Administration of Subanesthetic Dose of Ketamine and Electroconvulsive Treatment for Treatment Resistant Depression

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02522377
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Treatment Resistant Depression; Major Depressive Disorder; Severe Depression	Drug: Ketamine; Drug: Midazolam	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Administration of Subanesthetic Dose of Ketamine and Electroconvulsive Treatment on Alternate Week Days in Patients With Treatment Resistant Depression: A Double Blind Placebo Controlled Trial
• Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Mar 1, 2018
• Actual Study Completion Date: Mar 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine Infusions Subjects who are randomized to be on this group will receive a standard dose of ketamine interleaved with Electroconvulsive Treatments.	Drug: Ketamine; inter venous injections; Other Names: Ketalar Calypsol Ketanest Tekam
Active Comparator: Midazolam Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments.	Drug: Midazolam; inter venous injections; Other Names: Dormicum Hypnovel Versed

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. Montreal Cognitive Assessment (MOCA) at Last Infusion [visit 17]

   MoCA scores range between 0 and 30. Higher scores reflect higher cognition.

2. 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.

3. 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.

4. Responder Rate on HAMD-17 by Last Infusion [visit 17]

   Count of the patients who showed response (>50% decrease).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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 exclusion criteria for ketamine and/or midazolam infusion.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Foundation Center for Behavioral Health	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic

Investigators

• Principal Investigator: Murat Altinay, MD, The Cleveland Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 12, 2016

More Information

Publications

None provided.

• Responsible Party: Dr. Murat Altinay, Staff, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT02522377
• Other Study ID Numbers: Ketamine ECT
• First Posted: Aug 13, 2015
• Last Update Posted: Aug 29, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Dr. Murat Altinay, Staff, The Cleveland Clinic: Ketamine; Electroconvulsive Therapy; Major Depressive Disorder; Treatment Resistant Depression; electroconvulsive treatment; Severe depression
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Midazolam; Ketamine

Study Results

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 Detail	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.

Arm/Group Title	Ketamine Infusions	Midazolam
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine alternated with Electroconvulsive Treatments. Ketamine: intervenous injections	Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections
Period Title: Overall Study
STARTED	7	5
COMPLETED	3	5
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	Ketamine Infusions	Midazolam	Total
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine interleaved with Electroconvulsive Treatments. Ketamine: intervenous injections	Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections	Total of all reporting groups
Overall Participants	7	5	12
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	5 100%	12 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.1 (11.9)	37.6 (15.5)	38.5 (12.9)
Sex: Female, Male (Count of Participants)
Female	6 85.7%	4 80%	10 83.3%
Male	1 14.3%	1 20%	2 16.7%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	5 71.4%	4 80%	9 75%
Other	2 28.6%	1 20%	3 25%
Region of Enrollment (participants) [Number]
United States	7 100%	5 100%	12 100%

Outcome Measures

1. Primary Outcome

Title	Hamilton Depression Rating Scale (HAMD-17) at Last Infusion
Description	Change in HAMD-17 at Infusion 6. Scores range from 0 to 50, with higher scores representing more depression.
Time Frame	visit 17

Outcome Measure Data

Analysis Population Description

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/Group Title	Ketamine Infusions	Midazolam
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine alternated with Electroconvulsive Treatments. Ketamine: intervenous injections	Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections
Measure Participants	7	5
Mean (Standard Error) [score on a scale]	13.74 (2.62)	14.97 (2.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine Infusions, Midazolam
	Comments
	Type of Statistical Test	Superiority
	Comments	Superiority test based upon group differences pooled across infusions
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes main effect for treatment group and infusion number categorically. Satterthwaite DF=9.987.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.28
	Estimation Comments	Midazolam - Ketamine Infusions

2. Primary Outcome

Title	Montgomery Asberg Depression Rating Scale (MADRS) at Last Infusion
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was performed using mixed effect models. Maximum likelihood estimation allowed inclusion of all patients in analysis.

Arm/Group Title	Ketamine Infusions	Midazolam
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine alternated with Electroconvulsive Treatments. Ketamine: intervenous injections	Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections
Measure Participants	7	5
Mean (Standard Error) [score on a scale]	22.29 (4.52)	24.27 (5.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine Infusions, Midazolam
	Comments
	Type of Statistical Test	Superiority
	Comments	Superiority test based upon group differences pooled across infusions in mixed effect model
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes main effect for treatment group and infusion number categorically. Satterthwaite DF=7.836.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.98
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.40
	Estimation Comments	Midazolam - Ketamine Infusions

3. Secondary Outcome

Title	Montreal Cognitive Assessment (MOCA) at Last Infusion
Description	MoCA scores range between 0 and 30. Higher scores reflect higher cognition.
Time Frame	visit 17

Outcome Measure Data

Analysis Population Description

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/Group Title	Ketamine Infusions	Midazolam
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine alternated with Electroconvulsive Treatments. Ketamine: intervenous injections	Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections
Measure Participants	7	5
Mean (Standard Error) [score on a scale]	24.81 (0.96)	25.79 (0.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine Infusions, Midazolam
	Comments
	Type of Statistical Test	Superiority
	Comments	Superiority test based upon group differences pooled across infusions
Statistical Test of Hypothesis	p-Value	0.40
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes main effect for treatment group and infusion number categorically. Satterthwaite DF=9.987.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.12
	Estimation Comments	Midazolam - Ketamine Infusions

4. Secondary Outcome

Title	Hopkins Verbal Learning Test - Revised (HVLT-R) at Last Infusion
Description	The number of words remembered are recorded. Scores range from 0 to 12 with higher scores reflecting better acquisition.
Time Frame	visit 17

Outcome Measure Data

Analysis Population Description

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/Group Title	Ketamine Infusions	Midazolam
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine alternated with Electroconvulsive Treatments. Ketamine: intervenous injections	Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections
Measure Participants	7	5
Mean (Standard Error) [score on a scale]	9.42 (0.56)	11.20 (0.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine Infusions, Midazolam
	Comments
	Type of Statistical Test	Superiority
	Comments	Superiority test based upon group differences pooled across infusions
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes main effect for treatment group and infusion number categorically. Satterthwaite DF=9.3634.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.78
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.54
	Estimation Comments	Midazolam - Ketamine Infusions

5. Secondary Outcome

Title	Controlled Oral Word Association Test (COWAT) at Last Infusion
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Ketamine Infusions	Midazolam
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine alternated with Electroconvulsive Treatments. Ketamine: intervenous injections	Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections
Measure Participants	7	5
Mean (Standard Error) [number of words]	33.45 (2.83)	37.17 (3.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine Infusions, Midazolam
	Comments
	Type of Statistical Test	Superiority
	Comments	Superiority test based upon group differences pooled across infusions
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes main effect for treatment group and infusion number categorically. Satterthwaite DF=9.987.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.72
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.71
	Estimation Comments	Midazolam - Ketamine Infusions

6. Secondary Outcome

Title	Responder Rate on HAMD-17 by Last Infusion
Description	Count of the patients who showed response (>50% decrease).
Time Frame	visit 17

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine Infusions	Midazolam
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine alternated with Electroconvulsive Treatments. Ketamine: intervenous injections	Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections
Measure Participants	7	5
No Response	4 57.1%	4 80%
Response	3 42.9%	1 20%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine Infusions, Midazolam
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.01 to 7.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio of Midazolam (numerator) to Ketamine Infusions (denominator)

Adverse Events

Time Frame	3 weeks
Arm/Group Title	Ketamine Infusions		Midazolam
Arm/Group Description	Subjects who are randomized to be on this group will receive a standard dose of ketamine alternated with Electroconvulsive Treatments. Ketamine: intervenous injections		Subjects who are randomized to be on this group will receive midazolam infusions interleaved with Electroconvulsive Treatments. Midazolam: intervenous injections
All Cause Mortality
	Ketamine Infusions		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/5 (0%)
Serious Adverse Events
	Ketamine Infusions		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine Infusions		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)		0/5 (0%)
Psychiatric disorders
Suicidal Thoughts	1/7 (14.3%)	1	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.