Stanford researchers study controversial drug as treatment for psychotic major depression

STANFORD, Calif. - Sufferers of psychotic major depression, a severe and debilitating form of mental illness, improve slowly or not at all with standard medication. But researchers at Stanford University Medical Center have used the drug mifepristone, also known as RU-486, to treat these patients quickly and effectively.

'This could very much shift how we do things in psychiatry in the next few decades. It may be a way to get very rapid relief to people,' said Stanford psychiatry professor Charles DeBattista, MD.

The treatment is potentially controversial because mifepristone is widely known as a drug that induces abortions. Researchers have learned, however, that certain properties of the drug that lead to pregnancy termination can also help treat psychotic major depression.

About 15 percent of patients suffering from major depression experience psychotic symptoms such as paranoia and hallucinations. Antidepressant medications alone are usually ineffective for these patients, and combining antidepressants with antipsychotic drugs improve symptoms for only about 60 percent of them. Electroconvulsive therapy works in roughly 80 percent of patients who try it, DeBattista said, but many decline the treatment because of its stigma. In addition, patients undergoing electroconvulsive therapy or drug combinations may not see results for weeks or even months after starting treatment.

In the study, 30 patients received either a low, medium or high dose of mifepristone, each day for a week in addition to their standard medications. More than two-thirds of patients in the medium- and high-dose groups showed significant reductions in psychotic symptoms within seven days. During the week, more than 40 percent of the patients in these groups saw their symptoms of depression reduced by half or better, based on standard clinical measures for the disease.

Results from this phase-II, multi-center trial were published on the Web site of the journal Biological Psychiatry July 26. The journal also will publish the results in its Sept. 1 print edition.

'Some people in the study had been sick for years and were doing extremely well after just a week,' said Alan Schatzberg, MD, the Kenneth T. Norris Professor of Psychiatry and Behavioral Sciences and chair of the psychiatry department at Stanford. 'The treatment may be the equivalent of shock treatments in a pill without the morbidity.'

High levels of the steroidal hormone cortisol cause the extreme symptoms of psychotic depression. The excess hormone results from an overactive group of glands called the hypothalamic-pituitary-adrenal axis. Psychiatrists believe electroconvulsive therapy works by resetting this axis, returning it to a normal state. Mifepristone blocks one of the cortisol receptors and also may reset the axis, since improvements persisted for patients in the study even after they stopped taking the drug. Schatzberg said patients who receive a course of mifepristone probably will need to take an antidepressant as a maintenance drug, but they will not have to wait weeks or months for an improved mental state.

Mifepristone also has a low incidence of side effects compared to antidepressants and antipsychotics. Joe Belanoff, MD, lead author of the study and a staff physician at Stanford Hospital & Clinics, said mifepristone takes a rifle-shot approach as opposed to a shotgun approach. In studying the drug, researchers first investigated the biology behind psychotic depression and then looked for something to target it, rather than testing drugs first and researching how they act on the body later.

A double-blind, placebo-controlled study of mifepristone is under way, funded by Corcept Therapeutics based in Menlo Park, Calif. Corcept, which funded the current study, was founded by Belanoff and Schatzberg, and Stanford University is an investor in the company. Belanoff, who is also on the voluntary clinical faculty of the Stanford School of Medicine, serves as Corcept's CEO and Schatzberg heads the company's scientific advisory board.

When Belanoff and Schatzberg first wanted to study mifepristone for psychotic depression, it was banned in the United States because of its ability to induce abortions. Mifepristone also blocks receptors for progesterone, a steroidal hormone important in pregnancy and similar in structure to cortisol. In their initial study, Belanoff and Schatzberg gave five patients four doses each of the drug because that's all they could obtain. Now the federal Food and Drug Administration has put mifepristone on fast-track approval as a treatment for psychotic depression; it is the first drug for a psychiatric condition to be fast-tracked.

'This is a very different treatment,' Schatzberg said. 'We're using mifepristone as a lifesaver instead of an abortifacient.'


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