Metyrapone as Additive Treatment in Major Depression

Double-Blind, Placebo Controlled Trial of Metyrapone as Augmenting Agent in the Treatment of Major Depression

The purpose of this study is to test whether metyrapone is an effective and safe augmenting agent in the treatment of major depression.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Metyrapone

Detailed Description

The investigators' understanding of the neuroendocrine pathophysiology of depression has made significant progress in recent years, which should help to develop new remedies. Alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis are the most consistent pathological endocrine findings in depression. Hence, attempts have been made to treat depression by directly targeting HPA-axis activity. Currently, three major pathways are investigated:

• Administration of CRH-antagonists;
• Administration of glucocorticoid-receptor-antagonists; and
• Treatment with steroid-synthesis inhibitors like ketoconazole, aminogluthethimide or metyrapone.

The investigators' aim was to conduct the first prospective, randomized, placebo-controlled, double-blind clinical trial of metyrapone as additive treatment in depression. Metyrapone was preferred, since this compound inhibits selectively the 11β-hydroxylase and the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1), thereby exerting direct effects within the central nervous system (CNS). The additive approach was applied because the intended inclusion of severely depressed patients made a pure placebo group ethically challenging. Furthermore, the continuous use of an antidepressant allowed a standardized follow up after the double-blind period.

The hypotheses to be tested were, whether metyrapone exerts potentiating effects during a standard antidepressant therapy and whether an earlier onset-of-action and an improved overall and sustained treatment response can be achieved. Since GR/MR distribution as well as 11β-HSD-1 activities are subject to sexual dimorphism in humans, the sample was prospectively stratified for gender and balanced for treatment with two selected serotonergic antidepressants, allowing further analysis of gender effects and neuroendocrine treatment effects.

• Study Type: Interventional
• Enrollment: 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • Dept. of Psychiatry and Psychotherapy, UKE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of major depressive disorder; single or recurrent according to DSM-IV criteria (296.2 or 296.3)
• A minimum baseline Hamilton score of 18 points on the Hamilton Rating Scale for Depression (HamD; 21-item version)
• Age from 18 to 75 years
• A drug free period of at least 5 days from antidepressants, antipsychotics, mood stabilizers and all other medications except for mild antihypertensive agents
• A negative urinary drug screening diagnosis

Exclusion Criteria:

• A current DSM-IV diagnosis for other axis I psychiatric disorders
• Serious medical conditions, especially those associated with adrenal insufficiency
• Pregnancy, nursing or refusal to use a reliable method of birth control in women.

Participants were randomly assigned to a study group if they met these criteria.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Two psychometric criteria defined by the number of responders and time to onset-of-action. The number of responders was considered twice after 3 and 5 weeks by defining the treatment response as a 30% and 50% reduction
the course of concentrations of ACTH, cortisol, 11-deoxycortisol and DHEA.

Secondary Outcome Measures

Outcome Measure
Other psychometric scores, demographic parameters and side effects were considered as secondary variables.

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Investigators: Study Director: Holger Jahn, MD, University Hospital Hamburg-Eppendorf, Germany

Publications and helpful links

General Publications

• Jahn H, Schick M, Kiefer F, Kellner M, Yassouridis A, Wiedemann K. 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.

Study record dates

Study Major Dates

• Study Start: May 1, 1998
• Study Completion: July 1, 2001

Study Registration Dates

• First Submitted: July 29, 2005
• First Submitted That Met QC Criteria: July 29, 2005
• First Posted (ESTIMATE): August 1, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): August 12, 2005
• Last Update Submitted That Met QC Criteria: August 11, 2005
• Last Verified: July 1, 2005

More Information

Terms related to this study

• Keywords: Clinical trial; Major Depression; double-blind; randomized placebo-controlled trial; metyrapone
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Metyrapone
• Other Study ID Numbers: HH-PSY-ja-007