Inhibitors of steroid synthesis have been reported to exert antidepressive
effects, according to preliminary findings.
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.
Double-blind, randomized, placebo-controlled trial.
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.
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.
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.
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