Metyrapone May Be Effective as Additive Treatment of Major Depression

Laurie Barclay, MD

December 06, 2004

Dec. 6, 2004 — Metyrapone is effective as additive treatment for major depression, according to the results of a randomized, double-blind trial published in the December issue of the Archives of General Psychiatry.

"Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are the most consistent pathological endocrine findings in depression," write Holger Jahn, MD, from the University Hospital Hamburg-Eppendorf in Germany, and colleagues. "Inhibitors of steroid synthesis have been reported to exert antidepressive effects, according to preliminary findings."

In this study, 63 inpatients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depression and a baseline score of 18 points or higher on the Hamilton Rating Scale for Depression were randomized to one of two treatment groups receiving either placebo or metyrapone, 1 g per day, for the first three weeks during a five-week treatment with standard serotonergic antidepressants (nefazodone or fluvoxamine).

The primary outcome criteria were the number of responders and the time to onset of action, defined as the time point associated with at least a 20% reduction of baseline Hamilton Rating Scale for Depression scores. Treatment response was defined as 30% reduction of baseline Hamilton Rating Scale for Depression scores after three weeks and 50% reduction after five weeks. Analysis was by intent-to-treat.

At day 21, 23 of 33 patients receiving metyrapone had a positive treatment response compared with 13 of 30 patients receiving placebo (P = .031). At day 35, there were 19 responders in the metyrapone group and 10 responders in the placebo group (P = .047).

Onset of action was earlier in the metyrapone group, beginning in the first week (P < .006). Although cortisol remained largely unchanged, the plasma concentrations of corticotrophin and deoxycortisol were higher during metyrapone treatment (P < .05). Metyrapone treatment was well tolerated without serious adverse effects.

Study limitations were a short wash-out phase and HPA-axis activity characterized solely by morning cortisol concentrations.

"Metyrapone is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action," the authors write. "Although steroid-synthesis inhibitors are not quite ready for routine clinical application, the findings of this study clearly warrant further studies aimed at identifying subgroups of depressed patients who will benefit most from this approach and surrogate markers to find the optimal dose regimen."

One of the authors was supported by a fellowship from the Graduiertenkolleg 255 (Deutsche Forschungsgemeinschaft, Bonn, Germany). Novartis supplied the metyrapone used in this study.

Arch Gen Psychiatry. 2004;61:1235-1244

Reviewed by Gary D. Vogin, MD