Major Depressive Disorder, Severe Depression, Treatment Resistant Depression
Conditions
Keywords
Ketamine, Electroconvulsive Therapy, Major Depressive Disorder, Treatment Resistant Depression, electroconvulsive treatment, Severe depression
Brief summary
In this proof of concept study, the investigators plan to administer iv ketamine interleaved with ECT days. Patients with treatment resistant depression who are deemed to be eligible for ECT treatment will randomly be assigned to either ketamine or active placebo.
Detailed description
The study will compare the effects of standard ketamine dosing with an active placebo arm. Hypothesis 1: The investigators hypothesize that interleaved Electroconvulsive Treatment and active ketamine treatment will lead to a meaningful clinical improvement compared to Electroconvulsive Treatment and placebo treatment arm. Hypothesis 2: The investigators hypothesize that interleaved Electroconvulsive Treatment and active ketamine treatment will attenuate cognitive side effects. Methods and Design: Patients with treatment resistant depression who are deemed to be eligible for Electroconvulsive Treatment will randomly be assigned to either ketamine or active placebo Electroconvulsive Treatments: All patients (independent of their depression scores) will receive the same Electroconvulsive Treatment parameters: Bi-frontal brief pulse (0.5 miliseconds) Electroconvulsive Treatment administered by using Thymatron Electroconvulsive Treatment machine. Study blinding: Neither the patients, nor the treating psychiatrist or the nurse will be aware of the patient's assigned arm. The success of blinding will be tested after each ketamine treatment with a questionnaire given to the subject, raters, and treating physician.
Interventions
DRUGKetamine
inter venous injections
DRUGMidazolam
inter venous injections
Sponsors
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Males/females at least 18 years of age but no older than 65 years of age 2. Meet Diagnostic and Statistical Manual of Mental Disorders-4th Edition (DSM-IV) criteria for Major Depression or Bipolar Disorder, depressed phase, as determined by a clinician's diagnostic evaluation and confirmed by interview using the Mini International Neuropsychiatric Interview (MINI PLUS 5.0.0) 3. A current depressive episode that has lasted a minimum of 4 weeks. 4. Have \> 3 trials of antidepressants/augmentation strategies. 5. Have a support system capable of transporting the patient post-treatment.
Exclusion criteria
1. Meeting Diagnostic and Statistical Manual of Mental Disorders criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, mental retardation, pervasive developmental disorder. 2. Meeting Diagnostic and Statistical Manual of Mental Disorders criteria for other substance/alcohol dependence within the past 6 months or abuse in the past 3 months. 3. Patients who meet
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Depression Rating Scale (HAMD-17) at Last Infusion | visit 17 | Change in HAMD-17 at Infusion 6. Scores range from 0 to 50, with higher scores representing more depression. |
| Montgomery Asberg Depression Rating Scale (MADRS) at Last Infusion | visit 17 | Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montreal Cognitive Assessment (MOCA) at Last Infusion | visit 17 | MoCA scores range between 0 and 30. Higher scores reflect higher cognition. |
| Hopkins Verbal Learning Test - Revised (HVLT-R) at Last Infusion | visit 17 | The number of words remembered are recorded. Scores range from 0 to 12 with higher scores reflecting better acquisition. |
| Controlled Oral Word Association Test (COWAT) at Last Infusion | visit 17 | This is a verbal fluency measure. Outcome is the count of words that meet criteria within 1 minute, so the minimum is 0 and no fixed maximum exists. Higher scores reflect a better outcome. |
| Responder Rate on HAMD-17 by Last Infusion | visit 17 | Count of the patients who showed response (\>50% decrease). |
Countries
United States
Participant flow
Recruitment details
Patients with TRD who are admitted to the inpatient psychiatric to receive an acute series of ECT will randomly be assigned to one of the study arms.
Pre-assignment details
15 patients with TRD, who were referred to the Cleveland Clinic outpatient depression clinic or ECT service, were recruited in the study. 3 subjects were lost prior to randomization. 2 subjects were lost to follow up after the screening visit, and 1 subject withdrew consent after the baseline visit.12 patients were included in the final analysis.
Participants by arm
| Arm | Count |
|---|---|
| Ketamine Infusions Subjects who are randomized to be on this group will receive a standard dose of ketamine interleaved with Electroconvulsive Treatments.
Ketamine: intervenous injections | 7 |
| Midazolam Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments.
Midazolam: intervenous injections | 5 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Remission Achieved | 3 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Ketamine Infusions | Midazolam | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Continuous | 39.1 years STANDARD_DEVIATION 11.9 | 37.6 years STANDARD_DEVIATION 15.5 | 38.5 years STANDARD_DEVIATION 12.9 |
| Race/Ethnicity, Customized Race Caucasian | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 7 participants | 5 participants | 12 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 5 |
| other Total, other adverse events | 1 / 7 | 0 / 5 |
| serious Total, serious adverse events | 0 / 7 | 0 / 5 |
Outcome results
Primary
Hamilton Depression Rating Scale (HAMD-17) at Last Infusion
Change in HAMD-17 at Infusion 6. Scores range from 0 to 50, with higher scores representing more depression.
Time frame: visit 17
Population: Analysis was performed on all patients using a mixed effect model. Maximum likelihood estimation allowed for inclusion of all patients, even when loss to follow-up or remission occurred.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine Infusions | Hamilton Depression Rating Scale (HAMD-17) at Last Infusion | 13.74 score on a scale | Standard Error 2.62 |
| Midazolam | Hamilton Depression Rating Scale (HAMD-17) at Last Infusion | 14.97 score on a scale | Standard Error 2.85 |
p-value: 0.72Mixed Models Analysis
Primary
Montgomery Asberg Depression Rating Scale (MADRS) at Last Infusion
Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60
Time frame: visit 17
Population: Analysis was performed using mixed effect models. Maximum likelihood estimation allowed inclusion of all patients in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine Infusions | Montgomery Asberg Depression Rating Scale (MADRS) at Last Infusion | 22.29 score on a scale | Standard Error 4.52 |
| Midazolam | Montgomery Asberg Depression Rating Scale (MADRS) at Last Infusion | 24.27 score on a scale | Standard Error 5.93 |
p-value: 0.77Mixed Models Analysis
Secondary
Controlled Oral Word Association Test (COWAT) at Last Infusion
This is a verbal fluency measure. Outcome is the count of words that meet criteria within 1 minute, so the minimum is 0 and no fixed maximum exists. Higher scores reflect a better outcome.
Time frame: visit 17
Population: Analysis was performed on all patients using a mixed effect model. Maximum likelihood estimation allowed for inclusion of all patients, even when loss to follow-up or remission occurred.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine Infusions | Controlled Oral Word Association Test (COWAT) at Last Infusion | 33.45 number of words | Standard Error 2.83 |
| Midazolam | Controlled Oral Word Association Test (COWAT) at Last Infusion | 37.17 number of words | Standard Error 3.03 |
p-value: 0.34Mixed Models Analysis
Secondary
Hopkins Verbal Learning Test - Revised (HVLT-R) at Last Infusion
The number of words remembered are recorded. Scores range from 0 to 12 with higher scores reflecting better acquisition.
Time frame: visit 17
Population: Analysis was performed on all patients using a mixed effect model. Maximum likelihood estimation allowed for inclusion of all patients, even when loss to follow-up or remission occurred.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine Infusions | Hopkins Verbal Learning Test - Revised (HVLT-R) at Last Infusion | 9.42 score on a scale | Standard Error 0.56 |
| Midazolam | Hopkins Verbal Learning Test - Revised (HVLT-R) at Last Infusion | 11.20 score on a scale | Standard Error 0.56 |
p-value: 0.009Mixed Models Analysis
Secondary
Montreal Cognitive Assessment (MOCA) at Last Infusion
MoCA scores range between 0 and 30. Higher scores reflect higher cognition.
Time frame: visit 17
Population: Analysis was performed on all patients using a mixed effect model. Maximum likelihood estimation allowed for inclusion of all patients, even when loss to follow-up or remission occurred.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine Infusions | Montreal Cognitive Assessment (MOCA) at Last Infusion | 24.81 score on a scale | Standard Error 0.96 |
| Midazolam | Montreal Cognitive Assessment (MOCA) at Last Infusion | 25.79 score on a scale | Standard Error 0.97 |
p-value: 0.4Mixed Models Analysis
Secondary
Responder Rate on HAMD-17 by Last Infusion
Count of the patients who showed response (\>50% decrease).
Time frame: visit 17
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ketamine Infusions | Responder Rate on HAMD-17 by Last Infusion | Response | 3 Participants |
| Ketamine Infusions | Responder Rate on HAMD-17 by Last Infusion | No Response | 4 Participants |
| Midazolam | Responder Rate on HAMD-17 by Last Infusion | No Response | 4 Participants |
| Midazolam | Responder Rate on HAMD-17 by Last Infusion | Response | 1 Participants |
p-value: 0.5895% CI: [0.01, 7.2]Fisher Exact