Ketamine for Treatment Resistant Late-Life Depression

• ClinicalTrials.gov Identifier: NCT02556606
• Recruitment Status: Completed
• First Posted: September 22, 2015
• Results First Posted: August 9, 2021
• Last Update Posted: January 11, 2022
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Treatment Resistant Depressive Disorder
• Interventions: Drug: Ketamine; Drug: Midazolam
• Enrollment: 33

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Ketamine 0.10 mg/kg	Ketamine 0.25 mg/kg	Ketamine 0.50 mg/kg	Midazolam 0.03 mg/kg
Arm/Group Description	randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg	randomly assigned to a single 40 min infusion of either MID 0.03mg/Kg Midazolam: single 40 min infusion of MID 0.03mg/Kg
Period Title: Overall Study
Started	4	5	11	13
Completed	4	5	11	13
Not Completed	0	0	0	0

Baseline Characteristics

Arm/Group Title		Ketamine 0.10 mg/kg	Ketamine 0.25 mg/kg	Ketamine 0.50 mg/kg	Midazolam 0.03 mg/kg	Total
Arm/Group Description		randomly assigned to a single 40 min infusion of KET 0.1 mg/kg	randomly assigned to a single 40 min infusion of KET 0.25 mg/kg	randomly assigned to a single 40 min infusion of KET 0.50 mg/kg	randomly assigned to a single 40 min infusion of MID 0.03 mg/kg	Total of all reporting groups
Overall Number of Baseline Participants		4	5	11	13	33
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	4 participants	5 participants	11 participants	13 participants	33 participants
		66.75 (5.54)	61.8 (6.06)	60.91 (4.97)	62.15 (5.54)	62.24 (5.60)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	4 participants	5 participants	11 participants	13 participants	33 participants
	Female	0 0.0%	3 60.0%	3 27.3%	4 30.8%	10 30.3%
	Male	4 100.0%	2 40.0%	8 72.7%	9 69.2%	23 69.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	4 participants	5 participants	11 participants	13 participants	33 participants
	Hispanic or Latino	0 0.0%	1 20.0%	0 0.0%	1 7.7%	2 6.1%
	Not Hispanic or Latino	4 100.0%	4 80.0%	11 100.0%	12 92.3%	31 93.9%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	4 participants	5 participants	11 participants	13 participants	33 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	2 50.0%	3 60.0%	4 36.4%	7 53.8%	16 48.5%
	White	2 50.0%	2 40.0%	7 63.6%	6 46.2%	17 51.5%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores
Description	To determine the best performing intervention among three sub-anesthetic doses of a single ketamine (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and midazolam (0.03 mg/kg) in Veterans with LL-TRD as measured by the percentage of participants demonstrating at least a 50% reduction from pre-treatment baseline on Montgomery-Asberg Depression Rating Scale (MADRS; score range 0 - 60, higher scores meaning more severe depression) scores at 7 days post-infusion.
Time Frame	Day 7 post-infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine 0.10 mg/kg	Ketamine 0.25 mg/kg	Ketamine 0.50 mg/kg	Midazolam 0.03 mg/kg
Arm/Group Description:	randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg	randomly assigned to a single 40 min infusion of either MID 0.03mg/Kg Midazolam: single 40 min infusion of MID 0.03mg/Kg
Overall Number of Participants Analyzed	4	5	11	13
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	2 40.0%	8 72.7%	6 46.2%

2. Secondary Outcome

Title	Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS
Description	Patients with a day 7 treatment response (at least a 50% improvement from baseline in Montgomery-Asberg Depression Rating Scale [MADRS]) are followed until day 28 post-infusion; day 7 non-responders are not followed. Outcome measure is the percentage of patients who continue to be responder at day 28, and is interpreted as a measure of durability of efficacy.
Time Frame	28 days post-infusion follow-up

Outcome Measure Data

Analysis Population Description

Day 7 responders were followed until day 28 post-infusion or until relapse

Arm/Group Title	Ketamine 0.10 mg/kg	Ketamine 0.25 mg/kg	Ketamine 0.50 mg/kg	Midazolam 0.03 mg/kg
Arm/Group Description:	randomly assigned to a single 40 min infusion of KET 0.1 mg/kg	randomly assigned to a single 40 min infusion of KET 0.25 mg/kg	randomly assigned to a single 40 min infusion of KET 0.50 mg/kg	randomly assigned to a single 40 min infusion of MID 0.03 mg/kg
Overall Number of Participants Analyzed	0	2	8	6
Measure Type: Count of Participants; Unit of Measure: Participants
	0	1 50.0%	7 87.5%	4 66.7%

3. Other Pre-specified Outcome

Title	Change in Clinician-Administered Dissociative States Scale (CADSS)
Description	Change from pre-infusion baseline to end of infusion at 40 minutes after start of infusion on the Clinician-Administered Dissociative States Scale (CADSS; scale form 0 [no psychosis-like symptoms] to 90 [severe psychosis-like symptoms]) to assess psychosis-like side effect on day of infusion.
Time Frame	Baseline to 40 minutes after start of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine 0.10 mg/kg	Ketamine 0.25 mg/kg	Ketamine 0.50 mg/kg	Midazolam 0.03 mg/kg
Arm/Group Description:	randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg	randomly assigned to a single 40 min infusion of either MID 0.03mg/Kg Midazolam: single 40 min infusion of MID 0.03mg/Kg
Overall Number of Participants Analyzed	4	5	11	13
Mean (Standard Deviation); Unit of Measure: Score on CADSS scale
Pre-infusion baseline	1.41 (0.71)	0 (0)	0.09 (0.30)	0.23 (0.60)
End of infusion at 40 minutes	4.79 (2.39)	14.98 (6.70)	21.36 (20.53)	4.38 (6.73)

4. Other Pre-specified Outcome

Title	Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared)
Description	Change in EEG frontal gamma power from pre-infusion baseline to 30 minutes after start of infusion to assess engagement of the study drug with the N-methyl-D-aspartate receptor.
Time Frame	Baseline to 30 minutes after start of infusion

Outcome Measure Data

Analysis Population Description

Missing data due to poor data quality for KET 0.1 (n=1), KET 0.5 (n=3) or MID (n=3)

Arm/Group Title	Ketamine 0.10 mg/kg	Ketamine 0.25 mg/kg	Ketamine 0.50 mg/kg	Midazolam 0.03 mg/kg
Arm/Group Description:	randomly assigned to a single 40 min infusion of KET 0.1 mg/kg	randomly assigned to a single 40 min infusion of KET 0.25 mg/kg	randomly assigned to a single 40 min infusion of KET 0.50 mg/kg	randomly assigned to a single 40 min infusion of MID 0.03 mg/kg
Overall Number of Participants Analyzed	3	5	8	10
Mean (Standard Deviation); Unit of Measure: uV^2
Pre-infusion baseline	0.0019 (0.0004)	0.055 (0.0030)	0.0042 (0.0026)	0.0061 (0.0078)
30 minutes after start of infusion	0.0035 (0.0012)	0.0057 (0.0044)	0.0098 (0.0067)	0.004 (0.0027)

5. Other Pre-specified Outcome

Title	Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg)
Description	Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion
Time Frame	Baseline to 30 minutes after start of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine 0.10 mg/kg	Ketamine 0.25 mg/kg	Ketamine 0.50 mg/kg	Midazolam 0.03 mg/kg
Arm/Group Description:	randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg	randomly assigned to a single 40 min infusion of either MID 0.03mg/Kg Midazolam: single 40 min infusion of MID 0.03mg/Kg
Overall Number of Participants Analyzed	4	5	11	13
Mean (Standard Deviation); Unit of Measure: mm Hg
Pre-infusion baseline	154.25 (5.91)	142.2 (15.97)	132.91 (10.56)	125.54 (213.01)
30 minutes after start of infusion	152.75 (12.97)	148.2 (18.07)	160.36 (25.94)	116.62 (15.56)

6. Other Pre-specified Outcome

Title	Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg)
Description	Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion
Time Frame	Baseline to 30 minutes after start of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine 0.10 mg/kg	Ketamine 0.25 mg/kg	Ketamine 0.50 mg/kg	Midazolam 0.03 mg/kg
Arm/Group Description:	randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg	randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg	randomly assigned to a single 40 min infusion of either MID 0.03mg/Kg Midazolam: single 40 min infusion of MID 0.03mg/Kg
Overall Number of Participants Analyzed	4	5	11	13
Mean (Standard Deviation); Unit of Measure: mm Hg
Pre-infusion baseline	80.5 (7.05)	74.6 (13.37)	82.64 (4.72)	72.23 (9.36)
30 minutes after start of infusion	91.25 (14.24)	82.6 (18.53)	95.45 (16.01)	73.54 (12.29)

Adverse Events

Time Frame	28 days
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Ketamine 0.10 mg/kg		Ketamine 0.25 mg/kg		Ketamine 0.50 mg/kg		Midazolam 0.03 mg/kg
Arm/Group Description	randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg		randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg		randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg Ketamine: randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg		randomly assigned to a single 40 min infusion of either MID 0.03mg/Kg Midazolam: single 40 min infusion of MID 0.03mg/Kg
All-Cause Mortality
	Ketamine 0.10 mg/kg		Ketamine 0.25 mg/kg		Ketamine 0.50 mg/kg		Midazolam 0.03 mg/kg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/4 (0.00%)		0/5 (0.00%)		0/11 (0.00%)		0/13 (0.00%)
Serious Adverse Events
	Ketamine 0.10 mg/kg		Ketamine 0.25 mg/kg		Ketamine 0.50 mg/kg		Midazolam 0.03 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0.00%)		0/5 (0.00%)		0/11 (0.00%)		1/13 (7.69%)
Psychiatric disorders
Suicide attempt † [1]	0/4 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/13 (7.69%)	1
† Indicates events were collected by systematic assessment; [1] One participant made a suicide attempt four days after midazolam infusion. The event was determined unrelated to the intervention because this participant scored zero on the Columbia Suicide Severity Rating Scale one day before the attempt
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Ketamine 0.10 mg/kg		Ketamine 0.25 mg/kg		Ketamine 0.50 mg/kg		Midazolam 0.03 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100.00%)		5/5 (100.00%)		11/11 (100.00%)		13/13 (100.00%)
Cardiac disorders
Cardiac complaints † [1]	1/4 (25.00%)	1	3/5 (60.00%)	3	4/11 (36.36%)	4	7/13 (53.85%)	7
Eye disorders
Eye or ear complaints † [1]	3/4 (75.00%)	3	5/5 (100.00%)	5	4/11 (36.36%)	4	11/13 (84.62%)	11
Gastrointestinal disorders
Gastrointestinal complaints † [2]	4/4 (100.00%)	4	4/5 (80.00%)	4	8/11 (72.73%)	8	11/13 (84.62%)	11
General disorders
Sleep complaints † [1]	4/4 (100.00%)	4	5/5 (100.00%)	5	11/11 (100.00%)	11	13/13 (100.00%)	13
Other complaints † [1]	4/4 (100.00%)	4	5/5 (100.00%)	5	11/11 (100.00%)	11	13/13 (100.00%)	13
Nervous system disorders
Nervous system complaints † [1]	4/4 (100.00%)	4	5/5 (100.00%)	5	7/11 (63.64%)	7	11/13 (84.62%)	11
Reproductive system and breast disorders
Genital or urinary complaints † [1]	2/4 (50.00%)	2	3/5 (60.00%)	3	5/11 (45.45%)	5	6/13 (46.15%)	6
Sexual functioning complaints † [1]	3/4 (75.00%)	3	4/5 (80.00%)	4	9/11 (81.82%)	9	12/13 (92.31%)	12
Skin and subcutaneous tissue disorders
Skin complaints † [1]	4/4 (100.00%)	4	5/5 (100.00%)	5	7/11 (63.64%)	7	9/13 (69.23%)	9
† Indicates events were collected by systematic assessment; [1] Collected with the Patient Reported Inventory of Side Effects (PRISE); [2] Using the Patient Reported Inventory of Side Effects (PRISE) as a score of 1 or 2 (mild to moderate adverse event); scores over 2 indicate serious adverse event and are not reported in this section. Collected to day 7 due to smaller sample to day 28.

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

Results Point of Contact

• Name/Title: Marijn Lijffijt, PhD
• Organization: Michael E. DeBakey VA Medical Center
• Phone: 3618274395
• EMail: marijn.lijffijt@bcm.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Murphy N, Lijffijt M, Ramakrishnan N, Vo-Le B, Vo-Le B, Iqbal S, Iqbal T, O'Brien B, Smith MA, Swann AC, Mathew SJ. Does mismatch negativity have utility for NMDA receptor drug development in depression? Braz J Psychiatry. 2022 Jan-Feb;44(1):61-73. doi: 10.1590/1516-4446-2020-1685.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02556606
• Other Study ID Numbers: CLNA-001-14F
• First Submitted: June 25, 2015
• First Posted: September 22, 2015
• Results First Submitted: April 13, 2021
• Results First Posted: August 9, 2021
• Last Update Posted: January 11, 2022