Mifepristone for Depression?

[Anasazi23]

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Does anyone have any experience with this now phase-II level clinical trial? It seems to be gaining speed, with some impressive results. The link to the clinical trial details are here. The topic has come up a couple times in my c/l rotation through related cases, and was wondering if anyone has tried it off label yet. The side effects seem to have the potential for extreme caution, but the quick onset of action and supposed efficacy make the risk/benefit ratio interesting.

Some of the details:
Study Type: Interventional
Study Design: Treatment, Safety/Efficacy

Official Title: Antiglucocorticoid Therapy in Bipolar Depression with Mifepristone (RU486)

Further study details as provided by National Institutes of Health Clinical Center (CC):

Expected Total Enrollment: 110
Study start: August 7, 2002


Bipolar Depression is a severe illness with high rates of psychiatric comorbidity and increased mortality related to suicide and medical illness. Hypothalamic pituitary axis (HPA) hyperactivity are found in bipolar disorder related to depression and mixed states. Patients with bipolar disorder also have cognitive difficulties and endocrine disturbances may contribute to such dysfunction. Antiglucorticoid therapies are novel treatments of mood disorder. Preliminary data in psychotic depression suggesting that mifepristone (RU-486), a glucocorticoid receptor antagonist, has antidepressant and salutary cognitive effects in a matter of days. In this study we examine the effects of mifepristone in severe bipolar depression in a parallel, double blind placebo controlled experiment. Bipolar subjects maintained on either lithium or valproate, after washout or prior antidepressants have a detailed neuroendocrine assessment. Patients approximately or almost 75 will receive eight days of mifepristone versus placebo after which patients are blindly crossed over to the opposite arm. Patients and a group of matched controls approximately or almost 35 will be compared with neuroendocrine, cognitive, and neurophysiologic testing to fully characterize their phenotype and explore biomarkers of response. It is hypothesized that stigmata of HPA axis hyperactivity and cognitive impairment will be predictive of response to antiglucocorticoid therapy with mifepristone.

 

[Anasazi23]

Here's a nice basic physiology refresher page from the Psychiatric Times that ties it nicely into the treatment of depression.

http://www.psychiatrictimes.com/p040592.html

 

[Anasazi23]

Here's a link to the abstract of an impressive newer study.

 

[Doc Samson]

Wow! Actual clinical psychiatry... who knew we could talk about that here.

 

[sdn1977]

Well...I've been watching all day to see if someone would respond so it seems no one has actual experience - neither do I. But...I've read about it in my journals as well and I've a few questions actually...perhaps you could respond. First, why such a short tx period? Just to reset the HPA axis? If this is so, is it supposed that this reset is of a permanent nature & why pharmacologically would that happen? The drug half life is 20-54 hrs (depends upon the method of kinetic analysis) & this does not include the physiologic half life, so I can see the one study following for 21 days, but wouldn't you have to follow for much longer to see if the HPA axis actually "went back" to what it previously was - as is the case when you give dexamethasone, high dose,short term for chemo. Second, if you switch patients every 7 (or was it 8-can't remember) days...wouldn't you still be seeing effects from the HPA reset if your pt was in the tx arm? Finally, the study population seems very small for an drug study in such a "common" diagnosis. It seems the study design has problems which could be a source of criticisim later. Thanks for any input anyone has. I'm interested in following this method of treatment!

 

[Anasazi23]

First, why such a short tx period? Just to reset the HPA axis? If this is so, is it supposed that this reset is of a permanent nature & why pharmacologically would that happen? The drug half life is 20-54 hrs (depends upon the method of kinetic analysis) & this does not include the physiologic half life, so I can see the one study following for 21 days, but wouldn't you have to follow for much longer to see if the HPA axis actually "went back" to what it previously was - as is the case when you give dexamethasone, high dose,short term for chemo.

Apparently, it takes only a short time to 'reset' the HPA axis:

Administration of a GR antagonist results in an acute antiglucocorticoid effect, while presumably causing a compensatory upregulation of GR numbers, leading to enhanced negative feedback of the HPA axis. Initial clinical studies using the GR antagonist mifepristone (Mifeprex, RU-486) have been encouraging, but some clinical efficacy may have been masked by the prolonged administration of the drug (Murphy et al., 1993). Animal studies suggest that GR numbers are increased rapidly (within hours) after the administration of mifepristone, which may restore normal feedback, thus "resetting" the HPA axis (Lupien and McEwen, 1997). Such data suggest that a brief period of treatment with the GR antagonist may be adequate for restoring normal HPA axis function. This might reduce problems of noncompliance and side effects associated with longer-term administration.

Clearly, more long term studies will be exciting to follow as they treatment course is studied more carefully.