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Stanford Report, November 8, 2000

RU-486 may dramatically relieve psychotic depression

BY CHARLES CLAWSON

Preliminary trials suggest that the controversial drug RU-486, a recently approved abortifacient and emergency contraceptive, may provide sudden relief for psychotic depression, a disease normally very difficult to treat. Related findings suggest that hydrocortisone may also speed up treatment of non-psychotic depression.

"Some psychotically depressed patients are dramatically better within a few days," said Alan Schatzberg, MD, Kenneth T Norris Junior Professor and chairman of the department of psychology and behavioral sciences at Stanford. "They stop hearing voices and having pessimistic kinds of delusions, like they're dying or the world is ending. We've seen the response within a four-day study. This is fairly dramatic."

Traditionally, patients with psychotic depression receive one of two treatments: an anti-depressant administered in conjunction with an anti-psychotic drug, or electro convulsive therapy (ECT). Even when effective, both treatments are relatively slow, and can leave residual symptoms that last for months.

"With mifepristone (RU-486) there's a very quick intervention, the patients often feel better, and then we can put them on conventional anti-depressants without the anti-psychotics or ECT," Schatzberg said. "What's interesting is that the results are not effervescent. The patients feel better and it lasts. Nobody's had to come back, nobody's had to undergo ECT." The social implications of the treatment are profound, Schatzberg said, both because mifepristone might eliminate the need for shock treatments and because it comes from a drug with other uses that some people don't like.

Originally mifepristone was developed as a steroid treatment for Cushing's disease, to block the adrenal hormone cortisol. But since progesterone receptors and cortisol receptors are structurally related, mifepristone also blocks progesterone, an effect that makes it useful as an abortifacient and, in smaller doses, as an emergency contraceptive.

Research over the last 17 years has revealed that cortisol is extremely elevated in psychotically depressed patients. As a "stress" hormone, cortisol is released during times of significant stress as part of humans' "fight or flight" behaviors. In psychotic depression, the natural feedback loop involving cortisol is thought to be awry, with sustained levels of the hormone creating a chronic stress reaction. This in turn may cause the serious symptoms of psychotic depression, including hallucinations, sleep disturbances and memory problems.

"We believe that the cortisol receptor is involved in the cognitive problems of severely depressed patients, particularly those with psychosis," said Schatzberg. "And so blocking those receptors, we think, may be associated with a relatively rapid response to treatment."

In a preliminary trial, five psychotically depressed patients were treated with mifepristone and four showed marked improvement within about four days. Further studies are now underway and in need of volunteers.

One study, being conducted in conjunction with the company Corcept, tests dosing levels of mifepristone for psychotic depression. Over the next year, 70 patients will be studied upon receiving mifepristone for about a week.

"Usually we get a good sense after a week whether mifepristone's going to be useful or not," said Charles DeBattista, MD, assistant professor of psychiatry and director of the Depression Research Clinic. "For some patients it's been dramatically helpful in two or three days. For instance, one gentleman went from being severely depressed, with suicidal thoughts, severe fatigue, daily hallucinations, hearing voices that wouldn't stop, to being free of all those symptoms within a week. It's happened enough that we're pretty excited."

A second trial underway, also involving mifepristone, is designed to shed light on the biologic basis of psychotic depression, as distinguished from milder or non-depressive states.

About 90 patients will be studied over five years -- 30 individuals each from the psychotically depressed, non-psychotically depressed, and control categories. The landmark study, funded by the NIH, should provide crucial data for differentiating psychotic and non-psychotic depressions, which are thought to be distinct illnesses. As many as 15% of depressed patients suffer psychotic depression.

In the study, only psychotically depressed patients will receive mifepristone. Non-psychotically depressed patients will be eligible to participate in a second phase of the trial, testing whether the administration of hydrocortisone speeds up the response of a standard anti-depressant called Effexor. "One of our earlier studies suggested that non-psychotically depressed patients can have a rapid improvement in symptoms just with the administration of hydrocortisone," said DeBattista. The trial will be the first of its kind to study whether something as common as hydrocortisone can speed up response to anti-depressants.

"These are really innovative studies that may greatly impact the way we treat depression in the future," DeBattista added. Volunteers who feel they may qualify for the study as depressed or psychotically depressed individuals and are interested in participating should contact the Depression Research Clinic at (650) 725-4620 for an initial over-the-phone assessment.

Along with Schatzberg and DeBattista, the depression group includes Joseph Belanoff, a Stanford postdoctoral fellow working with Corcept; Steve Lindley, MD, PhD, clinical instructor in psychiatry at the Palo Alto VA; David Lyons, PhD, associate professor at the Stanford Primate Center; and psychiatry fellows Ben Flores, MD, and Shelly Flemming, PhD.