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

• Status: Recruiting
• Trial end date: 2022-09-01
• Target enrollment: 0
• Participant gender: All

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 ".

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Centre Hospitalier Rouffach
• Collaborator: University Hospital, Strasbourg, France
• Treatments: Antidepressive Agents; BB 1101; Dexamethasone; Dexamethasone acetate; Metyrapone; Norepinephrine; Serotonin; Serotonin and Noradrenaline Reuptake Inhibitors; Serotonin Uptake Inhibitors

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.