N-methyl-D-aspartate Antagonist (Ketamine) Augmentation of Electroconvulsive Treatment for Severe Major Depression

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01260649
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arms: 2
• Actual Duration (Months): 24
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Electroconvulsive therapy (ECT), is considered the most effective treatment for severe treatment resistant major depressive disorder (MDD), but it requires about 3 weeks of treatments and can cause considerable acute deficits in memory. It would be a major advance in treatment if ECT could work faster with fewer treatments and result in decrease incidence of memory problems. Ketamine is an excellent candidate for augmentation of ECT because of its acute effects on depression, its short half-life, and its safety profile when given at low doses. Ketamine is given as an infusion and could easily be incorporated into the routine management of patients undergoing ECT, but has never been evaluated prospectively in this context.

The investigators propose to assess the efficacy, feasibility, tolerability and safety of N-methyl-D-aspartate antagonist augmentation of ECT using ketamine.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: ketamine; Other: IV Saline; Procedure: ECT; Drug: Muscle Relaxant; Drug: Anesthetic Agents	Phase 4

Detailed Description

Aim #1: To assess the efficacy of ketamine augmentation in reducing time to remission of a major depressive episode (MDE).

Aim #2: To assess the efficacy of ketamine augmentation on ECT-related cognitive side effects.

Aim #3: To assess the feasibility, safety, and tolerability of ketamine augmentation of ECT.

Exploratory aim #4: We propose to assess the patterns of functional connectivity before, during and after ECT using standard clinical EEG to better characterize the effect of ECT and to correlate clinical effects with changes in EEG measurements.

Thirty (30) participants will be recruited over 24 months. Participants will be males and females, ages 18-60, with severe MDD (baseline score HAM_D-28 >= 20) deemed appropriate for ECT treatment by their treating physician, agreeing to receive ECT treatment as part of their clinical care, and able to provide informed consent.

Exclusion criteria are any other DSM-IV primary diagnoses including major depressive disorder with psychotic features, bipolar disorder, schizoaffective disorder, schizophrenia, dementia, any history of psychosis, substance use disorder (abuse or dependence with active use within the last 6 months), and any lifetime history of ketamine abuse or dependence, organic mental disorders, seizure disorder or chronic antiepileptic medications, severe or unstable medical illness, pregnancy.

Study procedures: eligible patients will be randomized to a double-blind administration of ketamine (0.5 mg/kg) or saline before the first three ECT treatments. Right Unilateral ECT (RUL-ECT) will be administered at 6 times the seizure threshold, using the d'Elia placement of the electrodes. Electroconvulsive therapy will be given 3 times per week, as per standard of care at MGH. Depression severity will be assessed weekly with the HAM-D 28 (the main outcome measure), administered by a clinician blinded to randomization.

The neuropsychological assessment battery is designed to include instruments sensitive to the cognitive impairment associated with depression in general and ECT treatment in particular will be repeated at baseline, at the end of acute treatment series and at 3 months follow-up.

Also patients will undergo repeated EEG monitoring, at baseline after one week of treatment and at follow up with the aim of possibly identifying EEG features associated with response.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Actual Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Oct 26, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ketamine ketamine (0.5 mg/kg) followed by anesthetic agent titrated to sedation and succinylcholine titrated to muscle relaxation Right unilateral ECT at 5-6x seizure threshold three times a week	Drug: ketamine; eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg) or IV Saline, followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care; Procedure: ECT; ECT will be administered as per standard of care; Drug: Muscle Relaxant; All participant will receive routine course of muscle relaxant with ECT as per standard of care; Drug: Anesthetic Agents; All participant will receive routine course of anesthetic agents with ECT as per standard of care
Placebo Comparator: placebo IV saline, followed by anesthestic agent titrated to sedation and succinylcholine titrated to muscle relaxation. Right unilateral ECT at 5-6x seizure threshold three times a week	Other: IV Saline; eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg) or IV Saline, followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care; Procedure: ECT; ECT will be administered as per standard of care; Drug: Muscle Relaxant; All participant will receive routine course of muscle relaxant with ECT as per standard of care; Drug: Anesthetic Agents; All participant will receive routine course of anesthetic agents with ECT as per standard of care

Outcome Measures

Primary Outcome Measures

1. Change in Hamilton Depression Rating Scale - 28 [baseline, one month]

   HAMD will be administered at every ECT treatment.The HAM D 28 is a 28 item scale with scores ranging from 0 to 83, with 0 being no depression and 83 being high levels of depression symptoms. The change in HAM S score was determined by the difference of the HAM D score at the last ECT administration and the baseline HAM D score. A negative change score reflects a decreased HAM D score between the first and last ECT administration and therefore a reduction in depressive symptoms.

Secondary Outcome Measures

1. Number of Participants With Cognitive Side Effects [3 months]

   will compare the incidence of participants with memory deficits between groups, as determined by incidents of clinician reported cognitive adverse events

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 and females between the ages of 18-65,

2. DSM-IV diagnosis of Major Depressive Disorder (MDD), without psychotic features

3. HAM-D-28 score of 20 or higher

4. requiring ECT treatment as part of their psychiatric care Comorbid anxiety disorders (OCD, Generalized anxiety, panic disorder) will be allowed as long as the clinician administering the SCID believes that they are not the primary diagnosis.

Exclusion Criteria:

1. MDD with a score of <20 on the HAM-D 28,

2. Other DSM-IV primary diagnoses including major depressive disorder with psychotic features, bipolar disorder, schizoaffective disorder, schizophrenia, dementia

3. any history of psychosis

4. substance use disorder (abuse or dependence with active use within the last 6 months), and any lifetime history of ketamine abuse or dependence;

5. organic mental disorders;

6. seizure disorder or chronic antiepileptic medications;

7. severe or unstable medical illness, including history of closed head injury resulting in loss of consciousness, medical contraindication to anesthesia or to ECT (i.e. recent myocardial infarction, increased intracranial pressure)

8. current treatment with memantine

9. pregnancy, or females of reproductive age who are not using an accepted method of contraception (birth control pill, IUD, combination of barrier methods).

10. known hypersensitivity to ketamine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cristina Cusin, MD, Instructor HMS, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01260649
• Other Study ID Numbers: 2010P001672
• First Posted: Dec 15, 2010
• Last Update Posted: May 22, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Cristina Cusin, MD, Instructor HMS, Massachusetts General Hospital: Electroconvulsive treatment; ketamine; Major Depression; Treatment-resistant Major Depressive Disorder
• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Ketamine; Anesthetics

Study Results

Participant Flow

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	ketamine (0.5 mg/kg) followed by anesthetic agent titrated to sedation and succinylcholine titrated to muscle relaxation Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care	IV saline, followed by anesthestic agent titrated to sedation and succinylcholine titrated to muscle relaxation. Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care
Period Title: Overall Study
STARTED	8	9
COMPLETED	6	8
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Ketamine	Placebo	Total
Arm/Group Description	ketamine (0.5 mg/kg) followed by anesthetic agent titrated to sedation and succinylcholine titrated to muscle relaxation Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care	IV saline, followed by anesthestic agent titrated to sedation and succinylcholine titrated to muscle relaxation. Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care	Total of all reporting groups
Overall Participants	6	8	14
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 100%	7 87.5%	13 92.9%
>=65 years	0 0%	1 12.5%	1 7.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.43 (15.62)	48.75 (12.22)	48.57 (13.20)
Sex: Female, Male (Count of Participants)
Female	4 66.7%	7 87.5%	11 78.6%
Male	2 33.3%	1 12.5%	3 21.4%
Region of Enrollment (participants) [Number]
United States	6 100%	8 100%	14 100%

Outcome Measures

1. Primary Outcome

Title	Change in Hamilton Depression Rating Scale - 28
Description	HAMD will be administered at every ECT treatment.The HAM D 28 is a 28 item scale with scores ranging from 0 to 83, with 0 being no depression and 83 being high levels of depression symptoms. The change in HAM S score was determined by the difference of the HAM D score at the last ECT administration and the baseline HAM D score. A negative change score reflects a decreased HAM D score between the first and last ECT administration and therefore a reduction in depressive symptoms.
Time Frame	baseline, one month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	ketamine (0.5 mg/kg) followed by anesthetic agent titrated to sedation and succinylcholine titrated to muscle relaxation Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care	IV saline, followed by anesthestic agent titrated to sedation and succinylcholine titrated to muscle relaxation. Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care
Measure Participants	6	8
Mean (Standard Deviation) [units on a scale]	-17.50 (6.53)	-14.00 (14.20)

2. Secondary Outcome

Title	Number of Participants With Cognitive Side Effects
Description	will compare the incidence of participants with memory deficits between groups, as determined by incidents of clinician reported cognitive adverse events
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	ketamine (0.5 mg/kg) followed by anesthetic agent titrated to sedation and succinylcholine titrated to muscle relaxation Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care	IV saline, followed by anesthestic agent titrated to sedation and succinylcholine titrated to muscle relaxation. Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care
Measure Participants	6	8
Count of Participants [Participants]	0 0%	1 12.5%

Adverse Events

Arm/Group Title	Ketamine		Placebo
Arm/Group Description	ketamine (0.5 mg/kg) followed by anesthetic agent titrated to sedation and succinylcholine titrated to muscle relaxation Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care		IV saline, followed by anesthestic agent titrated to sedation and succinylcholine titrated to muscle relaxation. Right unilateral ECT at 5-6x seizure threshold three times a week ketamine: eligible patients will be randomly assigned to a double-blind administration of ketamine (0.5 mg/kg), followed by the routine anesthetic agent and muscle relaxant. ECT will be administered as per standard of care
All Cause Mortality
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/8 (0%)
Serious Adverse Events
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Body pain	0/6 (0%)	0	1/8 (12.5%)	1
Psychiatric disorders
Racing Thoughts	0/6 (0%)	0	1/8 (12.5%)	1
Other (Not Including Serious) Adverse Events
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		3/8 (37.5%)
Cardiac disorders
Heart pounding/tightness in chest	1/6 (16.7%)	1	0/8 (0%)	0
Ear and labyrinth disorders
Fluid in right ear	0/6 (0%)	0	1/8 (12.5%)	1
General disorders
Fatigue	0/6 (0%)	0	1/8 (12.5%)	1
Hepatobiliary disorders
Increased Blood sugar	0/6 (0%)	0	1/8 (12.5%)	1
Musculoskeletal and connective tissue disorders
Jaw pain	1/6 (16.7%)	1	0/8 (0%)	0
Nervous system disorders
Short term memory impairment	0/6 (0%)	0	1/8 (12.5%)	1
Dizziness	0/6 (0%)	0	1/8 (12.5%)	1
Numbness in feet and body	1/6 (16.7%)	1	0/8 (0%)	0
Tingling in feet	1/6 (16.7%)	1	0/8 (0%)	0
Psychiatric disorders
Sedation	0/6 (0%)	0	1/8 (12.5%)	1
Agitation	0/6 (0%)	0	1/8 (12.5%)	2
Anxiety	1/6 (16.7%)	1	0/8 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.