Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial

Arch Gen Psychiatry. 2004 Dec;61(12):1235-44. doi: 10.1001/archpsyc.61.12.1235.


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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adult
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Cortodoxone / blood
  • Dehydroepiandrosterone / blood
  • Depressive Disorder, Major / blood
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Double-Blind Method
  • Drug Synergism
  • Drug Therapy, Combination
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Fluvoxamine / pharmacology
  • Fluvoxamine / therapeutic use
  • Humans
  • Male
  • Metyrapone / pharmacology
  • Metyrapone / therapeutic use*
  • Middle Aged
  • Piperazines
  • Placebos
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Treatment Outcome
  • Triazoles / pharmacology
  • Triazoles / therapeutic use


  • Antidepressive Agents
  • Enzyme Inhibitors
  • Piperazines
  • Placebos
  • Triazoles
  • Dehydroepiandrosterone
  • nefazodone
  • Adrenocorticotropic Hormone
  • Fluvoxamine
  • Cortodoxone
  • Metyrapone