April 19

Abortion Pill Tested in clinical Trials for Severe Depression – NYT

Abortion Pill Tested in clinical Trials for Severe Depression_NYT

Mon, 28 Oct 2002

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.

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