RU-486 - Mifepristone
Tested for Treatment of Depression
The New York Times reported that Corcept Therapeutics is
testing the controversial abortion pill, Mifepristone (formerly known as
RU-486, brand name, Mifreprex), in clinical trials for the treatment of severe
depression.
The article uncritically transcribed the sponsors' optimistic pitch about
"encouraging findings" : "Of the 30 patients in the recent study, those who
took mifepristone for seven days at dosages higher than those used for
abortions showed substantial and rapid improvement in their symptoms, the
researchers found. The drug produced only mild side effects in the study."
However, toward the end of the article we learn that one of the 30 patients,
"a 49-year-old man, had died during the study." (not exactly a "mild side
effect") We also learn that this patient "had been taking 11 other medications
in addition to mifepristone...the man died from congestive heart failure,
brought on by high blood pressure and heart disease."
The Times reporter accepted on faith the sponsors' claim: "it was unlikely
that the death was related to his participation in the clinical trial."
Not reported by the Times, is the fact that the FDA issued Dear Doctor letters
on April 19, 2002, warning about reported severe adverse drug reactions in
patients taking Mifepristone: several reports of ruptured ectopic
pregnancies--including a death from hemorrhage; two cases of sepsis (one
fatal); and a heart attack in a 21 year old woman.
http://www.fda.gov/medwatch/SAFETY/2002/mifeprex_deardoc.pdf
http://www.fda.gov/cder/drug/infopage/mifepristone/mifepristone-qa_4_17_02.htm#1
Two questions arise--though neither was raised by The Times
reporter:
1. Did the NY Times ascertain whether the dead man had been taking
antidepressants and / or anti-psychotics as well as the abortion pill? If so,
he was at increased risk inasmuch as those drugs, singly and in combination,
are known to produce heart failure and high blood pressure.
Whatever the merit of the theory promoted by investigators and the sponsoring
company, the study design--and inclusion of patients taking drug
cocktails--does not appear to meet scientific or safety standards.
2. Was the scientific merit and safety of this experiment evaluated by
independent medical experts and an independent institutional review board?
Critics might say that this study is an illustration of how conflicts of
interest corrupt the integrity of clinical trials. [See also, AHRP Infomail,
Duke Survey of Clinical Trials: Conflicts of Interest Violate Ethics, Oct 27,
2002]
~~~~~~~~~~~~~~~~~~~
http://www.nytimes.com/2002/10/22/health/psychology/22PILL.html?pagewanted=print&position=top
THE NEW YORK TIMES
October 22, 2002
Abortion Pill May Help Treat Severe Form of Depression
By ERICA GOODE
Mifepristone, once called RU-486, is best known as the abortion pill.
But some scientists believe that the drug may eventually serve another, far
less controversial, purpose: treating a particularly fierce and intractable
form of depression.
Two small studies, the latest appearing last month in the journal Biological
Psychiatry, have found that mifepristone is effective in helping people whose
severe depression is accompanied by delusional beliefs or hallucinations. Of
the 30 patients in the recent study, those who took mifepristone for seven
days at dosages higher than those used for abortions showed substantial and
rapid improvement in their symptoms, the researchers found. The drug produced
only mild side effects in the study.
Encouraged by such findings, Corcept Therapeutics, the small California
pharmaceutical company that financed the second study, has applied to the Food
and Drug Administration for approval to market mifepristone for psychotic
depression, and two large clinical trials of the drug are in progress. (Danco
Laboratories of New York manufactures and distributes mifepristone, sold as
Mifeprex, for ending pregnancy.)
Dr. Joseph K. Belanoff, a psychiatrist and Corcept's chief executive, said the
drug could be available within five years "if everything went well" and
mifepristone was found to be safe, as used in the study, and effective for the
disorder. Dr. Belanoff was also the lead author of the study published in the
journal in September.
If mifepristone does reach the market, it will be the first medication
specifically approved for psychotic depression, which psychiatrists say is the
most difficult form of depression to treat.
The illness accounts for 15 percent to 19 percent of the cases of severe
depression diagnosed in the United States, according to a study by Dr. Maurice
M. Ohayon and Dr. Alan Schatzberg of the Stanford medical school to appear
soon in The American Journal of Psychiatry. Dr. Schatzberg, Stanford's
chairman of psychiatry, is a founder of Corcept and a shareholder in the
privately held company.
Patients with psychotic depression often suffer from delusions, believing, for
example, that they deserve punishment for imagined crimes or that they have
terminal illnesses.
Psychiatrists have traditionally treated psychotically depressed patients with
some combination of antidepressants, antipsychotic drugs and electroshock
therapy, an approach that has yielded only moderate success. But the
investigators hope that mifepristone, which patients would take for a short
period then return to the usual course of treatment, will relieve symptoms
more quickly and effectively.
A chemical compound used for abortions may seem an odd candidate for a
depression drug. But mifepristone attracted the attention of researchers for
good reason.
Mifepristone induces abortion by blocking the action of progesterone, a
hormone necessary for implanting a fertilized egg in the lining of the uterus.
But in higher doses, the drug also blocks another hormone, cortisol, which is
secreted by the adrenal glands and plays a critical role in the body's
response to stress. Patients with psychotic depression, studies have shown,
often have elevated levels of cortisol.
Dr. Anthony Rothschild, a professor of psychiatry at the University of
Massachusetts Medical School, who has studied psychotic depression, said he
and Dr. Schatzberg had hoped to test RU-486 as a treatment in the late 1980's.
"You just couldn't get it because of the political controversy," Dr.
Rothschild said.
Dr. Dennis Charney, the director of the mood and anxiety disorders research
program at the National Institute of Mental Health, said scientists at first
assumed that the elevated cortisol levels found in some severely depressed
patients were only indirectly related to their illness.
In the last few years, however, researchers have demonstrated that stress
hormones can have a significant effect on brain areas involved in memory
formation, emotion and other mental functions. The preliminary studies of
mifepristone, said Dr. Charney, an author of a commentary accompanying the
recent journal article, suggest that cortisol may be directly connected to the
delusions and severe depression that patients experience.
Such research, he said, "suggests that cortisol may be mediating a lot of the
symptoms associated with mood disorders."
Prednisone, a drug closely related to cortisol, can sometimes produce mood
changes and psychosis as side effects, Dr. Charney noted.
Still, he said, more research is required before the effectiveness of
mifepristone can be confirmed. The study published last month, for example,
was not double-blinded, a protection that prevents the experimenters from
knowing whether a patient is taking the drug being tested or a dummy pill.
Dr. Belanoff said the results of the first large double-blinded clinical
trial, of 200 patients at 25 medical centers around the country, would be
available early next year. A second trial is in the early stages.
Dr. Belanoff confirmed that one patient in the first clinical trial, a
49-year-old man, had died during the study. But he said an autopsy concluded
that the man, who had been taking 11 other medications in addition to
mifepristone, died from congestive heart failure, brought on by high blood
pressure and heart disease, and that it was unlikely that the death was
related to his participation in the clinical trial.
Even if mifepristone wins approval as a treatment for psychotic depression,
the drug's controversial history may make it difficult to dispense, perhaps
restricting its use to hospital wards. When, in 2000, the F.D.A. finally
approved Mifeprex for abortions, it placed tight restrictions on its use. And
the continuing debate over chemical abortion will probably ensure that similar
restrictions are applied to mifepristone in any form, even one intended to
help the most severely depressed patients.
Copyright The New York Times Company
Last Updated on
02/20/2005
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