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Trial record 18 of 336 for:    "Depressive Disorder" [DISEASE] AND Rating AND Reuptake

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

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ClinicalTrials.gov Identifier: NCT03491696
Recruitment Status : Recruiting
First Posted : April 9, 2018
Last Update Posted : January 10, 2019
Sponsor:
Collaborator:
University Hospital, Strasbourg, France
Information provided by (Responsible Party):
Ludovic C. Jeanjean, Centre Hospitalier Rouffach

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 ".


Condition or disease Intervention/treatment Phase
Depressive Disorder Hormone Disturbance Drug: Metyrapone Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 14 participants
Intervention Model: Single Group Assignment
Intervention Model Description: 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effects of the Addition of Metyrapone to Antidepressant Therapy in Depression With Dexamethasone Suppression Test Non-suppression.
Actual Study Start Date : December 22, 2018
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Experimental: Patients
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
Association of Selective Serotonin Reuptake Inhibitor or Serotonin and Norepinephrine Reuptake Inhibitor and METYRAPONE. Duration of the association : 28 days.




Primary Outcome Measures :
  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). [ Time Frame: day 29 ]

    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.



Secondary Outcome Measures :
  1. 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). [ Time Frame: day 0 (selection) ; day 17, day 29, day 60 ]

    Clinical evaluation supervised by an investigator. 17 items, each score is summed to the total score. Total range : 0 to 54, higher value represent a severe disorder. Scores are classified as normal (<9), mild depression (10 to 13), mild to moderate depression (14 to 17), and moderate to severe depression (>17).

    In this study included patients with a baseline score >18, lower values is considered as better outcome.


  2. 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). [ Time Frame: day 0 (selection) ; day 17, day 29, day 60 ]
    Clinical evaluation supervised by an investigator. 14 Items. Each item is scored on a scale of 0 (not present) to 4 (severe) and summed to the total score, total score range of 0-56, higher value represent severe disorder, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.

  3. 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). [ Time Frame: day 0 (selection) ; day 17, day 29, day 60 ]
    Clinical evaluation by the patient himself. 21 individual scale items are scored on a 4-point continuum (0=least, 3=most), summed to the totale score with a total score range of 0-63. Higher scores represent severe disorder.

  4. 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). [ Time Frame: day 0 (selection) ; day 17, day 29, day 60 ]

    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". Present a blood cortisol rate at 8AM <120nmol/L at day 29 is considered as a change to a "suppressor" status and is considered as a better outcome.

    The purpose of this monitoring is evaluate the kinetic of cortisol's control restitution and the stability of a phenomena.




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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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).

  • Persistent symptomatology despite treatment with a selective serotonin reuptake inhibitor or a well-conducted serotonin and norepinephrine reuptake inhibitor (inclusion score >18 on the Hamilton-17 item scale (HAMDS-17)).
  • 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.

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03491696


Contacts
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Contact: Ludovic C. Jeanjean, Intern +33 6 30 11 09 13 ludovic.jeanjean@icloud.com

Locations
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France
Hopitaux Universitares de Strasbourg Recruiting
Strasbourg, Bas Rhin, France, 67000
Contact: Jack Foucher, MD    +33 3 88 11 69 21    CEMNIS@chru-strasbourg.fr   
Contact: Ludovic C. Jeanjean, Intern    +33 6 30 11 09 13    ludovic.jeanjean@icloud.com   
Sub-Investigator: Jack Foucher, MD         
Principal Investigator: Ludovic C. Jeanjean, Intern         
Centre Hospitalier de Rouffach Recruiting
Rouffach, Haut Rhin, France, 68250
Contact: Alexis Erb, MD    +33 389787018    a.erb@ch-rouffach.fr   
Contact: Ludovic C. Jeanjean, Intern    +33 6 30 11 09 13    ludovic.jeanjean@icloud.com   
Principal Investigator: Alexis Erb, MD         
Sub-Investigator: Fabrice Duval, MD         
Principal Investigator: Ludovic C. Jeanjean, Intern         
Sponsors and Collaborators
Centre Hospitalier Rouffach
University Hospital, Strasbourg, France
Investigators
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Principal Investigator: Ludovic C. Jeanjean, Intern Centre Hospitalier de Rouffach

Publications:

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Responsible Party: Ludovic C. Jeanjean, Intern, Principal Investigator, Centre Hospitalier Rouffach
ClinicalTrials.gov Identifier: NCT03491696     History of Changes
Other Study ID Numbers: 2018-A00628-47
2018-000807-18 ( EudraCT Number )
First Posted: April 9, 2018    Key Record Dates
Last Update Posted: January 10, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ludovic C. Jeanjean, Centre Hospitalier Rouffach:
Depressive disorder
Metyrapone
Dexamethasone Suppression Test
Antidepressive association
Hypothalamic-pituitary-adrenal axis
Cortisol
Selective Serotonin Reuptake Inhibitor
Serotonin and Norepinephrine Reuptake Inhibitor

Additional relevant MeSH terms:
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Depression
Depressive Disorder
Serotonin and Noradrenaline Reuptake Inhibitors
Endocrine System Diseases
Behavioral Symptoms
Mood Disorders
Mental Disorders
Dexamethasone
Dexamethasone acetate
Norepinephrine
BB 1101
Metyrapone
Antidepressive Agents
Serotonin
Serotonin Uptake Inhibitors
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Psychotropic Drugs