Ketamine Anesthesia for Improvement of Depression in ECT

Study Overview
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Brief Summary
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The purpose of this prospective randomized clinical trial is to determine if patients receiving ketamine as a part of general anesthesia during electroconvulsive therapy (ECT) rather than standard of care will have improvement in symptoms of depression after a course of ECT treatments. The investigators hypothesize that utilization of ketamine for induction of general anesthesia during ECT treatments will improve symptoms of depression better than standard care. This study is ONLY open to patients eligible to receive healthcare services through the Department of Veterans Affairs at the VA Puget Sound, which means service in the active military, naval or air service or separation under any condition other than dishonorable. Qualifications for VA health care benefits can be found at va.gov.

Detailed Description
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The purpose of this prospective randomized clinical trial is to determine if patients receiving ketamine as a part of general anesthesia during electroconvulsive therapy (ECT) rather than standard of care will have improvement in symptoms of depression after a course of ECT treatments. The investigators hypothesize that utilization of ketamine for induction of general anesthesia during ECT treatments will improve symptoms of depression better than standard care. For induction of general anesthesia for ECT, patients will receive either 1mg/kg of methohexital (standard arm) or 1.0 mg/kg IV ketamine (experimental arm) intravenously (IV) for the duration of their ECT index course over 2-3 weeks. The primary outcome in this trial is change in symptoms of depression assessed by standard questionnaires: Patient Health Questionnaire 9 (PHQ9) and Hamilton Depression Rating Scale (HAM-D) score changes from baseline and final ECT administration. Secondary outcomes are changes in cognitive status as assessed by the Montreal Cognitive Assessment (MoCA) scale, quality of seizures and after seizure, changes in serum metabolites (including kynurenine, D/L-serine and other glutamate intermediates) after treatment and need for further ECT courses (relapse) within 1 year after initial course. Approximately 50 veterans with the diagnosis of major depressive disorder older than 18 years of age undergoing ECT will be randomized and blinded to the intervention. Operative ECT clinicians will not be blinded; clinicians evaluating patients will be blinded. Exclusion criteria for this study include uncontrolled hypertension, blood pressure > 180/90 mmHg at the pre-anesthesia clinic visit, renal failure, neurologic disorders (e.g. epilepsy, space occupying lesions, traumatic brain injuries in the past 6 months), myocardial infarction in the past 6 months, known allergies or adverse reactions to ketamine, American Society of Anesthesiology Physical Class greater than 3, concomitant psychosis, schizophrenia or current abuse of alcohol or illicit substances and pregnancy. The long term objective of this trial is to systematically characterize ketamine's effect on depression outcomes utilizing validated scoring tools, its safety profile throughout an ECT index course, ketamine's effect on seizure quality and changes in novel translational endpoints to better understand mechanisms of action of ketamine and its potential role in treatment of psychiatric disorders.

Official Title
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Ketamine vs. Methohexital Anesthesia for Improvement of Major Depressive Disorder in Electroconvulsive Therapy

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Ketamine
* Drug: Methohexital


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: outpatients or inpatients at the Puget Sound VA with diagnosis of major depressive disorder or bipolar 1 or 2 over the age of 18 undergoing index course ECT Exclusion Criteria: uncontrolled hypertension (blood pressure > 180/90 mmHg at the pre-anesthesia clinic visit) renal failure neurologic disorders (e.g. epilepsy, space occupying lesions, traumatic brain injuries in the past 6 months) myocardial infarction in the past 6 months known allergies or adverse reactions to ketamine American Society of Anesthesiology Physical Class greater than 3 concomitant psychosis schizophrenia or current abuse of alcohol or illicit substances and pregnancy (any trimester)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine Interventional Arm<br>1.0 mg/kg IV ketamine (experimental arm) intravenously (IV) for the duration of their ECT index course over 2-3 weeks | Drug: Ketamine<br>* Ketamine anesthesia for ECT index course with measurement cerebral metabolic regional oximetry, EEG seizure quality, cognitive scoring and serum metabolites.<br>* Other names: Ketalar;|
| Active Comparator: Methohexital Control Arm<br>1mg/kg of methohexital (standard arm) intravenously (IV) for the duration of their ECT index course over 2-3 weeks | Drug: Methohexital<br>* Methohexital anesthesia for ECT index course with measurement cerebral metabolic regional oximetry, EEG seizure quality, cognitive scoring and serum metabolites.<br>* Other names: Brevital;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Depression Patient Health Questionnaire 9 (PHQ9) Scoring | Evaluate the efficacy and safety of repeat anesthetic ketamine dosing during a complete index course of ECT compared with methohexital using change in a validated depression scoring tool (Patient Health Questionnaire 9) administered 24 hours prior to starting an ECT index course treatment (baseline) with a PHQ9 score 72 hours after the last/final ECT session for approximately fifty patients. The PHQ9 Scoring ranges from 0 to 27 in order to monitor depression severity over time for newly diagnosed patients or patients in current treatment for depression. | Change from Baseline Score 24 hours prior to starting ECT to PHQ9 score 72 hours following last ECT session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Soluble Amino Acid Metabolomic Biomarkers | Measurement of biomarkers before/after ECT index course serum aqueous metabolites from patient venous blood drawn from intravenous line specifically concentration of serine, tryptophan, quinolinic acid, kynurenine in mcg/dL using mass spectrometry. Samples are collected 30 minutes prior to first ECT session and within 30 minutes after final ECT treatment session. | 30 minutes prior to first ECT session and within 30 minutes after final ECT session | 
| ECT Seizure Duration | This trial will measure intra-operative seizure length/duration (in seconds) using a standard ECT machine which helps the ECT machine operator determine the total length of time a patient is seizing during each ECT seizure session. An index course of ECT treatment typically involves 6 to 12 seizures titrated to a patient's response. The investigators will record the length of seizure for every treatment session for every patient. | Length of each intraoperative ECT seizure during an index course typically 6-12 individual seizures measure from start of seizure in operating room to end of seizure in operating room. | 
| Change in Montreal Cognitive Assessment (MoCA) Scoring | Evaluate the efficacy and safety of repeat anesthetic ketamine dosing during a complete index course of ECT compared with methohexital using change in a validated cognitive scoring tool (Montreal Cognitive Assessment MoCA) administered 24 hours prior to starting an ECT index course treatment (baseline) with a MoCA score 72 hours after the last/final ECT session for approximately fifty patients. The MoCA Scoring ranges from 0 to 30 in order to rapidly screen for mild cognitive dysfunction. | Change from Baseline Score 24 hours prior to starting ECT to MoCA score 72 hours following last ECT session | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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major depressive disorder, electroconvulsive therapy, metabolomics, treatment resistant depression, anesthesiology, ketamine, prospective randomized clinical trial