Effects of the Addition of Metyrapone to Antidepressant Therapy in Depression With Dexamethasone Suppression Test Non-suppression.

NCT03491696 | Unknown Phase 4

• 2 other identifiers: 2018-A00628-472018-000807-18
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 2

Brief Summary

The hypothesis of a link between depression and Hypothalamic-Pituitary Axis (HPA) dysfunction is now experienced. Since a first description in 1949 this link has made the HPA one of the most investigated hormonal axis in depression. Many studies have demonstrated quantitative variations of circulating cortisol in situation of depression including increasing of basal concentration of blood cortisol or Adrenocorticotropic Hormone (ACTH). Furthermore there is an attenuated negative feedback performance of the blood cortisol on the release of ACTH and cortisol. This attenuation seems to be a consequence of a bluntness of sensibility of the hypothalamic cells and their Glucocorticoids Receptors type 2. Actually it seems that these phenomena are included in a diversion of the cortisol's action. From a function of acute stress management, with short-time exposures, the cortisol become one of the factors increasing an allostatic load, or resulting of this increase, maintaining a permanent state of stress, an inertia delay to adaptation and facilitating the emergence of psychiatric disorders. This lack of function can be estimated by the Dexamethasone Suppression Test (DST) which, by stimulation attempting of feedback mechanisms by Dexamethasone (which has cortisol-like properties), can show a non-suppressor population with HPA bluntness. If this biological feature isn't a biological marker of depression, because of a lack of specificity and sensibility, is notably associated with a poor outcome and higher risks of suicidal behaviors and pharmacological resistance. Many studies have explored possibilities of action on the HPA to treat depression or improve antidepressant specific therapeutics, with inconstant results. One of the most promising molecule seems to be Metyrapone, a reversible inhibitor of the 11ß-hydroxylase enzyme which transform desoxycorticosterone and 11deoxycortisol to respectively corticosterone and cortisol. There have been several open label studies which aim to explore the possibility of an effect of the combination between Metyrapone and antidepressant molecules. This led to two randomized double blind controlled versus placebo studies whose conclusions are divergent. These conclusions and their heterogeneity lead to think that there is a sub-population which could be better responder to this type of association. Physiopathological knowledges and preliminary observations in DST non-suppressor population by using anti-glucocorticoids therapies , makes it possible to consider possible that responsive sub-population can be defined by the feature " DST non-suppressor ".

Conditions

Depressive Disorder; Hormone Disturbance

Keywords

Depressive disorder; Metyrapone; Dexamethasone Suppression Test; Antidepressive association; Hypothalamic-pituitary-adrenal axis; Cortisol; Selective Serotonin Reuptake Inhibitor; Serotonin and Norepinephrine Reuptake Inhibitor

Outcome Measures

Primary Outcomes (1)

• Blood cortisol rate during a Dexamethasone Suppression Test after 28days of treatment by association METYRAPONE and antidepressant (Serotonin Selective Reuptake Inhibitor or Serotonin and Norepinephrine Reuptake Inhibitor).

  Test protocol is defined as proposed by Carroll et al. and as used in routine at the "Pôle 8-9" service at Rouffach's Hospital. It suppose : 0h : Administration of 1mg of Dexamethasone orally. 8h - 16h - 23h : Blood Cortisol measure. The significative threshold of 120nmol/ml is defined, as used in previous studies of the research team. Included patients present a cortisol at 8AM \> 120nmol/L, they are considered as "non-suppressor". Presenting a blood cortisol rate at 8AM \<120nmol/L at day 29 is considered as a change to a "suppressor" status and is considered as better outcome.

  day 29

Secondary Outcomes (4)

• Changes from baseline in Hamilton Depression Scale 17 items with 28days of treatment by association METYRAPONE and antidepressant (Serotonin Selective Reuptake Inhibitor or Serotonin and Norepinephrine Reuptake Inhibitor).

  day 0 (selection) ; day 17, day 29, day 60

• Changes from baseline in Hamilton Anxiety Scale with 28days of treatment by association METYRAPONE and antidepressant (Serotonin Selective Reuptake Inhibitor or Serotonin and Norepinephrine Reuptake Inhibitor).

  day 0 (selection) ; day 17, day 29, day 60

• Changes from baseline in Beck Depression Inventory with 28days of treatment by association METYRAPONE and antidepressant (Serotonin Selective Reuptake Inhibitor or Serotonin and Norepinephrine Reuptake Inhibitor).

  day 0 (selection) ; day 17, day 29, day 60

• Changes from baseline in Cortisol Blood Rates During a Dexamethasone Suppression Test with 28days of treatment by association METYRAPONE and antidepressant (Serotonin Selective Reuptake Inhibitor or Serotonin and Norepinephrine Reuptake Inhibitor).

  day 0 (selection) ; day 17, day 29, day 60

Study Arms (1)

Patients

EXPERIMENTAL

It is an open label study, designed with 14 patients, men and women, from 18 to 60 years old, hospitalized for a characterized depressive episode (as defined by International Classification of Diseases version 10 criteria). They have to be refractory to an antidepressant treatment prescribed in primary care medicine and have a Dexamethasone Suppression Test (DTS) non-suppression status. All patients included will take the association of SSRI/SNRI and METYRAPONE for 28 days.

Drug: Metyrapone

Interventions

Metyrapone DRUG

Association of Selective Serotonin Reuptake Inhibitor or Serotonin and Norepinephrine Reuptake Inhibitor and METYRAPONE. Duration of the association : 28 days.

Patients

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Present International Classification of Diseases version 10 (ICD-10) diagnostic criteria:
• of moderate (F32.1) or severe depressive episode without psychotic symptoms (F32.2).
• or recurrent depressive disorder, current moderate episode (F33.1) or current severe episode without psychotic symptoms (F33.2).
• Present an alteration of the hypothalamic-pituitary response to the Dexamethasone Suppression Test defined by a non-suppression of cortisol production (defined by a DST\>120nmol/L at 8h).
• Have signed an informed consent to participate indicating a clear understanding of the study objectives and all procedures required by the study and agree to participate and abide by the requirements and restrictions inherent in the study.
• Have a body mass index between 18 and 25 kg/m2 included.
• Be affiliated to or beneficiary from a social security program.

You may not qualify if:

• Not being able to give free and informed consent (including patients with judiciary protection).
• Have a psychiatric condition other than characterized depression.
• For women: being pregnant as determined by a blood or urine pregnancy test or breastfeeding.
• Have an acute or chronic clinically significant disease that the investigator believes may interfere with patient safety during the study, or may place the patient at undue risk or interfere with the study objectives (particularly endocrinopathies, neuro-endocrinopathies or somatic conditions such as renal, adrenal or cardiac failure).
• Have a significant suicidal risk (RSD\>5 scale).
• Previous treatment with carbamazepine, long-acting neuroleptics, monoamine oxidase inhibitors, electroconvulsive-therapy.
• Have recently taken (\<15 days) any medication that occasionally interferes with neuroendocrine and hypothalamic-pituitary adrenal function: steroidal anti-inflammatory drugs, gluco/mineralo-corticoid analogues, potassium-saving diuretics, Mifepristone, Ketoconazole.
• Recent benzodiazepine consumption (defined as less than 5 times the half-life of the molecule concerned).
• Have a recent (\<1 year) history of substance abuse or drug addiction.
• Drink more than 40 g/day (1 glass\[25 cl\] of beer with 3° alcohol=7.5 g ; or 1 glass\[25 cl\] of beer with 6° alcohol=15 g ; or 1 glass\[12.5 cl\] of wine with 10° alcohol=12 g ; or 1 glass\[4cl\] of aperitif with 42° alcohol=17 g).
• Have a recognized contraindication to Metyrapone including manifest adrenocortical insufficiency and hypersensitivity to Metyrapone or any of the excipients.

Sponsors & Collaborators

• Centre Hospitalier Rouffach: lead
• University Hospital, Strasbourg, France: collaborator

Study Sites (2)

Hopitaux Universitares de Strasbourg

Strasbourg, Bas Rhin, 67000, France

RECRUITING

Centre Hospitalier de Rouffach

Rouffach, Haut Rhin, 68250, France

RECRUITING

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MeSH Terms

Conditions

Depressive Disorder; Endocrine System Diseases

Interventions

Metyrapone

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Ludovic C. Jeanjean, Intern

  Centre Hospitalier de Rouffach

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ludovic C. Jeanjean, Intern

CONTACT

+33 3 88 11 69 21; ludovic.jeanjean@icloud.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Intern, Principal Investigator

Model Details: It is an exploratory open label study with a single group, considered as a population of interest. Datas will be reported to existing knowledges and could not be a evidence of an effect but a suggestion for eventual future studies which have to be controlled versus placebo.

Study Record Dates

• First Submitted: March 24, 2018
• First Posted: April 9, 2018
• Study Start: December 22, 2018
• Primary Completion: June 1, 2022
• Study Completion: September 1, 2022
• Last Updated: September 9, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (2)