Metyrapone as Additive Treatment in Major Depression

I've written before about the potential for modulation of the glucocorticoid system for the treatment of depression. Mifepristone (RU-486) is a drug that blocks cortisol receptors. It is being tested to see if it can be used to treat psychotic depression and bipolar depression. Now there is a study that shows benefit from treatment with metyrapone (Metopirone).

Metyrapone currently is used in a test to assess the functioning of the pituitary gland. It inhibits an enzyme, steroid 11-beta hydroxylase, which is necessary for the production of cortisol. If the pituitary gland is functioning properly, it should produce a greater amount of adrenocorticotropic hormone (ACTH) when metyrapone is given. This is because the pituitary detects a drop in the amount of available cortisol, and responds by secreting ACTH, in an effort to coax the adrenal glands to produce more cortisol. The study cited here was intended to see if metyrapone might have a therapeutic effect for treatment of major depression, it addition to its established use as a test agent.

Metyrapone as Additive Treatment in Major Depression
A Double-blind and Placebo-Controlled Trial
Holger Jahn, MD; Mildred Schick, MD; Falk Kiefer, MD; Michael Kellner, MD; Alexander Yassouridis, PhD; Klaus Wiedemann, MD
Arch Gen Psychiatry. 2004;61:1235-1244.

Background Inhibitors of steroid synthesis have been reported to exert antidepressive effects, according to preliminary findings.

Objective To test whether the addition of metyrapone to standard antidepressants induces a more rapid, more efficacious, and sustained treatment response in patients with major depression.

Design Double-blind, randomized, placebo-controlled trial.

Setting Hospitalized care.

Patients Sixty-three inpatients with a DSM-IV diagnosis of major depression and a baseline score 18 points or higher on the Hamilton Rating Scale for Depression.

Interventions Random allocation to 2 treatment groups receiving either placebo or metyrapone (1 g/d) for the first 3 weeks during a 5-week treatment with standard serotonergic antidepressants (nefazodone or fluvoxamine).

Main Outcome Measures Primary outcome criteria were the number of responders and the time to onset of action. Responder rates were considered twice after 3 and 5 weeks with a definition of treatment response as 30% and 50% reduction, respectively, of baseline Hamilton Rating Scale for Depression scores. Onset of action was defined as the time point at which at least a 20% reduction of baseline Hamilton Rating Scale for Depression scores occurred.

Results Using intention-to-treat analysis, we found that a higher proportion of patients receiving metyrapone showed a positive treatment response at day 21 (23 of 33 patients) and at day 35 (19 of 33 patients) compared with placebo patients (day 21: 13 of 30 patients; Fisher exact P = .031; day 35: 10 of 30 patients; Fisher exact P = .047). The clinical course of patients treated with metyrapone showed an earlier onset of action (Kaplan-Meier analysis; log-rank test P<.006) beginning in the first week. The plasma concentrations of corticotropin and deoxycortisol were significantly higher during metyrapone treatment (multivariate analysis of covariance, P<.05), whereas cortisol remained largely unchanged. Metyrapone treatment was well tolerated without serious adverse effects.

Conclusions Metyrapone is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action. A better treatment outcome compared with standard treatment and a sustained antidepressive effect were observed.

This study is a small, preliminary investigation; it is way too early to think of it as having any clinical significance. Despite that, there are two reasons to care about it. One, it confirms that new approaches to treatment of depression are possible; two, it shows that it may be possible to treat depression by manipulating the hypothalamic-pituitary-adrenal axis without causing a major disruption in the balance of circulating hormones.

Notice that, in the study cited above, cortisol levels did not change much. This was a short-term finding; it remains to be seen if long-term use of metyrapone would have the same result. If so, it would tend to alleviate some concerns about the safety of the treatment.