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Mifepristone may ease psychotic depression.

SAN FRANCISCO -- Results from the first large double-blind trials of an antiglucocorticoid agent for the treatment of psychotic depression suggest that subsets of patients may respond to mifepristone therapy, Dr. Charles DeBattista said.

Separate results from a smaller, uncontrolled study of hydrocortisone augmentation in nonpsychotic depressed patients also showed promise, he said at a psychopharmacology congress sponsored by the Neuroscience Education Institute.

Taken together, the results suggest that some depressed patients may benefit from glucocorticoid augmentation while others may benefit from glucocorticoid antagonism. "It sounds counterintuitive, but it may really represent different biologies and different subtypes of depression--psychotic and nonpsychotic depression," said Dr. DeBattista, director of the outpatient depression and psychopharmacology clinics at Stanford (Calif.) University.

Neither strategy has been approved for clinical use. The unpublished studies were funded and conducted by Corcept Therapeutics Inc., a private company founded by Stanford physicians that has applied to the Food and Drug Administration for approval to market mifepristone for psychotic depression. Phase III clinical trials of mifepristone for psychotic depression are underway, and the FDA has granted fast-track status for review.

Mifepristone, a progesterone antagonist that is approved for use with misoprostol to induce abortion, also is a potent glucocorticoid receptor antagonist in doses higher than those used to end pregnancy. Interest in mifepristone as an anti-depressant grew from the observation of high cortisol levels in patients with psychotic depression, he said.

Previous results from a double-blind, placebo-controlled crossover study of five patients with psychotic major depression and an open-label study of three different dosages in 30 patients with psychotic major depression showed that mifepristone rapidly reduced depressive and psychotic symptom scores in most patients at doses of 600 mg/day or higher taken for 4-7 days. The benefits persisted for 3 weeks after stopping therapy.

The current studies of mifepristone each included about 100 patients with psychotic depression. In the first study, patients could be on other therapies as well, and they averaged four psychotropic medications per patient. They were randomized to the addition of 600 mg mifepristone or placebo for 1 week and followed for another 3 weeks. No significant differences between groups were seen in depressive or psychotic symptom scores before or after treatment.

"These were patients who were hospitalized and on multiple medications. It's very difficult to show an effect above all these other treatments." Dr. DeBattista said. There was a suggestion, however, that patients whose symptoms did improve after 7 days of mifepristone augmentation were more likely to achieve remission of depressive or psychotic symptoms by the end of the study.

The second study followed the same protocol in patients who were not taking other antidepressants or antipsychotics. This time, the mifepristone group showed significantly lower psychotic symptom scores after 1 week and psychotic symptoms improved more rapidly compared with the placebo group. The differences between groups were sustained over 3 more weeks.

Mifepristone seemed to be well tolerated; rates of side effects did not differ between groups. If taken long term by pre-menopausal women, however, mifepristone could delay menses or cause breakthrough bleeding, he cautioned.

In a separate small, placebo-controlled study of nonpsychotic depressed patients, a single 15-mg pulse of hydrocortisone given over a 2-hour infusion significantly improved mood within 24 hours compared with patients given only saline.

If taken for long periods of time, glucocorticoids can cause "lots of mischief" by inducing depression or mania, he cautioned, but use as acute therapy may provide some benefit.

Dr. DeBattista has been a consultant for, or received funding from, the maker of venlafaxine, Wyeth Pharmaceuticals. He also is a past employee of Corcept Therapeutics and is a current stockholder and paid consultant for the company.


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Title Annotation:Adult Psychiatry
Author:Boschert, Sherry
Publication:Clinical Psychiatry News
Geographic Code:1USA
Date:Jun 1, 2004
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