Efficacy of Deep Anaesthesia With Isoflurane as a Fast-response Antidepressant Agent

Study Overview
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Brief Summary
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In this study the investigators will submit patients with treatment resistant depression to deep anesthesia with isoflurane to get 15 minutes of cortical burst suppression on electroencephalogram, once a week for six weeks. The follow up will be for 6 months. The aim is to evaluate the change in depression severity during the entire period.

Detailed Description
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This study protocol will measure the efficacy of deep anesthesia, until burst suppression rate of 80% or more measured with Bi-spectral Index (BIS), with the volatile anesthetic Isoflurane. The investigators will select 30 subjects. The participants will be separated into 2 arms of 15 individuals. One arm called ISOAD will keep the oral treatment with antidepressants. The second arm, called ISO, will do a washout of any oral medications for depression. Both groups will go under six sessions, once per week, of deep anesthesia and will be followed up for 6 months to evaluate the survival of the antidepressant effect, if any effect happens. Before the anesthesia occurs, blood samples will be drawn to measure Brain-derived neurotrophic factor and investigators will apply depression rating scales such as MADRS and Hamilton - 17 , Young mania Scale, UKU scale for side effects, electroencephalogram will be recorder to be compared with the data shown on BIS. All the anesthesia procedure will be done with induction with propofol, fentanyl and muscular relaxant, to facilitate the tracheal intubation and compliance with the mechanical ventilator,based on body weight in standard dosages. Isoflurane will be set to 2,4% ( 2 cam) until Burst suppression rate >80% is achieve. Then the anesthesia will be maintained for 15 minutes, then the flow of anesthetic gas will be ended and the patient will be allowed to awake and discharged home when the anesthesiologist decide based on Aldrete Kroulik scale. After the 6th session the participant will return in one week to final evaluation. All the patients that shows improvement in depression scores will enter the phase 2 with one visit every 15 days for 2 months and then once a month until the 6th month. The non responders of the ISO group will start oral antidepressant sertraline to evaluate any potentialization effect of the intervention and be allocated in ISOPOT group. Those from ISOAD group (Isoflurane plus oral antidepressants) that did not respond to the intervention will be discontinued from the study and their data used in the study as non-responders. Those from ISOPOT group that did not improve their depression scores after 4 weeks will be discontinued from the study and the data computed as non-responders.

Official Title
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Efficacy of Deep Anaesthesia With Isoflurane as a Fast-response Antidepressant Agent in Treatment Resistant Depression Patients : Proof of Concept

Conditions
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Depressive Disorder, Major, Treatment Resistant Depression, Depressive Episode

Intervention / Treatment
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* Drug: Isoflurane
* Drug: Sertraline Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Treatment resistant depression on depressive state with or without psychiatric comorbidities for anxious features moderate to severe condition measured by Montgomery Asperger Depression Rating Scale and Hamilton Depression rating scale - 17 be between 18 and 60 years old IF female, do not be pregnant and use a trustable contraceptive method can read and write in Portuguese language will to be in all the phases of the study have agreed with free will to participate classified as American Society of Anesthesiologists - Physical Status 1 or 2 by a certified anesthesiologist Suicide ideation measured by Montgomery Asperger Depression Rating Scale on item 10 less than 4 Exclusion Criteria: drug abusers in the last 6 months, except for nicotine use of benzodiazepines or lamotrigine less then 15 days from the first session family history of malignant hyperthermia Suicidal ideation on item 10 of Montgomery Asperger Depression Rating Scale more than 4 Suicide attempt one month prior the study begins

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: We will have two groups, one arm with oral antidepressants and other arm without oral antidepressants, no placebo, no control. Everyone receives the intervention. Those who respond to treatment, will be followed for 24 weeks, those who do not respond, if not in the oral antidepressant group, will star oral antidepressants and be followed for 24 weeks
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ISO<br>Patients not taking oral medications for depression. They will receive the study intervention consisting in general anesthesia with the volatile anesthetic gas Isoflurane until burst suppression is detected in electroencephalogram more than 80% of the time for 15 minutes. | Drug: Isoflurane<br>* Deep anesthesia with isoflurane to achieve burst suppression pattern for more than 80% of the time for 15 minutes measured in electroencephalogram and Bi-Spectral Index<br>|
| Experimental: ISOAD<br>Patients in treatment with oral medications for depression, will receive intervention consisting in general anesthesia with the volatile anesthetic gas Isoflurane until burst suppression is detected in electroencephalogram more than 80% of the time for 15 minutes | Drug: Isoflurane<br>* Deep anesthesia with isoflurane to achieve burst suppression pattern for more than 80% of the time for 15 minutes measured in electroencephalogram and Bi-Spectral Index<br>|
| Experimental: ISOPOT<br>Patients that where from ISO arm, that did not respond to intervention consisting in general anesthesia with the volatile anesthetic gas Isoflurane until burst suppression is detected in electroencephalogram more than 80% of the time for 15 minutes They will now, start taking sertraline as oral medication for depression to asset the enhancement of oral treatment after Isoflurane challenge. | Drug: Sertraline Pill<br>* Patients that did not respond to Isoflurane treatment, will star on sertraline to evaluate any enhancement in antidepressant efficacy after pre-treatment with isoflurane<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Depression severity - MADRS | Any reduction in Montgomery Asperger Depression Rating Scale ( 0 to 60 , lower score means less depression severity) | Six days after the last session | 
| Reduction in Depression - HDRS 17 | Any reduction in Hamilton Depression rating scale 17 ( 0 to 49, lower score means less depression severity | Six days after the last session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Udvalg for Kliniske Undersøgelser - side effects rating scale | Development and tolerability of collateral effects using the Udvalg for Kliniske Undersøgelser - side effects rating scale ( 0 to 43 - lower score means less side effects) | From 6th day after the first intervention up to week 24th | 
| Change in Depression severity MADRS | Any change in Montgomery Asperger depression ratings scale ( 0 to 60 , lower score means less depression severity) | From 6th day after the intervention up to week 24th | 
| Change in Depression severity HDRS17 | Any change in Hamilton depression ratings scale 17 ( 0 to 49, lower score means less depression severity) | From 6th day after the intervention up to week 24th | 
| Magnitude MADRS | The amount of the reduction, if any, in Montgomery Asperger Depression Rating Scale ( 0 to 60 , lower score means less depression severity) | From 6th day after the intervention up to week 24th | 
| Magnitude HDRS 17 | The amount of the reduction, if any, in Hamilton Depression rating scale 17 ( 0 to 49, lower score means less depression severity) | From 6th day after the intervention up to week 24th | 
| Survival of the effect - HDRS 17 | For how long the Hamilton Depression rating scale 17 remains below the initial value (lower value means less depression) in each participant that had variation in this scale | After the 6th session through 24th week | 
| Survival of the effect - MADRS | For how long the Montgomery Asperger Depression Rating Scale remains below the initial value (lower value means less depression) in each participant that had variation in this scale | After the 6th session through 24th week | 
| Enhance HDRS 17 | The magnitude, if any, of the change in Hamilton Depression rating scale 17 measured in patients that did not achieve any primary outcome in the first phase of the study after started sertraline as oral antidepressant. | After the 10th visit through the 24th week | 
| Enhance MADRS | The magnitude, if any, of the change in Montgomery Asperger Depression Rating Scale measured in patients that did not achieve any primary outcome in the first phase of the study after started sertraline as oral antidepressant. | After the 10th visit through the 24th week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Isoflurane, Anesthesia, Treatment resistant depression, Deep anesthesia, Burst suppression, Depressive episode