Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)

• ClinicalTrials.gov Identifier: NCT01920555
• Recruitment Status: Completed
• First Posted: August 12, 2013
• Results First Posted: April 17, 2018
• Last Update Posted: June 19, 2018
• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Mental Health (NIMH); Baylor College of Medicine; Icahn School of Medicine at Mount Sinai; Stanford University; University of Texas; Yale University
• Information provided by (Responsible Party): Maurizio Fava, MD, Massachusetts General Hospital

• 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 Depression
• Interventions: Drug: Ketamine; Drug: Placebo Midazolam
• Enrollment: 99

Participant Flow

Recruitment Details
Pre-assignment Details	The screening period served as a wash-out period for any prohibited medications that could be discontinued safely. Discontinuation of medications were discussed in consultation with the prescribing clinician.

Arm/Group Title	Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam (Active Placebo)
Arm/Group Description	Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion Placebo Midazolam: Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion
Period Title: Overall Study
Started	18	20	22	20	19
Completed	14	16	21	17	18
Not Completed	4	4	1	3	1
Reason Not Completed
Physician Decision	1	2	1	2	0
Lack of Efficacy	2	0	0	0	0
Travel Difficulties	1	1	0	0	1
Lost to Follow-up	0	1	0	1	0

Baseline Characteristics

Arm/Group Title		Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam (Active Placebo)	Total
Arm/Group Description		Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion Placebo Midazolam: Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion	Total of all reporting groups
Overall Number of Baseline Participants		18	20	22	20	19	99
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants	99 participants
		43.1 (11.9)	45.5 (14.6)	48.6 (12.9)	47.4 (10.1)	45.6 (13.8)	46.04 (12.64)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants	99 participants
	Female	10 55.6%	9 45.0%	11 50.0%	8 40.0%	11 57.9%	49 49.5%
	Male	8 44.4%	11 55.0%	11 50.0%	12 60.0%	8 42.1%	50 50.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants	99 participants
	Hispanic or Latino	1 5.6%	0 0.0%	2 9.1%	0 0.0%	0 0.0%	3 3.0%
	Not Hispanic or Latino	17 94.4%	20 100.0%	20 90.9%	20 100.0%	19 100.0%	96 97.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
BMI; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants	99 participants
		25.2 (3.1)	24.9 (3.7)	25.3 (5.7)	26.1 (3.8)	26.3 (4.1)	24.96 (4.08)
Abnormal and Clinically Significant Labs [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants	99 participants
CBC		0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Chemistry		0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Hormonal Measures (testosterone, SHBG, Free T)		0 0.0%	2 10.0%	0 0.0%	0 0.0%	0 0.0%	2 2.0%
Hormonal Measures (DHEA)		0 0.0%	0 0.0%	0 0.0%	1 5.0%	0 0.0%	1 1.0%
Hormonal Measures (remaining tests)		0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Pregnancy Test		0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Urine Toxicology Screen		0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
		[1] Measure Description: Collected at Screening and Day 0 (Day 0 is pre-treatment) CBC, Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, Glucose, Uric Acid),Hormonal Measures in female subjects: Estradiol, Progesterone, FSH, LH, SHBG, Testosterone; Free testosterone, Hormonal Measures in male subjects: Testosterone, free testosterone, SHBG, DHEA, Progesterone, TSH, Pregnancy Test, Urine Tox Screen

Outcome Measures

1. Primary Outcome

Title	Hamilton Rating Scale for Depression - 6 Items
Description	The HAMD6 is a 6-item clinician-rated scale, where clinicians rate the presence of depression symptoms (i.e., depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, somatic symptoms) on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. One item (i.e., somatic symptoms) is rated on only a 3-point scale, ranging from 0-2. The possible scale range is 0-22, where higher values represent more severe depression. This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. In this study, the HAMD6 was used to assess symptoms occurring in the past 24 hours.
Time Frame	A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3

Outcome Measure Data

Analysis Population Description

Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.

Arm/Group Title		Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:		Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed		18	20	22	20	19
Mean (Standard Deviation); Unit of Measure: units on a scale
Day 0	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants
		12.5555556 (1.8221585)	12.7500000 (2.4894514)	12.5909091 (1.4690162)	12.6315789 (2.0872770)	13.0526316 (2.2967050)
Day 1	Number Analyzed	16 participants	20 participants	22 participants	20 participants	19 participants
		7.5000000 (4.3204938)	9.2631579 (3.6944719)	5.8636364 (4.4859087)	6.9000000 (4.5061362)	10.6666667 (3.3606722)
Day 3	Number Analyzed	15 participants	19 participants	22 participants	20 participants	19 participants
		6.8000000 (4.6167397)	8.4736842 (4.9818384)	5.9047619 (4.3000554)	7.2000000 (3.8196170)	9.0555556 (4.5435439)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.14
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.18
	Confidence Interval	(2-Sided) 95%; -5.93 to -0.43
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.79
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.13
	Confidence Interval	(2-Sided) 95%; -3.75 to 1.49
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.01
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.79
	Confidence Interval	(2-Sided) 95%; -7.35 to -2.24
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.04
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.76
	Confidence Interval	(2-Sided) 95%; -6.37 to -1.15
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.72
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.04
	Confidence Interval	(2-Sided) 95%; -5.04 to 0.95
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.80
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -3.18 to 2.46
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.14
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.12
	Confidence Interval	(2-Sided) 95%; -5.97 to -0.44
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.72
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.84
	Confidence Interval	(2-Sided) 95%; -4.65 to 0.96
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Montgomery-Asberg Depression Rating Scale (MADRS)
Description	The MADRS is a 10-item clinician-rated scale measuring depression severity. Symptoms are rated on a 7-point scale, where 0 = "not present", and 1-6 represent increasing severity. Values 2, 4, and 6 have specific anchoring text (e.g., 2="Difficulties in starting activities." 4="Difficulties in starting simple routine activities which are carried out with effort, 6="Complete lassitude. Unable to do anything without help.") Values 1, 3, and 5 do not have specific text. The possible scale range is 0-60, where higher values represent higher severity. In this study, the MADRS was used to rate symptoms occurring in the past 3 days.
Time Frame	A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0 and 3.

Outcome Measure Data

Analysis Population Description

Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.

Arm/Group Title		Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:		Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed		18	20	22	20	19
Mean (Standard Deviation); Unit of Measure: units on a scale
Day 0	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants
		33.8333333 (5.9334545)	34.4500000 (8.4571676)	31.5909091 (3.9359042)	32.6500000 (5.8873191)	33.6315789 (7.0884141)
Day 3	Number Analyzed	15 participants	19 participants	21 participants	20 participants	18 participants
		19.6666667 (10.8144524)	22.6315789 (11.7294052)	14.7619048 (8.9883523)	17.1000000 (11.5708345)	24.8333333 (10.5286723)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were four pairwise comparisons of interest (see Analysis 1-4), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.33
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.15
	Confidence Interval	(2-Sided) 95%; -12.44 to 2.14
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were four pairwise comparisons of interest (see Analysis 1-4), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.53
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.16
	Confidence Interval	(2-Sided) 95%; -9.03 to 4.72
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were four pairwise comparisons of interest (see Analysis 1-4), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.02
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.85
	Confidence Interval	(2-Sided) 95%; -16.56 to -3.15
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were four pairwise comparisons of interest (see Analysis 1-4), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.08
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.72
	Confidence Interval	(2-Sided) 95%; -14.52 to -0.93
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Clinical Global Impressions-Severity (CGI-S)
Description	The CGI-S is a clinician rated single-item scale: "How depressed is the patient at this time?", rated on a 7-point response scale: 1 = Normal, not at all depressed, 2 = Borderline depressed, 3 = Mildly depressed, 4 = Moderately depressed. 5 = Markedly depressed, 6 = severely depressed, 7 = Among the most severely depressed patients. When rating patients, clinicians were asked to consider the past 24 hours.
Time Frame	A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

Outcome Measure Data

Analysis Population Description

Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.

Arm/Group Title		Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:		Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed		18	20	22	20	19
Mean (Standard Deviation); Unit of Measure: units on a scale
Day 0	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants
		5.0000000 (0.7669650)	5.2000000 (0.6958524)	4.8636364 (0.6396021)	5.2000000 (0.7677719)	5.000000 (0.7453560)
Day 1	Number Analyzed	16 participants	19 participants	22 participants	20 participants	18 participants
		3.5625000 (1.4591664)	4.2631579 (1.2401660)	3.2727273 (1.2792043)	3.5000000 (1.1002392)	4.555556 (0.7838234)
Day 3	Number Analyzed	15 participants	19 participants	21 participants	20 participants	18 participants
		3.4000000 (1.6388149)	3.7368421 (1.4848159)	3.1428571 (1.3887301)	3.3000000 (1.4545754)	4.1666667 (1.3394468)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.08
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.03
	Confidence Interval	(2-Sided) 95%; -1.83 to -0.22
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.82
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -1.02 to 0.51
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00720
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.28
	Confidence Interval	(2-Sided) 95%; -2.02 to -0.54
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.04884
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.05
	Confidence Interval	(2-Sided) 95%; -1.81 to -0.29
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.48
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) 95%; -1.70 to 0.28
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.82
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -1.32 to 0.55
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.16
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.00
	Confidence Interval	(2-Sided) 95%; -1.91 to -0.09
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.27
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.86
	Confidence Interval	(2-Sided) 95%; -1.78 to 0.07
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Clinical Global Impressions-Improvement (CGI-I) Scale
Description	The CGI-I is a clinician rated single-item scale: "Compared to the patient's condition at admission, how much has the patient changed?", rated on a 7-point response scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. In this case, "admission" referred to the CGI-S screening assessments performed between Day -28 an -7, one conducted during the screening visit, and a second rating conducted by a remote, independent rater.
Time Frame	A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

Outcome Measure Data

Analysis Population Description

Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.

Arm/Group Title		Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:		Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed		18	20	22	20	19
Mean (Standard Deviation); Unit of Measure: units on a scale
Day 0	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants
		3.8888889 (0.3233808)	4.0500000 (0.2236068)	4.1363636 (0.7101613)	4.0000000 (0.4588315)	4.1578947 (0.6021404)
Day 1	Number Analyzed	16 participants	19 participants	22 participants	20 participants	18 participants
		3.0625000 (1.4361407)	3.3684211 (1.0651305)	2.6363636 (0.9021379)	3.0500000 (1.2343760)	3.6111111 (0.6076850)
Day 3	Number Analyzed	15 participants	19 participants	22 participants	20 participants	18 participants
		2.9333333 (1.2798809)	2.8421053 (1.2588865)	2.5714286 (0.9258201)	2.5500000 (1.0990426)	3.1666667 (1.0431852)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.54
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.54
	Confidence Interval	(2-Sided) 95%; -1.25 to 0.17
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.78 to 0.58
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.03
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.98
	Confidence Interval	(2-Sided) 95%; -1.64 to -0.31
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.54
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95%; -1.24 to 0.11
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.96 to 0.57
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.93 to 0.51
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.52
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95%; -1.35 to 0.06
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.54
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -1.33 to 0.10
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Symptoms of Depression Questionnaire (SDQ)
Description	The SDQ is a 44-item self-report scale, which aims to measure depression more comprehensively by including the assessment of symptoms in the anxiety-depression spectrum, including symptoms of irritability, anger attacks, and anxiety. Items are rated on an 6-point Likert scale, where participants are asked to rate if a specific symptom (e.g. "How has your mood been over the past 24 hours?") is normal for him or her (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The total scale score is calculated by averaging across the items, resulting in a possible range from 1 to 6. Higher scores indicate greater depression severity. When rating, patients were asked to consider their symptoms during the past 24 hours.
Time Frame	A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

Outcome Measure Data

Analysis Population Description

Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.

Arm/Group Title		Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:		Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed		18	20	22	20	19
Mean (Standard Deviation); Unit of Measure: units on a scale
Day 0	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants
		3.5164141 (0.5081856)	3.4636364 (0.5416735)	3.5392562 (0.5838397)	3.4113636 (0.4336652)	3.4264507 (0.4719770)
Day 1	Number Analyzed	16 participants	19 participants	22 participants	20 participants	18 participants
		2.5752843 (0.7091841)	2.9096195 (0.7123910)	2.3109504 (0.6315677)	2.6113636 (0.500567)	2.9200573 (0.6464210)
Day 3	Number Analyzed	15 participants	18 participants	21 participants	20 participants	18 participants
		2.5106061 (0.7158120)	2.7828283 (0.7398734)	2.5573593 (0.9017779)	2.5909091 (0.5736341)	2.8751353 (0.6668931)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.74
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.08
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.45
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.02
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.61
	Confidence Interval	(2-Sided) 95%; -1.01 to -0.21
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.80
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -0.72 to 0.10
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.88
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.83 to 0.18
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.53 to 0.44
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.88
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.15
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.88
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.76 to 0.19
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Clinical Positive Affect Scale (CPAS)
Description	The CPAS is a 16-item self-report scale to assess the level to which participants experience persistent distress due to feeling that they have not returned to their normal or premorbid state. Items (e.g., "I look forward to things") are rated on a 5-point scale (0=not at all, 1=very much less than normal, 2=much less than normal, 3=slightly less than normal, 4=same as best or normal self). The possible scale range is 0 to 64, with higher scores indicating greater recovery from depression. Patients were asked to rate their experience of the past 24 hours.
Time Frame	A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

Outcome Measure Data

Analysis Population Description

Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.

Arm/Group Title		Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:		Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed		18	20	22	20	19
Mean (Standard Deviation); Unit of Measure: units on a scale
Day 0	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants
		19.3333333 (12.1896774)	20.5000000 (15.4357753)	20.6363636 (11.7008158)	21.2500000 (14.6785737)	21.2631579 (12.1052886)
Day 1	Number Analyzed	16 participants	19 participants	22 participants	20 participants	18 participants
		35.2500000 (20.9936498)	27.0526316 (18.8516833)	40.8696964 (19.5284785)	33.0000000 (16.2642650)	24.4444444 (15.2053482)
Day 3	Number Analyzed	15 participants	18 participants	21 participants	20 participants	16 participants
		38.8666667 (22.8666667)	28.3888889 (20.2459550)	39.7619048 (22.5319878)	37.4500000 (18.7096232)	33.3750000 (15.8445574)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.49
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.18
	Confidence Interval	(2-Sided) 95%; -0.94 to 23.29
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; -10.19 to 12.93
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.03
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.54
	Confidence Interval	(2-Sided) 95%; 5.31 to 27.77
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.82
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.68
	Confidence Interval	(2-Sided) 95%; -2.81 to 20.16
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.11
	Confidence Interval	(2-Sided) 95%; -8.83 to 19.05
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.64
	Confidence Interval	(2-Sided) 95%; -19.87 to 6.59
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.64
	Confidence Interval	(2-Sided) 95%; -5.26 to 20.53
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.80
	Confidence Interval	(2-Sided) 95%; -8.31 to 17.91
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Snaith-Hamilton Pleasure-Scale (SHAPS)
Description	The SHAPS is a 14-item self-report scale to measure hedonic tone. Items (e.g., "I would enjoy reading a book, magazine, or newspaper.") are rated on a 4-point scale (1=strongly disagree, 2=disagree, 3=agree, 4=strongly agree). Either of the 'disagree' responses scores 1 point, and either of the 'agree' responses scores 0 points, for a total scale range of 0-14. Higher scores indicate greater inability to experience pleasure. Patients were asked to rate their experience of the past 24 hours.
Time Frame	A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

Outcome Measure Data

Analysis Population Description

Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.

Arm/Group Title		Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:		Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed		18	20	22	20	19
Mean (Standard Deviation); Unit of Measure: units on a scale
Day 0	Number Analyzed	18 participants	20 participants	22 participants	20 participants	19 participants
		7.2222222 (3.9040786)	7.5500000 (3.9132030)	6.5909091 (3.2316749)	7.3500000 (4.1961762)	6.4736842 (3.7471237)
Day 1	Number Analyzed	16 participants	19 participants	22 participants	20 participants	18 participants
		3.9375000 (4.2812576)	5.7368421 (4.2536534)	2.22727273 (3.5748036)	4.3000000 (4.5664682)	5.0000000 (4.6272848)
Day 3	Number Analyzed	15 participants	18 participants	21 participants	20 participants	16 participants
		3.5333333 (3.3777987)	6.3888889 (4.5262488)	3.0000000 (3.7815341)	3.6500000 (4.8370826)	4.2500000 (3.8384024)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.21
	Confidence Interval	(2-Sided) 95%; -3.99 to 1.56
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.17
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; -1.90 to 3.43
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.30
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.74
	Confidence Interval	(2-Sided) 95%; -5.32 to -0.16
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 1: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) 95%; -3.35 to 1.93
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.1 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -3.25 to 2.66
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.2 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.39
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.76
	Confidence Interval	(2-Sided) 95%; -0.06 to 5.59
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 0.5 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -3.91 to 1.58
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
	Comments	Ketamine 1.0 mg/kg vs. midazolam at Day 3: As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm's method to protect family-wise error rate in the presence of multiple testing.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -3.22 to 2.35
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Clinician-Administered Dissociative States Scale (CADSS) Scores During Infusion
Description	The CADSS is a 23-item self-report scale for the assessment of dissociative states. It is a reliable, valid self-report instrument. The severity of each dissociative symptom ranges from 0 (not present) to 4 (extreme). The total score is calculated by summing across items, with a total possible range of 0-92. The CADSS was administered right before infusion, and 40, 80 minute and 120 minutes after the start of infusion. The timeframe is "at this moment".
Time Frame	Day 0/baseline at 0, 40, 80, and 120 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:	Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed	18	20	22	20	19
Mean (Standard Deviation); Unit of Measure: units on a scale
Minute 0	0.1111111 (0.4714045)	0.1000000 (0.4472136)	0 (0)	0.1000000 (0.3077935)	0.4210526 (1.01739326)
Minute 40	3.0000000 (5.0758946)	4.0500000 (4.2608993)	14.2727273 (9.6076644)	24.6842105 (17.7108022)	2.6842105 (3.5127171)
Minute 80	0.4444444 (0.7838234)	0.1000000 (0.4472136)	0.7727273 (2.1141658)	1.8000000 (2.9664794)	1.1578947 (1.8337320)
Minute 120	0.0555556 (0.2357023)	0 (0)	0.1363636 (0.6396021)	0.6500000 (1.5985191)	0.5789474 (0.9015905)

9. Secondary Outcome

Title	Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)
Description	The Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor for clinical worsening or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.
Time Frame	Screening Visit and Days 0, 1, 3, 5, 7, 14 and 30 combined

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:	Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed	18	20	22	20	19
Measure Type: Count of Participants; Unit of Measure: Participants
Screening: # with suicidal ideation/behavior	17 94.4%	15 75.0%	17 77.3%	14 70.0%	17 89.5%
Follow-Up: # with suicidal ideation/behavior	15 83.3%	9 45.0%	10 45.5%	6 30.0%	13 68.4%

10. Secondary Outcome

Title	Number of Participants With Abnormal and Clinically Significant CBC and Chemistry Labs by Treatment
Description	CBC; Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, Glucose, Uric Acid) Testing was performed by study site laboratories and used institutional normal lab value ranges.
Time Frame	Day 3 and Early Termination Visit (approximately 3 weeks following intervention)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine 0.1mg	Ketamine 0.2mg	Ketamine 0.5mg	Ketamine 1.0mg	Midazolam 0.045mg
Arm/Group Description:	Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion	Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed	18	20	22	20	19
Measure Type: Count of Participants; Unit of Measure: Participants
Chemistry ALT(SGPT)	0 0.0%	1 5.0%	0 0.0%	0 0.0%	0 0.0%
Chemistry AST(SGOT)	0 0.0%	1 5.0%	0 0.0%	0 0.0%	0 0.0%
Chemistry Total Bilirubin	0 0.0%	1 5.0%	0 0.0%	0 0.0%	0 0.0%
Chemistry Remaining Tests	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
CBC	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Adverse Events

Time Frame	Number of patients with adverse events post infusion (treatment) up to 30 days.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Ketamine 0.1mg		Ketamine 0.2mg		Ketamine 0.5mg		Ketamine 1.0mg		Midazolam (Active Placebo)
Arm/Group Description	Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion		Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion		Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion		Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion		Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion Placebo Midazolam: Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion
All-Cause Mortality
	Ketamine 0.1mg		Ketamine 0.2mg		Ketamine 0.5mg		Ketamine 1.0mg		Midazolam (Active Placebo)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Serious Adverse Events
	Ketamine 0.1mg		Ketamine 0.2mg		Ketamine 0.5mg		Ketamine 1.0mg		Midazolam (Active Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Psychiatric disorders
Suicide Attempt †	0/18 (0.00%)	0	1/20 (5.00%)	1	0/22 (0.00%)	0	0/20 (0.00%)	0	0/19 (0.00%)	0
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Ketamine 0.1mg		Ketamine 0.2mg		Ketamine 0.5mg		Ketamine 1.0mg		Midazolam (Active Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/18 (94.44%)		18/20 (90.00%)		14/22 (63.64%)		17/20 (85.00%)		10/19 (52.63%)
Blood and lymphatic system disorders
White Blood Cell Count Decreased †	1/18 (5.56%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Cardiac disorders
Blood Pressure Increase †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		2/20 (10.00%)		0/19 (0.00%)
Tachycardia †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		1/20 (5.00%)		0/19 (0.00%)
Hypertension †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		1/20 (5.00%)		0/19 (0.00%)
Gastrointestinal disorders
Nausea †	2/18 (11.11%)		0/20 (0.00%)		3/22 (13.64%)		3/20 (15.00%)		0/19 (0.00%)
Vomiting †	1/18 (5.56%)		1/20 (5.00%)		1/22 (4.55%)		1/20 (5.00%)		0/19 (0.00%)
Dyspepsia †	0/18 (0.00%)		2/20 (10.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Diarrhea †	1/18 (5.56%)		0/20 (0.00%)		1/22 (4.55%)		0/20 (0.00%)		0/19 (0.00%)
Increased Appetite †	1/18 (5.56%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
General disorders
Dizziness †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		1/20 (5.00%)		0/19 (0.00%)
Presyncope †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Hepatobiliary disorders
Hepatic Enzyme Increased †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Infections and infestations
Tooth Abscess †	0/18 (0.00%)		0/20 (0.00%)		1/22 (4.55%)		0/20 (0.00%)		0/19 (0.00%)
Gastroenteritis Viral †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		1/19 (5.26%)
Respiratory Tract Infection †	0/18 (0.00%)		0/20 (0.00%)		1/22 (4.55%)		0/20 (0.00%)		0/19 (0.00%)
Sinusitis †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		1/19 (5.26%)
Upper Respiratory Tract Infection †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		1/20 (5.00%)		0/19 (0.00%)
Viral Upper Respiratory Tract Infection †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Injury, poisoning and procedural complications
Exposure to Toxic Agent †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Fall †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Musculoskeletal and connective tissue disorders
Back Pain †	1/18 (5.56%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		1/19 (5.26%)
Pain In Extremity †	1/18 (5.56%)		0/20 (0.00%)		1/22 (4.55%)		0/20 (0.00%)		0/19 (0.00%)
Arthralgia †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		1/19 (5.26%)
Nervous system disorders
Headache †	3/18 (16.67%)		2/20 (10.00%)		1/22 (4.55%)		3/20 (15.00%)		0/19 (0.00%)
Asthenia †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Loss of Consciousness †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Psychiatric disorders
Depression †	1/18 (5.56%)		1/20 (5.00%)		1/22 (4.55%)		0/20 (0.00%)		0/19 (0.00%)
Abnormal Dreams †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		1/20 (5.00%)		1/19 (5.26%)
Insomnia †	1/18 (5.56%)		0/20 (0.00%)		0/22 (0.00%)		1/20 (5.00%)		0/19 (0.00%)
Poor Quality Sleep †	1/18 (5.56%)		0/20 (0.00%)		0/22 (0.00%)		1/20 (5.00%)		0/19 (0.00%)
Suicidal Ideation †	1/18 (5.56%)		0/20 (0.00%)		1/22 (4.55%)		0/20 (0.00%)		0/19 (0.00%)
Dissociation †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		1/20 (5.00%)		0/19 (0.00%)
Initial Insomnia †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		1/19 (5.26%)
Intentional Self-Injury †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		1/19 (5.26%)
Malaise †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Overdose †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Self Injurious Behavior †	0/18 (0.00%)	0	0/20 (0.00%)	0	0/22 (0.00%)	0	0/20 (0.00%)	0	1/19 (5.26%)	1
Reproductive system and breast disorders
Blood Testosterone †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Respiratory, thoracic and mediastinal disorders
Nasal Congestion †	0/18 (0.00%)		0/20 (0.00%)		1/22 (4.55%)		0/20 (0.00%)		1/19 (5.26%)
Cough †	0/18 (0.00%)		0/20 (0.00%)		1/22 (4.55%)		0/20 (0.00%)		0/19 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis †	0/18 (0.00%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		1/19 (5.26%)
Dermatitis Contact †	0/18 (0.00%)		1/20 (5.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Vascular disorders
Flushing †	1/18 (5.56%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Hot Flush †	1/18 (5.56%)		0/20 (0.00%)		0/22 (0.00%)		0/20 (0.00%)		0/19 (0.00%)
Vertigo †	0/18 (0.00%)		0/20 (0.00%)		1/22 (4.55%)		0/20 (0.00%)		0/19 (0.00%)
† Indicates events were collected by systematic assessment

Limitations and 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.

Results Point of Contact

• Name/Title: Maurizio Fava, MD
• Organization: Massachusetts General Hospital
• Phone: 617-724-2513
• EMail: MFAVA@mgh.harvard.edu

Publications:

HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56-62. doi: 10.1136/jnnp.23.1.56. No abstract available.

Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967 Dec;6(4):278-96. doi: 10.1111/j.2044-8260.1967.tb00530.x. No abstract available.

Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382.

Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration; 1976.

Nierenberg AA, Bentley KH, Farabaugh AH, Fava M, Deckersbach T. The absence of depressive symptoms is not the presence of wellness: validation of the Clinical Positive Affect Scale. Aust N Z J Psychiatry. 2012 Dec;46(12):1165-72. doi: 10.1177/0004867412459810. Epub 2012 Sep 18.

Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 Jul;164(7):1035-43. doi: 10.1176/ajp.2007.164.7.1035.

Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995 Jul;167(1):99-103. doi: 10.1192/bjp.167.1.99.

Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998 Jan;11(1):125-36. doi: 10.1023/A:1024465317902.

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

Feeney A, Hoeppner BB, Freeman MP, Flynn M, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, DeBattista C, Ionescu DF, Cusin C, Papakostas GI, Jha MK, Fava M. Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study. J Clin Psychiatry. 2022 Nov 14;84(1):22m14491. doi: 10.4088/JCP.22m14491.

Feeney A, Hock RS, Freeman MP, Flynn M, Hoeppner B, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, Debattista C, Ionescu DF, Fava M, Papakostas GI. The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study. Eur Neuropsychopharmacol. 2021 Aug;49:122-132. doi: 10.1016/j.euroneuro.2021.04.024. Epub 2021 Jun 3.

Freeman MP, Hock RS, Papakostas GI, Judge H, Cusin C, Mathew SJ, Sanacora G, Iosifescu DV, DeBattista C, Trivedi MH, Fava M. Body Mass Index as a Moderator of Treatment Response to Ketamine for Major Depressive Disorder. J Clin Psychopharmacol. 2020 May/Jun;40(3):287-292. doi: 10.1097/JCP.0000000000001209.

Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, Ionescu DF, Mathew SJ, Chang LC, Iosifescu DV, Murrough J, Debattista C, Schatzberg AF, Trivedi MH, Jha MK, Sanacora G, Wilkinson ST, Papakostas GI. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020 Jul;25(7):1592-1603. doi: 10.1038/s41380-018-0256-5. Epub 2018 Oct 3. Erratum In: Mol Psychiatry. 2019 Jan 7;:

• Responsible Party: Maurizio Fava, MD, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01920555
• Other Study ID Numbers: RAP-003; 271201100006I-0-27100007-1 ( U.S. NIH Grant/Contract )
• First Submitted: August 8, 2013
• First Posted: August 12, 2013
• Results First Submitted: December 28, 2017
• Results First Posted: April 17, 2018
• Last Update Posted: June 19, 2018