in psychosis, as measured by the BPRS. Based on these encouraging results, the Company conducted two clinical trials, the 02 study and 03 study, which were double-blind, placebo-controlled safety and efficacy studies in which a total of 429 patients were enrolled.
The 02 study showed that CORLUX was well tolerated and that there were no discernible problems with drug interactions between CORLUX and commonly prescribed antipsychotic and antidepressant medications. The 03 study demonstrated with statistical significance that patients in the CORLUX group were more likely than patients in the placebo group to achieve a 50% reduction in the BPRS PSS at Day 7 sustained to Day 28. In a fourth trial, an open label study of the safety of retreatment in patients with a favorable response to treatment in the 02 and 03 studies, it was indicated that patients tolerated their retreatment well. Twenty-eight patients participated in this study.
About Psychotic Major Depression
PMD is a serious psychiatric disorder that affects approximately three million people annually in the United States. It is more prevalent than either schizophrenia or manic depressive illness. The disorder is characterized by severe depression accompanied by delusions, hallucinations or both. People with PMD are approximately 70 times more likely to commit suicide than the general population and often require lengthy and expensive hospital stays. There is no FDA-approved treatment for PMD.
Special Protocol Assessments (SPA)
The SPA is a process that provides for an official FDA evaluation of Phase III clinical study protocols. The SPA provides trial sponsors with binding written agreement that the design and analysis of the studies are adequate to support a license application submission if the study is performed according to the SPA and the results are successful. The SPA agreement may only be changed by the sponsor company or the FDA by a written agreement, or if the FDA becomes aware of a substantial scientific issue essential to product efficacy or safety. There can be no assurance that the Company's efforts to obtain marketing approval for CORLUX will be successful.
About Corcept Therapeutics Incorporated
Corcept Therapeutics Incorporated is a pharmaceutical company engaged in the development of drugs for the treatment of severe psychiatric and neurological diseases. Corcept's lead product, CORLUX(TM), is currently in Phase III clinical trials for the treatment of the psychotic features of psychotic major depression. The drug is administered orally to PMD patients once per day for seven days. CORLUX, a potent GR-II antagonist, appears to mitigate the effects of the elevated and abnormal release patterns of cortisol seen in PMD. Corcept is also conducting a clinical trial to evaluate the safety and efficacy of our product in improving cognition in patients with mild to moderate Alzheimer's disease. For additional information about the company, please visit http://www.corcept.com.
Forward Looking Statements
Statements made in this news release, other than statements of historical fact, are forward-looking statements, including, for example, statements relating to our PMD clinical development program, FDA agreements and the timing of the start and completion of pivotal Phase III trials. Forward- looking statements are subject to a number of known and unknown risks and uncertainties which might cause actual results to differ materially from those expressed or implied by such statements. For example, there can be no assurances with respect to the commencement, efficacy, safety, completion or success of clinical trials, there can be no assurances with respect to the regulatory process or regulatory approvals, there can be no assurances with respect to commercial success, and financial projections and trial timetables may not be accurate. Risk factors are set forth in the Company's SEC filings, all of which are available from our website (http://www.corcept.com) or from the SEC's website (http://www.sec.gov). We disclaim any intention or duty to update any forward-looking statement made in this news release.
--------------------------------------------------------------------------------
Source: Corcept Therapeutics Incorporated
Posted by Elroy on May 29, 2005, at 18:36:54
In reply to Re: Mifepristole (RU-486) lowers cortisol? » lvrlife111, posted by poop'd-out on August 26, 2004, at 14:30:00
My understanding is that if RU486 is successful in re-setting the HPA Axis (which it is in a high percentage of cases) that the short-term therapy of RU486 administration - generally four to seven days - is the full extent of treatment. That's it. You're curede (it's the high level of cortisol that is creating the anxiety and / or depression - read up on info concerning Cushing's patients who have severe depression or anxiety: when the offending tumor is removed - that is causing the high cotisol - their anxiety and / or depression goes away immediately!). Some more treatment resistant people may not be "cured" immediately, but they then respond quickly to AD therapy whereas they did not before. A small percentage end up not having a positive effect or having a relapse months / years later.
Do a search on internet (I prefer using http://alltheweb.com/) with the terms "Mifepristone" (that's how it's actually spelled, for RU486) and "cortisol" and "depression". I got back over 400 results, so plenty of material to review.
Elroy
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> >
> >
> I don't know if you are still following this thread but I was curious as to how long you felt good for after taking mifepristone. Was it just for that day, or was it sustained for a week or so?
>
> Thanks,
> Beth
>
This is the end of the thread.
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