Ignite Creation Date:
2024-05-06 @ 11:20 AM
Last Modification Date:
2024-10-26 @ 12:43 PM
Study NCT ID:
NCT03491696
Status:
UNKNOWN
Last Update Posted:
2020-09-09
First Post:
2018-03-24
Brief Title:
Effects of the Addition of Metyrapone to Antidepressant Therapy in Depression With Dexamethasone Suppression Test Non-suppression
Sponsor:
Centre Hospitalier Rouffach
Organization:
Centre Hospitalier Rouffach
Study Overview
Official Title:
Effects of the Addition of Metyrapone to Antidepressant Therapy in Depression With Dexamethasone Suppression Test Non-suppression
Status:
UNKNOWN
Status Verified Date:
2020-09
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 cortisols 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 isnt 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
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 cortisols 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 isnt 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
Detailed Description:
Depression is now a public health issue concerning 300 billion people in the World it is the leading cause of disability according to the World Health Organization and 800 000 persons die each year by committing suicide Despite the finding of specific and efficiency treatments recommended by main guidelines a first prescription of antidepressant Specific Serotonin Reuptake Inhibitor SSRI or Serotonin and Norepinephrine Reuptake Inhibitors SNRI is associated with a remission in only 35 to 45 Using switch strategies in case of non-response and the fact that the number of antidepressant molecules stagnates from few decades lead patients to refractory disease and heavy care like using of mood-stabilizers molecules Electro-Convulsive Therapy or Repetitive Trans-cranial Magnetic Stimulation To avoid therapeutic escalation and limit collateral consequences it seems to be essential to understand physiopathological feature of each patient and proposing adapted treatment in front of early signs of resistance
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 a flattened rhythm of diurnal secretion an early nadir and a disappearance of the morning secretion peak Moreover it has be observed an anarchic rhythm and an increased amplitude of the secretion peaks 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 GR2 This bluntness seems to be consequence of genetic and epigenetic factors including maternal behaviors but also inflammation status with cytokines activation and abnormalities into the GR2 recycling process with persistence of altered receptors
Actually it seems that these phenomena are included in a diversion of the cortisols 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 isnt 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 if the study of Jahn et al have showed a significative amelioration of clinical response by association SSRI with Metyrapone the Antiglucocorticoid Augmentation of Anti-Depressants in Depression ADD Study concluded that this improvement is not significative in clinical routine practice
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
This is a multicenter open-label study in 14 patients men and women aged 18 to 60 years hospitalized following a characterized depressive episode with alteration of the response by the hypothalamic-pituitary axis to the Dexamethasone restriction test and resistant to an antidepressant treatment proposed in primary care medicine The main investigator centre will be the Rouffach Hospital Centre the co-investigator centre will be the Strasbourg University Hospital Hôpitaux Civils de Strasbourg
Patients eligible for the study will present
A characterized depressive episode defined according to International Classification of Diseases version 10 ICD-10 criteria
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 Depression Scale 17 items
An alteration of the hypothalamic-pituitary response to the Dexamethasone Suppression Test DST defined by a non-suppression of cortisol production after taking 1mg of Dexamethasone defined by a blood cortisol120nmolL at 8AM
For the duration of the study the psychotropic treatment previously prescribed before admission will remain unchanged
This is an exploratory pilot study The primary purpose is to assess the possibility of obtaining a normalized biological response to the Dexamethasone Suppression Test by the addition of short-term Metyrapone therapy to antidepressant therapy
Secondary purposes are
To determine if this effect is accompanied by a clinical improvement in depression defined by a sufficient decrease on the Hamilton Depression Scale 17 items score below 18
To determine if such an effect persists at distance 1 month from taking Metyrapone without modifying the initial psychotropic treatment
In the case of highlighting of a effect new study protocols in particular controlled studies versus placebo could be proposed
The study will be conducted in a hospital setting and according to good clinical practice It will include
A pre-selection visit at the beginning of hospitalisation including a clinical examination somatic and psychiatric routine biological examinations a review of medical and surgical history and previous and current treatments
An evaluation of the hypothalamic-pituitary axis by a dynamic Dexamethasone Suppression Test the interpretation of the results and their announcement to the patient by a physician
An inclusion visit including verification of inclusion and exclusion criteria and a presentation of the study to the patient with consent Day 0
Treatment with Metyrapone 1 gram per day divided into four 250mg doses in the morning at 8AM at noon 12PM in the evening at 6PM and at 10PM This administration scheme was chosen because it has already been published in the literature in a similar context Treatment will be given for 4 weeks without interruption and on a consistent dosing schedule Day 2- Day 29
Three evaluations of the hypothalamic-pituitary axis by a Dexamethasone Suppression Test respectively at Day 17 Day 29 and Day 60 interpretation of the results and their announcement to the patient by a physician The Day 29 evaluation is the only measure used for the primary outcome
A final study visit including a psychiatric clinical examination The decision to continue or modify psychotropic treatment will depend on the clinical situation observed
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 a flattened rhythm of diurnal secretion an early nadir and a disappearance of the morning secretion peak Moreover it has be observed an anarchic rhythm and an increased amplitude of the secretion peaks 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 GR2 This bluntness seems to be consequence of genetic and epigenetic factors including maternal behaviors but also inflammation status with cytokines activation and abnormalities into the GR2 recycling process with persistence of altered receptors
Actually it seems that these phenomena are included in a diversion of the cortisols 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 isnt 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 if the study of Jahn et al have showed a significative amelioration of clinical response by association SSRI with Metyrapone the Antiglucocorticoid Augmentation of Anti-Depressants in Depression ADD Study concluded that this improvement is not significative in clinical routine practice
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
This is a multicenter open-label study in 14 patients men and women aged 18 to 60 years hospitalized following a characterized depressive episode with alteration of the response by the hypothalamic-pituitary axis to the Dexamethasone restriction test and resistant to an antidepressant treatment proposed in primary care medicine The main investigator centre will be the Rouffach Hospital Centre the co-investigator centre will be the Strasbourg University Hospital Hôpitaux Civils de Strasbourg
Patients eligible for the study will present
A characterized depressive episode defined according to International Classification of Diseases version 10 ICD-10 criteria
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 Depression Scale 17 items
An alteration of the hypothalamic-pituitary response to the Dexamethasone Suppression Test DST defined by a non-suppression of cortisol production after taking 1mg of Dexamethasone defined by a blood cortisol120nmolL at 8AM
For the duration of the study the psychotropic treatment previously prescribed before admission will remain unchanged
This is an exploratory pilot study The primary purpose is to assess the possibility of obtaining a normalized biological response to the Dexamethasone Suppression Test by the addition of short-term Metyrapone therapy to antidepressant therapy
Secondary purposes are
To determine if this effect is accompanied by a clinical improvement in depression defined by a sufficient decrease on the Hamilton Depression Scale 17 items score below 18
To determine if such an effect persists at distance 1 month from taking Metyrapone without modifying the initial psychotropic treatment
In the case of highlighting of a effect new study protocols in particular controlled studies versus placebo could be proposed
The study will be conducted in a hospital setting and according to good clinical practice It will include
A pre-selection visit at the beginning of hospitalisation including a clinical examination somatic and psychiatric routine biological examinations a review of medical and surgical history and previous and current treatments
An evaluation of the hypothalamic-pituitary axis by a dynamic Dexamethasone Suppression Test the interpretation of the results and their announcement to the patient by a physician
An inclusion visit including verification of inclusion and exclusion criteria and a presentation of the study to the patient with consent Day 0
Treatment with Metyrapone 1 gram per day divided into four 250mg doses in the morning at 8AM at noon 12PM in the evening at 6PM and at 10PM This administration scheme was chosen because it has already been published in the literature in a similar context Treatment will be given for 4 weeks without interruption and on a consistent dosing schedule Day 2- Day 29
Three evaluations of the hypothalamic-pituitary axis by a Dexamethasone Suppression Test respectively at Day 17 Day 29 and Day 60 interpretation of the results and their announcement to the patient by a physician The Day 29 evaluation is the only measure used for the primary outcome
A final study visit including a psychiatric clinical examination The decision to continue or modify psychotropic treatment will depend on the clinical situation observed
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2018-000807-18 | EUDRACT_NUMBER | None | None |