![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 26. This is the beginning of the thread.
Posted by jrbecker on July 28, 2004, at 20:42:50
Neurocrine, Inc. in alliance with GSK will push forward with a Phase I trial of a CRF1 antagonist compound by year-end 2004.
http://biz.yahoo.com/prnews/040728/law105_1.html
Neurogen, Inc., in collaboration with Aventis,
has stated that it will go ahead with a compound of its own in 2005.Other companies developing these compounds include Janssen (J&J), Pfizer, and Bristol-Myers Squibb.
Posted by SLS on July 28, 2004, at 22:55:19
In reply to CRF1 antagonists back in clinical trials, posted by jrbecker on July 28, 2004, at 20:42:50
> Neurocrine, Inc. in alliance with GSK will push forward with a Phase I trial of a CRF1 antagonist compound by year-end 2004.
How long does it take for a drug to go from Phase I to final approval?
- Scott
Posted by jrbecker on July 29, 2004, at 9:49:02
In reply to Re: CRF1 antagonists back in clinical trials, posted by SLS on July 28, 2004, at 22:55:19
> > Neurocrine, Inc. in alliance with GSK will push forward with a Phase I trial of a CRF1 antagonist compound by year-end 2004.
>
>
> How long does it take for a drug to go from Phase I to final approval?
>
>
> - Scotthere's a rough synopsis...
http://www.phrma.org/newmedicines/newmedsdb/phases.pdf
Posted by cpallen79 on July 30, 2004, at 12:21:43
In reply to Re: CRF1 antagonists back in clinical trials, posted by SLS on July 28, 2004, at 22:55:19
I have to admit that the CRF idea is pretty exciting. From my understanding (again I'm no whiz at science) they stop the effects of cortisol, and that could possibly be of huge benefit in preventing depressive episodes. Please correct me if I'm wrong.
> > Neurocrine, Inc. in alliance with GSK will push forward with a Phase I trial of a CRF1 antagonist compound by year-end 2004.
>
>
> How long does it take for a drug to go from Phase I to final approval?
>
>
> - Scott
Posted by linkadge on July 30, 2004, at 19:00:42
In reply to Re: CRF1 antagonists back in clinical trials, posted by cpallen79 on July 30, 2004, at 12:21:43
I read some literature that suggested that mifestiprone had a powerful antipoopout effect for SSRI users who had lost the responce to SSRI's
Linkadge
Posted by SLS on July 31, 2004, at 6:24:20
In reply to very promising, posted by linkadge on July 30, 2004, at 19:00:42
> I read some literature that suggested that mifestiprone had a powerful antipoopout effect for SSRI users who had lost the responce to SSRI's
>
>
> Linkadge
Do you remember where you saw that? I have only seen references to its use as monotherapy. Please post some links if you can. Thanks.
- Scott
Posted by linkadge on July 31, 2004, at 9:01:20
In reply to Re: very promising » linkadge, posted by SLS on July 31, 2004, at 6:24:20
Not exactly sure. Just somewhere on a seach engine. They noticed that when they gave mice adenalectomies they had enhanced neurogenesis over regular mice during times of stress.
If neurogenesis is the end target of antidepressants, than a normalized adrenal system could theoretically enhance an antidepressant's neurotrophic effects.
Linkadge
Posted by SLS on July 31, 2004, at 10:53:00
In reply to Re: very promising, posted by linkadge on July 31, 2004, at 9:01:20
> Not exactly sure. Just somewhere on a seach engine. They noticed that when they gave mice adenalectomies they had enhanced neurogenesis over regular mice during times of stress.
>
> If neurogenesis is the end target of antidepressants, than a normalized adrenal system could theoretically enhance an antidepressant's neurotrophic effects.
My doctor and I are thinking seriously about trying mifepristone. I haven't even asked my pharmacist how to go about getting it yet, though. I doubt my insurance would cover it, although I could present them with literature to support its use in an attempt to appeal their initial refusal. Even though one is to undergo a course of treatment lasting for only 7 days, it would probably be expensive at 600mg per day. I suspect that I would need some sort of periodic maintenance treatment anyway, seeing as how averse my brain is to mental health. If I go this route, I'll definitely keep you posted.
- Scott
Posted by linkadge on July 31, 2004, at 12:40:28
In reply to Re: very promising » linkadge, posted by SLS on July 31, 2004, at 10:53:00
I too would really like to try RU-486. My worst depression and suicidiality comes when I am under stress.
Some studies show that individuals who are predisposed to depression show abnormal neural reactions to stress.
Abnormal cortisol can alter the function the
5ht-1a recepton, which can have a profound effect on mood, an hippocampal neurogenesis.
Linkadge
Posted by Pfinstegg on July 31, 2004, at 23:48:59
In reply to Re: very promising » linkadge, posted by SLS on July 31, 2004, at 10:53:00
Please do keep us informed if you are able to take a trial of mefipristone! From what I have read, this is the best drug presently available for cutting down excessive/abnormally timed cortisol production. Do you know what your 24-hour, AM and PM cortisol levels are, and whether you suppress normally with the DST test? I think it would be wonderful to have this information before and after taking mefipristone. I did those before and after TMS- they were all abnormal before, and normal after. I do have to take booster treatments of TMS about every four months, although now it has been 5 months and I'm still OK (normal Beck score)
Posted by sb417 on July 31, 2004, at 23:57:50
In reply to Re: very promising » linkadge, posted by SLS on July 31, 2004, at 10:53:00
Hi SLS. I'm very interested to hear about mifepristone. I had asked my doctor about it, but I guess it's used only experimentally now, right? If you do try it, please keep us informed.
Posted by Pfinstegg on August 1, 2004, at 0:53:11
In reply to Re: very promising » linkadge, posted by SLS on July 31, 2004, at 10:53:00
It's now approved as an abortifacient. I believe that, if you have a willing doctor, he can submit a special form to Danco, the company who makes it in the US, for "compassionate use". He'd be able to ask for the amount he wanted. But I have no idea how much it would cost, either.
As an alternative, would you consider going into the Stanford study? Or one at NIH?
Posted by sb417 on August 1, 2004, at 1:01:37
In reply to Obtaining mefipristone » SLS, posted by Pfinstegg on August 1, 2004, at 0:53:11
Hi Pfinstegg. Thanks for posting this information. I have bookmarked it.
Posted by Larry Hoover on August 1, 2004, at 7:07:13
In reply to Re: Obtaining mefipristone » Pfinstegg, posted by sb417 on August 1, 2004, at 1:01:37
> Hi Pfinstegg. Thanks for posting this information. I have bookmarked it.
Sorry if my correction seems pedantic, but when I went to Pubmed (which does not do fuzzy searches), I had only 3 hits, until I found the spelling mistake.
I am amazed to discover that RU-486 (mifepristone) is a modified polyunsaturated fatty acid, more specifically, a derivative of prostaglandin type E1.
Please do let us know if anyone gives this drug a try.
Thanks,
Lar
Posted by SLS on August 1, 2004, at 8:02:38
In reply to Re: very promising » SLS, posted by Pfinstegg on July 31, 2004, at 23:48:59
> Please do keep us informed if you are able to take a trial of mefipristone! From what I have read, this is the best drug presently available for cutting down excessive/abnormally timed cortisol production. Do you know what your 24-hour, AM and PM cortisol levels are, and whether you suppress normally with the DST test? I think it would be wonderful to have this information before and after taking mefipristone. I did those before and after TMS- they were all abnormal before, and normal after. I do have to take booster treatments of TMS about every four months, although now it has been 5 months and I'm still OK (normal Beck score)
Hi Pfinstegg.It has been a long time since the tests were done, but I was a DST non-suppressor, and I tested positive on the "spit test". I don't know any of the specifics.
I doubt that I will make mifepristone the next thing I try. I would rather try Cymbalta first. However, I'm not sure the FDA is being all that cooperative. They are supposed to reach a decision by the end of September. I guess it really depends on them. They keep pushing back the actionable date. Perhaps they want to put some distance between approval and the media blitz on the SSRI suicide thing. Of course, it could be something as simple as everyone being on vacation.
How did you go about getting you cortisol tested?
Wouldn't be neat if all you had to do was to take mifepristone for one week every 6 months to reset the HPA and stay well? You could save yourself a semiannual trip to Atlanta.
- Scott
Posted by SLS on August 1, 2004, at 8:04:23
In reply to Re: corrected spelling mifepristone, posted by Larry Hoover on August 1, 2004, at 7:07:13
:-)
Posted by Pfinstegg on August 1, 2004, at 10:09:24
In reply to Re: corrected spelling mifepristone, posted by Larry Hoover on August 1, 2004, at 7:07:13
Thank you, Lar- not pedantic at all- just needed in order to search properly! I have been hoping for a couple of years now that someone in the Stanford or NIH studies would find Psychobabble and post their experiences. I have read that it's promising enough to have been "fast-forwarded" by the FDA, but I'd love to know how long its effects last, whether people suffer any side-effects, etc. When I find out, I'll definitely share the information.
Posted by Pfinstegg on August 1, 2004, at 10:43:22
In reply to Re: very promising » Pfinstegg, posted by SLS on August 1, 2004, at 8:02:38
Hi Scott. It would be wonderful to just take a week of mifepristone, as needed! It's a huge nuisance to fly to Atlanta every few months for three days of treatment. I feel pretty certain that my HPA axis has been permanently set into overdrive by csa, as Nemeroff suggests does happen, so that I just need to keep doing what I can to lower it towards normal. The TMS has been by far the best treatment I've yet had- far better than any medications- and I am hoping that it will be approved in 2005-6. Then I can drive in and get 20 minutes of treatment as needed in my home town! (and insurance will pay)
As to getting the cortisol tests done- after I learned about its central role here on Babble, I made an appointment with an endocrinologist, and asked for them. He gave me a very hard time at first, saying they weren't indicated because I didn't appear Cushingoid, but he finally agreed to do them. I had a 24-hour urinary cortisol, an AM and PM salivary cortisol, and the DST suppression test. When the tests came back, he was stunned that they were all abnormal! From what you are saying, it sounds as though, in addition to to DST non-suppression (indicating that you have chronically overactive, probably hypertrophied adrenals due to stimulation by too much ACTH), you also had salivary cortisol that was high in the evening- as you know, it's supposed to peak in the morning, and then steadily drop during the day, reaching its lowest levels by 11 or 12 PM. It sounds like we are much the same, cortisol-wise. I'm assuming that, if more people with refractory depression and major traumas in childhood had these tests, they would find exactly the same thing.
I know lots of people are awaiting Cymbalta, but that there has been a delay of more than a year. Would you mind telling me how it's supposed to work? Thanks! And please post if you hear any more news about mifepristone.
Posted by sb417 on August 1, 2004, at 23:38:13
In reply to Re: very promising » SLS, posted by Pfinstegg on August 1, 2004, at 10:43:22
> He gave me a very hard time at first, saying they weren't indicated because I didn't appear Cushingoid, but he finally agreed to do them.
>Hi Pfinstegg. I've been told by several endocrinologists that it is possible to have Cushing's Disease or Cushing's Syndrome even in the absence of classic Cushingoid features.
By the way, I am interested to know where you have the TMS treatments. Of course, if you'd prefer not to tell me because of privacy and confidentiality, that's OK with me.
Posted by Pfinstegg on August 2, 2004, at 0:14:50
In reply to Pfinstegg » Pfinstegg, posted by sb417 on August 1, 2004, at 23:38:13
Hi sb. You are right about Cushing's Syndrome. After all my cortisol tests were found to be abnormal, I was given a sort of ad hoc diagnosis of "Depression with Endocrine Features". From what I have learned, severe depression always has "endocrine features". It's just that they aren't usually looked for.
I'm glad to tell you where I went: to Dr. Mark Hutto in Atlanta. He and Dr. Steven Best, near Chicago, are the only two experienced, recomended psychiatrists who use TMS "off-label"in the US. If you are interested in looking into TMS, you could consider the studies currently being carried out by Neuronetics. They have manufactured a TMS device, and it is currently being tested by psychiatrists in 14 centers across the states. It sounds nearly identical to the TMS I had, except that the device is of a slightly newer design. By carrying out such a large study, they hope to get FDA approval fairly quickly. One important consideration- it's free! They have a website if you are interested.
Posted by jrbecker on August 2, 2004, at 10:27:27
In reply to Re: Pfinstegg » sb417, posted by Pfinstegg on August 2, 2004, at 0:14:50
Corcept Therapeutics' CORLUX (Mifepristone) aka RU-486. In phase III study for psychotic major depression. Granted fast-track status by FDA...http://biz.yahoo.com/prnews/040503/sfm086_1.html
http://www.corcept.com/mech.htm
http://www.corcept.com/pmd.htm
http://www.corcept.com/reference.htman NIMH study of mifepristone for Bipolar disorder
http://www.clinicaltrials.gov/ct/show/NCT00043654?amp;order=1
http://www.neurotransmitter.net/newdrugs.html
Posted by jrbecker on August 2, 2004, at 10:34:41
In reply to Re: CORLUX (Mifepristone), posted by jrbecker on August 2, 2004, at 10:27:27
from the headlines today. interesting...
http://www.newscientist.com/news/news.jsp?id=ns99996226
Hormone levels turn mouse mums fearless05:00 01 August 04
NewScientist.com news service
Mouse mothers become fearless when levels of a particular hormone drop, reveals a new study. This gives mothers the courage to ferociously attack any would-be assailants to their offspring.In response to scary or stressful situations, the brain secretes corticotropin-releasing hormone (CRH), which triggers a complex cascade of hormones that ready the body for action, such as raising blood sugar levels. It also feeds into the part of the brain which generates feelings of fear and anxiety. Elevated levels of CRH have been linked with symptoms of depression in both rodents and humans.
But lactating females have chronically low levels of CRH in the brain, which is thought to make them generally less anxious. For example, studies in humans show that nursing women are less perturbed, both physiologically and emotionally, by stressful situations.
Stephen Gammie and colleagues at the University of Wisconsin, Madison, US wondered if lowered CRH might also be responsible for a mother’s fearless bravery.
To test their theory, the team injected three different concentrations of CRH or a saline solution into the brains of nursing mothers and then placed a male her nesting cage. Compared to controls, who immediately assaulted the male, mice injected with the two higher doses of CRH showed almost no maternal aggression. Their response was delayed, their attacks less frequent and much shorter.
Stressful jobs
Mothers with the lowest levels of CRH attacked intruding males more than 20 times for the duration of about 45 seconds.“Low levels CRH seem to be necessary for maternal protective behaviour. It makes evolutionary sense for mothers to increase aggression because it’s critical for them just to keep the kids alive,” says Gammie. Unbalanced levels of CRH in humans may also be connected with post-partum depression, he says.
For the past few years, pharmaceutical companies have been working to develop CRH receptor blockers, like antalarmin, as a treatment for anxiety disorders, depression and post traumatic stress disorder. The drugs could have a performance-enhancing effect on people with extremely stressful jobs.“In war, soldiers are under high stress constantly,” says Tracy Bale, who works on CRH and depression at University of Pennsylvania. “In those cases, a CRH blocker might help.”
However, results with animal studies suggest that responses could be highly sex-dependant. And, adds Bale, the dose would be critical because CRH is involved with many other bodily functions, including glucose metabolism. Blocking too much CRH might hinder performance more than it helps.
Journal reference: Behavioral Neuroscience (DOI: 10.1037/0735-7044.118.4.000)
Anna Gosline
Posted by jrbecker on August 2, 2004, at 11:58:32
In reply to CRF and nuturing, posted by jrbecker on August 2, 2004, at 10:34:41
Neuropsychopharmacology (2004) 29, 1538-1545, advance online publication, 5 May 2004;
doi:10.1038/sj.npp.1300471Improvements in Neurocognitive Function and Mood Following Adjunctive Treatment with Mifepristone (RU-486) in Bipolar Disorder
Allan H Young, Peter Gallagher, Stuart Watson, Dolores Del-Estal, Bruce M Owen and I Nicol Ferrier
Stanley Research Centre, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, UKCorrespondence: Professor AH Young, Stanley Research Centre, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, Leazes Wing, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. Tel: +44 (0)191 282 4473; Fax: +44 (0)191 282 5708; E-mail: a.h.young@ncl.ac.uk
Received: 26 January 2004
Revised: 18 March 2004
Accepted: 23 March 2004
ABSTRACT
High cortisol levels are found in severe mood disorders, particularly bipolar disorder. Hypercortisolaemia may cause or exacerbate both neurocognitive impairment and depressive symptoms. We hypothesized that antiglucocorticoid treatments, particularly corticosteroid receptor antagonists, would improve neurocognitive functioning and attenuate depressive symptoms in this disorder. To test this hypothesis, 20 bipolar patients were treated with 600 mg/day of the corticosteroid receptor antagonist mifepristone (RU-486) or placebo for 1 week in a double-blind crossover design. Over the total 6 weeks of the study, neurocognitive and neuroendocrine function were evaluated at baseline, days 21 and 42. Mood symptoms were evaluated weekly. Nineteen subjects completed the protocol; there were no drop-outs due to adverse events. Following treatment with mifepristone, selective improvement in neurocognitive functioning was observed. Spatial working memory performance was significantly improved compared to placebo (19.8% improvement over placebo). Measures of verbal fluency and spatial recognition memory were also improved after mifepristone. Beneficial effects on mood were found; Hamilton Depression Rating Scale scores were significantly reduced compared to baseline (mean reduction of 5.1 points) as were Montgomery-Asberg Depression Rating Scale scores (mean reduction of 6.05 points). No significant change occurred after placebo. These data require replication but provide preliminary evidence that glucocorticoid receptor antagonists may have useful cognitive-enhancing and possibly antidepressant properties in bipolar disorder.Keywords: bipolar disorder; antiglucocorticoid; glucocorticoid receptor; cortisol; mood; memory
INTRODUCTION
Bipolar disorder is a chronic and recurrent illness, with a lifetime incidence of at least 1% (Kessler et al, 1994). Although the illness is defined by the occurrence of mania, the depressed phase predominates (Judd et al, 2002, 2003) and represents the greatest therapeutic challenge. Pronounced neurocognitive dysfunction is also frequently described in symptomatic bipolar patients and there is increasing evidence of specific impairments which may persist in euthymia and therefore represent a relatively enduring abnormality (Ferrier et al, 1999; Ferrier and Thompson, 2002; Thompson et al, 2000). It has been suggested that abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function may cause or exacerbate both neurocognitive impairment and depressive symptoms (McQuade and Young, 2000; Sapolsky, 2000).Indirect evidence for this link is found in conditions, such as Cushing's syndrome, which are characterized by a chronic elevation of endogenous cortisol levels and have consistently been shown to be associated with significant neurocognitive impairment (Forget et al, 2000; Mauri et al, 1993; Starkman et al, 2001; Whelan et al, 1980) and a high incidence of depression, which notably resolves with correction of the hypercortisolaemia (Dorn et al, 1997).
In healthy volunteers, both acute (Lupien and McEwen, 1997) and subchronic (Young et al, 1999) administration of the synthetic steroid, hydrocortisone, causes reversible impairments in neurocognitive function. Several studies have reported reduced verbal declarative memory function (Newcomer et al, 1999). This may be the result of a specific deficit in memory retrieval (de Quervain et al, 2000, 2003), although there is evidence to suggest that working memory function may be more sensitive than declarative memory to the effects of elevated corticosteroid levels (Lupien et al, 1999; Young et al, 1999).
In mood disorders, the greatest incidence of HPA axis abnormalities are found in bipolar and psychotic unipolar disorder (Rush et al, 1996) and reduction of cortisol levels in these conditions may therefore ameliorate depression and improve neurocognitive functioning (Reus and Wolkowitz, 2001). In keeping with this view, preliminary data suggests that cortisol synthesis inhibitors may be antidepressant (Brown et al, 2001). However, they are associated with a significant side effect burden and their efficacy may be compromised by the increased production of other neuroactive steroids.
At high doses, the progesterone receptor antagonist mifepristone (RU-486) is an antagonist of the glucocorticoid receptor (GR) subtype of corticosteroid receptor. Preliminary reports have found that mifepristone and the novel GR antagonist ORG-34517 have antidepressant effects in both psychotic and nonpsychotic unipolar depression, particularly in subjects with high rates of hypercortisolaemia (Belanoff et al, 2002; Høyberg et al, 2002).
We therefore sought to establish proof-of-concept for the use of GR antagonists in the treatment of bipolar disorder. We hypothesized that mifepristone administration would both enhance neurocognitive functioning¾specifically in domains that are most sensitive to the effects of elevated corticosteroids¾and improve depressive symptoms.
METHODSSubjects
Patients aged 18-65 years with a diagnosis of bipolar disorder, confirmed using the Structured Clinical Interview for DSM-IV (SCID) (First et al, 1995), were recruited from services in North East of England. A specific attempt was made to recruit those with residual depressive symptoms. Illness characteristics, clinical ratings, and medication history were determined by trained psychiatrists using full history, case-note, and medication review and standardized rating scales. Patients' medication had been unchanged for 6 weeks prior to participation and remained so throughout the study period. Seventeen were taking at least one mood stabilizer, with 13 taking at least one antidepressant and 11 taking an antipsychotic.
After a complete description of the study, written informed consent was obtained from all participants; the study received full approval from the local ethics committee.
Procedure
Following an initial baseline assessment of neurocognitive function and mood, and basal neuroendocrine profiling (day 0), patients were randomly allocated to receive either 600 mg mifepristone (taken orally at 08 00 once a day) or placebo for 7 days. Administration of medication was in a double-blind design. Mood ratings were taken after the week's treatment (day +7) and then at weekly intervals (day +14 and day +21). At day 21, the groups crossed over and the alternative treatment (placebo or mifepristone) administered for 7 days, again with ratings taken following the week's treatment (day +7) and at weekly intervals (day +14 and day +21). Neurocognitive function was assessed on three occasions over the study period: at baseline and at day +21, after each treatment. Neuroendocrine profiling was performed at baseline, after the week's treatment period (day +7) and then day +21.
Neurocognitive Testing
Based on previous research on the effects of corticosteroids on neurocognitive function (de Quervain et al, 2000, 2003; Lupien et al, 1999; Newcomer et al, 1999; Young et al, 1999), it was predicted that the principal cognitive domains which would be most sensitive to changes in HPA axis function were working memory and verbal declarative memory. The primary neurocognitive battery therefore consisted of two tests:
The Spatial Working Memory Task: This computerized test of working memory from the Cambridge Neuropsychological Test Automated Battery (CANTAB; CeNeS Pharmaceuticals, Cambridge, UK) requires subjects to search through an increasing number of (three, four, six, and eight) boxes to locate hidden tokens. As the token is never located in the same box more than once, 'between search errors' are committed when the subject returns to search a box in which a token has previously been located.
The Rey-Auditory Verbal Learning Test (Rey-AVLT): This test of verbal learning, includes indices of initial and delayed recall and recognition. A list of 15 words (List A) is read out to the subject five times, which they are required to recall after each trial. A different list of 15 words (List B) is then read once, followed by recall of this list. Finally, subjects are required to recall words from List A without an additional presentation of that list. After a 30 min delay, recall of List A is again tested, followed by a recognition trial of words from List A. The number of words correctly recalled or recognized are recorded. Alternative forms of the test were used on each visit.A secondary battery was also included which examined a broader range of neurocognitive domains, incorporating additional measures of learning and memory, attention and executive function:
Short-term memory span: This was tested across both phonological and spatial domains. The Wechsler forward digit span test requires subjects to repeat verbatim a string of digits which sequentially increases in length until the consecutive failure of two trials of the same digit span length. The CANTAB spatial span task was utilized to assess the subjects' ability to remember a serial sequence of squares as they change color.
Visuo-spatial learning and memory: This was assessed using the CANTAB pattern and spatial recognition tests. The pattern recognition task requires the subject to learn a series of 12 abstract patterns before being presented with pairs of patterns. Subjects are required to identify the familiar one. The test consists of two sets of 12 stimuli. For the spatial recognition test, the subject must learn the on-screen spatial position of five serially presented squares, with a subsequent forced-choice recognition between two locations. A total of four trials of five stimuli are completed. Alternative forms of both tests were used on each visit.
Executive function: This was tested using an established verbal fluency test (naming words beginning with one of three given letters; 60 s for each) with the overall total correct responses recorded. The Wechsler backward digit span, which requires the monitoring of information held in working memory, was also administered using the same method as the forward span test. Alternative forms of both tests were used on each visit.
Attention: This was assessed using the digit symbol subtest from the Wechsler Adult Intelligence Scale; a test requiring rapid copying of symbols paired with numbers in 90 s. Alternative forms of the test were used on each visit. A computerized continuous performance task¾Vigil (Cegalis and Bowlin, 1991)¾was also employed. In this random-interval 'A-K' form, subjects are required to respond to the target letter 'K' only when it is preceded by the letter 'A' from among a stream of random letters over an 8 min period.
All pen-and-paper tasks were administered according to standardized instructions (Lezak, 1995) and computerized tests from the CANTAB according to the manual protocols, on a personal computer fitted with a color touch-screen monitor. For all subjects, testing began at 1300 and took approximately 75 min to complete.Symptoms
With respect to symptomatic improvement, the antidepressant effect of mifepristone was the principal focus, therefore the outcome measures of interest were the 17-item Hamilton Depression Rating Scale (HDRS17; Hamilton, 1960) and the Montgomery-Asberg Depression Rating Scale (MADRS; Montgomery and Asberg, 1979). Other secondary scales consisted of the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) and the Young Mania Rating Scale (YMRS; Young et al, 1978).
Neuroendocrine Assessment
To profile plasma cortisol secretion, subjects were canulated in the antecubital fossa at 1230 and blood samples collected at 30 min intervals from 1300 to 1600. Subjects fasted throughout this period, remained semi-supine and did not sleep. Cortisol levels were determined by using Corti-cote radioimmunoassay kits (ICN Pharmaceuticals, Costa Mesa, California). The interassay coefficient of variation for cortisol was less than 8%, and the intra-assay variation was less than 9% across the assay range.
Statistical Analysis
Neurocognitive data were analyzed by repeated measures analysis of covariance (ANCOVA) with 'treatment' (mifepristone or placebo) and, where tests had more than one level, 'level', as the within-subject factors. As differential learning effects may occur depending upon the order of treatment administration, 'order' (mifepristone first or placebo first) was entered as a between-subjects factor and 'baseline' performance as a covariate. Main effects were further examined as the mean difference (and 95% confidence interval (CI) of the difference) between treatments (mifepristone or placebo), expressed as a change from baseline performance (Altman et al, 2000). Mood symptoms were also expressed as the mean change (95% CI) from baseline for each treatment and analyzed by paired t-test. All cited p-values were two-tailed, with a significance level set at 0.05. Analyses were performed using SPSS vs 9 (SPSS, 1998).
RESULTS
One patient was excluded from the study because of self-discontinuation of lithium prophylaxis. Data from 19 patients were available for analysis.Patients were aged between 26 and 63 years (mean=49 years, SD=11) and had no current or past diagnosis of substance abuse or dependence. At baseline, all patients had persistent depressive symptoms, with 17 fulfilling SCID criteria for current depressive episode (see ratings below). The median length of current depressive episode in the group was 7 months (mean=13.5, SD=15.7). Depressive symptoms had a mean score of 23 (SD=10) on the MADRS and of 18 (SD=10) on the HDRS17. The mean MADRS and HDRS17 scores of the three patients without a specific episode were 8 (SD=5) and 4 (SD=1), respectively. The average YMRS score in the whole group was 4 (SD=4).
Nine patients had previously attempted suicide. The median number of hospitalizations in the group was 3.
Neurocognitive Testing
Data are presented in Table 1.
Table 1
Neurocognitive Test Results
Primary Outcome MeasuresA significant ANCOVA main effect of treatment was found in the between search error rate of the spatial working memory task. Subsequent analysis of this significant main effect revealed that, following mifepristone treatment, the error rate was significantly reduced from baseline (t=2.89, df=18, p=0.010). However no significant change occurred following placebo (t=1.39, df=18, p=0.181). Direct comparison of the treatments revealed a significant advantage of mifepristone over placebo in the percentage improvement (calculated for each individual subject) in error rate from baseline (mean difference=19.8%, 95% CI=4.3-35.2; t=2.69, df=18, p=0.015) (see Figure 1). Order of treatment administration did not appear to be a confounding factor. The improvement following mifepristone was not significantly different in the group who received mifepristone first compared to the group who received it second. Again there was no difference in the response to placebo between these groups (p>0.2 for all). There was also no ANCOVA main effect of order or treatment by order interaction (see Figure 2). There were no significant main effects of treatment on any outcome measure from the Rey-AVLT (total correct, long-term recall or recognition).
Figure 1
Mean (SEM) percentage improvement in Spatial Working Memory between search error rate from baseline. See main text for statistics.
Figure 2
Mean (SEM) percentage improvement in Spatial Working Memory between search error rate from baseline following mifepristone or placebo, separated by group (subjects receiving mifepristone first vs those receiving placebo first).
Secondary outcome measures ANCOVA main effects of treatment was found in both verbal fluency and spatial recognition memory (see Table 1).For verbal fluency, the number of words correctly produced was significantly greater than at baseline following mifepristone treatment (t=3.34, df=18, p=0.004) with no significant difference following placebo (t=1.57, df=18, p=0.133). Direct comparison of each treatment, expressed as a percentage improvement from baseline, did not significantly differ (mean difference=1.60%, 95% CI=-9.89 to 13.10; t=0.29, df=18, p=0.773). For the spatial recognition task, direct comparison of mifepristone vs placebo, expressed as a percentage change in error rate from baseline, revealed a trend towards a lower error rate following mifepristone (mean difference=27.2%, 95% CI=-1.81 to 56.17; t=1.97, df=18, p=0.064).
Symptoms
At +14 days, following treatment with mifepristone, depression rating scores from the HDRS17 and MADRS had significantly improved from baseline levels (see Table 2). No significant change was observed at any time point following placebo. Direct comparison of the advantage of mifepristone over placebo at this time point (+14 days), however, failed to reach statistical significance for either HDRS17 scores (mean difference=2.32, 95% CI=-2.08 to 6.71; t=1.107, df=18, p=0.283) or MADRS scores (mean difference=2.26, 95%CI=-3.36 to 7.89; t=0.845, df=18, p=0.409).
Table 2
Symptom Ratings at Baseline and Weekly Following Mifepristone or Placebo
An independent samples t-test was used to confirm that the order of treatment administration was not a confounding factor. There was no significant difference in response to the active treatment, between the group receiving mifepristone first or the group receiving it second in either HDRS17 scores (t=0.054, df=17, p=0.958) or MADRS scores (t=0.554, df=17, p=0.587).Of the secondary scales, BPRS scores were also found to be significantly lower at +14 days following mifepristone treatment, with no change following placebo (see Table 2). Again, however, comparison of the advantage of mifepristone over placebo at this time point failed to reach statistical significance (mean difference=1.11, 95% CI=-3.00 to 5.22; t=0.564, df=18, p=0.579). YMRS scores did not significantly differ from baseline at any time point. A post hoc analysis was performed on all symptom effects, after the exclusion of the three patients who did not fulfill SCID criteria for a current depressive episode. The improvement from baseline at +7 days remained significant for all measures (p<0.05).
Neuroendocrine Measures
A highly significant ANOVA main effect was observed (F=20.6, df=4,68, p<0.0001), with cortisol levels being significantly higher following mifepristone treatment (day +7) compared to all other visits (see Figure 3). A significant diurnal rhythm was evident in the effect of time (F=21.6, df=6,102, p<0.0001), although there was no interaction between visit and time (F=1.18, df=24,408, p=0.29). No other significant effects were observed.
Figure 3
Cortisol levels (nmol/l) at baseline, after 1 week treatment (day +7) and +21 days following mifepristone or placebo.
An exploratory post hoc analysis revealed that the area under the curve (AUC) cortisol output at baseline correlated positively with the percentage improvement in spatial working memory error rate following mifepristone administration (rs=0.460, N=19, p=0.048). No relationship was found between cortisol AUC and the error rate following placebo (rs=0.286, N=19, p=0.235).
DISCUSSION
These data suggest that the GR antagonist mifepristone selectively improves neurocognitive function and may be antidepressant in bipolar disorder. Spatial working memory function was significantly improved from baseline compared to placebo (see Figure 1). Subtle improvements in secondary measures of verbal fluency and spatial recognition memory were observed. Ratings of depression (HDRS17 and MADRS) and total BPRS scores were also significantly reduced compared to baseline after treatment with mifepristone, but not after treatment with placebo. The pattern of symptomatic response was identical on all these objective rating scales. The superiority of mifepristone when directly compared to placebo, however, failed to reach significance, possibly due to a lack of statistical power. The symptomatic improvement was evident 2 weeks after the initiation of treatment, faster than would be expected from conventional therapeutic strategies in bipolar disorder. Future studies will need to ascertain how this improvement can be maintained.GR dysfunction may be of etiological importance in bipolar disorder. This notion is supported by neuroendocrine studies which have shown that 43% of depressed bipolar patients are DST nonsuppressors (Rush et al, 1996) and that the dexamethasone/corticotropin releasing hormone (dex/CRH) test is abnormal during relapse, recovery (Rybakowski and Twardowska, 1999; Schmider et al, 1995; Watson et al, in press) and in apparently healthy subjects with genetic loading for mood disorders (Lauer et al, 1998). It is also supported by post-mortem studies which show evidence of reduced GR mRNA expression in post-mortem brain tissue samples from patients with bipolar disorder (Knable et al, 2001; Lopez et al, 2003; Webster et al, 2002). The efficacy of mifepristone may therefore be secondary to its action at the GR. This is further supported by the finding that many antidepressant drugs increase GR binding and/or number in brain tissue, suggesting that GR regulation may be one aspect of the therapeutic mechanism of action of antidepressants (and mood stabilizers) and that the ability of a drug to regulate GR number may be a good predictor of therapeutic efficacy in patients with hypercortisolaemia (McQuade and Young, 2000).
It may, however, seem paradoxical that a disorder associated with reduced function of the GR may be treated using a GR antagonist. A recent study has reported a persistent reduction in glucocorticoid bioactivity after a single dose of mifepristone (200 mg) which normalized 2 weeks after the treatment (Heikinheimo et al, 2003). This adds support to the notion that mifepristone potentially acts by 'resetting' the homeostatic set point of the HPA axis (Belanoff et al, 2002).
Interestingly, RU-486 was the only GR antagonist examined in a recent study to increase both mineralocorticoid receptor (MR) and GR binding in the frontal cortex (Bachmann et al, 2003). This may underpin the selective pattern of improvement in neurocognitive function seen in the present study, which was restricted to tests which have been shown to be sensitive to frontal lobe dysfunction (Owen et al, 1995). The improvement in neurocognitive function was demonstrated at a point at which mood symptoms did not differ either from baseline or when compared to placebo. This suggests that the cognitive enhancing effect is not simply related to improvement in depressive symptoms.
It is perhaps surprising that¾given the well-documented effects of corticosteroids at the hippocampus¾mifepristone had no effect on verbal declarative memory function. This may be due to a difference in the sensitivity of the tests to detect changes in the relatively small number of patients in the study. Alternatively, it may be due to the timing of the neurocognitive assessments. Due to the preliminary nature of the study and the limited number of times neurocognitive testing can reliably be carried out, the assessments were performed at baseline and then 14 days after cessation of each treatment. This time point was selected so as to avoid the acute effects of the drug (when brain GR would be occupied and peripheral cortisol levels are greatly elevated; see Figure 3) and examine the longer term antiglucocorticoid effects (Heikinheimo et al, 2003). Greater improvements may have been observed if neurocognitive function was assessed at an earlier time-point. Also, the possibility of order effects cannot entirely be ruled out (see Figure 2), but these are difficult to assess due to a reduction in sample size if measured separately by the order of treatment administration.
There were no drop-outs due to side effects in either phase of the study and no patients experienced a manic relapse. This is the largest double-blind, placebo-controlled study of mifepristone in mood disorders and the first in bipolar disorder. However, the number of patients studied was relatively small and this preliminary result requires confirmation in studies of larger numbers of patients with bipolar depression; preferably in a between-subjects design, thereby avoiding the problems inherent in a crossover design. In addition, although high rates of hypercortisolaemia and other HPA axis abnormalities occur in bipolar disorder (and may influence the response to mifepristone) we cannot be sure of the prevalence of GR dysfunction in the cohort of patients recruited for our study. Although the correlation observed in the present study between baseline basal cortisol levels and the neurocognitive response to mifepristone (spatial working memory error rate) may suggest that patients with the greatest HPA axis abnormality respond better to GR antagonists. In future studies, HPA axis function should be fully profiled at baseline, as both a predictor of response to antiglucocorticoids and as a method of ascertaining the degree of 'normalization' of the axis following treatment.
The results of the present study add direct support to the notion that the GR is an important modulator of neurocognition and mood in bipolar disorder and that adjunctive administration of drugs that specifically target this receptor may be of therapeutic benefit. Our results require replication but provide preliminary evidence that GR antagonists selectively improve neurocognitive function and may have antidepressant properties in bipolar disorder. Such drugs hold promise for the treatment of bipolar disorder.
Acknowledgements
We thank the Stanley Medical Research Institute for their generous support of this study. We thank the subjects who participated in this study. We are grateful to Margaret Smith who was responsible for facilitating patient care. We are also grateful to Mel Leitch and Dorothy Nelson for performing the neuroendocrine assays, Dr Bernard Browne for assistance with patient recruitment and to Dr Andrea Hearn for help with the completion of clinical ratings. We thank Anne Maule for assistance with the preparation of the paper.
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http://www.nature.com/cgi-taf/DynaPage.taf?file=/npp/journal/v29/n8/full/1300471a.html
Posted by sb417 on August 2, 2004, at 20:54:46
In reply to Re: Pfinstegg » sb417, posted by Pfinstegg on August 2, 2004, at 0:14:50
Hi Pfinstegg. Thank you very much for all that information. I will discuss it with my doctor. Perhaps you know this, but I just learned from "THE MERCK MANUAL" that there is a distinction between Cushing's Syndrome and Cushing's Disease: "Whereas the term Cushing's syndrome has been applied to the clinical picture resulting from cortisol excess regardless of the cause, hyperfunction of the adrenal cortex resulting from ACTH excess has frequently been referred to as Cushing's disease, implying a particular physiologic abnormality. Patient's with Cushing's disease may have a basophilic or a chromophobe adenoma of the pituitary gland." I was also interested to see that the Dexamethasone Suppression Test for depression is slightly different from the DST test for adrenal gland dysfunction. I think the dosage of dexamethasone is different, and the timing may be different as well.
Thanks again for your help.
Posted by sb417 on August 2, 2004, at 20:59:13
In reply to Re: Pfinstegg » Pfinstegg, posted by sb417 on August 2, 2004, at 20:54:46
Hi. For those of you who click on the link I provided in the above post, the link is wrong because I didn't give the complete title. I always thought "THE MERCK MANUAL" was the correct, complete title, but I was wrong. The one I was referring to in my above post is "THE MERCK MANUAL OF DIAGNOSIS AND THERAPY" Seventeenth Edition.
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