Conditions: Adolescent Suicide Adolescent Depression
Keywords: Intravenous Ketamine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if intravenous ketamine reduces suicidal thinking compared to an active placebo (midazolam) in adolescents who have treatment resistant depression and a recent history of a suicide event (defined as a suicide attempt, emergency room evaluation for suicidal thinking, or a transition to inpatient care for suicidality in the past 120 days).

The primary objective of this study is to determine whether ketamine reduces suicidal ideation (as measured via the C-SSRS, recent ideation scale) relative to an active control, midazolam, 48-hours after first administration in adolescents with TRD at high suicide risk.

Detailed description:
The main purpose of the study is to examine the safety, efficacy, response predictors, and post-treatment trajectory of adolescents with TRD and high suicide risk following a highly conservative repeat dosing ketamine infusion paradigm (four infusions of 0.5mg/kg each over two weeks) compared to an active control, midazolam. Those who are randomized to midazolam and remain ill have the option to cross-over to ketamine in the open phase. All participants will be followed closely for four months post-treatment and treated with standard of care depression treatment (medication management and cognitive behavioral therapy). Brain-based predictors of anti-suicidal responses will be assessed via connectome predictive modeling (CPM), examining functional brain circuits via fMRI before and after treatment.

Given the unregulated use of ketamine in the community at widely varying doses and frequencies, the safety data gathered from this highly conservative repeat dosing paradigm is critical to inform the field about potential risks. Efficacy data at rapid, short-term, and intermediate-term (4 month) timepoints will be critical to determining whether a larger study is warranted in this population. The assessment of brain-based predictors of response through the integration of functional neuroimaging adds an important measure of biological engagement that will inform subsequent studies and stands to contribute towards the goal of personalized medicine (i.e. determining not only if a treatment works, but in whom).

Aim 1: To evaluate the safety of treating adolescents with TRD at high suicide risk with a conservative repeat-dosing ketamine paradigm followed by standard of care treatment over 4 months. Hypothesis: We anticipate no untoward effects on medical outcomes (cardiovascular function and bladder health) or cognitive function (measured via Cogstate).

Aim 2: To evaluate the 48-hour impact of ketamine on suicidal ideation compared to midazolam, and to identify connectome phenotypes predictive of ideation post-treatment. Hypothesis: Ketamine will reduce suicidal thinking (Columbia Suicide Rating Scale, recent ideation subscale) compared to midazolam. CPM will identify networks predictive of ideation, validated via k-fold or leave-one-out cross-validation within the sample. The network measures obtained at this fixed ketamine dose will inform the design of larger clinical trials.

Aim 3 (exploratory): To describe the trajectory of suicidal thinking, depressive symptoms, and use of mental health resources in both ketamine responders and non-responders over 4 months.

In July of this year (2024), the NIMH DSMB determined that Study 2000029003 will not be able to enroll enough individuals to be sufficiently powered to test the efficacy of Ketamine in treating adolescents with Major Depressive Disorder (MDD) and suicidal ideation (the primary aim of the study). Subsequently, the study was closed to enrollment

Arms:
arm 1: Participants will receive four Ketamine infusions over two weeks, each 0.5mg/kg over 40 minutes. arm 2: Participants will receive four Midazolam infusions over two weeks, each 0.045mg/kg over 40 minutes.

Interventions: intervention 1: Ketamine Infusion intervention 2: Midazolam Infusion
Intervention descriptions: intervention 1: Participants will receive four Ketamine infusions over two weeks, each 0.5mg/kg over 40 minutes. intervention 2: Participants will receive four Midazolam infusions over two weeks, each 0.045mg/kg over 40 minutes.

Protocol document:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL
Interventional Drug or Biologic
Reducing Adolescent Suicide Risk: 
Safety, Efficacy, and Connectome 
Phenotypes of Intravenous Ketamine
Protocol Number
2000029003
Protocol Version
4.7 05SEPT2024
PRINCIPAL INVESTIGATOR:
Name: Michael Bloch, MD, MS 
Department: Child Study Center 
Telephone Number: (203)745-9921
Email Address: Michael.bloch@yale.edu
IND Number: 152866
IND Holder: Michael Bloch, MD, MS 
NCT Number: NCT04613453
Study Phase (1, 2, 3, or 4-postmarketing): Phase 2
Confidentiality Statement: The information contained in this document is confidential. It is 
intended solely for the Investigators, potential Investigators, consultants, or applicable 
independent ethics committees. It is understood that this information will not be disclosed to 
others without prior written authorization from the principal investigator, except where 
required by applicable local laws.
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Contents
1
. Protocol Summary ............................................................................................................7
1.1
Synopsis.......................................................................................................................7
1.2
Schema ........................................................................................................................8
1.3
Schedules of Activities................................................................................................8
2
Introduction.......................................................................................................................12
2.1
Study Rationale..........................................................................................................12
2.2
Background................................................................................................................12
2.2.1
Preclinical Experience........................................................................................12
2.2.2
Clinical Experience ............................................................................................13
2.2.3
Background/prevalence of research topic ..........................................................17
2.3
Risk/Benefit Assessment...........................................................................................19
2.3.1
Known Potential Risks.......................................................................................19
2.3.2
Known Potential Benefits ..................................................................................25
3
Objectives & Endpoints....................................................................................................26
3.1
Overall objectives......................................................................................................26
3.2
Primary Objective......................................................................................................26
3.3
Secondary Objectives ................................................................................................26
3.4
Exploratory Objectives..............................................................................................26
3.5
Outcome Variables ....................................................................................................26
3.5.1
Primary Outcome Variables...............................................................................26
3.5.2
Secondary Outcome Variables...........................................................................27
3.5.3
Exploratory Outcome Variables.........................................................................27
4
Study Design.....................................................................................................................28
4.1
Overall Design...........................................................................................................28
4.1.1
Study Date Range and Duration.........................................................................28
4.1.2
Number of Study Sites .......................................................................................28
4.1.3
Number of Participants.......................................................................................28
4.2
Scientific Rationale for Study Design .......................................................................29
4.3
Justification for Dose.................................................................................................29
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4.4
End of Study Definition.............................................................................................30
5
Study Population...............................................................................................................31
5.1
Inclusion Criteria.......................................................................................................31
5.2
Exclusion Criteria......................................................................................................32
5.3
Lifestyle Considerations............................................................................................32
5.4
Screen Failures...........................................................................................................33
5.5
Strategies for Recruitment and Retention..................................................................33
6
STUDY INTERVENTION...............................................................................................34
6.1
Study Intervention(s) Administration........................................................................34
6.1.1
Study Intervention Description...........................................................................40
6.1.2
Dosing and Administration ................................................................................41
6.2
Preparation/Handling/Storage/Accountability ..........................................................41
6.2.1
Acquisition and accountability...........................................................................41
6.2.2
Formulation, Appearance, Packaging, and Labeling..........................................42
6.2.3
Product Storage and Stability .............................................................................42
6.2.4
Preparation .........................................................................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding .......................................42
6.4
Study Intervention Compliance.................................................................................42
6.5
Concomitant Therapy ................................................................................................42
6.5.1
Rescue Medicine ................................................................................................43
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL................................................................................43
7.1
Discontinuation of Study Intervention.......................................................................43
7.2
Participant Discontinuation/Withdrawal from the Study...........................................44
7.3
Lost to Follow-Up .....................................................................................................44
8
STUDY ASSESSMENTS AND PROCEDURES ............................................................44
8.1
Efficacy Assessments ................................................................................................44
8.2
Safety and Other Assessments...................................................................................45
8.2.1
Safety..................................................................................................................45
8.2.2
Biomarkers/Neuroimaging Assessments............................................................46
8.3
Adverse Events and Serious Adverse Events ............................................................47
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8.3.1
Definition of Adverse Events (AE)....................................................................47
8.3.2
Definition of Serious Adverse Events (SAE).....................................................47
8.3.3
Classification of an Adverse Event ....................................................................47
8.3.4
Relationship to Investigational Product .............................................................47
8.3.5
Time Period and Frequency for Event Assessment and Follow-Up...................48
8.3.6
Adverse Event Reporting ...................................................................................49
8.3.7
Serious Adverse Event Reporting ......................................................................49
8.3.8
Reporting Events to Participants........................................................................50
8.3.9
Events of Special Interest...................................................................................50
8.3.10
Reporting of Pregnancy......................................................................................50
8.3.11
Pharmacokinetics ...............................................................................................46
8.4
Unanticipated Problems.............................................................................................50
8.4.1
Definition of Unanticipated Problems (UP).......................................................50
8.4.2
Unanticipated Problem Reporting......................................................................51
8.4.3
Reporting Unanticipated Problems to Participants ............................................51
9
STATISTICAL CONSIDERATIONS .............................................................................53
9.1
Statistical Hypotheses................................................................................................53
9.2
Sample Size Determination .......................................................................................53
9.3
Populations for Analyses...........................................................................................54
9.4
Statistical Analyses....................................................................................................54
9.4.1
General Approach ..............................................................................................54
9.4.2
Analysis of the Primary Efficacy Endpoint(s) ...................................................54
9.4.3
Analysis of the Secondary Endpoint(s)..............................................................55
9.4.4
Safety Analyses..................................................................................................56
9.4.5
Baseline Descriptive Statistics ...........................................................................56
9.4.6
Planned Interim Analyses...................................................................................57
9.4.7
Sub-Group Analyses ..........................................................................................57
9.4.8
Tabulation of Individual participant Data..........................................................57
9.4.9
Exploratory Analyses.........................................................................................57
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS57
10.1
Regulatory, Ethical, and Study Oversight Considerations ........................................57
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10.1.1
Informed Consent Process..................................................................................58
10.1.2
Study Discontinuation and Closure....................................................................59
10.1.3
Confidentiality and Privacy................................................................................60
10.1.4
Future Use of Stored Specimens and Data .........................................................60
10.1.5
Key Roles and Study Governance......................................................................61
10.1.6
Safety Oversight.................................................................................................61
10.1.7
Clinical Monitoring............................................................................................62
10.1.8
Quality Assurance and Quality Control..............................................................63
10.1.9
Data Handling and Record Keeping...................................................................64
10.1.10
Protocol Deviations ........................................................................................65
10.1.11
Publication and Data Sharing Policy ..............................................................66
10.1.12
Conflict of Interest Policy...............................................................................67
10.2
Additional Considerations .........................................................................................67
10.3
Abbreviations ............................................................................................................67
10.4
Protocol Amendment History....................................................................................69
11
REFERENCES..............................................................................................................70
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STATEMENT OF COMPLIANCE
SIGNATURE OF PRINCIPAL INVESTIGATOR
Protocol Title: Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome 
Phenotypes of Intravenous Ketamine
Version and Date:  
The signatory agrees to the content of the reflected version of the clinical study protocol. 
He/she will conduct the study as presented and in compliance with all applicable regulations 
including those outlined in International Council for Harmonization (ICH) Good Clinical 
Practice (GCP) and the Code of Federal Regulations.
Name of Investigator:  
Affiliation:  
Signature: 
Date:  
Signed copies of this signature page are stored in the sponsor’s study file and investigator site 
file.
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1 . Protocol Summary
This document is a protocol for a human research study. The purpose of this protocol is to 
ensure that this study is to be conducted according to ICH GCP guidelines, and according to 
CFR 21 Part 312, other applicable government regulations and Institutional research policies 
and procedures.
1.1
Synopsis
Primary Objective
The primary objective of this Phase 2 study is to determine whether ketamine rapidly reduces 
suicidal ideation (as measured by the C-SSRS, recent ideation subscale) compared to an 
active control, midazolam, in adolescents at high suicide risk (meeting criteria for SRI- 
resistant depression (having failed at least one antidepressant)AND having a suicidal event 
within the 120 days prior to enrollment).
Secondary Objectives
The secondary objectives of this study are to closely monitor the safety (cardiovascular 
function, bladder health, and cognitive function) and tolerability of a conservative repeat dosing 
ketamine paradigm and to identify functional connectome signatures predictive of efficacy or 
modified by treatment.
Exploratory objectives include describing the trajectory of mental health outcomes (suicidality, 
depressive symptoms, mental health resource utilization) over 4 months in ketamine 
responders and non-responders.
Study Duration
7 years, participant duration is 18 weeks (20 weeks for those who cross over to open ketamine)
Study Design
Parallel, double-blind, placebo-controlled RCT with option to cross-over to active treatment in 
open phase
Number of Study Sites
1) Yale University/Yale New Haven Hospital
Study Population
Adolescents (13 to 17 years old, inclusive) with SRI-resistant depression AND a history of a 
suicidal event within 120 days prior to enrollment. .A suicide event is defined as either a suicide 
attempt (i.e. act of potentially self-injurious behavior with explicit or inferred intent to die –OR– 
degree of suicidal ideation requiring an emergency evaluation or a transition to higher level of 
care (e.g. intensive outpatient program, partial hospital program, inpatient)). Participants will be 
recruited through the Yale New Haven Health System through inpatient, intensive outpatient, 
emergency, and subspecialty clinical services. We do not plan to advertise in the community 
for this study.
Number of Participants
N = 40-66 (Last subject enrollment date is planned for 8/31/26)
Primary Outcome Variables
Columbia-Suicide Severity Rating Scale (C-SSRS), recent ideation subscale, 48-hours after 
receiving first blinded treatment
Secondary and Exploratory Outcome Variables (if applicable)
Montgomery Asberg Depression Rating Scale; Children’s Depression Rating Scale-Revised; 
Clinical Global Impression; Systematic Assessment for Treatment Emergent Effects; Cogstate 
battery; Pre- and post-treatment functional connectome (derived from multimodal combination 
of task-based and resting state fMRI); mental health utilization (number of emergency, 
intensive outpatient, partial hospital, or inpatient visits during open phase)
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1.2
Schema
1.3
Schedules of Activities
The total number of study visits from Baseline through study completion is 24 for those who 
progress directly from phase A1 to B (i.e. those who are either randomized to ketamine or 
who have a significant clinical response to midazolam) and is 30 for those who complete 
phases A1, A2 (open ketamine), and B. Please see the 2 separate tables of study events that 
follow.
Study Schedule for Double Blind Treatment (Phase A1)—All participants
Phase A1
Visit No.
1
2
3
4
5
6
7
Procedures
Screening
D0
(Baseline)
D1
D2
D3
D8
D10
D11
Blinded Intervention – 
Phase A1 a
X
X
X
X
Permission and Assent
X
Diagnostic Interview
X
MINI-KID
X
Physical Exam
X
Demographics Form
X
Diagnosis & Treatment History 
Form
X
Family History Form
X
Medications Form
X
MRI Safety Questionnaire
X
Vital signs
X
X
X
X
X
Lab tests b
X
ECG
X
X
Urine toxicology
X
X
X
Urine pregnancy test c
X
X
Safety Planning Session
X
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Phase A1
Visit No.
1
2
3
4
5
6
7
Procedures
Screening
D0
(Baseline)
D1
D2
D3
D8
D10
D11
MRI Imaging
X
X
AE assessment 
(SAFTEE-SI)
X
Xd
X
X
X
X
PK Blood draw e
X
Clinical questionnaires
C-SSRS
X
X
X
X
X
X
X
MADRS
X
X
X d
X
X
X
X
CGI
X
X
X
X
X
X
CDRS-R
X
X
X
PSC
X
X
TEASAP
X
X
X
MASC
X
X
CADSS
X
X
X
X
X
X
BHS
X
X
ASQ
X
X
CTQ
X
Edinburgh Handedness 
Inventory
X
Wechsler Abbreviated 
Scale of Intelligence
X
Cogstate neurocognitive 
battery
X
X
Guess form
X
Breaking the Blind f
X
a. Subjects will be randomly assigned to receive either 0.5 mg/kg IV ketamine OR 0.045 
mg/kg IV midazolam. Both medications will be infused over 40 minutes Subjects will not 
receive more than 40 mg ketamine or 3.6 mg midazolam
b. Labs will include: CBC with differential, complete metabolic panel (including electrolytes, 
LFTs, BUN, creatinine, and glucose), TFTs, a serum pregnancy test for WOCBP, and 
routine urinalysis
c.
WOCBP will have a weekly urine pregnancy test prior to the first treatment of the week
d. These assessments will occur by phone
e. Blood for pharmacokinetics will be drawn pre-infusion; and 40, 80, 110, and 230 minutes 
post-infusion start. Total blood volume collected will not exceed 30 mL/day
f.
After breaking the blind, participants will be separated into two groups, with separate 
schedules: Open Schedule #1: Subjects assigned to midazolam who did not respondin 
Phase A1 will proceed to Phase A2; Open Schedule #2: All other subjects will proceed 
directly to Phase B
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Study Schedule for Open Treatment (Phase A2)— Only Open Schedule #1 participants
Phase A2
Visit No.
8
9
10
11
12
13
Procedures
Study 
Day
D15
D16
D17
D22
D24
D25
Open Intervention – 
Phase A2a
X
X
X
X
Vital signs
X
X
X
X
ECG
X
Urine toxicology
X
X
Urine pregnancy test b
X
X
MRI Imaging
X
AE assessment 
(SAFTEE-SI)
X
X d
X
X
X
X
PK Blood draw c
X
Clinical questionnaires
C-SSRS
X
X
X
X
X
MADRS
X
X d
X
X
X
X
CGI
X
X
X
X
X
CDRS-R
X
PSC
X
TEASAP
X
X
MASC
X
CADSS
X
X
X
X
X
BHS
X
ASQ
X
Cogstate neurocognitive battery
X
a.
Subjects will receive 0.5 mg/kg IV ketamine over 40 minutes. Subjects will not 
receive more than 40 mg ketamine.
b.
WOCBP will have a weekly urine pregnancy test prior to the first treatment of 
the week
c.
Blood for pharmacokinetics will be drawn pre-infusion; and 40, 80, 110, and 230 
minutes post-infusion start. Total blood volume collected will not exceed 30 
mL/day
d.
These assessments will occur by phone
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Study Schedule for Open Follow-up (Phase B)—All Participants (Open schedule #1 
subjects are two weeks delayed relative to Open schedule #2 subjects due to their 
participation in Phase A2)
Phase B
Visit 
#
8
9-10
11
1124-
15
18-c
19 c
220-c
23 c
24
Open Schedule 
#2
(A1 -> B)
Stud 
y  
Day*
D17
D24, 
D31
D3 
8
D45, 
D52, 
D59
D66
D73, 
D80, 
D87
D94
D101
,   
D108
,   
D115
D122
End of 
Study 
D126
Visit 
#
14
15-
16
17
18-
20
21
22-c
24
25 c
26-c
28
29 c
30
Open Schedule
#1 
(A1 -> A2 -> B)
Stud 
y  
Day*
D31
D38, 
D45
D5 
2
D59, 
D66, 
D73
D80
D87, 
D94, 
D101
D108
D115
,   
D122
,   
D129
D136
End of 
Study 
D140
CBT
X
X
X
X
X
Medication Management
X
X
X
X
X
X
X
ECG
X
X
Lab tests a,d
X
X
Urine toxicology
X
X
Physical Exam and
X
Vital Signs
X
Clinical questionnaires
C-SSRS
X
X
X
X
X
X
X
X
X
X
MADRS
X
X
X
X
X
X
X
X
X
X
CGI
X
X
X
X
X
X
X
X
X
X
CDRS-R
X
X
X
X
PSC
X
X
X
X
TEASAP
X
X
X
X
MASC
X
X
X
X
CADSS
X
X
X
X
BHS
X
X
X
X
ASQ
X
X
X
X
Cogstate 
Neurocognitive
X
X
X
X
MRI Imaging
X b
AE assessment 
(SAFTEE-GI)
X
X
X
X
X
AE assessment 
(SAFTEE-SI)
X
X
X
X
X
Discharge Discussion
X
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Phase B
Visit 
#
8
9-10
11
1124-
15
18-c
19 c
220-c
23 c
24
Open Schedule 
#2
(A1 -> B)
Stud 
y  
Day*
D17
D24, 
D31
D3 
8
D45, 
D52, 
D59
D66
D73, 
D80, 
D87
D94
D101
,   
D108
,   
D115
D122
End of 
Study 
D126
Visit 
#
14
15-
16
17
18-
20
21
22-c
24
25 c
26-c
28
29 c
30
Open Schedule
#1 
(A1 -> A2 -> B)
Stud 
y  
Day*
D31
D38, 
D45
D5 
2
D59, 
D66, 
D73
D80
D87, 
D94, 
D101
D108
D115
,   
D122
,   
D129
D136
End of 
Study 
D140
*For the open phase, study visits may be scheduled +/- 2 days for weekly visits and +/- 3 days for 
monthly batteries.
a. Labs will include: CBC with differential, complete metabolic panel (including electrolytes, LFTs,
BUN, creatinine, and glucose), TFTs, and routine urinalysis
b. This MRI scan will only be administered for subjects on Open Schedule #2 (proceeded directly from 
Phase A1 to Phase B). Subjects on Open Schedule #1 will have had their Day 17 MRI during phase 
A2
c.
These weekly mood and AE assessments can occur by phone if the participant is clinically stable 
during the final 8 weeks
d. Any spontaneous reports of abdominal pain, increased urinary frequency, urge incontinence, or 
other urinary or gastrointestinal symptoms can prompt an early medical and laboratory evaluation, if 
necessary
2 Introduction
2.1
Study Rationale
1) Suicide is the second leading cause of death in young people, and major depressive disorder 
increases the risk of adolescent death by suicide 30-fold. There have been no major updates to 
evidence-based pediatric prescribing recommendations since the TORDIA trial completed 13 years 
ago (recommending switching to a different selective serotonin reuptake inhibitor (SSRI) and adding 
CBT) and there are no evidence-based rapid-acting pharmacologic interventions to reduce suicide 
risk.
This evidence gap results in increased off label prescribing of untested medications in high- 
risk adolescents, ranging from second generation antipsychotics to ketamine. Careful, 
developmentally informed research on the safety, efficacy, and response predictors to 
ketamine is urgently needed.
The main purpose of the study is to examine the safety, efficacy, response predictors, and 
post-treatment trajectory of adolescents with SRI-resistant depression and high suicide risk 
following a highly conservative repeat dosing ketamine infusion paradigm (four infusions of 
0.5mg/kg each over two weeks) compared to an active placebo, midazolam. Those who are 
randomized to midazolam and remain ill have the option to cross-over to ketamine in the 
open phase. All participants will be followed closely for four months post-treatment and 
treated with standard of care depression treatment (medication management and cognitive 
behavioral therapy).
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Brain-based predictors of anti-suicidal responses will be assessed via connectome predictive 
modeling (CPM), examining functional brain circuits via fMRI before and after treatment. 
Given the unregulated use of ketamine in the community at widely varying doses and 
frequencies, the safety data gathered from this highly conservative repeat dosing paradigm is 
critical to inform the field about potential risks. Efficacy data at rapid, short-term, and 
intermediate-term (4 month) timepoints will be critical to determining whether a larger study 
is warranted in this population. The assessment of brain-based predictors of response through 
the integration of functional neuroimaging adds an important measure of biological 
engagement that will inform subsequent studies and stands to contribute towards the goal of 
personalized medicine (i.e. determining not only if a treatment works, but in whom).
2.2
Background
2.2.1
Preclinical Experience
Ketamine is an FDA-approved anesthetic agent that is commonly used to induce surgical 
anesthesia due to its low incidence of significant respiratory depression and hypotension. Its 
anesthetic effects are thought to be directly related to non-competitive inhibition of NMDA 
receptors. The majority of NMDA receptors in the forebrain consist of heterotetramers of the 
subunits NR1, NR2A, and NR2B; these subunits combine to form a cation channel, 
permeable to both sodium and calcium, that is dually gated by voltage and glutamate.
Ketamine binds non-selectively to all common NMDA receptor subtypes at a site within the 
open channel and thereby blocks the entry of calcium. Ketamine’s antidepressant actions 
have been hypothesized to relate to selective inhibition of NMDA receptors on inhibitory 
interneurons in prefrontal cortex1, as well as NMDA-receptor independent actions of the 
metabolite hydroxynorketamine (HNK) stimulatory actions at AMPA receptors2. Intravenous 
ketamine has a typical onset of action within 1–2 minutes and a short elimination half-life (2- 
4 hours)3, with effects rapidly dissipating following termination of the infusion. Ketamine 
undergoes hepatic metabolism to norketamine via cytochrome P450 enzymes, with further 
metabolism of norketamine to secondary metabolites of hydroxynorketamines and 
dehydronorketamine3 (see also 2.1.2.a, Fig 1).
Ketamine has increasingly been used in adult psychiatric populations at lower and slower 
doses than used in anesthesia, with increasing evidence for it efficacy as a rapid 
antidepressant4. Esketamine, the s-enantiomer of ketamine, (trade name Spravato) was 
recently FDA-approved for treatment resistant depression when given in conjunction with an 
oral antidepressant, for treatment-resistant depression.
Ketamine has a wide therapeutic window and has been used safely in Pediatrics for over 
50 years for sedation prior to medical procedures and dentistry5-7. Ketamine is in fact used 
more frequently in Pediatrics than in adult populations, typically at doses of 1mg/kg – 
4.5mg/kg IV over 60 seconds when used as an anesthetic agent. While treatment resistant 
depression and suicide are significant problems in the pediatric population, experience with 
ketamine and esketamine for psychiatric use in this population is limited. A small open-label 
trial8 and a few case reports9,10 have described the successful use of ketamine in pediatric 
patients with refractory psychiatric conditions (see also, Clinical Experience, 2.1.2), however 
it is not FDA-approved for this purpose. Studies of Spravato in pediatric patients with 
psychiatric disorders are ongoing. Preclinical data suggests that ketamine may reverse 
depressive phenotypes in adolescent rats11. While the anesthesia literature suggests that single 
doses of ketamine in the clinical range are clearly tolerated in adolescent populations, animal 
studies of repeat or high-dose ketamine exposure in animals suggest that it has the potential
13
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for neurotoxicity (irreversible neuronal apoptosis, Olney lesions, cognitive deficits)12-14, 
particularly at early developmental stages. The toxicity threshold of repeat ketamine exposure 
is not known in adult or pediatric populations, and thus repeat dosing must be approached 
with caution and appropriate monitoring.
2.2.2
Clinical Experience
2.2.2.1
Ketamine single dose adolescent study—tolerability, pharmacokinetics
We recently completed a randomized, midazolam-controlled single-dose crossover trial of 
ketamine in adolescents (13 to 17 years) with treatment-resistant depression (TRD) (N=17) 
(NCT02579928). Participants had a primary DSM-5 diagnosis of Major Depressive Disorder 
(MDD) and a Children’s
Depression Rating Scale-Revised 
(CDRS-R) >40. Adolescents also 
must have failed at least one prior 
8-week trial of a standard 
antidepressant medication (e.g.
SSRI, SNRI) to meet TRD criteria. 
Exclusions included a lifetime 
history of psychotic disorders or 
mania, autism spectrum disorder, 
intellectual disability, substance 
use disorder, or active suicidal or 
homicidal ideation on presentation 
requiring inpatient hospitalization. 
Participants were required to 
remain on stable dosing of their 
current psychiatric medication 
regimen for the four weeks prior to 
the first infusion, and during the 
four-week trial itself. All 
participants underwent a physical 
examination and laboratory 
screening, and electrocardiography 
(ECG), and female participants 
received urine pregnancy testing. 
Treatments were randomly 
assigned by the pharmacy, with 
participants receiving a single 
infusion of either ketamine (0.5 
mg/kg over 40 minutes) or
midazolam (0.045 mg/kg) on Day 1, 
and the alternate compound 2 weeks 
later. Midazolam was chosen as an 
active placebo in keeping with its 
similar PK profile and precedent15.
Only the pharmacy was 
aware of drug identity, and 
all study personnel, 
including investigators,Fig 
2: Infusion side effects and PK
(A) CADSS scores are higher
at 1 hour compared to midazolam. (B) Ketamine transiently 
increases systolic blood pressure (SBP) and heart rate relative to 
baseline readings. Arrow indicates the end of the infusion. (C) 
Serum levels of ketamine and it’s three principle metabolites are 
shown at four post-infusion timepoints+p < 0.05 ++p < 0.01,
+++p < 0.001 timepoint versus baseline; ***p<0.001 ketamine 
versus midazolam
14
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raters, anesthesiologists, subjects, and data analysts, were blinded to randomization order. To 
further maintain blinding, efficacy raters were not present during infusions. On infusion days, 
two intravenous catheters were placed in each arm, one for medication infusion and the other 
for PK blood draws. An ECG was performed, and pulse, blood pressure, and pulse oximetry 
were checked every 5 minutes during the infusion, and every 15 thereafter. Acute dissociative 
side effects were assessed by the Clinician-Administered Dissociative States Scale 
(CADSS)16. A different trained rater, absent during the infusion and blinded to the intra- 
infusion ratings, administered pre-infusion baseline and post-infusion ratings, up to 14 days. 
The primary outcome was depression severity (Montgomery-Asberg Depression Rating Scale 
(MADRS)17) 24 hours post-infusion.
Of the 26 evaluated adolescents, 19 consented to the trial (7 did not meet criteria), and 17 
received the first infusion (one subject withdrew due to an undisclosed medical condition and 
the other had a panic attack prior to starting the infusion pump and decided to withdraw). Of 
the remaining 17, 16 completed both infusions (one subject improved after the first infusion 
(later determined to have been ketamine) and dropped out of the trial in order to receive 
community ketamine). The study sample had significant depressive symptoms (average 
screening CDRS of 63.2
(±17.1) and MADRS of 33.1 (±9.3)) and a relatively chronic disorder (average duration of 
current episode of 21 months (± 18.8), with a median of 12 months). The average participant 
age was 15.5 years, and all ages between 13 to 17 years old were represented. All participants 
had failed at least one antidepressant trial, but the sample on average had failed 3.24 (± 1.9) 
prior antidepressant treatments and 6.1 (± 5.5) total psychiatric medications.
Ketamine and midazolam treatments were well-tolerated and there were no serious adverse
events. Dissociative symptoms 
were observed with ketamine 
treatment, although they were 
time-limited (Fig 2A) and well 
tolerated. No significant 
dissociative symptoms were 
experienced in the days 
following the treatment. Aside 
from the participant who 
withdrew just prior to receiving 
infusion 1, no participants 
experienced significant 
dysphoria or panic, and no 
participants required emergent 
diazepam use. Hemodynamic 
data showed significant effects 
of ketamine and midazolam 
(Fig 2B), but there were no
Fig 3: Ketamine’s antidepressant effects in adolescents with TRD.
(A) Ketamine reduced depressive symptoms relative to midazolam, as 
measured via MADRS scores, 24 hours following infusion, paired t- 
test (n=16). (B) 76% of the sample had a significant clinical response 
to ketamine (i.e. a greater than 50% reduction in MADRS within the 
first three days following treatment). 35% of the sample had a 
significant antidepressant response to midazolam. These groups share 
5 participants who had a response to both. (C) Timecourse depicting 
actual average MADRS scores after ketamine or midazolam: in 
pairwise comparisons, ketamine significantly reduces depressive 
symptoms relative to midazolam over fourteen days, with significant 
separation at Days 1, 5, 6, 10, and 14 (independent t-tests at each
data point), *p<0.05 ketamine vs midazolam
15
serious hemodynamic events. 
Ketamine raised systolic blood 
pressure (SBP) up to 55 
minutes after infusion start (i.e. 
15 minutes following the 
termination of the infusion), 
and minimally raised diastolic 
blood pressure (DBP). Four 
subjects (of 17) met criteria for
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adolescent Stage 2 hypertension (140/90)18 during the ketamine infusion, but none persisted 
past the end of the infusion and none exceeded 150/95. Ketamine also raised heart rate (HR) 
with an increase from baseline up to 100 minutes post-infusion start, although no participant 
had a HR exceeding 120 beats per minute.
PK data were obtained and processed through our collaboration with Dr. Zarate (NIMH), 
including serum ketamine (K), norketamine (NK), hydroxynorketamine (HNK), and 
dehydronorketamine (DHNK) at baseline, 40m, 80m, 100m, and 230m post-infusion start 
(Fig 2C). While there is no adult comparison group built into this study design, the ranges of 
ketamine and NK are similar to those reported in adult PK studies using the same dose, 
timepoint, and analysis lab19. When compared with this published adult data, adolescents 
show 1.5 times greater HNK concentrations and five-fold lower concentrations of DNHK at 
all timepoints. These findings are intriguing given the purported NMDA-independent 
therapeutic actions of HNK2, but require verification in a sample directly comparing 
adolescents and adults.
2.2.2.2
Ketamine single dose adolescent study—efficacy
The primary outcome for this study (NCT02579928) was the MADRS at Day 1, 
comparing ketamine to midazolam. Ketamine significantly reduced MADRS scores 
compared to midazolam at Day 1 following infusion (midazolam: 24.13 ±12.08, 95% CI:
18.21 to 30.04, versus ketamine: 15.44 ±10.07, 95% CI: 10.51 to 20.37, mean difference of - 
8.69 ±15.08, 95% CI: -16.72 to -0.65, df=15, p= 0.036) (Fig 3A). There were no significant 
carryover effects observed in the trial. In the sixteen participants who completed both phases 
of the study, the average MADRS score at pre-infusion baseline was 31.88 (±9.82, 95% CI:
27.06 to 36.69) for midazolam and 30.56 (±10.63, 95% CI: 25.36 to 35.77) for ketamine. The 
mean difference between treatment arms at baseline was -1.31 (±8.73, 95% CI -7.89 to 5.27, 
df=15, p=0.68). Individual participants were assessed for significant clinical responses to 
ketamine or midazolam, which were defined as a greater than 50% reduction in MADRS 
score within three days of treatment (Fig 3B). Participants were significantly more likely to 
respond to ketamine than midazolam (McNemar χ2=4.0, df=1, p=0.046). 77% of the sample 
had a response to ketamine, which comprised 8 participants responding only to ketamine, and 
5 participants demonstrating a response to both ketamine and midazolam. 35% of the sample 
responded to midazolam, comprised of the 5 participants who responded to both infusions, 
and a single participant who responded only to midazolam and not to ketamine. Three 
participants did not respond to either infusion. Fig 3C displays the time-course data, showing 
that a significant separation of ketamine from midazolam persists until 14 days (the latest 
timepoint).
2.2.2.3
Neuroimaging of depressed adolescents treated with ketamine
A small subset of participants from the above trial participated in resting state functional 
MRI imaging, imaged at 3 timepoints in an early pilot
(N=3; baseline, 24-hours after infusion 1 and 24- 
hours after infusion 2). Imaging consisted of a 
structural scan (3D, T1, T2) and a resting-state run in 
order to examine resting state functional connectivity 
(FC) in these subjects. FC both between and within 
pre-identified canonical networks were compared 
(default mode, salience, sensorimotor, subcortical, 
frontoparietal, and medial frontal). Of the three
subjects, two had a significant clinicalresponse to
Fig 4. Functional connectivity changes
post-ketamine in adolescents.
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ketamine, while the third did not. Ketamine responders showed increased within-subcortical 
network functional connectivity whereas the ketamine non-responder did not. (Fig 4). This 
data demonstrates that imaging adolescents in a ketamine clinical trial at rapid timepoints is 
feasible.
2.2.2.4
Adolescent repeat ketamine dosing experience
The antidepressant and anti-suicidal effects of a single dose of ketamine are ephemeral4, 
and repeat dosing strategies have been employed to extend the duration of wellness in 
adults20,21. Based on our case report showing rapid, potent antidepressant and anti-suicidal 
effects of ketamine in a severely ill teenage boy with a repeat dosing paradigm10, we obtained 
pilot funding for a repeat dosing study (NCT03889756). This pilot study recruited a more 
severe depression phenotype, requiring 2 prior failed antidepressant trials, and did not have a 
restriction on suicidal ideation as the initial crossover trial did. The design was a 2-phase 
design: a 3-week parallel, midazolam-controlled double blind phase followed by a 6 month 
open phase in which participants assigned to midazolam who remained depressed could 
receive open ketamine and all participants received standard of care depression treatment.
This design also incorporated a limited number of symptom triggered-maintenance ketamine 
infusions during the open phase in those who responded to ketamine. We have run 3 
participants through this protocol, all 3 of whom completed the blinded phase, and two of 
three completed the open phase. Two did not respond to ketamine, but improved in the open 
phase, and one responded to ketamine (antidepressant and anti-suicidal responses (suicidal 
ideation measured via MADRS item 10 and SSI-5)) and relapsed in the fourth month.
2.2.3
Background/prevalence of research topic
Youth suicide: Suicide is now the second leading cause of death in young people in the 
United States (10 to 34 years)22 and is globally the leading cause of death in female 
adolescents (15 to 19 years)23. Suicide is a complex behavior that represents a convergence of 
genetic24, biological, psychological, social, and cultural factors25, and methods to reduce teen 
suicide are a top mental health priority26. A significant challenge to the task is that many, if 
not most, of the risk factors associated with youth suicide are either fixed (genetic or 
biological factors, perfectionism, low socioeconomic status, LGBTQ status, parental 
separation, divorce, or death, and parental psychiatric disorder)25 or historical (personal or 
family history of a suicide attempt27, early adverse experiences including physical or sexual 
abuse28). Thus, the identification of modifiable risk factors is essential. Major depressive 
disorder increases the risk of adolescent suicide by 30-fold29 and is associated with 
hopelessness, another potent suicide risk factor30. Suicide risk is further increased with 
treatment-resistance31 and in the months following discharge from an inpatient psychiatric 
unit32. This work is significant as it tests a novel, rapid-acting anti-suicidal intervention in 
high-risk adolescents.
Pediatric patients deserve evidence-based care: Pharmacologic anti-suicidal interventions 
for pediatric patients do not currently exist, and evidence-based medications for pediatric 
TRD are similarly scarce33. The sole strong recommendation for Child Psychiatrists for 
adolescents with TRD comes from the Treatment of Resistant Depression in Adolescents trial 
(TORDIA (N=334)34), which completed over a decade ago. There have been no major
NIMH-sponsored trials for pediatric TRD since, and once practitioners have followed the 
TORDIA recommendation to switch to a different selective serotonin reuptake inhibitor 
(SSRI) and add cognitive behavioral therapy (CBT), they are stranded in non-evidence based 
territory33. Lack of evidence has not prevented children from becoming depressed, nor has it
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stopped Child Psychiatrists from attempting to help them. The result is that our highest risk 
children are increasing exposed to interventions with uncertain efficacy and higher harm 
potential (e.g. the escalated use of atypical antipsychotics35). The adolescent brain is a unique 
pharmacologic substrate, with active maturation of monoaminergic36 and glutamatergic37 
systems thought to underlie mood disorders and suicide38,39, highlighting the need for 
pediatric-specific evidence. This work is significant as it will provide the first evidence for a 
pharmacologic treatment beyond TORDIA recommendations in youth with TRD and high 
suicide risk.
Pediatric ketamine: community use without data or safety monitoring: Clinical 
communities are now well aware that ketamine, a glutamatergic modulator, rapidly reduces 
depression and suicidal thinking in adults with TRD40. Consistent with the sad reality of the 
pediatric evidence base33, promising interventions in adults will be used off-label in Child 
Psychiatry practice if they are available35, and ketamine is no exception41,42. While there is 
case report data10 and a small open-label trial8 suggesting potential utility in pediatric 
depression and suicidality, placebo-controlled assessments are critical to separate genuine 
pharmacologic from non-specific effects, to allow for an informed risk/benefit analysis.
While we have recently demonstrated that a single dose of ketamine is superior to an active 
placebo, midazolam, in adolescents with TRD (see Clinical Experience, 2.2.2), repeat 
dosing presents additional safety concerns in pediatric patients. While repeat dosing appears 
to extend the duration of wellness in adults20, animal studies raise specific neurotoxicity 
concerns regarding high-dose exposures in developing populations13,14, in addition to age- 
neutral concerns regarding cardiovascular, hepatobiliary, urothelial, neurocognitive, and 
abuse potential risks raised by human studies of heavy recreational ketamine users43-45. The 
use of off-label ketamine in pediatric communities occurs without oversight, regulation, or 
the evidence based needed to determine dosing and safety monitoring strategies. This work is 
significant in providing safety, efficacy, and symptom trajectory data for a conservative 
repeat dosing ketamine paradigm in adolescents.
Clinical need for predictive models of treatment response: Psychiatry suffers from a lack 
of predictive power in choosing treatments for patients. Indicators that predict the presence, 
quality, and durability of antidepressant46 and anti-suicidal responses47 and that generalize to 
novel cohorts of patients remain elusive. For example, a promising finding of ketamine 
enhancing whole brain connectivity48, recently failed to replicate in a novel dataset31.
Replication and validation are inherent to the term “predicts”, which is too often used loosely 
as a synonym for “correlates with”. True prediction means that a finding in one data set will 
also hold for novel subject, and evaluation of markers using either cross-validation or 
external data is needed for clinical utility 49,50. Establishing predictive models is necessary to 
translate biological findings into clinical tools.
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Connectome-Based Predictive Modeling (CPM) as a promising data-driven approach: 
Functional connectivity analyses generated from fMRI data have produced useful data about 
brain wiring in health and disease across the lifespan, and the NIH’s investment in the initial 
Human Connectome Project51 indicates the importance of this modality. Despite the 
excitement, we lack clinically oriented tools that can take advantage of this connectivity
Fig. 5: Connectome-based Predictive Modeling (CPM) Schematic: In CPM, atlases and connectivity data are 
used to generate subject-specific connectivity matrices, then edge strength (the elements of the connectivity 
matrix) can be regressed with a subject score (suicidal ideation in this case, labeled SI) and a predictive model 
relating connectivity to SI can be built. These models then identify the relevant functional phenotypes 
(essentially the edges and their strength) associated with SI. The models are validated (internally) through 
cross-validation and tested for significance. Derived networks (the functional phenotypes) are complex and 
span the whole brain.
information. We have developed connectome-based predictive modeling (CPM) as a data- 
driven approach to relate brain functional organization to behavior 52-57. There are several 
critical components to this computational technique that enhance individual differences and 
improve generalizability in heterogenous populations, which are necessary for a tool with any 
clinical utility. First, as a step towards individualized medicine, we utilize individualized 
functional brain atlases that are specific to both the patient and their brain state (from one task 
to another and at rest), which improve model prediction58. Second, our methods rely on 
perturbing cognitive circuits across multiple Research Domain Criteria (RDoC) domains 
using tasks. Just as a heart can appear normal at rest, stressing the heart may reveal important 
pathology. We have showing that “stressing” brain circuits significantly improves the ability 
to detect individual differences, particularly compared to rest59. Finally, modeling methods 
that are designed to generalize across multiple behaviors and diagnostic groups are needed60. 
For example, while task conditions are likely better at generating models of behaviors related 
to the circuits they perturb, it is unlikely that a single task can be developed that is optimal for 
complex dimensions of interest, like suicidal ideation. Instead, methods that use data from 
several tasks, tweaking the brain circuits along multiple dimensions, are thought to span the 
functional space sufficiently, such that the optimal rotation can be found to maximally 
separate subjects along the ideation axis, leading to better predictive models that generalize 
across heterogeneous groups of patients, as we have shown in autism61, ADHD53, and cocaine 
use disorder62. This work is significant as it integrates a predictive brain-based approach63 
into a clinical trial design in order to identify the functional phenotypes, or fingerprints64, 
predictive of post-treatment suicidal ideation in high-risk adolescents, and how those are 
modified with a rapid-acting treatment. The data generated here will be internally validated
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with cross-validation, and will provide a strong foundation for external validation in larger 
subsequent trials and independent data sets.
2.3
Risk/Benefit Assessment
2.3.1
Known Potential Risks
(1) Ketamine: Ketamine has a wide margin of safety and is usually given in doses of 1mg/kg
– 4.5mg/kg IV over 60 seconds when used a sole anesthetic agent. It has been used routinely 
in pediatrics for over 40 years, typically at higher doses than proposed in the current study. 
Ketamine has been used to treat treatment-refractory depression in adults at Yale for over 20 
years, with robust evidence for medical and psychiatric safety. There are several potential 
risks associated with ketamine use. These include 1) Cardiovascular: elevated blood 
pressure and pulse rate (relatively common and are dose-dependent) and very rare changes in 
cardiac rhythm. 2) Respiration: respiratory rate is frequently elevated; however, with high 
dose administration severe respiratory depression and apnea have been reported (<1.5% of 
transient apneic events at anesthetic doses in pediatric emergency room settings. Ketamine 
also has rarely been associated with laryngospasm. 3) Eyes: ketamine has been associated 
with slight elevations in intraocular pressure. 4) Gastrointestinal: Anorexia, nausea and 
vomiting have been observed, however this is usually not severe. Vomiting has been seen in
<4% of children in emergency room sedation settings. 5) Neurological: enhanced skeletal- 
muscular tone resulting in tonic clonic movements have rarely been observed with acute 
administration. 6) Hepatobiliary: While not listed as an acute risk in ketamine’s safety 
insert, case series data in people who recreational abuse ketamine have shown laboratory 
signs of hepatic inflammation. 7) Urinary: in people who recreationally abuse ketamine, 
bladder inflammation and cystitis have been reported, which appear to be both dose and 
frequency dependent. 8) General: Anaphylaxis, local pain at injection site and transient rash 
have been described at the case report level. 9) Psychological: ketamine has been associated 
with a variety of transient symptoms including, but not limited to anxiety, dysphoria, 
disorientation, insomnia, flashbacks, hallucinations, and psychotic episodes. Emergence 
reactions have occurred in approximately 12% of subjects given anesthetic doses of 
ketamine. These symptoms usually last no more than a few hours. However, recurrences have 
taken place up to 24 hours after the anesthetic dose administration. Recovery agitation after 
ketamine iv sedation in the pediatric emergency room has been seen in <1.5% of children. It 
is also believed that the incidence of the psychological disturbances is reduced with the use of 
lower doses. No residual adverse psychological effects are known to have resulted from the 
medical use of ketamine. 10) Substance abuse/dependence: Ketamine has been reported as 
a drug of abuse. Reports suggest that Ketamine dependence and tolerance are possible 
following prolonged administration. A withdrawal syndrome with psychotic features has 
been described following discontinuation of long-term ketamine use. Therefore, ketamine 
should be prescribed and administered with caution. It is unclear whether exposure to 
ketamine in the laboratory can result in ketamine use or abuse. All participants are 
encouraged not to participate if they have concerns about the possibility of ketamine abuse.
Also, they are asked to contact us immediately if they become aware of a desire to use or 
abuse ketamine. All participants are advised that we would refer them to an appropriate 
treatment facility if necessary. In our experience doing research with ketamine, we are 
unaware of individuals abusing ketamine as a result of study participation. Unknown risks of 
repeated dosing: Not all of the risks of repeat ketamine dosing may be known, despite this 
paradigm being conservative.
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(2) Midazolam: Midazolam is used frequently in the pediatric emergency room and in 
sedation settings, either as a sole agent for anxiolysis, or in combination with other sedatives 
and anesthetics for more complex or prolonged procedures. It is typically given at doses of 
0.5-0.5mg/kg over 2 minutes, depending on the intended level of sedation (mild versus deep 
sedation). It has been used routinely in Pediatrics since the 1990’s, typically at higher doses 
than those described in this study. There are several potential risks associated with 
midazolam use: 1) Cardiovascular: decrease in blood pressure (hypotension in <3% of 
pediatrics patients at sedation dosing ref) and very rarely, changes in cardiac rhythm. 2) 
Respiration: apnea, cough, hiccups, decreased tidal volume and respiratory rate (transient 
apnea has been reported in <3% of pediatric patients at sedation dosing); with high dose 
administration severe respiratory depression, airway obstructions, apnea, and respiratory 
arrest have been reported. 3) Eyes: may cause nystagmus 4) Gastrointestinal: can be 
associated with nausea and vomiting (<3% of adult patients). 5) Neurological: may cause 
drowsiness, headache, over-sedation; like all benzodiazepines, midazolam has amnestic 
properties, more notable as dose increases 6) General: Anaphylaxis, local pain at injection 
site and transient rash have been reported. 7) Psychological: midazolam can be associated 
with paradoxical agitation (particularly in the elderly or in very young children), however is 
estimated at <1% of patients; there are also rare reports of emergence delirium, euphoria, and 
hallucinations, although these are associated with higher dosing that proposed here, 
Additionally, fast-acting reversal medications are available (flumazenil) that can terminate 
midazolam’s effects should the patient experience side effects during the infusion. 8) 
Substance abuse/dependence: As with all benzodiazepines, physical and psychological 
dependence is associated with prolonged use. The four-dose infusion paradigm proposed in 
the study is not expected to produce any physiological dependence. As all benzodiazepines 
have some abuse potential, midazolam should be prescribed and administered with caution. 
Midazolam is used frequently in pediatric medical settings, at higher doses administered over 
shorter periods of time, and this use has not been linked with subsequent addition problems. 
That said, all participants are encouraged not to participate if they have concerns about the 
possibility of midazolam abuse. Also, they are asked to contact us immediately if they 
become aware of a desire to use or abuse midazolam. All participants are advised that we 
would refer them to an appropriate treatment facility if necessary.
(3) MRI: Magnetic resonance (MR) is a technique that uses magnetism and radio waves, not 
x-rays, to take pictures and measure chemicals of different parts of the body. The United 
States FDA has set guidelines for magnet strength and exposure to radio waves, and we 
carefully observe those guidelines. Participants will be watched closely throughout the MR 
study. Some people may feel uncomfortable or anxious.  If this happens to a participant, he 
or she may ask to stop the study at any time and will be taken out of the MR scanner. On rare 
occasions, some people might feel dizzy, get an upset stomach, have a metallic taste or feel 
tingling sensations or muscle twitches. These sensations usually go away quickly we ask 
participants to tell the research staff if they occur.
There are some risks with an MR study for certain people. If subjects have a pacemaker 
or other metal objects inside the body, they may not be in this portion of the study because 
the strong magnets in the MR scanner might cause harm. Another risk is the possibility of 
metal objects being pulled into the magnet and hitting the subject. To lower this risk, all 
people involved with the study must remove all metal from their clothing and all metal 
objects from their pockets. We also ask all people involved with the study to walk through a 
detector designed to detect metal objects. No metal can be brought into the magnet room at 
any time. Also, once the participant is in the magnet, the door to the room will be closed so
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that no one from outside accidentally goes near the magnet. We ask subjects to read and 
carefully answer the questions on the MR Safety Questionnaire related to personal safety.
This MR study is for research purposes only and is not in any way a complete health care 
imaging examination. The scans performed in this study are not designed to find 
abnormalities. The principal investigator, the lab, the MR technologist, and the Magnetic 
Resonance Research Center are not qualified to interpret the MR scans and are not 
responsible for providing a health care evaluation of the images. If a worrisome finding is 
seen on a participant scan, a radiologist or another physician will be asked to review the 
relevant images. Based on his or her recommendation (if any), the principal investigator or 
consulting physician will contact the participant and their parent to inform them of the 
finding and recommend seeking medical advice as a precautionary measure. The decision for 
additional examination or treatment would lie only with the participant/parent and their 
physician. The investigators, the consulting physician, the Magnetic Resonance Research 
Center, and Yale University are not responsible for any examination or treatment received 
based on these findings. The images collected in this study are not a health care MR exam 
and for that reason, they will not be routinely made available for health care purposes.
(4) Blood drawing/intravenous placement: Bruising or thrombosis can occur with 
placement of the intravenous line. A total of 70cc will be drawn over 2 weeks (30cc at 
baseline, 40cc on first infusion day (Day 1)), which equates to 1.2cc/kg – 2.0cc/kg (based on 
average weights of 13-17yo adolescents). For those who cross over to open ketamine at the 
end of week two, an additional 40cc will be drawn on the first open infusion day (i.e. a total 
of 110cc over the first 3 study weeks, equating to 1.7cc/kg - 2.4cc/kg based on average male 
and female adolescent weights). This amount drawn is considerably less than the 9.5cc/kg 
over 8-week requirement set by the review board. The risks of blood draws include brief pain 
at the time of needle insertion, bruising, swelling at needle site and rarely, fainting or 
infection.
(5) Psychiatric evaluation, rating scales and questionnaires: These are all non-invasive, 
should add no risk, and have been used without difficulty or adverse events in previous 
studies with a similar population. The major disadvantage is the time taken to completethem.
(6) Clinical Deterioration: There is a risk that a participant may experience an increase of 
suicidality or depressive symptoms due to the natural course of the illness, poor response to 
ketamine administration, or receipt of active placebo (midazolam) during the blinded phase 
(these patients will be offered ketamine treatment after Day 11). Because subjects will be 
asked to refrain from changing any psychotropic medication over the course of the blinded 
phase of the study, clinical progress will be monitored closely with frequent assessments, 
ratings scale, and contact with clinic personnel. The following are criteria for evaluation and 
possible pharmacological and/or non-pharmacological treatments: (1) an increase of 25% in 
C-SSRS or MADRS score at any time over the course of treatment, and (2) new-onset of 
suicidal ideation or an increase in suicidal ideation. In the event that a subject is judged to 
remain significantly depressed and/or at increased risk for suicidality at the end of the study, 
we will help make appropriate referrals to outpatient providers, intensive outpatient programs 
or inpatient psychiatric hospitals as clinically indicated. Investigators may continue close 
monitoring of significantly “at-risk” subjects until such referrals are provided and available to 
the study participant. Additionally, the standard of care treatment for a child or adolescent 
who insufficiently responds to initial antidepressant therapy is to try another antidepressant or 
add an additional medication. By participating in this trial, the child or adolescent would be 
delaying the standard of care change in their medication by 2-4 weeks.
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(7) Confidentiality: All information that is collected in connection with this study will 
remain confidential and will only be disclosed as required by U.S. or state law. This studyis
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covered under an NIH Certificate of Confidentiality, which is important given our periodic 
urine drug testing. Every foreseeable precaution to protect confidentiality will be taken.
Nevertheless, despite such precautions, there is a potential risk for a loss of confidentiality 
due to reasons beyond our control (e.g., computer hacking).
(8) Remote Assessments: Like online shopping, videoconferencing technology has some 
privacy and security risks. It is possible that information could be intercepted by 
unauthorized people (hacked) or otherwise shared by accident. This risk can’t be completely 
eliminated, however Yale has approved the use of an encrypted version of zoom for 
videoconferencing sessions because the appointments take place over a secure encrypted 
network. When meeting with the team remotely for study-related activities, participants 
should be in a private space.
(9)
RISK MITIGATION PLANS:
1. Permission and Assent. At the point of enrollment into the study, a researcher will describe 
the protocol and specific procedures, as well as risks and benefits associated with the study 
participation, to the participant and his or her parent(s). The researcher will answer any 
questions the participant and their family might have regarding the protocol. Families are also 
encouraged to discuss the study with their outpatient psychiatrist. Once the family has had 
time to fully digest the procedures, risks, and benefits, the researcher will ask the participant 
to sign and IRB-approved assent form and their parents or guardians to sign an IRB-approved 
permission form agreeing to participate in the study. If there are two parents or guardians, 
both most provide permission and each must sign a separate permission form. Following the 
permission, at the beginning of the visit, the subject will be briefed on the specific procedures 
to be administered and will have an opportunity to ask additional questions. The researchers 
will remind subjects and their families that participation is voluntary and that the protocol can 
be stopped at any time with no obligation to continue and no penalties whatsoever. Refusal to 
participate will not affect the subject’s relationship with any clinics at Yale or the hospital or 
their ability to seek medical care. Participants and families are given a copy of the signed 
permission forms. Original paper forms will be stored in a separate locked file cabinet in a 
locked office. These forms are not stored with any data or other PHI, and they do not have 
subject ID numbers on them. In the case of electronic consenting, originals will be stored in 
Part 11-complaint RedCap.
2. Protection Against Risks Enumerated Above
(1) Ketamine Administration: The dose of ketamine established in prior research (0.5 
mg/kg over 40 minutes) will be used in this study to minimize risks. The maximum total 
single dose allowed in this study will be 40mg, corresponding to a weight of 80kg, as 
suggested by the FDA. In order to minimize the acute ketamine risks described above, vital 
signs will be monitored regularly throughout and for the first hour following the ketamine 
infusion. An ACLS-trained physician will be present for all infusions, with access to rescue 
equipment. Subjects will be monitored for at least 2 hours following ketamine infusion by Dr. 
Bloch or another study physician. A study doctor (Principal Investigator (PI) of the trial) will 
be present at all times during the infusion and recovery. In the event that a research subject 
has a significant psychiatric event requiring hospitalization, they will be treated on the 
adolescent unit (LV2) at Yale Psychiatric Hospital (YPH). Emergent medical care would be 
provided at Yale-New Haven Hospital. All participants will be asked not to engage in 
demanding work for the first 3 days after the ketamine infusion. If participants develop
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psychiatric symptoms, we may admit them to the hospital. Hospitalization may be 
involuntary if patients are in imminent danger of harming themselves or others.
The permission forms will provide a description of what participants may experience 
during the intravenous ketamine infusion at a dose of 0.5 mg/kg over the course of 40 
minutes, so that they will be well prepared for possible responses to ketamine. Participants 
will be told that some people have reported mildly decreased concentration or a “hangover” 
on the day after ketamine infusion. A research nurse will be present throughout the study to 
monitor the patient’s response and note any changes in physical or mental state. A research
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clinician will be present throughout the study to offer support and to help clarify the progress 
of the test day in case the medication causes feelings of confusion. the study PI and the study 
psychologist will also be available. The physician would be informed in case of any 
significant changes in the patient’s physical or mental state. The trained research nurse will 
also offer support and provide consistent “reality testing” for individuals experiencing 
confusion or transient psychosis. Oral diazepam (5mg) will be kept available to control 
markedly distressing behavioral effects of ketamine, should they emerge. Oral ondansetron 
(4-8mg) will be kept available to control any significant nausea or vomiting.
All participants will be asked to contact the study team at any time if any unpleasant 
effects occur. All participants will be given a card, which provides contact information for the 
study PI and study staff. All participants have close scheduled contact with study physicians 
and raters (twice weekly during acute blinded phase; weekly in open phase). Participants will 
be instructed and encouraged to contact the treatment team between scheduled meetings 
should their distress worsen. In order to enroll in the study, patients must not have a lifetime 
history of substance abuse or dependence, thereby reducing the risk of ketamine substance 
abuse/dependence by study participants.
(2) Midazolam Administration: The weight-based midazolam dosing established in prior 
ketamine trials in adults (0.045mg/kg) will be used to minimize risks, as this is considered a 
very low dose compared to the sedation literature. The maximum total dose allowed in this 
study will be 3.6mg per infusion, corresponding to a weight of 80kg. Midazolam has one of 
the shortest half-lives of all of the benzodiazepines, and thus adverse events relating to the 
drug typically are not observed more than 30 minutes following drug administration. In order 
to minimize the risks of midazolam described above, subjects will be medically screened 
prior to enrollment in the study, and participants will have identical hemodynamic monitoring 
as described above for ketamine infusions.
(3) MRI risks: All subjects will be screened for any contraindications to MRI scanning 
using the Yale University MRI Safety Questionnaire. Additionally, all participants will walk 
through a ferromagnetic detector prior to entering the MRI. MRI procedures will only be 
performed by trained personnel of the Magnetic Resonance Resource Center. Any subject 
who is distressed in the MR scanner and asks to terminate an MR imaging session will be 
removed immediately. During the permission process, we will ensure the subject understands 
that they may withdraw from the study at any time. If anything unusual in the MR scans is 
noticed by the research staff, the images will be shown to a neuroradiologist, Dr. Robert 
Fulbright, who will decide if the subject should be informed and a follow-up clinical exam 
recommended. A clinical follow-up will not be provided by the research program and must 
be pursued independently via the subject’s health care provider.
(4) Blood drawing/intravenous placement: The risks of blood draws and intravenous line 
placements are rare, and when these are done under sterile conditions by trained personnel 
the occurrence is even more remote. Numbing spray and distraction techniques will be 
offered prior to offset the discomfort of iv placement, as is commonly done in Pediatric 
medical settings. On the first infusion day, when pharmacokinetic labs are drawn, blood 
draws will occur off of the non-infusing iv in order to prevent the discomfort of repeated 
needle sticks. A total of 70cc will be drawn over 3 weeks (30cc at baseline, 40cc on first 
infusion day (Day 1)). For those who cross over to open ketamine at the end of week two, an 
additional 40cc will be drawn on the first open infusion day (i.e. a total of 110cc over the first 
3 study weeks). This amount ranges from 1.6cc/kg for a 45kg adolescent to 1.1cc/kg for a
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65kg adolescent (weight range of 45kg – 65kg for 13-17yo girls and boys). This amount is 
well below the maximum of 9.5cc/kg over 8 weeks.
(5) Psychiatric evaluation, rating scales, and questionnaires: In order to minimize risks 
associated with the psychiatric ratings and ensure the accuracy of reporting, these measures 
will be administered by trained research staff and supervised by a study physician. 
Participants will be informed that they do not need to answer any question on the rating 
scales or questionnaires that make them feel uncomfortable. Participants will also be 
informed they can take a break if they become tired from any of the questions or ratings.
(6) Clinical deterioration: Given the high-risk population in this study, safety planning and 
frequent risk assessment are critical. A safety planning module is included in the baseline 
visit, which will be conducted in collaboration with our study CBT therapist. The safety 
planning module is described in more detail in Section 6.1, Study Intervention 
Administration, Baseline Visit. In brief, the safety plan module focuses on the development 
of an individualized safety plan that includes support from multiple individuals and includes 
internal and external coping strategies to be implemented should the participant experience 
suicidal urges. A copy of the plan is provided to the participant, parents, and uploaded into 
their EPIC medical record.
At each visit, risk assessment is an important component of interactions between participants 
and staff. During the double-blind phase, a credentialed clinician meets with the participant 
before discharge from each study visit to make a clinical determination of risk of imminent 
harm to self or others. Determination of risk involves inquiring about the presence and 
intensity of suicidal thinking, differentiating between passive and active thoughts, evaluating 
the presence of risk and protective factors, and inquiring about plans, access, and intent. In 
the follow-up phase of the trial, a risk assessment and review of safety plan is conducted at 
each clinical visit, as is our standard clinical practice. The assessment occurs during the CBT 
session during the first 8 weeks, and during the medication management check-in during the 
last 8 weeks once CBT has ended.
In the event that a participant is deemed to be an imminent safety risk to themselves or others 
while at a study visit, they will be transported to the Emergency Room for evaluation. For 
times in between visits, participants and parents will be given a phone number for 24-access 
to a clinical staff member. For any calls to this number, risk assessments are conducted over 
the phone, with appropriate referral to emergency services if warranted. Any no shows to 
study appointments will be vigorously pursued.
If a participant shows significant worsening of symptoms, he or she will be offered removal 
from the study and evaluated for clinically appropriate pharmacological and non- 
pharmacological treatments by a clinic psychiatrist in collaboration with their community 
psychiatric provider. If a patient is doing poorly during the blinded phase, a thorough 
discussion will take place between the subject, his or her guardian, study physicians and 
outpatient treaters as to whether subject is able to continue until Day 11, at which time they 
would be offered open ketamine treatment on Day 15 (assuming that they were receiving 
midazolam during the blinded phase). Patients will be informed that the decision to initiate a 
course of psychotropic medication will not affect their eligibility to participate in future 
studies, to receive treatment at the Yale Child Study Center or Yale New Haven Hospital, or 
to receive treatment on a private basis from a referring clinician. In the event that a subject is 
judged to remain significantly depressed and/or at increased risk for suicidality at the end of
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the study, we will help make appropriate referrals to intensive outpatient programs or 
inpatient psychiatric hospitals as clinically indicated, in collaboration with their community 
psychiatric provider(s). Investigators may continue close monitoring of significantly “at risk” 
subjects until such referrals are provided and available to the study participant.
Another risk for mental illness and clinical deterioration is the experience of abuse (for 
example parental abuse of a child or intimate partner violence). As mandated reporters, any 
suspicion of abuse of a minor must be reported to the Department of Children and Families 
(DCF) in Connecticut. In the event that abuse is suspected, any participant would be provided 
a list of additional resources and possible referrals. While every participant must have an 
outpatient mental health provider in place in order to participate, we will provide additional 
information for trauma focused programs (e.g. the Yale Childhood Violent Trauma Center). 
We will also provide a list of additional support resources (e.g. DCF and the state of 
Connecticut mental health services (211) provide a number of support groups for intimate 
partner violence, sexual assault and incest, and overall mental health).
(7) Confidentiality risks: Private identifiable information will be collected (name, date of 
birth, age, telephone number, address, medical and psychiatric history, diagnoses, laboratory 
tests, and psychiatric rating scores) but will be kept confidential and will not be divulged in 
any publication emanating from this work. Please see section 10.1.2, for the protections in 
place to mitigate confidentiality risks. The Sponsor-Investigator is responsible for monitoring 
the data and conducting performance safety reviews every six months. The Sponsor- 
Investigator, the Yale the Human Investigation Committee (HIC)/IRB, and the NIMH DSMB 
have the authority to stop or modify the study. The Sponsor-Investigator will evaluate any 
adverse events and determine whether they affect the Risk/Benefit ratio of the study and 
whether modifications to the protocol or permission/assent forms are required. A summary of 
all adverse events will be reported to the IRB, at a minimum, when annual re-approval of the 
protocol is sought, and to the DSMB. The summary will include the number of subjects 
enrolled and a summary of graded adverse events to date.
(8) Remote Assessments: Subjects will be encouraged to complete assessments in person 
whenever feasible and safe. When remote sessions take place, it is possible that information 
could be intercepted by unauthorized people (hacked) or otherwise shared by accident. This 
risk can’t be completely eliminated, however Yale has approved the use of an encrypted 
version of zoom for videoconferencing sessions because the appointments take place over a 
secure encrypted network.
When video sessions are conducted, they will be performed on an encrypted zoom 
platform. Video sessions can be conducted on the subjects’ cell phone, tablet or personal 
computer enabled with a camera/microphone and internet connection.
Subjects will be instructed to use their home computer or personal device, and not a shared 
or work device, and use a home (private) Wi-Fi network, and not free (public) Wi-Fi for your 
internet connection. All zoom appointment links will be sent by email to the subject with 
password protected links.
2.3.2
Known Potential Benefits
Ketamine arm: While there may be no direct benefit from a subject’s participation in this 
study, the success of ketamine as a rapid-acting antidepressant in adult patients, as well as our 
promising preliminary data in pediatric subjects, suggest that adolescent subjects may receive
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a significant benefit. Given the current design, all subjects will be exposed to the potentially 
beneficial intervention.
Midazolam arm: While the active placebo medication is not expected to significantly relieve 
depressive symptoms, the high frequency of contact with a child psychiatrist and research 
staff may provide a benefit to subjects. Patients with have scheduled contact with Child 
Psychiatry twice weekly during the blinded phase, when they may be receiving the active 
placebo. They will also have 24/7 access to a Child Psychiatrist for any patient-initiated 
contact. Midazolam is a benzodiazepine that is also utilized to ameliorate anxiety symptoms 
in many patients. All patients who receive midazolam during the blinded phase, and remain 
significantly depressed or suicidal at Day 11, will be offered active ketamine treatment.
Brain imaging: No direct benefits to the subject are to be expected.
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Societal Benefits: The potential benefits to society of these investigations are considerable. 
Youth suicide and treatment-resistant depression continue to be a major public health 
problem with tragic cost to the individual, the family, and the community. The present study 
may improve our understanding of depression and suicidality by providing a pharmacologic 
rationale for developing novel treatments. The neuroimaging component of this study will 
provide knowledge on the complex networks that predict suicidal ideation after receiving 
ketamine, and how those networks change with treatment. The knowledge gained in this 
study could benefit patients and society at large because we may learn important information 
about brain organization and how it relates to behavior, and could facilitate future research on 
identifying which individuals might respond to this pharmacologic anti-suicidal intervention, 
one of the main goals of personalized medicine.
2.3.3 Assessment of Potential Risks and Benefits
We judge this study to fall into the following Pediatric risk category:
45 CFR 46.405: Research involving greater than minimal risk but presenting the prospect of 
direct benefit to the individual subjects
21 CFR 50.52: Clinical investigations involving greater than minimal risk but presenting the 
prospect of direct benefit to the individual subjects
Ketamine arm: Given the efficacy of ketamine as a rapidly-acting antidepressant and 
anxiolytic in adults and in our preliminary data in pediatric patients with treatment-resistant 
depression, ketamine also may alleviate symptoms of depression and anxiety in adolescents.
Midazolam arm: Midazolam has been previously used for short-term anxiolysis in both 
children and adults, so it may reduce anxiety symptoms temporarily (for minutes to hours). 
While the active placebo medication is not expected to alleviate symptoms of depression or 
anxiety over the longer term, the high level of contact with Pediatric Psychiatry (scheduled 
contact 7 out of the 14 days post-infusion), as well as 24/7 access to Child Psychiatry may 
directly benefit the subjects.
3 Objectives & Endpoints
3.1
Overall objectives
The objectives of this 7-year, single site, clinical trial are (1) to compare the efficacy, safety, 
and tolerability of a fixed dose of intravenous ketamine (0.5mg/kg over 40 minutes) 
compared to an active placebo, midazolam (0.045mg/kg over 40 minutes) in adolescents (13 
to 17 years old; N=20-33 per group) at high suicide risk, (2) to identify connectome 
signatures associated with suicidal ideation post-treatment using CPM, and (3) to define the 
trajectory of suicidal thinking and mood symptoms in both ketamine responders and non- 
responders when experimental treatment is followed by standard of care (medication 
management based on the Children’s Texas Depression algorithm65 plus 8 weeks of cognitive 
behavioral therapy (CBT)). We define adolescents at high suicide risk as those with SRI- 
resistant depression (defined as having remained depressed despite an SRI trial at ≥ 6 weeks 
at therapeutic dosing) AND having a suicidal event within the 120 days prior to enrollment 
(suicide events include suicide attempts, as well as high levels of suicidal ideation that 
require an emergency evaluation or a transition to a higher level of care (e.g. intensive 
outpatient program, partial hospital program, inpatient)66.
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3.2
Primary Objective
The primary objective of this study is to determine whether ketamine reduces suicidal 
ideation (as measured via the C-SSRS, recent ideation scale) relative to an active placebo, 
midazolam, 48-hours after first administration in adolescents with SRI- resistant 
depression at high suicide risk.
3.3
Secondary Objectives
The secondary objectives of this study are to closely monitor the safety (cardiovascular 
function, bladder health, laboratory values (complete blood count and complete metabolic 
panel), and cognitive function) and tolerability of a conservative repeat dosing ketamine 
paradigm and to identify functional connectome signatures predictive of efficacy or modified 
by treatment.
3.4
Exploratory Objectives
To describe the trajectory of important mental health outcomes (suicidality, depressive 
symptoms, mental health resource utilization) over 4 months in ketamine responders and non- 
responders.
3.5
Outcome Variables
3.5.1
Primary Outcome Variables
We have chosen the C-SSRS, recent ideation subscale, as our primary outcome measure, 
which will be measured at 48-hours after the first blinded infusion (and prior to the 
administration of the second blinded infusion). The C-SSRS is a well-validated instrument in 
adolescent populations67 and adapts well to pediatric clinical trials68. This outcome will 
assess the most severe level of ideation experienced since the last visit (i.e., since Study Day 
1, when the participant received the first blinded treatment).
3.5.2
Secondary Outcome Variables
Clinical secondary outcomes: We have chosen to use the MADRS17 as the depression 
outcome measure for the rapid timepoint (48 hours) and to measure both the MADRS and the 
CDRS-R69 at the short-term timepoint (Day 11). This choice is based on our experience using 
these scales in pediatric trials of rapid-acting agents (2.1.2) and adult ketamine studies that 
demonstrate that the MADRS shows increased sensitivity to the acute changes70 as compared 
to the Hamilton Depression Rating Scale (on which the CDRS-R is based 69).
Safety outcomes: Vital signs are recorded at each infusion visit and a physical exam, 
laboratory screening (liver function tests, renal function tests, thyroid function test, and 
urinalysis), and electrocardiogram (ECG) are conducted at baseline. In addition to baseline 
medical clearance, participants will receive an ECG, liver function tests, renal function tests 
(blood urea nitrogen and creatinine), and urinalysis half-way through the open phase and at 
the study conclusion. Any spontaneous reports of abdominal pain, increased urinary 
frequency, urge incontinence, or other urinary or gastrointestinal symptoms will prompt an 
early medical and laboratory evaluation. Adverse events will be systematically assessed at 
every visit during phases A1 and A2 using the Systematic Assessment for Treatment 
Emergent Events (SAFTEE-SI)71, which examines in a systematic fashion all possible 
treatment-emergent side effects and probes specific adverse symptoms. Any adverse 
reactions to the medication or protocol will be carefully explored and documented.
Documentation of any spontaneously reported side effects or adverse events is completed at 
every visit using the case report form. In phase B, adverse events will be assessed by the
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SAFTEE-GI on weekly visits, and systematically by the SAFTEE-SI with monthly batteries. 
Participants will be provided an adverse event log to track the development of any signs or 
symptoms of substance abuse, and will undergo repeat urine toxicology screening (weekly 
during ketamine treatment; halfway through the open phase, and end of open phase). The 
Cogstate battery will be used to track neurocognitive function during this study, which 
assesses attention, working memory, psychomotor function, associative learning, and 
executive functioning.
Neuroimaging outcomes: All MRI-eligible participants will be imaged at 3 timepoints: (T1) 
Baseline, (T2a) Day 3, and (T2b) Day 17 (see Fig 5). A series of 4 tasks designed to enhance 
neurocognitive differences across individuals will directly tap into specific fundamental 
cognitive processes, based on the Behavioral Assessment Methods for RDoC Constructs 
report72. See section 6.2.5, Biomarkers, for a description of tasks and acquisition protocols. 
Subject performance on all tasks will be recorded via button presses during the scan and pre- 
treatment versus post-treatment behavior will be analyzed. Finally, one run of resting-state 
will be collected at the start of the experiment and a structural scan will be completed at the 
end (3D, T1- and T2-weighted).
3.5.3
Exploratory Outcome Variables
There is no post-market surveillance data of ketamine in any psychiatric population and the 
symptom trajectory after ketamine treatment, when followed by CBT and medication 
management, is not known. All participants will have weekly assessments of mood, 
suicidality, and adverse events (MADRS, C-SSRS, CGI, SAFTEE-SI) and monthly mood 
and cognitive batteries (Fig 1). We will also collect data regarding engagement with the 
mental health system (e.g. any visits to the emergency room for psychiatric purposes, any 
change in the level of care). At the end of the blinded phase, participants will be assessed for 
treatment response (response is defined as a 50% reduction in C-SSRS (suicidality) or 
MADRS (depression)). All participants meeting criteria for a response (ketamine or 
midazolam) will be tracked for time to relapse.
4 Study Design
4.1
Overall Design
The project is composed of two phases (Fig 1): The first phase (Phase A1) will consist of 
a double-blind, midazolam-controlled parallel design trial to evaluate the safety and 
efficacy of a conservative multiple IV infusion ketamine paradigm (four infusions over two 
weeks, each 0.5mg/kg over 40 minutes) compared to midazolam (four infusions over two 
weeks, each 0.045mg/kg over 40 minutes). Investigators will be blind to the treatment 
assignment during this phase, and raters absent from the infusion paradigm will perform 
blinded clinical efficacy ratings. The second phase will consist of an open arm extension 
phase, in which those who received midazolam will be offered active treatment if they remain 
suicidal or depressed (Phase A2), and all participants will be followed closely for four months 
while being treated with medication management and an 8-week course of CBT (Phase B). For 
study participants taking psychotropic medications (i.e., antidepressants, antipsychotics, mood 
stabilizers, anticonvulsants, or any other CNS drug used to treat symptoms of MDD), they will 
remain on those medications at fixed doses during the blinded phase (or through the 2nd week 
of the open phase if they go on to receive open ketamine). Medication management and CBT
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will begin post-ketamine (or post-midazolam in those that have a significant response to the 
active placebo) treatment. Those who did not respond to ketamine will be followed at the same 
frequency and treated with medication management and 8 weeks of weekly CBT.
4.1.1
Study Date Range and Duration
The total expected study date range is 7 years to enroll 40-66 adolescent subjects. There are 
two possible study durations for individual participants: (1) 4 months and 2 weeks (i.e.18 
weeks = 126 days) for those who are (a) initially randomized to ketamine OR (b) are initially 
randomized to midazolam and have clinical improvement; or (2) 4 months and 4 weeks (i.e. 
20 weeks = 140 days) for those who are initially randomized to midazolam, do not have a 
significant clinical response, and opt to receive open ketamine.
4.1.2
Number of Study Sites
This is a single site clinical trial that will take place at Yale University, New Haven, CT. 
Clinical assessments will primarily occur at the Child Study Center at the Yale School of 
Medicine, neuroimaging will take place at the Magnetic Resonance Resource Center 
(MRRC) at the Yale School of Medicine, and infusion treatments will take place at the Yale 
Psychiatric Hospital at Yale New Haven Hospital. All three of these locations are within 0.5 
miles of each other.
4.1.3
Number of Participants
We aim to enroll 40-66 adolescents over the course of 7 years (see Sample Size 
Determination in 9.2 for further justification)). Based on our prior experience, we expect to 
screen roughly 90 potential participants to enroll the target number of 40-66 by August 31, 
2026.
4.2
Scientific Rationale for Study Design
(1) Ketamine vs. esketamine: The pediatric landscape differs substantially from the adult 
landscape on the relative uses of ketamine and esketamine. In adults, dose response data for 
esketamine has been more thoroughly described73 compared to ketamine74,75. In pediatrics, 
dose response data are not available for either compound (the current Janssen pediatric 
esketamine study includes a dose response, but those data are not yet available). There is also 
considerable weight variability in the adolescent population given the growth that occurs 
across the age range of interest (13 to 17 years old), and thus the weight-based dosing of 
intravenous ketamine is desirable. A potential limitation of ketamine versus esketamine is its 
intravenous mode of administration, however our adolescents have tolerated both single and 
repeat dosing paradigms (10 and 2.2.2) well. Finally, ketamine is what is being used off-label 
in our pediatric communities41,42, and gathering the safety data that will be produced here is 
of utmost importance.
(2) Repeat dose vs. single dose design: Our primary efficacy endpoint is 48 hours following 
the administration of a first ketamine dose compared to midazolam, which may raise 
questions about the need for repeated dosing. In our first trial, while we maintained 
separation from placebo on antidepressant measures out to 14 days, the longest timepoint 
assessed, the patients who remained in contact all subsequently relapsed. Repeat dosing is 
thought to extend the duration of wellness in adults with no differences detected between 
twice-weekly versus thrice-weekly dosing20. We have demonstrated that adolescents tolerate 
repeat dosing (10 and 2.2.2) and have proposed a conservative repeat dosing paradigm here 
(four ketamine doses over 2 weeks). We have opted to refine our protocol from 2.2.2.4 by
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condensing the blinded phase from three to two weeks, and the open phase from six months 
to four. There is no standardized dosing protocol in adolescents, and we have opted to reduce 
the amount of time participants are exposed to the placebo intervention. The antidepressant 
efficacy of a single ketamine dose (14 days in our small sample, section 2.2.2) is longer than 
that typically reported in adult studies (little clinical benefit after day five74), and it is not 
known what duration of response to expect in adolescents with repeat dosing. While it is 
tempting to speculate that the enhanced plasticity potential of the developing brain76 may 
enhance ketamine’s plasticity inducing effects77 compared to adults, there is simply no data at 
this point, and the results generated here will inform the design of a larger, more definitive 
trial. As roughly 2/3 adult participants who relapsed off esketamine did so by 4 months73, we 
feel that this is a reasonable timeframe for the open phase and will enhance retention.
4.3
Justification for Dose
As a dose response for ketamine’s psychiatric effects in pediatrics does not exist, the use of a 
single dose (0.5mg/kg over 40 minutes) is a potential criticism. We have chosen this design 
given (1) our promising efficacy signal at this dose in adolescents (Fig 3), (2) our PK data 
showing blood levels of ketamine and metabolites in line with the ranges published in adult 
studies (Fig 2), and (3) the adult study suggesting 0.5mg/kg as superior to 0.1mg/kg, 
0.2mg/kg, and 1.0mg/kg doses74. We believe that our measures of biological engagement 
(connectome phenotypes predictive of ketamine response, ketamine modulation of 
connectome phenotypes, and the pre-/post-treatment behavioral data we will obtain from the 
reward, working memory, response inhibition, and social perception tasks used in building 
the CPM models) will provide important measures of target engagement that can be 
leveraged in designing a larger, more definitive trial, that will potentially include a dose 
response.
4.4
End of Study Definition
We plan to enroll subjects for this trial until our original enrollment target has been met (66 
participants) or until August 31, 2026, whichever arrives first. The date of August 31, 2026 
was chosen because it allows for us to enroll at least 40 subjects given our current 
recruitment pace under the amended study inclusion/exclusion criteria.
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5 Study Population
Study Population: Adolescents (13 -17 years old) with “high suicide risk”, operationally 
defined as having both SRI-resistant depression (having failed at least one antidepressant) 
AND having had a suicidal event within the 120 days prior to enrollment (i.e. a suicide 
attempt OR suicidal ideation requiring an emergency room visit or escalation of care 
(intensive outpatient, partial hospital program, and inpatient unit).
Selection rationale: Here we have defined “high suicide risk” as the combination of SRI- 
resistant depression and having had a suicide event within 120 days of enrollment, an 
adaption of the criteria of the Treatment of Adolescent Suicide Attempters (TASA) study78. 
While TASA required only a depressive disorder (not necessarily a treatment resistant 
disorder), we feel that SRI-resistance is an important selection criterion as it (1) increases the 
risk for suicide31, (2) is associated with reduced placebo responses in clinical trials of mood 
disorders79, and (3) provides a stronger ethical justification for use of an experimental 
medication where the risks are not clearly defined. SRI-resistant populations may also have 
higher degrees of hopelessness80, which is also a potent risk factor for suicide30. We are 
further enriching our population for suicidal ideation by including only those patients with a 
suicide event in the 120 days prior to enrollment. As defined by the Columbia Classification 
Algorithm of Suicide Assessment, a suicide event includes bona fide suicide attempts and 
degrees of suicidal thinking that necessitate emergency services or higher levels of 
psychiatric care81. Patients with high ideation that require emergency services often make 
attempts on subsequent follow-up and are similar to patients presenting with an actual 
attempt on a wide range of clinical features in cross-sectional and longitudinal studies82,83.
Even passive ideation about wanting to be dead is a risk for completed suicide84.
5.1
Inclusion Criteria
Eligibility will be determined by the PI or by an appropriately trained designee, using the 
below requirements and a participant and parent interview.
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria:
2) Ages 13-17 years, inclusive
3) Meet DSM-5 criteria for Major Depressive Disorder by structured interview (MINI-KID+)
4) Children’s Depression Rating Scale, Revised (CDRS-R) score ≥45 at screening
5) Continued clinically significant depressive symptoms despite an SRI trial (e.g. SSRI or 
SNRI) of adequate dose and duration, meaning at least 6 weeks at therapeutic dosing, 
including at least 4 weeks of stable dosing
6) Suicide event within the past 120 days (i.e. a suicide attempt (defined as an act of 
potentially self-injurious behavior with explicit or inferred intent to die) –OR– degree of 
suicidal ideation requiring an emergency evaluation or a transition to higher level of care (e.g. 
intensive outpatient program, partial hospital program, inpatient)
7) Columbia Suicide Severity Rating Scale ideation score of ≥ 1 at screening
8) Medically and neurologically healthy on the basis of physical examination, medical 
history, and the clinical judgement of the evaluating physician.
9) Parents able to provide written informed permission and adolescents must additionally 
provide assent.
10) Stated willingness to comply with all study procedures and availability for the duration 
of the study
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11) Provision of signed and dated parental permission and adolescent assent form. If there are 
two parents or guardians, both must provide permission and each must sign a separate 
permission form.
5.2
Exclusion Criteria
An individual who meets any of the following criteria will be excluded from 
participation in this study:
1) History of psychotic disorder, manic episode, or autism spectrum disorder diagnosed by 
MINI-KID
2) History of substance dependence diagnosis by MINI-KID (excluding tobacco) or active 
substance use (including current alcohol use or positive urine toxicology)
3) Intellectual disability (IQ<70) per medical history
4) Pregnancy (urine pregnancy tests on the day of the first infusion of each treatment week 
for menstruating girls) or lactation
5) Prior participation in a ketamine study, prior clinical psychiatric treatment with ketamine, 
or prior recreational use of ketamine
6) Pre-existing cardiovascular disease or untreated or unstable hypertension
7) Body weight greater than 80 kgs
8) Currently taking benzodiazepines or other medications that may cause respiratory 
depression, or lamotrigine, which is hypothesized to interfere with ketamine’s mechanism of 
action
9) Inability to provide written parental permissions and adolescent assent according to the 
Yale Human Investigation Committee (HIC) guidelines in English.
For participation in the fMRI scans only (participants with contraindications or intolerance to 
fMRI may still participate in all other portions of the trial, providing they meet all other 
inclusion/exclusion criteria):
10) Any contraindication to MRI including severe claustrophobia, or metal in the body 
(including mental dental braces)
5.3
Lifestyle Considerations
During the study, participants are asked to:
1. Take proper pregnancy precautions as follows:
o
Women: During the treatment phase and for at least 30 days after the last dose of 
study medication, contraception is required for female participants of childbearing 
potential (i.e. have had their first menstrual cycle and are not surgically sterile).
Sexual abstinence is strongly recommended; however
heterosexually active female subjects must practice an acceptable form of 
contraception.

Acceptable methods of contraception include the following:

Hormonal contraception being taken for at least 1 month prior to screening.

Intrauterine device (IUD).
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
Condom with spermicide (cream, spray, foam, gel, suppository, or polymer 
film).

Diaphragm with spermicide (with or without condom).

Cervical cap with spermicide (with or without condom).

Vaginal sponge impregnated with spermicide used with a condom.

Sexual abstinence is strongly recommended and subjects who practice total 
abstinence from sexual intercourse as their preferred lifestyle are not 
required to use additional contraception. For each subject, the reliability of 
sexual abstinence will be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the subject.
o
Men: During the treatment phase and for at least 90 days after the last dose of 
study medication, contraception is required for male participants of childbearing 
potential (i.e. have reached spermarche and have not been vasectomized for at 
least 3 months prior to screening). Sexual abstinence is strongly recommended; 
however, heterosexually active male subjects must:

Practice an acceptable method of contraception with his female partner 
from those listed above (see examples of contraception provided above for 
female subjects).

Use a condom if his partner is pregnant.

Agree not to donate sperm.
2. Not engage in demanding work for the first 3 days after the treatment infusions (i.e. 
during the weekdays of the 2-week blinded phase, and the 2-week open phase if they go 
on to receive open ketamine).
3. Not drive or operate heavy machinery 24 hours after an infusion.
4. Attend all scheduled appointments.
5. Refrain from using any illegal substances, including alcohol (urine toxicology tests are 
regularly administered to monitor any illicit substance use)
5.4
Screen Failures
Please see detailed screening procedures as described in section 6.1. Briefly, after an initial 
phone screen to rule out any clear exclusion from the study protocol, potential subjects will 
be scheduled for a screening visit at the Yale Child Study Center or undergo a screening visit 
through telepsychiatry assessment. At the screening visit, a member of our research team will 
discuss all aspects of the study: its purpose, the procedures that will be performed, any/all 
risks of the procedures, possible benefits, and possible alternative treatments. If the patient is 
considered eligible for the study and agrees to proceed, the patient and his/her 
parents/guardians will be asked to sign the assent and parental permission forms, 
respectively.
Once consented, the participant will undergo a standard clinical evaluation consisting of 
psychiatric history, physical, laboratory and mental status exams with one of the study 
doctors as described in detail in section 6.1, Screening. The purpose of the screening 
procedures is to ensure that the participants meets all inclusion/exclusion criteria. If the 
subject is potentially traveling a long distance for the study, screening may be conducted 
over two sessions where consenting, all the necessary assessments and psychiatric history 
is gathered remotely and then an in-person visit is scheduled at a later time to complete 
physical exam and laboratory assessments. Subjects who fail screening may re-screen at a 
later date in certain circumstances (e.g. if they fail screening due to taking a restricted
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medication (e.g. lamtrotrigine) but later discontinue this medication their outpatient 
providers and wish to re-screen).
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5.5
Strategies for Recruitment and Retention
We will conduct outreach and education with our most likely recruitment sources, which 
include 3 inpatient units in the Yale system ((1) Winchester 1, 14 years old and younger, (2) 
Liberty Village 2, 14 to 17 years old, and (3) Washington Square 3 (16 to 25 years old)), the 
adolescent intensive outpatient unit, Pediatric Emergency services, and the in-home child 
services team. We have existing close relationships with all of these sites, and outreach will 
consist of a lecture describing the study and population of interest, and leaving fliers with 
inclusion and exclusion criteria, as well as study staff contact information. We do not plan to 
have any direct advertising or recruitment to patients or the public and expect the majority of 
patients to come through the referral of physician or mental health provider. Based on our 
prior experience with these studies, we expect that we may receive some direct patient 
inquiries by virtue of being listed on ClinicalTrials.gov. In order to potentially expand the 
geographic area for enrollment we will offer remote assessment and CBT 
treatment/medication management during the open-phase of the trial when clinically 
appropriate and at the preference of the family.
Enrollment in research will not disrupt, hold, or alter placement of the patient in the clinically 
appropriate level of care. Similarly, research participation will not result in a reduction of 
participant contact with trained pediatric mental health providers for monitoring and safety 
assessment.
This 2-phase study requires a significant amount of participant contact with the research 
team. In the first phase (2 weeks), participants have a half-day of baseline assessments and an 
hour-long fMRI scan. Then there are 4 treatment days where participants receive ketamine or 
midazolam, and an additional 1-hour fMRI scan prior to the second treatment. In our 
experience with a similarly designed ketamine study in adolescents, we have had 100% 
retention through the blinded phase. Our participants have tolerated the treatments well, and 
in general they express feeling like the treatments and interactions are of value.
In the open phase (4 months), participants who received placebo but remain significantly 
symptomatic will be offered open ketamine according to the schedule described above. There 
is one additional neuroimaging session in the first week of the open phase, and participants 
are asked to have labs drawn, an ECG, and urinalysis at the end of months 2 and 4 for safety 
monitoring. All participants are offered 8 weeks of weekly CBT and medication 
management. Participants have weekly mood assessments and monthly mood and cognitive 
batteries. While there are some retention risks with the open phase, particularly in those who 
do not respond to ketamine, we believe that the close attention, medication management, and 
CBT provided by the study is superior to what is generally provided in Child Psychiatry 
outpatient clinics, which have a severe shortage of providers.
To ensure that the inherent costs of participating (e.g. transportation) are not a significant 
barrier to joining the study if it is clinically appropriate to do so, compensation is provided to 
offset costs related to travel and time.
Participants will be paid $40 for completing the 2-week double blind phase. For those that 
meet criteria for crossing over to the open ketamine phase, they will receive an additional $40 
for completing the 2-week open treatment phase. They will receive the following 
compensation in the open phase:
Completing all 4 visits and rating scales in Month 1: $80 
Completing all 4 visits and ratings scales in Month 2: $80 
Completing all 4 visits and rating scales in Month 3: $80
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Completing all 5 visits and rating scales in Month 4: $80
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Payments will be made using a Bank of America pre-paid debit card. Subjects will be paid at 
the end of the last completed visit for that compensation block.
6 STUDY INTERVENTION
6.1
Study Intervention(s) Administration 
Screening:
After an initial phone screen to rule out any clear exclusion from the study protocol, 
potential subjects will be scheduled for a screening visit at the Yale Child Study Center or 
undergo a screening visit through telepsychiatry assessment. At the screening visit, a 
member of our research team will discuss all aspects of the study: its purpose, the 
procedures that will be performed, any/all risks of the procedures, possible benefits, and 
possible alternative treatments. All potential participants will have the opportunity to 
discuss study participation without their parents or guardians present. If the patient is 
considered eligible for the study and agrees to enroll, the patient and his/her 
parents/guardians will be asked to sign the assent and parental permission forms, 
respectively.
Once consented, the participant will undergo a standard clinical evaluation consisting of 
psychiatric history, physical, laboratory and mental status exams with one of the study 
doctors. This assessment includes collection of detailed information about all prior 
psychiatric therapies, including dose, duration of treatment, side effects, and partial efficacy. 
The participant and his/her parent/guardian will also receive a clinical diagnostic interview 
using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI- 
KID)85. Additionally, the participant and his/her parent/guardian will complete clinical 
ratings related to the participant’s 1) depressive and suicidality symptoms and 2) symptoms 
of other commonly comorbid psychiatric conditions. A medical assessment including vital 
signs, physical exam, baseline serum labs (i.e. CBC with differential, complete metabolic 
panel (CMP) (including electrolytes, LFTs, BUN, creatinine and glucose), TFTs, a serum 
pregnancy test, and routine urinalysis) and urine drug screen will be completed prior to 
enrollment. Participants must be medically and neurologically healthy on the basis of 
physical examination, medical history, and the clinical judgement of the evaluating physician 
in order to participate. Examples of medical rule-outs include but are not limited to: unstable 
hypertension, recent severe neurologic injury, a history or current signs/symptoms of liver or 
renal insufficiency, and current diagnoses of cardiac, vascular, pulmonary, gastrointestinal, 
endocrine, neurologic, hematologic, rheumatologic, or metabolic disorders that are deemed 
clinically significant based on investigator judgement. If the subject is potentially traveling a 
long distance for the study, screening may be conducted over two sessions where consenting, 
all the necessary psychiatric assessments and history is gathered remotely and then an in- 
person visit is scheduled at a later time to complete medical assessment -- physical exam and 
laboratory assessments.
We will also request that participants and their families sign a release to speak with their 
current psychiatric care providers, in order to confirm the relevant aspects of the history, to 
answer any questions about the trial, and to facilitate ongoing collaboration. We will also 
send a written letter to these providers. We will describe the frequency of study contact 
(several days a week during the treatment period, then weekly during the follow-up phase). 
We will review how the study visits may integrate with the participant’s ongoing mental 
health schedule. We will strongly encourage continuous contact between the outpatient and 
study teams, particularly if a participant reports potential side effects or worsening symptoms.
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We will ensure that the outpatient team has the contact information for the study team, 
including the PI and the 24-hour clinical access number. The clinical assessment will take 
approximately 2 hours.
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Female subjects of childbearing potential will require urine/serum pregnancy testing prior 
to enrollment in the protocol. Because full confidentiality regarding pregnancy cannot be 
entirely guaranteed, these testing requirements and the limited scope of confidentiality will be 
made known to all subjects during the permission and assent procedure. In this manner, 
young women who would not be comfortable with pregnancy testing or sharing the results of 
such testing can “opt out” of the study at the time of the initial assent, without having to 
declare specific reasons. If the pregnancy test is positive, the subject will not be able to 
participate in the protocol.
Additionally, in order to participate in this protocol, the pediatric subject will need to be 
asked questions about his/her prior and/or current illicit drug use and undergo drug testing 
(urine). Because drug use will exclude the minor from participating, the parent may ask why 
the child or adolescent was asked not to participate or to leave the study. Therefore, parents 
and/or minors who are uncomfortable with questions about drug use can "opt out" of the 
study at the time of initial permission, without having to declare specific reasons. If subjects 
choose not to enroll, then any previously collected drug test results will be destroyed.
Adolescent drug use information will not be shared with parents unless the study team 
feels that the minor is exhibiting behaviors that would pose an immediate threat to the minor 
or to others. The PI or co-investigator will ask the minor if the study team can share the drug 
testing results with parents. If the minor declines, the study team will refer the minor for 
evaluation based upon the clinical judgment of the Principal Investigator. In all cases, the 
safety and well-being of the minor will be protected. We will explicitly inform parents and 
minors, in the permission and assent documents, and orally with regard to these guidelines. 
As an NIH-funded study, drug use information is protected under a Certificate of 
Confidentiality.
If the adolescent participant meets all inclusion and exclusion criteria, they will be scheduled 
for Baseline and treatment visits.
Baseline (Study Day 0, Visit 1)
Baseline visits will generally be conducted on Mondays in order to facilitate flow into the 
established treatment procedures at Yale Psychiatric Hospital’s Interventional Psychiatry 
Service (IPS), in which ketamine treatments are administered on Tuesdays and Thursdays. 
Baseline assessments include clinical questionnaires and neuroimaging. Participants will 
present to the Child Study Center to complete the clinical questionnaires and obtain a weight, 
then will walk with research staff to the MRRC (~5 minute walk) in order to complete the 
one-hour neuroimaging scan.
Clinical Questionnaires on the Baseline Day are as follows:
1) C-SSRS: assessment of suicidal ideation and behavior in clinical and research settings66,86
2) CDRS-R: a standardized rating scale that assesses depression severity in children and 
adolescents69
3) MADRS: a standardized rating scale that assesses depression severity in children and 
adolescents17
4) Pleasure Scale for Children (PSC)87: a standardized rating scale to assess anhedonia88
5) Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP): a rating 
scale designed to detect increased behavioral activation and suicidality89
6) Multidimensional Anxiety Scale for Children (MASC): a multidimensional assessment of 
anxiety in children and adolescents90
7) CADSS: interviewer administered items that evaluate dissociative symptoms 16
8) Clinical Global Impressions (CGI): a widely used instrument used to assess overall severity
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of illness and symptom improvement on 1-7 point scales91,
9) Beck Hopelessness Scale (BHS): instrument to assess hopelessness92
10) Adolescent Stress Questionnaire (ASQ): a 56-item instrument for measuring current 
stressors across a range of domains 93
11) Childhood Trauma Questionnaire (CTQ): a self-report screening measure for maltreatment 
histories94
12) Edinburgh Handedness Inventory
13) Wechsler Abbreviated Scale of Intelligence
14) Cogstate neurocognitive battery
The participant and their family will be introduced to the study CBT therapist. During this 
introduction they will complete a Safety Planning Module together. The safety planning 
module focuses on the development of an individualized safety plan that includes support 
from multiple individuals and includes internal and external coping strategies to be 
implemented should the participant experience suicidal urges. We emphasize with 
participants and their parents that the creation of the safety plan is a collaboration between 
the patient, therapist, and parents, and that all involved must understand steps for and 
assessment of safety.
The safety plan includes the following: identification of risk behaviors, identification of 
coping strategies, identification of family support and others to provide support, creation for 
plan of ‘In case of emergency’, identification of resources to call in crisis (including the 24- 
hour access number for a study clinician (e.g., doctor, therapist, or psychologist), and 
signature from child or adolescent, parent, and therapist (indicating all on board with plan). 
Copies of the completed plan will be provided for the participant, the participant’s family, 
and uploaded into their EPIC medical record. We ask families to place the plan in an easily 
accessible locations (e.g. on the refrigerator, bedroom wall). If the adolescent wishes to use 
a smartphone, they may also take a picture of the plan using the phone’s camera function.
The MRI scan will last approximately 1 hour and will include a combination of anatomical 
and functional (task and rest) scans. Subjects will perform 4 tasks (Table 1) during each scan 
session. The MRI scans will take place on one of the 3T Siemens scanners located at the 
Magnetic Resonance Research Center. A licensed MR technician will perform all MR scans, 
and all scans will use standard clinical sequences. A member of the research team will 
accompany the subjects to the MRRC and will stay with them for the duration of the scan.
All planned MR sequences are currently FDA-approved MR imaging sequences; none exceed 
the FDA Guidelines for 3T MR imaging systems. Tasks performed during the experiment 
sessions will include:
1. Card guessing task (e.g.,95): In this reward response task, subjects will be shown a card on 
a screen and will have to guess whether the number on the other side of the card is less than
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or greater than five. The card will then be flipped over and subjects will receive reward 
feedback based on their response.
2. N-back task96,97: Subjects will be asked to watch a set of pictures (or words) and push a 
button if a new picture (or word) is different than the previous item (1-back condition) or 
than the item that came two items before (2-back condition).
3. Response inhibition task/Stop-Signal (e.g.,98): Subjects will see items on the screen and 
either respond (go trial) or not respond (no-go trial), depending on the presented item.
4. Understanding mental states task: Subjects will be asked to infer the perspective of others, 
either by looking at photographs of their eyes and labeling the photographed subjects’ 
emotions99, or by responding to questions that require them to interpret social “hints” in 
vignettes100.
5. Perception: Subjects will passively watch images on the screen or listen to sounds through 
headphones. Possible stimuli include flashing checkerboards, movie clips, beeps and tones, 
blank screens, etc.
6. Resting state run: Subjects will be asked to stay still with eyes open during the resting runs. 
There is no task involved.
Phase A1: Blinded Intervention (Visits 2 – 7):
Subjects will receive four infusions of either ketamine (0.5mg/kg IV) or midazolam 
(0.045mg/kg IV) over a two-week period. Infusions are delivered over 40 minutes while on 
continuous cardiac monitoring and pulse oximetry; they will be monitored for 2 hours post- 
infusion (or until pharmacokinetic blood draws are complete on Day 1, 230 minutes post- 
infusion)
First Blinded Infusion (Day 1, Visit 2)
The participant will be instructed to follow American Society of Anesthesiologists NPO 
guidelines the night before the infusion. These guidelines allow milk or a light meal 6 hours 
prior to the procedure and clear liquids up to 2 hours prior to the procedure. Subjects will 
present to the Child Study Center to complete pre-infusion questionnaires and receive a urine 
toxicology (and urine pregnancy, if applicable) test. Pre-infusion clinical measures are the C- 
SSRS, MADRS, and CGI.
The participant will then walk to the Interventional Psychiatry Service (IPS) at Yale 
Psychiatric Hospital with research staff (~ 5 minute walk). One hour prior to the infusion, 
two IVs will be placed, one to administer the infusion, and the second to facilitate blood 
collection for pharmacokinetic blood draws. The blinded infusion will be administered over a 
40-minute period, either ketamine at a dose of 0.5mg/kg, or midazolam at a dose of 0.045 
mg/kg, randomized by the Investigational Drug Service. Doses of both medications not to 
exceed a maximum total dose corresponding to a weight of 80kg.
Ketamine and midazolam administrations will be performed on the IPS service at YPH under 
ACLS-accredited physicians with experience with midazolam-controlled ketamine studies, 
including those conducted in pediatric populations. During the infusion, vital signs are 
recorded every 5 minutes. Once the infusion is complete, they are recorded every 15 minutes. 
The psychotomimetic side effects of ketamine or midazolam, and the mental status of the 
participant will also be monitored every hour for two hours following the infusion.
Pharmacokinetic blood draw timepoints are pre-infusion, 40-minutes post-infusion start (i.e. 
as the infusion is completing), 80 minutes, 110 minutes, and 230 minutes. These timepoints 
were chosen for consistency with the published adult PK literature and with our previous 
pediatric ketamine work. Participants will be monitored through the 230-minute timepoint, at
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which time they will be released with a parent or guardian. Prior to visit discharge, research 
staff will use the SAFTEE-SI to systematically assess for potential adverse events. In 
addition, a credentialed clinician will review the participant’s individualized safety plan and 
make a clinical determination of risk of imminent harm to self or others. Assessment of risk 
involves inquiring about the presence and intensity of suicidal thinking, differentiating 
between passive and active thoughts, evaluating the presence of risk and protective factors, 
and inquiring about plans, access, and intent. If a participant were deemed to be an imminent 
safety risk to themselves or others, they would be transported to the Emergency Room for 
further evaluation.
Remote follow-up (Day 2, Visit 3): Participants will be contacted by phone to follow-up 
regarding mood (MADRS) and any potential adverse events (SAFTEE-SI). A member of 
the research staff will speak with both the participant and a parent and will confirm return 
instructions for the following day. This day is purposefully designed to be a day with low 
scheduled interaction given the large number of procedures and interactions on Days 1 and
3. Participants will be reminded that study staff, study physicians, and the PI are all 
available should there be any questions, concerns, or problems. This assessment may be 
done either by telephone or through telepsychiatry video assessment.
Primary Outcome (48-hour C-SSRS), Neuroimaging, Second Blinded Infusion (Day 3, 
Visit 4): Participants will again be instructed to follow American Society of 
Anesthesiologists NPO guidelines the night before the infusion (milk or a light meal 6 hours 
prior to the procedure, and clear liquids up to 2 hours prior to the procedure). Participants will 
present to the Child Study Center to complete the pre-infusion questionnaires (C-SSRS, 
MADRS, CGI). Note that this administration of the C-SSRS is the primary outcome of the 
efficacy portion of the study. The timeframe for the clinical measures is “since last visit”.
Participants will then walk to the MRRC with research staff (~5 minute walk) in order to 
complete the second neuroimaging scan. Tasks and rest conditions will be identical to those 
described above (Baseline visit). Following neuroimaging, participants will walk with 
research staff across the street to the Interventional Psychiatric Service (~1 minute walk). A 
single IV will be placed, as there are no pharmacokinetic blood draws on this or subsequent 
infusions. As above, the blinded infusion will be administered over a 40-minute period, either 
ketamine at a dose of 0.5mg/kg, or midazolam at a dose of 0.045 mg/kg, as previously 
determined by the Investigational Drug Service.
Ketamine and midazolam administrations will be performed on the IPS service at YPH under 
ACLS-accredited physicians with experience with midazolam-controlled ketamine studies, 
including those conducted in pediatric populations. During the infusion, vital signs are 
recorded every 5 minutes. Once the infusion is complete, they are recorded every 15 minutes. 
The psychotomimetic side effects of ketamine or midazolam, and the mental status of the 
participant will also be monitored every hour for two hours following the infusion. Prior to 
visit discharge, research staff will use the SAFTEE-SI to systematically assess for adverse 
events. As with all infusion visits, a credentialed clinician will make a clinical determination 
of risk of imminent harm to self or others. After two hours, if participants have returned to 
baseline mental and physical status, they will be discharged in the care of their parent or 
guardian.
Third and Fourth Blinded Infusions (Days 8 and 10, Visits 5 and 6):
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Participants will present to the Child Study Center for pre-infusion questionnaires (Days 8 
and 10) and urine toxicology (and urine pregnancy, as applicable) (Day 8), and will have 
been instructed to follow the same NPO guidelines as previous infusions. Infusion procedures 
for the third and fourth blinded infusions are identical to those described for the second 
blinded infusion.
Mood/Cognitive Battery, Breaking of the Blind (Day 11, Visit 7):
All participants will return on study day 11 (Visit 7) for assessment of the mood and 
cognitive measures described in the Schedule of Activities. Important secondary clinical 
outcomes will be collected on this date, including the MADRS and the CDRS-R. After all 
clinical measures are collected and response criteria are calculated, the PI will contact the 
Investigational Drug Service in order to break the blind. The Investigational Drug Service 
will provide the treatment assignment for the participant in writing via electronic 
communication.
The PI will discuss the clinical and treatment results with the participant and their family. In 
the event that the participant had been randomized to ketamine, they will proceed to the open 
phase (Phase B, which includes CBT and medication management as standard of care 
treatment) regardless of treatment response. In the event that the participant had been 
randomized to midazolam and they did not experience a treatment response, they will be 
offered open ketamine treatment (Phase A2) prior to progressing to Phase B. In the event the 
participant was randomized to midazolam and they did experience a significant treatment 
response, they will proceed to Phase B and will not be offered any open ketamine treatments.
Phase A2: Open Ketamine Intervention for Midazolam Non-responders (Visits 8 – 13): 
Participants will follow an identical schedule to that described for the blinded phase (Phase 
A1) above, with the exception that the four infusions will be ketamine treatments (open 
treatment in which both the participant and the study physicians are aware of the treatment). 
In brief, the following days have the following treatments (please see detailed descriptions in 
Phase A1) for procedures each day:
First Open Ketamine Infusion (Day 15, Visit 8), includes pharmacokinetic blood draw 
Phone Follow-up (Day 16, Visit 9)
Neuroimaging (Third Scan), Second Open Ketamine Infusion (Day 17, Visit 10) 
Third Open Ketamine Infusion (Day 22, Visit 11)
Fourth Open Ketamine Infusion (Day 24, Visit 12) 
Mood Cognitive Battery (Day 25, Visit 13)
Phase B: Open Phase with Standard of Care Depression Treatment 
(Visits 8 – 24 for participants proceeding directly from Phase A1) 
(Visits 14 – 30 for participants proceeding from Phase A2)
At this point in the trial, all subjects will have completed any trial-associated infusion 
procedures. All of the remaining clinical interventions (8 weeks of weekly CBT and 
medication management according to the modified Texas Children’s Medication Algorithm) 
are considered standard of care depression treatments.
For the first 8-weeks (Visits 8-15 in those proceeding directly from A1; Visits 14 – 21 for 
those proceeding from A2), the general assessment schedule will be weekly meetings.
These meetings will include a 45-minute CBT session, a 15-minute medication 
management visit, and a limited amount of clinical ratings (C-SSRS, MADRS,
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CGI, SAFTEE-GI). The study team aims to integrate study procedures and clinical care to 
facilitate ease of participation for study families and to rational information flow through the 
visits. Visits will begin with the study assessments, and those scores will be passed on to the 
CBT therapist and Child Psychiatrist. The CBT session will follow, and any important 
information will be relayed to the Psychiatrist conducting the medication check component of 
the visit. A risk assessment and review of the safety plan occurs at every visit, as is our 
standard clinical practice.
In the event that pandemic- or public health-related conditions preclude a participant from 
attending one of the above in-person sessions, the session may need to be conducted via 
telehealth. Any telehealth appointments must follow the requirement for the presence of a 
parent or guardian in the home during the telehealth session. When clinically appropriate, 
families may also choose to conduct these sessions remotely via video telehealth sessions. 
Sessions will only be conducted via telehealth when this is preferred by the family and 
judged to be clinically appropriate by both the CBT therapist and PI/study doctor.
In the group who progressed directly from phase A1, the third neuroimaging session (Day 17, 
Visit 8) will occur prior to the therapy and medication management session (see study 
schedule of activities). Every fourth week, a more extensive mood and cognitive battery will 
be completed. At the end of this 8-week period (Day 66, Visit 15 in those from A1, and Day 
80, Visit 21 in those from A2), participants will have a medical surveillance battery 
consisting of an ECG, serum labs, urinalysis, and urine toxicology. The 8-week course of 
CBT is slated to end at this time.
For the final 8-weeks (Visits 16- 24 in those proceeding directly from A1; Visits 22- 30 in 
those proceeding from A2), weekly mood and AE check-ins can occur by telephone or via 
video telehealth visit if the participant is clinically stable. The monthly mood and cognitive 
batteries will still occur in person and can coincide with continued 15-minute medication 
management visits.
Participants may request to continue weekly visits in-person visits (rather than remote visits) 
during this time, and any phone assessments that are indicative of clinical deterioration will 
prompt an unscheduled, in-person visit. A final set of medical surveillance labs will be 
collected at the end of this 8-week period, as above (Day 122, Visit 23 in those from A1, and 
Day 136, Visit 29 in those from A2).
Weekly mood assessments are estimated to take approximately 30 minutes to complete and 
monthly mood and cognitive batteries are estimated to take 1.5-2 hours to complete.
Participants will have a final in-person visit on the day of study discharge (Day 126, Visit 24 
in those progressing directly from A1; Day 140, Visit 30 in those progressing from A2).
On Study Visits
Please see the detailed description of study visits and procedures in section above and 
summarized on the Schedule of Activities (Section 1.3)
End of Study and Follow-up
The study has a significant follow-up phase built in following the acute blinded phase 
intervention (the 4-month open phase). The study is considered completed at the end of the 4- 
month open phase. During the follow-up phase, important safety, efficacy, and resource 
utilization measures are collected (see section 3.5, Outcome Variables). Participants who 
withdraw from the study early will be offered continued follow-up for mood and cognitive
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assessments if they are amenable to such. Participants may request copies of their lab results 
or clinical ratings if they would like a copy for their records or to share with their outpatient 
mental health provider. Any incidental or concerning findings revealed in the neuroimaging
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portion of the study will be reported to the patient, who will be encouraged to follow-up with 
a medical provider outside of the study.
6.1.1
Study Intervention Description
Ketamine (Ketalar) has FDA approval as a sole anesthetic agent for diagnostic and 
surgical procedures that do not require skeletal muscle relaxation. Ketamine has been 
increasingly used as a rapid-acting antidepressant in adult populations with treatment- 
resistant depression4, but it is not FDA-approved for this indication. As of March 5th, 2019, 
the FDA granted approval to Spravato (esketamine) nasal spray, in conjunction with an oral 
antidepressant, for the treatment of depression in adults who have tried other antidepressant 
medicines but have not benefited from them (treatment-resistant depression). Esketamine is 
the s-enantiomer of ketamine. Because of the risk of serious adverse outcomes resulting from 
sedation and dissociation caused by Spravato administration, and the potential for abuse and 
misuse of the drug, it is only available through a restricted distribution system, under a Risk 
Evaluation and Mitigation Strategy (REMS). An open-label trial8 and several case reports 
have described the successful use of ketamine in pediatric patients with refractory psychiatric 
conditions (see also, Clinical Experience, 2.1.2), however it is not FDA-approved for this 
purpose. Studies of Spravato in pediatric patients with psychiatric disorders are ongoing.
Ketamine hydrochloride injection USP 50 mg/ml, 10 ml vials, will be procured by the 
Investigational Drug Service (IDS), a specialized pharmacy at Yale (obtained from the 
manufacturer or supplier of FDA-approved ketamine that is currently in use by the Yale New 
Haven Hospital IDS). The medication dose used in the protocol (0.5mg/kg infused over 40 
minutes) is substantially lower than doses that are used for anesthesia (1mg/kg – 4.5mg/kg IV 
over 60 seconds). The maximum number of ketamine infusions in this protocol is four, and 
the maximum total dose per infusion is 40mg per infusion (corresponding to a weight of 
80kg). The PI holds a therapeutic license for administering controlled substances.
Midazolam HCl (Versed, the active placebo in this study) is FDA approved in children 
and adolescents for sedation, and is often used as an anxiolytic agent prior to induction of 
general anesthesia with other anesthetic agents, or as a sole sedating agent for minor 
procedures. Midazolam hydrochloride injection USP 5 mg/ml, 1 ml vials, will also be 
procured by the IDS (obtained from the manufacturer or supplier of FDA-approved 
midazolam that is currently in use by the Yale New Haven Hospital IDS) . The medication 
dose used in the protocol (0.045mg/kg infused over 40 minutes) is substantially lower than 
doses that are used for anesthesia (0.5mg - 2mg IV push, repeated every 2-3 minutes to a 
maximum of 10mg). The maximum number of midazolam infusions in this protocol is four, 
and the maximum total dose per infusion is 3.6mg (corresponding to a weight of 80kg). As 
with ketamine, the PI holds a therapeutic license for administering controlled substances.
6.1.2
Dosing and Administration
Infusions (Day 1, 3, 8, and 10, Visits 2 - 6): Subjects who, in the opinion of the PI, are 
eligible to continue with the protocol procedures (after the results of the screening/baseline 
measures and diagnostics are considered) will present to the Interventional Psychiatry Service 
(IPS) at Yale Psychiatric Hospital for the first infusion on Study Day 1. The participant will 
be instructed to follow American Society of Anesthesiologists NPO guidelines the night 
before the infusion. These guidelines allow milk or a light meal 6 hours prior to the procedure 
and clear liquids up to 2 hours prior to the procedure. One hour prior to the infusion, IV’s will 
be placed, two IV’s on days that include bloodwork (ketamine metabolites on Day 1 only)
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and one IV on infusion days without bloodwork (Day 3, 8, and 10). The infusion will be 
administered over a 40-minute period, either ketamine at a dose of 0.5mg/kg, or midazolam 
at a dose of 0.045 mg/kg (doses of both medications not to exceed a maximum total dose 
corresponding to a weight of 80kg).
Ketamine and midazolam administrations will be performed on the IPS service at YPH under 
ACLS-accredited physicians with experience with midazolam-controlled ketamine studies, 
including those conducted in pediatric populations. The participant’s vital signs will be 
monitored every 5 minutes during the infusion and every 15 minutes thereafter up to two 
hours following the infusion. The psychotomimetic side effects of ketamine or midazolam, 
and the mental status of the participant will also be monitored every hour for two hours 
following the infusion. During this acute phase of the study, patients will receive four 
infusions, scheduled on Study Days 1, 3, 8, and 10 (corresponding to visits 2 – 6). All 
participants will return on Study Day 11 (Visit 7) for extensive mood and cognitive measures. 
After the mood and cognitive battery on Study Day 11, the blind will be broken to determine 
which arm the participant was randomized to. Those who were randomized to midazolam and 
remain symptomatic will be offered open ketamine, will be treated as described above on 
Study Days 15, 17, 22, and 24 (Visits 8-12), and will have a follow-up post-ketamine mood 
and cognitive battery on Study Day 25 (Visit 13).
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Acquisition and accountability
Ketamine hydrochloride injection USP 50 mg/ml, 10 ml vials manufactured by Hikma 
pharmaceuticals will be acquired from wholesaler McKesson or from the manufacturer or 
supplier that is being used by the Yale New Haven Hospital Investigative Drug Service at the 
time of medication preparation.
Midazolam hydrochloride injection USP 1 mg/ml, 5 ml vials manufactured by Hikma 
pharmaceuticals will be acquired from wholesaler McKesson or from the manufacturer or 
supplier that is being used by the Yale New Haven Hospital IDS at the time of medication 
preparation.
6.2.2
Formulation, Appearance, Packaging, and Labeling
The formulation, appearance, packaging, and labeling of Ketamine and Midazolam can be 
found in the package inserts included in this application. Investigational drug accountability 
and management (purchase, storage, preparation, dispensing, and disposition) will be 
conducted by Yale-New Haven Health IDS Pharmacy.
6.2.3
Product Storage and Stability
Investigational drugs will be stored per package insert. All vials will be used as single dose 
vials.
Ketamine: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. 
Protect from light.
Midazolam: Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [See 
USP Controlled Room Temperature].
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6.2.4
Preparation
Ketamine will be diluted in sodium chloride 0.9% to a total volume of 100mL, delivered 
intravenously at a rate of 150 mL/hr
Midazolam will be diluted in sodium chloride 0.9% to a total volume of 100mL, delivered 
intravenously at a rate of 150 mL/hr
6.3
Measures to Minimize Bias: Randomization and Blinding
Participants will be randomized to ketamine or midazolam in the double-blind phase by the 
Investigational Drug Service, 1:1. Only the Investigational Drug Service will know the 
identity of the experimental compound. Medication labels in the double-blind phase read 
“Ketamine or Midazolam”, followed by “Investigational Study Drug”. All medication 
infusion solutions are made to a total volume of 100mL so that infusion instructions are 
identical, protecting the blind for the nursing staff. Although this is a double-blind study, 
additional measures are being taken to protect the blind. Efficacy raters will not be present 
during the infusions, i.e. there will be separate raters for intra-infusion ratings (side effect 
ratings scales) and for efficacy.
The first phase of this trial is a double blind, randomized controlled trial. At the end of the 
blinded phase, there will be a scheduled breaking of the blind in order to proceed to the open 
phase of the trial. After the clinical ratings are complete on Study Day 11, the Investigational 
Drug Service will be contacted, and they will send a written electronic communication to the 
PI with the randomization information for that subject. This information is needed in order to 
determine whether the participant meets criteria to proceed to open ketamine administration 
in the following phase.
6.4
Study Intervention Compliance
The study intervention will be administered on site by medical staff in the presence of a 
member of the study team, therefore intervention compliance will be assured.
6.5
Concomitant Therapy
Participants are allowed to remain on their current psychiatric medications in this study. This 
design choice was made for several reasons. For patients with difficult-to-treat depression, a 
complete washout of medications is potentially problematic and may contribute to: (1) acute 
worsening of mood resulting in hospitalization or suicide; (2) inflation of baseline scores, 
which may bias response rates; and (3) a systematic selection bias due to elimination of 
participants who cannot tolerate drug withdrawal and who refuse to consider a washout. We 
also believe that continuing current medications approximates the “real world” conditions in 
which ketamine is given to pediatric patients off-label. We ask that patients refrain from any 
dose or agent changes during the blinded phase of the protocol (or the first two weeks of the 
open protocol if they qualify to receive open ketamine). The open phase of the protocol 
includes medication management based on the Texas children’s medication algorithm65, an 
adaptation that allows for antipsychotic augmentation.
There are, however, several medication restrictions (see exclusion criteria 5.2) to avoid any 
potential interactions with the investigation medications. These include a prohibition of
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benzodiazepines or any other standing medications that have significant respiratory 
depressive activities. Lamotragrine (Lamictal) is also a restricted medication as its biological 
action is thought to potentially inhibit ketamine’s antidepressant actions at the mTOR 
pathway.
6.5.1
Rescue Medicine
An ACLS-trained physician with access to airway equipment will be present throughout the 
infusions (although we believe that the likelihood of a serious event at the doses proposed in 
this study is low). Subjects will be monitored for at least 2 hours following ketamine or 
midazolam infusion by Dr. Bloch. A study doctor (Principal Investigator (PI) of the trial) will 
be present at all times during the infusion and recovery. In the event, that a research subject 
has a significant psychiatric event requiring hospitalization, they will be treated on the 
adolescent unit (LV2) at Yale Psychiatric Hospital (YPH). Emergent medical care would be 
provided at Yale-New Haven Hospital.
Oral diazepam (5mg) will be kept available to control markedly distressing behavioral effects 
of ketamine, should they emerge. Oral ondansetron (4-8mg) will be kept available to control 
any significant nausea or vomiting. Please also see section 2.3.1, Risk Mitigation Plans.
7 STUDY INTERVENTION DISCONTINUATION 
AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Patients may withdraw at any time or be dropped from the study, at the discretion of the PIs, 
should medical contraindications develop, if intolerable adverse reactions occur, if the patient 
becomes manic or psychotic, or if the patient worsens to such a degree that further 
participation puts the patient at risk (e.g., active suicidality). If a patient worsens during the 
blinded phase, a thorough discussion will occur with the patient, their family, their outpatient 
psychiatrist, and the treatment team to discuss the risks and benefits of continuing in the 
study. If the participant has been randomized to midazolam and is still symptomatic, then 
they are able to receive ketamine at the end of the blinded phase (two weeks maximum). The 
PI must assess subjects who decide to withdraw from the study to ensure their care is 
transitioned to the provider
If a participant needs to be hospitalized during the blinded phase, all efforts will be made to 
have them hospitalized within the Yale New Haven Hospital (YNHH) System. As soon as the 
study team is aware, they will reach out to the treating physician at the participant’s location. 
The team will discuss the participant’s clinical status and the main study requirements during 
the 2-week double blind phase (including avoiding benzodiazepines and refraining from 
making changes to standing medications). Study treatments occur at the Yale Psychiatric 
Hospital and the clinical units will be aware of the study through recruitment outreach, which 
we hope will facilitate working through any clinical or logistical challenges to meet the best 
interest of the patient. If a participant is hospitalized outside of the YNHH system, the study 
team will still make every effort to reach and collaborate with their clinical staff.
7.2
Participant Discontinuation/Withdrawal from the Study
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Subjects may withdraw voluntarily at any time for any reason. An investigator may 
discontinue or withdraw a participant from the study for the following reasons:
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
Pregnancy

Significant study intervention non-compliance

If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant

Disease progression that requires discontinuation of the study intervention

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Study termination
The occurrence of a hospitalization or other suicide event per se is not on its own a sufficient 
reason for automatic removal. Any serious adverse event will prompt a review of the current 
risks and benefits of study participation with the participant, their family, and any other 
medical personnel involved in their care. Recommendations of whether to continue or to 
discontinue will be based on a consensus of what is believed to be in the best interest of the 
participant at that time.
The reason for participant discontinuation or withdrawal from the study will be recorded in 
the participant binder by the relevant clinician. Subjects who sign the informed assent form 
(with corresponding parental permissions) and are randomized but do not receive the study 
intervention may be replaced. Subjects who sign the informed assent form (with 
corresponding parental permissions), and are randomized and receive the study intervention, 
and subsequently withdraw, or are withdrawn or discontinued from the study, will not be 
replaced.
7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she does not respond to phone or 
email communications. After 2 weeks a letter will be sent to their address and they will be 
informed of their discontinuation from the study.
Any no-shows to study visits will be vigorously pursued. The following actions will be taken 
if a participant fails to return to the clinic for a required study visit:
• The site will attempt to contact the participant and their parent and reschedule the 
missed visit as soon as possible. Research staff will counsel the participant on the 
importance of maintaining the assigned visit schedule and ascertain if the participant 
wishes to and/or should continue in the study.
• If the participant or parent are unable to be reached, a member of the study team will 
check the participant’s electronic medical record to ascertain whether any new visits 
have occurred to psychiatric or medical services within the YNHH system.
• Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts will be documented in the 
participant’s medical record or study file.
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
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8 STUDY ASSESSMENTS AND PROCEDURES
8.1
Efficacy Assessments
Please also see section 3.5 Outcome Variables and the Schedule of Activities, which includes 
both efficacy and baseline assessments.
1) C-SSRS: assessment of suicidal ideation and behavior in clinical and research settings66,86- 
Primary outcome at Study Day 3; administered at baseline, prior to each infusion during blinded 
phase; administered weekly in open phase
2) CDRS-R: a standardized rating scale that assesses depression severity in children and 
adolescents69- administered at baseline, at Day 11, and in monthly mood and cognitive batteries
3) MADRS: a standardized rating scale that assesses depression severity in children and 
adolescents17- administered at baseline, prior to each infusion during the blinded phase; 
administered weekly in the open phase
4) Pleasure Scale for Children (PSC)87: a standardized rating scale to assess anhedonia88- 
administered at baseline, at Day 11, and in monthly mood and cognitive batteries
5) Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP): a rating 
scale designed to detect increased behavioral activation and suicidality89- administered at 
baseline, at Day 11, and in monthly mood and cognitive batteries
6) Multidimensional Anxiety Scale for Children (MASC): a multidimensional assessment of 
anxiety in children and adolescents90- administered at baseline, at Day 11, and in monthly mood 
and cognitive batteries
7) Clinical Global Impressions (CGI): a widely used instrument used to assess overall severity 
of illness and symptom improvement on 1-7 point scales91- administered at baseline, prior to 
each infusion during the blinded phase; administered weekly in the open phase
8) Beck Hopelessness Scale (BHS): instrument to assess hopelessness92- administered at 
baseline, at Day 11, and in monthly mood and cognitive batteries
9) Adolescent Stress Questionnaire (ASQ): a 56-item instrument for measuring current 
stressors across a range of domains93
8.2
Safety and Other Assessments
8.2.1
Safety
1) Vital signs are recorded at each infusion visit
2) Baseline: a physical exam, laboratory screening (liver function tests, renal function 
tests, thyroid function test, and urinalysis), and electrocardiogram (ECG) are 
conducted
3) Follow-up medical surveillance: participants will receive an ECG, liver function tests, 
renal function tests (blood urea nitrogen and creatinine), and urinalysis half-way 
through the open phase and at the study conclusion
4) Adverse reactions will be systematically assessed at visits as detailed in the Schedule 
of Activities. Staff will use the Systematic Assessment for Treatment Emergent 
Events (SAFTEE-GI or SAFTEE-SI)71, as described in the Schedule of Activities, 
which examines in a systematic fashion all possible treatment-emergent side effects 
and probes specific adverse symptoms. Any reactions to the medication or protocol 
will be carefully explored and documented. Documentation of any spontaneously
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reported or inquiry-elicited side effects or adverse events is completed at every visit 
using the case report form.
5) Any spontaneous reports of abdominal pain, increased urinary frequency, urge 
incontinence, or other urinary or gastrointestinal symptoms will prompt an early 
medical and laboratory evaluation. Participants will be provided an adverse event log 
to track the development of any signs or symptoms of substance abuse and will 
undergo repeat urine toxicology screening (weekly during blinded infusions or open 
ketamine treatment; halfway through the open phase, and end of open phase).
6) The Cogstate battery will be used to track neurocognitive function during this study, 
which assesses attention, working memory, psychomotor function, associative 
learning, and executive functioning; it is administered at baseline, Day 11, and in the 
monthly mood and cognitive batteries
8.2.2
Pharmacokinetics
On the first infusion day (Day 1) of the blinded phase, pharmacokinetic blood samples with 
be collected, to be analyzed by our collaborator, Dr. Carlos Zarate, at the NIMH. To facilitate 
participant comfort, two intravenous catheters will be placed on that day, one for the infusion 
and the other to draw off of for PK blood samples. Timepoints are as follows: pre-infusion, 
40-minutes post infusion start, 80 minutes, 110 minutes, and 230 minutes. Total blood 
volume to be drawn that day is not to exceed 30mLs. In the event that a participant crosses 
over in the open phase to receive ketamine, there will be an identical procedure for the first 
infusion (Day 15).
8.2.3
Biomarkers/Neuroimaging Assessments
There are no serum biomarkers being collected as part of this study. Neuroimaging measures 
could, however, be considered biomarkers. We plan to scan participants at 3 timepoints: 
baseline, Day 3 (prior to second blinded infusion), and Day 17 (prior to second open infusion 
in those who crossover to open ketamine, and at a comparable timepoint to those receiving 
CBT and medication management in the open phase).
Total magnet time will be under 1 hour for each scanning session. Continuous performance 
tasks: A series of 4 tasks designed to enhance neurocognitive differences across individuals 
will directly tap into specific fundamental cognitive processes, based on the Behavioral 
Assessment Methods for RDoC Constructs report72. Positive Valence. To perturb reward 
circuitry, the (i) card guessing task will be used95,101,102, which has been extensively validated, 
shows good construct validity, psychometric properties, and characterization of individual 
differences72, and has been used in clinical populations103-108. Cognitive Systems. The 
constructs of working and declarative memory will be simultaneously probed using a version 
of the common, extensively validated (ii) N-back task 96,97,109. The construct of response 
inhibition will be assessed using the (iii) stop-signal paradigm98,110. This task has been 
extensively validated72, shown to have good construct validity and reliability 111,112, and used 
in clinical populations 110. Social Processes. To probe perception and understanding of others, 
the (iv) Reading the Mind in the Eyes Test will be used99. This task can be used in clinical 
populations 113 and in adults without ceiling effects 99. Its revised version has been shown to 
have good reliability and construct validity113-115. Subject performance on all tasks will be 
recorded via button presses during the scan and pre-treatment versus post-treatment behavior 
will be analyzed. Finally, one 6-minute run of passive movie-watching, one 6-minute run of
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resting-state, and a structural scan will be completed (3D, T1- and T2-weighted).
Acquisition Protocol: The imaging protocol will match the Human Connectome Project 
(HCP) protocols as closely as possible. Imaging will be performed on a 3T Siemens Prisma, 
32-channel head coil. T1-weighted anatomic slices (FLASH: 72 slices 2mm thick, 
TR=300ms, TE=2.47ms, FoV=220mm, matrix=192x192, Flip angle= 70º, bandwidth = 
300Hz/pixel) aligned with the AC-PC providing whole-brain coverage including the 
cerebellum. Each of the 4-task runs and 1-resting-state run will be acquired over 6 minutes 
(total of 30 minutes of connectivity data) using multiband EPI (voxel size 2mm3)116, 8 TRs to 
achieve steady-state, matrix 104x90, multiband=8, flip=52o, TE=33ms, TR=720ms, 72 slices, 
FOV=208x180mm (584 frames per run). Structural data will be obtained using 3D T1- 
weighted MPRAGE: thickness 0.7mm, matrix size=224×224, TR=2400ms, TE=2.14ms, Flip 
angle=8°, and a T2-weighted 3D SPACE, thickness 0.7mm, matrix size= 224×224, 
TR=3200ms, TE=56ms, Flip angle =variable, isotropic 0.7mm voxel resolution. The total 
MRI session is less than 60 minutes.
8.3
Adverse Events and Serious Adverse Events
8.3.1
Definition of Adverse Events (AE)
Adverse event (AE) means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
8.3.2
Definition of Serious Adverse Events(SAE)
An AE or suspected adverse reaction is considered "serious" (SAE) if, in the view the 
Sponsor-Investigator, it results in any of the following outcomes:

death,

a life-threatening adverse event,

inpatient hospitalization or prolongation of existing hospitalization,

a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions,

a congenital anomaly/birth defect, or

An important medical event that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.
8.3.3
Classification of an Adverse Event 
Severity
Adverse events will be graded according to [name grading scale, e.g. CTCAE v5.0]. For AEs 
not included in the protocol defined grading system, the following guidelines will be used to 
describe severity.

Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.
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
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference withfunctioning.

Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating. Of note, the term “severe” does not necessarily equate to “serious”.
Relationship to Investigational Product
All AEs must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. 
In a clinical trial, the study product must always be suspect.

Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an 
abnormal laboratory test result, occurs in a plausible time relationship to study 
intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if 
necessary.

Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the study 
intervention, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.

Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s 
clinical condition, other concomitant events). Although an AE may rate only as 
“possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as 
appropriate.

Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments).

Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There 
must be an alternative, definitive etiology documented by the clinician.
Expectedness
The Principal Investigator will determine the expectedness of each AE based on the listed 
adverse event section of the Reference Safety Information in the most recent US package 
insert.
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An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information described in the US Package Insert.
8.3.4
Time Period and Frequency for Event Assessment and Follow-Up
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor.
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution.
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE.
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode.
The principal investigator or other clinician seeing the participant will record all reportable 
events with start dates occurring any time after parental permission and assent is obtained 
until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. 
At each study visit, the participant will be asked about the occurrence of AE/SAEs since the 
last visit. Events will be followed for outcome information until resolution or stabilization.
8.3.5
Adverse Event Reporting
Adverse events will be reported to the FDA, Yale IRB, the DSMB, and NIMH (see Table 2 
below for reporting requirements) in accordance with all local applicable laws and 
regulations.
8.3.6
Serious Adverse Event Reporting
The identification of SAEs will begin when a member of the research team reports an adverse 
event. The site PI or her designee will conduct prompt investigations of all reported adverse 
events. All SAEs will be documented on an SAE form, entered in the appropriate CRF, and 
communicated to the appropriate team members.
Reporting to the Yale IRB
SAEs will be reported to the Yale IRB in accordance with IRB Policy 710 (see also section 
8.4, Unanticipated Problems). We will additionally report SAEs to the IRB that may be 
expected in the clinical population but are considered severe in nature (e.g. attempted suicide, 
psychiatric or medical hospitalization) regardless of their potential relationship to the study
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interventions. All adverse events that involve risk but do not meet the prompt reporting 
requirements described in Policy 710 will be reported to the IRB in summary form at the time 
of continuing review.
Reporting to the FDA
For studies conducted under an IND, there are two types of Safety Reports submitted to FDA:

7-Calendar-Day FDA Telephone or Fax Report: The sponsor-investigator will 
directly notify the FDA, within 7 calendar days after initial receipt of the information, 
of any adverse event that is fatal or life-threatening, unexpected, and considered at 
least possibly related to the investigational product.

15-Calendar-Day FDA Written Report: The sponsor-investigator will directly notify 
the FDA within 15 calendar days after initial receipt of the information, of any serious 
adverse event (other than those that are fatal or life-threatening) that is unexpected 
and considered at least possibly related to the investigational product.
Serious Adverse Events which do not meet the criteria for expedited reporting will be 
reported to the FDA in the IND Annual Report.
Table 2
Reporting to
Description of Event
Timeframe
Other
Yale IRB
Adverse events or injuries that 
are serious, unexpected, and at 
least possibly related;
Within 5 calendar days 
of the Principal 
Investigator becoming 
aware of the event.
UPIRSO Reporting Form (710 FR 
4)
Adverse events or injuries that 
are non-serious, expected, or 
unrelated
At the time of continuing 
review.
Reported to the IRB in summary 
form; such summary may be a 
simple brief statement that events 
have occurred at the expected 
frequency
and level of severity as previously 
documented
Deaths not attributed to the 
research (e.g., from “natural 
causes,” accidents, or 
underlying disease when
the Principal Investigator has 
ruled out any connection 
between the study procedures 
and the subject’s
death)
At the time of continuing 
review.
Reported to the IRB in summary 
form; such summary may be a 
simple brief statement that events 
have occurred at the expected 
frequency
and level of severity as previously 
documented
FDA
Any adverse event that is fatal 
or life-threatening, 
unexpected, and considered at 
least possibly related to the 
investigational product.
Within 7 calendar days 
after initial receipt of the 
information,
MedWatch Form FDA 3500
Any serious adverse event 
(other than those that are fatal 
or life-threatening) that is 
unexpected and considered at
Within 15 calendar days 
after initial receipt of the 
information,
MedWatch Form FDA 3500
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Reporting to
Description of Event
Timeframe
Other
least possibly related to the 
investigational product.
Serious Adverse Events which 
do not meet the criteria for 
expedited reporting
IND Annual Report
NIMH DSMB
Death Definitely, Probably, or 
Potentially Related
Immediately (within 5 
business days)
The SAE should be reported as 
soon as possible to the NIMH 
DSMB, within 5 business days for 
deaths related to study 
participation. The SAE will also be 
included in the SAE section of the 
next DSMB Report.
Serious Adverse events; 
Unexpected: and Definitely, 
Probably, or Potentially 
Related
DSMB Immediately 
(within 5 days)
The SAE should be reported as 
soon as possible to the NIMH 
DSMB, within 5 business days 
for unexpected serious adverse 
events related to study
participation The SAE will also be 
included in the SAE section of the 
next DSMB Report.
Serious Adverse events; 
Expected events: regardless of 
relation to study (related and 
unrelated)
DSMB Tri-Annually
The SAE will be listed in the SAE 
section of the DSMB Report 
(currently a tri-annual report). No 
need to notify the DSMB on an 
immediate basis.
Serious Adverse events; 
Unexpected: and Unlikely or 
NOT Related
DSMB Tri-Annually
The SAE will be listed in the SAE 
section of the DSMB Report 
(currently a tri-annual report). No 
need to notify the DSMB on an 
immediate basis.
Death Unlikely or NOT 
Related
DSMB Tri-Annually
The SAE will be listed in the SAE 
section of the DSMB Report 
(currently a tri-annual report). No 
need to notify the DSMB on an 
immediate basis.
NIMH
Program 
Officer
Deaths related to study 
participation
Reported immediately 
(no later than within 5 
business days) of the 
principal investigator 
first learning of the death
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Reporting to
Description of Event
Timeframe
Other
Unexpected Serious Adverse 
Events related to study 
participation
10 business days of the 
study team becoming 
aware of the SAE.
All reports must be made in 
writing to the NIMH Program 
Official (PO). These reports should 
indicate that the monitoring 
entities (i.e., the PI and IRB, 
DSMB) and appropriate regulatory 
entities (e.g., OHRP, FDA) have 
been notified in accordance with 
the approved monitoring plan and 
federal regulations. Reports should 
be submitted to the monitoring 
entity (e.g., a DSMB or ISM) at 
least annually on a schedule 
determined by the monitoring 
entity’s policy. Monitoring entities 
may require more frequent 
reporting.
AEs and SAEs that are
Summary should be
deemed expected and/or
submitted to the NIMH
unrelated to the study,
PO with the annual
progress report.
8.3.7
Reporting Events to Participants
The AEs and SAEs that will be reported to participants are determined by the Yale IRB in 
accordance with Yale IRB Policy 710.
8.3.8
Events of Special Interest
Not applicable.
8.3.9
Reporting of Pregnancy
Female participants will receive a serum pregnancy test with baseline screening labs. Urine 
pregnancy tests will be administered at the start of the week (prior to any infusion) during the 
blinded phase and in the event of a cross-over to open ketamine. Because full confidentiality 
regarding pregnancy cannot be entirely guaranteed, these testing requirements and the limited 
scope of confidentiality will be made known to all subjects during the permission and assent 
procedures. In this manner, young women who would not be comfortable with pregnancy 
testing or sharing the results of such testing can “opt out” of the study at the time of the initial 
assent, without having to declare specific reasons. If the pregnancy test is positive, the subject 
will not be able to participate in the protocol. Please see also section 5.3, Lifestyle 
Considerations, which details contraceptive requirements.
8.4
Unanticipated Problems
8.4.1
Definition of Unanticipated Problems (UP)
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria:
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1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the 
research procedures described in the protocol-related documents, such as the IRB- 
approved protocol and informed permission document and (b) the characteristics 
of the subject population being studied; AND
2. Is related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); AND
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, legal, or social harm) than was 
previously known or recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or 
non-medical in nature, and include – but are not limited to – serious, unexpected, and related 
adverse events and unanticipated adverse device effects
8.4.2
Unanticipated Problem Reporting
UPIRSOs will be reported by the PI to the IRB in accordance with Yale IRB Policy 710, 
using the appropriate forms found on the website. All study-related events involving risk but 
NOT meeting the prompt reporting requirements described in IRB Policy 710 will be 
reported to the IRB in summary form at the time of continuing review. If appropriate, such 
summary may be a simple brief statement that events have occurred at the expected 
frequency and level of severity as previously documented.
Events that require prompt reporting include adverse events, if the events are unexpected, 
related, and serious, and may include subject complaints, protocol deviations, and other 
untoward events involving risk. Prompt reporting entails the following timeframes:
1. Events that may require a temporary or permanent interruption of study activities 
to avoid potential harm to subjects will be reported to the IRB immediately (if 
possible), followed by a written report to the IRB using the UPIRSO Reporting 
Form (710 FR 4) no more than 5 calendar days after the PI becomes aware of the 
event
2. Internal events (those occurring at a study site under the jurisdiction of the Yale 
IRB) will be reported to IRB within 5 calendar days of the PI becoming aware of 
the event
The following events may represent UPIRSOs that should be promptly reported:
o
Adverse device effects that are unanticipated;
o
Adverse events or injuries that are serious, unexpected, and related;
o
Breaches of confidentiality involving risks;
o
DSMB reports, interim analyses, or other oversight committee/monitoring reports 
altering the risk/benefit profile by identification of increased risks;
o
Revisions to safety information, such as Investigational New Drug (IND) Safety 
Reports, SUSARS and MedWatch Reports, that meet the definition of a UPIRSO;
o
New information indicating an unexpected increase in risks or decrease in potential 
benefits (e.g.literature/scientific reports or other published findings);
o
Protocol deviations, violations, or other accidental or unintentional changes to the 
protocol or procedures involving risks or with the potential to recur;
o
Unapproved changes made to the research to eliminate an apparent immediate hazard 
to a subject;
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o
Other problem or finding (e.g., loss of study data or forms) that an investigator or 
research staff member believes could influence the safe conduct of the research.
UPIRSOs will also be reported to the DSMB, OHRP and the NIMH PO within 10 business 
days of the investigator learning of the event. UPIRSOs that are also AEs would additionally 
be reported to the FDA according to the schedules described in Table 2.
Suspensions or Terminations and Serious or Continuing Noncompliance
Any suspension or termination of approval of the study by the FDA/DSMB/OHRP/IRB must 
include a statement of the reason(s) for the action and must be reported promptly to the 
NIMH PO within 3 business days of receipt. Serious or continuing noncompliance will be 
Reported to the NIMH PO within 10 business days of IRB determination
According to HHS regulations 45 CFR 46.103(a) and (b)(5), The Yale Human Research 
protection Program has written procedures to ensure that the following incidents related to 
regulatory requirements pertaining to research conducted under an OHRP- approved 
assurance are promptly reported to OHRP: a) Any unanticipated problems involving risks to 
subjects or others; b) Any serious or continuing noncompliance with this policy or the 
requirements or determinations of the IRB; and c) Any suspension or termination of IRB 
approval.
8.4.3
Reporting Unanticipated Problems to Participants
The unanticipated problems that will be reported to participants are determined by the Yale 
Institutional Review Board (IRB) in accordance with IRB Policy 710.
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9 STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
Aim 1: To evaluate the safety of treating adolescents with SRI-resistant depression at high 
suicide risk with a conservative repeat-dosing ketamine paradigm followed by standard of 
care treatment over 4 months.
Hypothesis: We anticipate no untoward effects on medical outcomes (cardiovascular 
function and bladder health) or cognitive function (measured via Cogstate).
Aim 2: To evaluate the 48-hour impact of ketamine on suicidal ideation compared to 
midazolam, and to identify connectome phenotypes predictive of ideation post-treatment.
Hypothesis: Ketamine will reduce suicidal thinking (Columbia Suicide Rating Scale, 
recent ideation subscale) compared to midazolam. CPM will identify networks 
predictive of ideation, validated via k-fold or leave-one-out cross-validation within the 
sample. The network measures obtained at this fixed ketamine dose will inform the 
design of larger clinical trials.
Aim 3 (exploratory): To describe the trajectory of suicidal thinking, depressive symptoms, 
and use of mental health resources in both ketamine responders and non-responders over 4 
months.
9.2
Sample Size Determination
The original effect size calculation was based on power analysis of a single, randomized- 
controlled trial of ketamine involving 80 adult subjects using the Scale for Suicidal Ideation. 
As noted below (in italics), there are additional sources of information that were used in 
recalculating the anticipated range of possible effect sizes for important primary and 
secondary outcomes in this trial and the anticipated sample size has been readjusted to 40- 
66 subjects.
Primary outcome (suicidality, as measured by the C-SSRS recent ideation subscale: to 
detect an effect size of 0.75117 of ketamine versus midazolam at this rapid timepoint with 
80% power at the two-sided 0.05 significance level, using a two sample t-test, a sample size 
of 30 subjects per group is required. An additional 3 subjects per group will be enrolled to 
accommodate a 10% attrition rate, requiring a total sample size of 33 subjects per group 
(N=66).
Rationale for the Revised Anticipated Effect Size: 0.75-0.85 for the Primary Outcome

The power calculation for the original grant proposal was based on a randomized, 
midazolam-controlled trial of 80 adult subjects with Major depression and suicidal 
ideation, which demonstrated an effect size of 0.75 at 1 day following initial infusion on 
the Scale for Suicidal Ideation. 117 (BLUE in Figure 6)

A meta-analysis which included data from 176 individual adult participants from 10 randomized 
controlled trials of ketamine for depression including adults with treatment-resistant depression 
and suicidal ideation demonstrated an effect size of 0.85 at 1 day following initial infusion as 
measured on the MADRS item 10 that measures suicidal ideation.119 (GRAY in Figure 6)
Secondary Aims Analyses: Secondary outcome analysis will apply the Benhamini-
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Hockberg procedure118 to control for multiple testing. For an alpha = 0.01 (corrected) for 
depression outcomes and 80% power, the minimal detectable effect size would be 0.91. Our 
prior studies with ketamine in depressed adolescents demonstrate an effect size of 0.75 for 
depression endpoints (MADRS) at rapid timepoints, and thus we are powered to 
approximately 60% to detect a difference for antidepressant outcomes.
Rationale for the Revised Anticipated Effect Size: 0.78-0.89 for the Depression 
Symptoms

Our original single-dose, midazolam-controlled, crossover trial in adolescents with 
treatment-resistant depression which provided the pilot data for this initial grant 
proposal demonstrated an effect size of 0.78 on the MADRS at day 1 for improving 
depressive symptoms.120 (ORANGE in Figure 6)

The meta-analysis which included data from 176 individual adult participants from 10 
randomized controlled trials of ketamine for depression including adults with 
treatment-resistant depression and suicidal ideation demonstrated an effect size of 0.89 
at day 1 following initial infusion for improving depression symptoms on the MADRS 
scale. 119 (YELLOW in Figure 6)
Given that even with our original sample size we were underpowered to detect secondary 
outcomes if we adjust for multiple hypothesis testing, we instead plan not to adjust for 
multiple comparisons in secondary analyses (use alpha=0.05) and treat the analyses as 
exploratory and limit reporting to point estimates and 95% CI without formal hypothesis 
testing.121
Imaging outcomes: The current study proposes to image 66 adolescents, half initially 
randomized to ketamine and half to midazolam. CPM has successfully built predictive 
models using only 25 subjects55, and thus we believe that 33 subjects per group is sufficient 
to perform the proposed treatment phenotyping. We have estimated an attrition rate of 10% 
based on previous experience with pediatric ketamine trials, although participant 
withdrawal generally occurs later in the course of the trial (while the imaging is occurring 
relatively early on). Even with an additional attrition of 15% for miscellaneous causes (e.g. 
braces, motion, severe claustrophobia), we still meet the threshold of 25 subjects. \We 
anticipate that a sample size between 40-66 will get us the necessary sample size to have 
the power to complete neuroimaging analysis (N≥25) with currently expected additional 
exclusion (e.g. due to braces and permanent retainers) or declining participation in the 
MRI portion of the study (e.g. due to claustrophobia or additional subject burden).
Figure 6 depicts power versus sample size for the four effect sizes discussed above. Table 3 
describes the anticipated power for sample sizes for the 4 possible anticipated effect sizes 
described above in the range of 30-66 subjects. Based on the above power calculations, we 
would need to enroll 46-58 subjects to have 80% power to detect a between-group 
difference in our primary outcome related to suicidal ideation and a total of 42-54 subjects 
to have 80% power to detect a between-group difference in our secondary exploratory 
outcomes.
Table 3: Power Calculation for Anticipated Effect Sizes regarding Suicidal Ideation 
and Depression Symptoms
Total 
Sample 
Size
Suicidal 
Ideation
Depression
d=0.75
d=0.85
d=0.78
d=0.89
30
50.9%
61.3%
54.1%
65.3%
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32
53.7%
64.3%
57.0%
68.3%
34
56.4%
67.1%
59.7%
71.1%
36
58.9%
69.8%
62.3%
73.7%
38
61.4%
72.2%
64.8%
76.1%
40
63.7%
74.5%
67.1%
78.3%
42
66.0%
76.7%
69.4%
80.3%
44
68.1%
78.6%
71.5%
82.2%
46
70.1%
80.5%
73.5%
83.9%
48
72.0%
82.2%
75.3%
85.5%
50
73.8%
83.8%
77.1%
86.9%
52
75.6%
85.2%
78.8%
88.2%
54
77.2%
86.5%
80.3%
89.4%
56
78.7%
87.8%
81.8%
90.5%
58
80.1%
88.9%
83.1%
91.5%
60
81.5%
89.9%
84.4%
92.4%
62
82.8%
90.9%
85.6%
93.2%
64
84.0%
91.7%
86.7%
93.9%
66
85.1%
92.5%
87.7%
94.5%
SAMPLE SIZES NEEDED TO ACHIEVE 80%
POWER
58
46
54
42
Table 3: Power Calculation for Anticipated Effect Sizes regarding Suicidal Ideation and Depression 
Symptoms. Table 3 depicts the power calculations for the anticipated range of observed effect sizes for 
suicidal ideation and depression symptoms for possible sample sizes in the current study assuming 
alpha=0.05 and a 100% completion rate. Sources utilized for the range of anticipated effect sizes for 
suicidal ideation and depression are outlined above. Shading of the effect sizes in the table correspond to 
the corresponding color of the power curve for that effect size in Figure 6.
Figure 6: Power Curve for Anticipated Effect Sizes regarding Suicidal Ideation and Depression 
Symptoms
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Figure 6: Power Curve for Anticipated Effect Sizes regarding Suicidal Ideation and Depression 
Symptoms. Figure 6 depicts the power curves for anticipated effect sizes for suicidal ideation (solid lines) 
and depressive symptoms (dashed lines) over the potential sample size range for this trial if granted a 2- 
year no cost extension. Sources utilized for effect sizes used for power calculations for suicidal ideation3-4 
and depression2,4 are described above.
9.3
Populations for Analyses
•
Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants)
•
Per-Protocol Analysis Dataset: defines a subset of the participants in the full analysis 
(ITT) set who complied with the protocol sufficiently to ensure that these data would 
be likely to represent the effects of study intervention according to the underlying 
scientific model
9.4
Statistical Analyses
9.4.1
General Approach
There are no RCTs testing ketamine’s rapid anti-suicidal effects in high-risk youth, and 
our ability to predict responses to treatment based on biological data is poor. The primary 
outcome is C-SSRS, recent ideation subscale, at 48-hours post-dose comparing participants 
who were randomized to ketamine to those who received the active placebo, midazolam. Key 
secondary outcomes include 48-hour MADRS and Day 11 C-SSRS, MADRS, and CDRS-R. 
CPM will be used to identify pre-treatment connectome fingerprints that predict treatment 
response and how circuits change post-treatment.
Data will be examined prior to analysis using descriptive statistics, presented as means ± 
SD or median (interquartile range) for continuous characteristics, and as frequencies (%) for 
categorical characteristics. Where appropriate, randomized groups will be compared on 
baseline continuous characteristics (e.g. age) using two-sample Welch’s t-test or Wilcoxon 
rank sum test, and on categorical characteristics using the chi-square test or Fisher’s exact 
test as appropriate. Continuous outcome measures will be assessed for normality using
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histograms and Q-Q plots, and transformations will be applied as necessary. Short-term 
outcomes will be analyzed by linear mixed models with rating scales as the dependent 
variables and baseline values, treatment, time (48 hours, Day 11), and treatment-by-time 
interaction as independent variables (fixed effects). Subjects will be modeled as a random 
effect to account for the correlated data from same subject. Linear contrasts will be used to 
estimate treatment group differences and 95% confidence intervals at each timepoint. We will 
formally test the predictive power of a variety of features associated with outcome in clinical 
trials in depression and suicidality by including them as covariate(s) separately and together 
(except for age and age-at-onset) in the analytical models described above.
9.4.2
Analysis of the Primary Efficacy Endpoint(s)
The primary outcome of C-SSRS at 48-hours will be compared between groups using an 
analysis of covariance (ANCOVA) model, with treatment group (ketamine versus
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midazolam) and baseline C-SSRS as the independent variables (covariates). Our primary 
analyses will be intent-to-treat using all available data.
9.4.3
Analysis of the Secondary Endpoint(s)
Safety outcomes: To examine the safety and tolerability of 4 doses of ketamine in this 
developmental population we will closely track adverse events and side effects in both the 
ketamine and midazolam treated groups for the duration of the study. We will use descriptive 
statistics to characterize the rates of these events for both groups and will use Fisher’s exact 
tests to test for differences between the groups.
Additional clinical outcomes: Short-term outcomes (e.g. MADRS, CDRS-R) will be 
analyzed by linear mixed models with rating scales as the dependent variables and baseline 
values, treatment, time (48 hours, Day 11), and treatment-by-time interaction as independent 
variables (fixed effects). Subjects will be modeled as a random effect to account for the 
correlated data from same subject. Linear contrasts will be used to estimate treatment group 
differences and 95% confidence intervals at each timepoint. We will formally test the 
predictive power of a variety of features associated with outcome in clinical trials in 
depression and suicidality by including them as covariate(s) separately and together (except 
for age and age-at-onset) in the analytical models described above. Comparison of response 
proportions: Response is defined as a 50% reduction in C-SSRS (suicidality) or MADRS 
(depression). The proportion of responders at rapid (48-hour) and short-term (Day 11) 
timepoints between treatment groups will be performed by the generalized linear mixed 
models with a random subject effect in which binary response outcome is modeled as a 
function of covariates including treatment, time, treatment by time interaction and baseline 
value. Depression status as a mediator of anti-suicidal response: Lastly, as exploratory 
analysis, to estimate the direct effect and indirect mediation effects of MADRS on the 
association of treatment with C-SSRS scores, we will fit multilevel mediation models122 
within multilevel structural equation modeling framework using Mplus software. We will 
also consider an alternative mediation analysis method within the mixed-effect modeling 
framework described by Bauer123. These secondary clinical outcomes shall be considered 
exploratory and used for hypothesis generating purposes for future studies as our statistical 
threshold will be set at p<0.05 and will not correct for multiple comparisons.
Neuroimaging/ CPM outcomes: FMRI data will be motion corrected using SPM12. Data 
will be analyzed using BioImage Suite124,125 and custom scripts in Matlab (Mathworks).
Linear and quadratic drift, mean signal from white matter, gray matter, cerebrospinal fluid, 
and a 24-parameter motion model (6 motion parameters, 6 temporal derivatives, and their 
squares) will be regressed from the data. Finally, data will be temporally smoothed with a 
zero mean unit variance Gaussian filter. Data from runs with excessive head motion (a priori 
as > 2 mm translation or > 3 degrees rotation during a single run) will be excluded. Head 
motion, calculated as mean frame-to-frame displacement, will be measured as a function of 
state between different task or rest runs to ensure that motion is not a primary driver of 
condition. Uniform smoothing will be run to remove residual effects of motion 126. The best 
performing individual atlas will initially be registered to individual participant space via 
concatenation of a series of linear and non-linear registrations between the functional images, 
2D and 3D anatomical scans as previously described58. From this step the individualized atlas 
will proceed and a custom atlas for each subject at each time point will be produced with 
information on the correspondence between nodes across (time and subject) atlases 
maintained. Connectivity matrices are then calculated for the different acquisition conditions 
and fed into the multidimensional CPM along with subject C-SSRS data.
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Multidimensional CPM algorithm: We have extended our original CPM framework by 
modifying the feature selection step to incorporate information from multiple connectivity 
matrices (from both task- and resting-state acquisitions). For the new feature selection step, 
we use canonical correlation analysis (CCA) instead of linear regression. CCA is a 
multivariate method for inferring information from cross-covariance matrices by finding 
linear combinations of the data that maximizes the correlation between the data (i.e. 
connectivity matrices from task and rest) and variable of interest (suicidal ideation as 
measured via the C-SSRS). Latent brain networks from multiple task conditions are used to 
predict latent behavioral profiles in a single modeling step. Similar to CPM, edges are 
selected if the CCA produces a significant correlation as measured by the likelihood test 
(using p-value threshold of 0.01). Once the most predictive edges are selected, the new 
projections of those edges estimated from the CCA are summed to form a single subject 
suicidal ideation summary score.
Model Validation: After the CPM model is built from the training data, it can be used to 
predict scores from connectome data for novel subjects. We will initially test leave-one-out 
analyses but as the size of the data set grows we will perform k-fold cross-validation (k=10).
Such test data sets allow performance to be evaluated using either the mean squared error 
(MSE) or the correlation between the predicted and observed behavioral values. Lower MSE 
and higher correlation indicate a more predictive model. Validation in novel subjects is aimed 
at demonstrating that the models generalize and are not simply over-fitting a specific set of 
data.
Connectome Changes: To examine the impact of treatment on the functional connectome 
identified above we can compare masked connectivity matrices across timepoints. Here the 
pre-treatment multidimensional CPM identifies edges and nodes that are associated with 
suicidal ideation. These model edges and nodes can be contrasted with data collected post- 
treatment (for both placebo and ketamine) to determine the extent to which treatment 
modifies this pre-treatment functional phenotype. This contrast can be performed with a 
paired t-test corrected for multiple comparisons and the change distribution can be compared 
with the change distribution from the placebo group to measure the significance of this 
change. Such connectivity changes can also be regressed with the pre- and post-treatment 
suicidal ideation score change to test the hypothesis that the extent of change in the functional 
connectome is associated with the degree of change in ideation score.
9.4.4
Safety Analyses
Please see section 9.4.3. Safety Outcomes and section 9.4.6 Planned Interim Analyses.
9.4.5
Baseline Descriptive Statistics
Data will be examined prior to analysis using descriptive statistics, presented as means ± SD 
or median (interquartile range) for continuous characteristics, and as frequencies (%) for 
categorical characteristics. Where appropriate, randomized groups will be compared on 
baseline continuous characteristics (e.g. age) using two-sample Welch’s t-test or Wilcoxon 
rank sum test, and on categorical characteristics using the chi-square test or Fisher’s exact 
test as appropriate. Continuous outcome measures will be assessed for normality using 
histograms and Q-Q plots, and transformations will be applied as necessary. Sex will be
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treated as a biological variable in our analyses. We will explicitly test for sex effects in all 
aspects of this work by building both joint and separate sex-based CPMs and then contrasting 
the nodes and edges identified in the separate models from the joint model to test for sex 
effects (paired t-test with correction for multiple comparisons based on the number of edges 
selected in the models).
9.4.6
Planned Interim Analyses
There is no interim analysis for efficacy outcomes.
Given the importance of monitoring safety outcomes with this experimental treatment, we 
have developed an interim safety analysis plan and stopping guidelines based on monitoring 
the rates of suicide events. Suicide events include suicide attempts, interrupted suicide events, 
and high levels of suicidal ideation that necessitate emergency evaluation or hospitalization. 
In addition to tables and listings of adverse and serious adverse events, these specific 
analyses will be presented to the DSMB at all meetings following study initiation.
1) Comparison of rates of suicide events between randomized groups (ketamine and 
midazolam) during the double-blind phase. A Fisher’s exact test will be used and if the p- 
value crosses the one-tailed 0.025 significance level (indicating a greater likelihood of events 
in the ketamine group), further enrollment and ketamine treatment will be stopped until the 
DSMB has reviewed the data and made a recommendation about study discontinuation.
2) Evaluation of the rate of suicide events in all participants who receive ketamine to 
determine if it is unacceptably higher than expected. We will compare the rate of suicide 
events in all subjects that receive ketamine (i.e. those initially randomized to ketamine and 
those that cross-over to receive ketamine following the double blind phase) to an acceptable 
rate of 33.8%/6 months. Using a one-sided 0.025 significance level, if the rate is significantly 
higher than 33.8%/6 months, further enrollment and ketamine treatment will be stopped, until 
the DSMB has reviewed the data and made a recommendation about study discontinuation.
In order to maintain the blind and the integrity of the study data, the study team has both a 
blinded and unblinded statistician. Any DSMB reporting of data by treatment group (i.e. 
blinded data) will be prepared solely by the unblinded statistician and sent directly to the 
DSMB liaison. The unblinded statistician will not discuss the results of these analyses with 
the rest of the study team in a manner which challenges the blind. Any relevant DSMB 
queries of this data will go directly to the unblinded statistician, and DSMB communications 
regarding ongoing reviews will proceed as detailed in the NIMH DSMB charter.
9.4.7
Sub-Group Analyses
NA
9.4.8
Tabulation of Individual participant Data
Coded individual participant data will be listed by measure and time point.
9.4.9
Exploratory Analyses
Weekly data on mood and suicidal ideation will be analyzed by mixed-effects regression 
methods to model the trajectories over the 4-month open phase, regardless of the treatment
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assignments. Significance changes of these data from D15 will be tested, with least square 
mean values estimated at each follow-up time points. These estimates and corresponding 95 
CI% will be compared across the 5 response groups. The number of ER, IOP, PHP, or 
inpatient visits between ketamine responders and non-responders will be compared by the 
Poisson or negative-binomial regression analysis. Paired t-tests will be used to compare the 
changes of mood and suicidal ideation in patients who did not have a response to midazolam 
in the blinded phase and went on to receive an open ketamine.
10SUPPORTING DOCUMENTATION 
AND OPERATIONAL 
CONSIDERATIONS
10.1 Regulatory, Ethical, and Study Oversight Considerations
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki.
Institutional Review Board (IRB) Review
The protocol will be submitted to the IRB for review and approval. Approval of the protocol 
must be obtained before initiating any research activity. Any change to the protocol or study 
team will require an approved IRB amendment before implementation. The IRB will 
determine whether informed permission and assent and HIPAA authorization are required. 
The IRB will conduct continuing review at intervals appropriate to the degree of risk, but not 
less than once per year. A study closure report will be submitted to the IRB after all research 
activities have been completed. Other study events (e.g. data breaches, protocol deviations) 
will be submitted per Yale University’s IRB's policies.
Study Modification
Any study modifications will be completed in writing to the protocol documents, 
permissions, and assents, and submitted to the Yale IRB for approval, as well as to the 
relevant regulatory authority prior to implementation. Version control will be used to track all 
changes, and only the most recent versions of IRB-approved documents will be used. If a 
modification causes a substantial change to permission or assent documents, participants and 
parents will be re-consented with the up-to-date documents.
In addition to IRB review and approval, the NIMH DSMB may require review of 
protocol/study modifications that are substantial, such as modifications to the eligibility 
criteria or study design. In ambiguous cases, the Sponsor-Investigator will inquire with the 
DSMB to ascertain if review is warranted.
10.1.1 Informed Consent Process
Informed Permission and Assent Processes

Only the most recent IRB-approved version of the informed permission and assent 
documents will be used to consent/assent potential subjects.

If there are two parents or guardians, both most provide permission and each must sign a 
separate permission form. Completed parental permission forms and the adolescent assent
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document must be obtained from every subject who takes part in a study prior to 
performing any study-related activities.

When a potential study subject is identified, the investigator or delegate discusses the 
study in detail with the participant and their parents. An explanation of the study, its risks 
and benefits, and what would be required of the subject is discussed. The potential subject 
and parents or guardians are given a copies of the informed parental permission form and 
assent documents to read in a quiet environment without distraction, including the option 
to take the form home to review and discuss with others. Ample time and opportunity are 
provided for the potential subject, parents, and/or legally authorized representative to ask 
about the details of the study, to consider other available options, and to decide whether 
to participate. All potential participants have the opportunity to discuss study participation 
without their parents or guardians present, to ensure maximum privacy and comfort in 
discussing any sensitive issues (e.g. pregnancy, drug use) and asking study-related 
questions, and to ensure that the adolescent is freely choosing to participate without any 
undue pressure or influence. All questions and concerns to both the adolescent and their 
parents/guardians are addressed throughout this process by the individual obtaining 
permission and assent.

The individual obtaining permission/assent will ensure to the degree possible, and based 
on his/her judgment, that the potential subject and parents or guardian have 
comprehended the information provided about the research. A short quiz at the end of the 
informed consent forms will aid in assessing understanding.

If a potential subject and parents/guardians decide to participate, the parents/guardians are 
asked to sign the permission form only after all questions and concerns have been 
addressed. The adolescent subject is similarly asked to sign the assent document only 
after all questions and concerns have been addressed

The permission forms and adolescent assent form must be signed and dated by the parents 
and participant, along with the individual obtaining consent.

This study will allow for e-consenting using the Part 11-compliant RedCap system. The 
RedCap ICF documents will be identical to their HIC-approved paper counterparts. While 
we anticipate that many or most study discussions and consenting will occur in person, 
the capacity for e-consenting allows flexibility should a participant want to take some 
more time to review the study documents at home after an initial discussion.  We may 
also remotely consent potential subjects when subjects need to travel a long distance in order 
to participate in the trial.
o
The e-consent process is as follows: Any time a permission/assent/consent process 
is conducted remotely, study staff will be present with the participant and their 
family via Zoom session. Participants and parents identify an electronic device to 
access REDCap and open the eConsent as a survey. Time is allotted for any 
additional review of the research study with the participant, answering questions, 
and completing the assessment quiz. Research staff review the results of the quiz 
and review any remaining questions. Participant signature is obtained in RedCap. 
In the part 11-compliant system, each participant and parent will have a unique 
login and password to verify their identity, which only they will know. Staff will 
then review the eConsent form to confirm it is filled out correctly and sign the 
eConsent as the ‘person obtaining consent’.
o
A compact PDF copy of the signed eConsent will be automatically stored in the 
File Repository. A copy of the signed eConsent can be provided to the participant 
and their family either as a paper or electronic document

All signed paper consents will be uploaded and stored in the same Part 11-compliant 
RedCap EDC. The paper original signed permission forms and adolescent assents will be 
kept in a locked filing cabinet in the Child Study Center.
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
A copy of the parental permission documents, adolescent assent, and any other 
documentation about the research (e.g., calendars, instructions) shall be provided to the 
subject and their parent or guardian.

Documentation of the permission and assent processes will be entered in the subject’s 
source documents (see section on Documentation Related to the Informed 
Permission/Assent Process below).
Additional Assent Information: Assent is an adolescent’s affirmative agreement to participate 
in research. Assent will be sought in addition to the permission of a legally authorized 
representative or surrogate when the individual is sufficiently cognitively capable of 
understanding the nature of his or her participation in a research study, failure to object will 
not be construed as assent (45 CFR 46.402(b); 21 CFR 50.3(n)). A child is any individual 
who at the time of enrollment in a research study has not attained the legal age for consent to 
treatments or procedures involved in the research under the applicable law of the jurisdiction 
in which the research will be conducted (45 CFR 46.402(a); 21 CFR 50.3(o)). In the state of 
Connecticut, the age of majority is 18. Assent will be documented through the adolescent 
signing an assent form. The assent form will be written in language that is appropriate to the 
child or adolescent subject’s maturity and cognitive level and used as part of the assent 
process to 1) describe the research study, including the research procedures, risks and 
benefits, and 2) obtain the child or adolescent’swritten agreement to participate in the study.
Informed Consent Process: If a participant turns 18 while participating in the study, their 
initial assent and parental permissions are no longer sufficient. Once the participant turns 18, 
they will now be asked to provide consent for the study, using a separate consent document. 
The informed consent document is identical to the permission form, with the content 
addressed to “you” rather than “your child or adolescent”. The same principles of informed 
consent apply, as described above for permission and assent.
Re-permission/re-assent/re-consent: If during the course of the study, the protocol has been 
modified in such a way that changes are made to the informed permission or assent forms, 
subjects who have already given their informed permission/provided their assent may be 
required by the IRB to be re-permissioned using the updated form. If the IRB determines that 
re-consenting is required or if it is deemed appropriate by the PI but in the absence of an IRB 
requirement, all subjects currently enrolled in the study must sign the updated informed 
permission form to acknowledge the changes. The subject may be re-consented at the next 
site visit unless otherwise stated by the IRB or Sponsor-Investigator.
Immediate hazards or issues of safety, however, should be communicated to the participant 
and the participant’s parent/guardian upon receipt of the new information or as directed by 
the Sponsor-Investigator. This communication shall be documented in the medical 
record/research chart by the individual who communicated the information to the participant.
Documentation of the Permission/Assent/Consent Process
The individual obtaining informed permission will document the process via a note or 
completion of the source document template. The documentation will include information 
pertinent to the Permission Process (initial consenting and all follow-up consenting through 
the completion of the study):
o
Name and title of person who explained the study
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o
Date(s) of study explanation (if different than date of document signing)
o
Name and title of person who obtained Informed Permission/Assent/Consent (if different 
than above)
o
The actual date Informed Permission/Assent was obtained
o
Individual(s) present when Informed Permission/Assent was obtained
o
Summary of the consenting process that describes that the study was discussed in detail 
including the study design, risk and potential benefits for their participation in the study, 
alternative treatments available, and voluntary nature of participation. In addition, 
indicate that sufficient time was provided for potential subject and their parents to 
read/review permission and assent forms and have questions answered to his or her 
satisfaction and has signed the document and received a copy, and has contact 
information if questions arise.
o
Score of quiz, list of any questions that were missed, and summary of discussion around 
missed questions
10.1.2 Study Discontinuation and Closure
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and the DSMB and 
will provide the reason(s) for the termination or suspension. Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants (please 
see Section 9.4.4, Safety Analyses)

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable
10.1.3 Confidentiality and Privacy
Subject confidentiality is held in strict trust by the research team. Subject medical record 
review will be limited to the just the elements needed to complete the study. Only authorized 
HIPAA and GCP trained study team members will be allowed to extract research data from 
medical records and enter it into RedCap. No direct subject identifiers will be entered into 
RedCap. All NIH-funded research is covered by a Certificate of Confidentiality, which 
applies to the current study. Each subject will be assigned a unique study number. A master 
list linking the unique study number to the human subject will be maintained in a locked 
drawer in the Child Study Center.
Clinical data, outcomes of diagnostic instruments, and research data will be collected by the 
principal investigator and other study personnel and stored in a locked file cabinet in a locked 
office. Data will be entered into a database on a password-protected computer in a locked 
office, by study personnel. Since this is an investigator-initiated study, the PI and study team 
will develop Clinical Research Forms (CRFs) for this study. These forms will be labeled with 
a unique random study code that cannot identify the patient. The key linking the code to the 
subject’s identifiable information will be kept in an electronic excel file which is kept in a 
password protected file, on a password protected computer on the secure Yale server. A paper 
copy of this “master file” will be kept in a locked file cabinet as noted above. This master file 
will be kept separately from any coded data so that the identity of the participant will not be 
disclosed. The results of the medical and psychiatric evaluations conducted as part of this
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research will be available to clinicians caring for the subject unless the participant requests 
otherwise. The Yale Human Investigation Committee may review records of this research. In 
the case of published reports of this study, the identities of all participants will be protected. 
All data obtained from subjects will be coded and stored in locked cabinets/password 
protected computer in an office that is locked to ensure confidentiality. Information that will 
breach subject confidentiality will not be shared. Rather, data will only be released upon 
written consent of the subject and will be available for review by the Yale Human 
Investigation Committee. The PI will also conduct periodic assessments to ensure that 
confidentiality provisions established at the onset of the study are maintained throughout the 
study and during data analysis. Additionally, all staff involved in the handling of subject data 
are/or will be trained on the requirements of HIPAA Privacy Rule and Human Subject 
Protection. If the PI should leave Yale, the PI will collaborate with her Department Chair and 
Faculty Advisor to ensure that proper and continued protection of individually identifiable 
information and protected health information continues.
10.1.4 Future Use of Stored Specimens and Data
Data will be kept in a locked filing cabinet whose access is only obtainable by study 
personnel and electronic clinical data will be kept on a password protected server. As an 
NIMH-funded study, data sharing through the NIMH Data Archive (NDA) is required. NDA 
is a large database where deidentified study data from many NIMH studies are stored and 
managed. Any researcher who requests access to the deidentified data of the NDA is bound to 
adhere to strict data safety practices and to avoid any attempts at deidentification. The 
intention to submit deidentified subject data to the NDA is included in permission and assent 
documents, and participants or guardians are able to opt out of this data sharing at any time.
Opting out of NDA data sharing does not in any way impact trial eligibility.
With the parental permission and participant’s assent, and as approved by the IRB, de- 
identified biological samples will be stored to examine the pharmacokinetics of ketamine 
metabolism in pediatric patients. The specimens will be coded in a way that allows linkage to 
the phenotypic data from each participant, maintaining the blinding of the identity of the 
participant. During the conduct of the study, the parents or an individual participant can 
choose to withdraw permission/assent to have biological specimens stored for future research. 
However, withdrawal of permission/assent with regard to bio sample storage may not be 
possible after the study is completed.
10.1.5 Key Roles and Study Governance
The Study team is led by the PI, Dr. Michael Bloch, MD, MS. Dr. Bloch will oversee all of 
the clinical trial operations, including patient screening, enrollment and consent, treatment, 
and follow up. His clinical team includes an efficacy rater who conducts the blinded ratings 
(this rater in not present during any of the ketamine or midazolam infusions), a pediatric 
psychotherapist with experience working with adolescents with CBT, and a clinical 
coordinator, who schedules patients and assessments, and also assists with the upkeep of 
regulatory binders and reports.
Dr. Gerard Sanacora, MD, PhD, serves as the Scientific Director of the Interventional 
Psychiatry Service (IPS, where medication treatments will occur during this study), and will 
act as a liaison between the study team and IPS to facilitate participant treatment flow.
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Dr. Angeli Landeros, MD, is an associate research scientist with extensive experience 
running pediatric depression clinical trials for rapid antidepressants with Dr. Bloch. She will 
assist with participant recruitment and trial logistics.
Dr. R. Todd Constable, PhD, serves as the co-Director of the Magnetic Resource Research 
Center. He will oversee the neuroimaging portion of the study, including leadership on MRI 
sequence parameters, development of the individualized node parcellation algorithm, data 
analysis and pre-processing, and connectcome-based predictive modeling algorithms.
Dr. Eugenia Buta, PhD is responsible for the statistical analysis of the clinical data and 
generating reports for the DSMB.
10.1.6 Safety Oversight
The study will have a NIMH constituted Data Safety Monitoring Board (DSMB) who will 
periodically review and evaluate the accumulated study data for participant safety, study 
conduct, progress, and efficacy. The PI will also conduct an internal review every six months 
to monitor data collection and management of timelines (e.g., implementing data quality 
assurance procedures; updating, editing, and data checking all files; ensuring that protocol 
procedures are being followed, as per the site’s related SOPs). Dr. Dai and the support 
services at the Yale Center for Analytic Science are experienced in study design, preparation 
of study forms, and management of data and preparation of reports related to the progress of 
each study, and will be responsible for preparing reports for the DSMB.
Safety Monitoring:
Participants are very closely monitored in this study, with twice weekly in-person visits 
during the 2-week blinded phase, and weekly visits during the 4-month open phase. The first 
8 weeks of the open phase will be in-person assessments that coincide with the weekly CBT 
that the patient is receiving. During the last 8 weeks of the open phase, weekly assessments 
may be either in person or over the phone if the participant is doing well. There are four 
monthly in-person full batteries that include mood and anxiety assessments, as well as 
cognitive testing. Finally, there are medical safety screens built into our protocol, such that an 
ECG, serum laboratory values (hematologic, hepatic, and renal function) and a urinalysis are 
obtained at baseline, the end of month 2 of the open phase, and the end of month 4 of the 
open phase. Any participant who presents with new symptoms or physical complaints will 
have a medical and laboratory exam prior to the scheduled timepoint.
The multidisciplinary clinical team (efficacy rater, clinical coordinator, psychotherapist, 
and other participating trial staff) is led by the PI, and meets weekly to coordinate treatment 
efforts, monitor each patient’s progress, and to determine whether further participation puts the 
patient at risk. The PI may discontinue a patient from study participation if it appears that the 
study is causing medical or psychiatric safety risks. A patient is also withdrawn at any time if 
he or she so requests or if a female patient becomes pregnant. At the end of the study or when 
a patient discontinues the study prematurely, efficacy evaluations are repeated. In addition, a 
physical exam, vital signs, weight, and laboratory measurements are obtained. Patients are also 
assessed for adverse experiences with the SAFTEE-GI and SAFTEE-SI.
Please also see section 9.4.4, Safety Monitoring, regarding ongoing safety monitoring at the 
group level.
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10.1.7 Clinical Monitoring
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is compliant with currently approved protocol/amendment(s), 
with GCP, and with applicable regulatory requirement(s). The main features are below.

Monitoring for this study will be performed by NIMH Clinical Research Education, 
Support and Training Program (CREST)

Monitoring will be conducted throughout the study, and involve targeted data 
verification of key data variables

The site PI will be provided copies of monitoring reports within 10 days of each visit 
and will be provided to the NIMH DSMB liaison within 30 days of the visit.

Details of clinical site monitoring are documented in the CMP. The CMP describes 
who will conduct the monitoring, at what frequency monitoring will be done, at what 
level of detail monitoring will be performed, and the distribution of monitoring 
reports.

The site will perform internal quality management of study conduct, data collection, 
documentation and completion. An individualized quality management plan will be 
developed to describe the site’s quality management.
10.1.8 Quality Assurance and Quality Control
The clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion. An individualized quality 
management plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices 
(GMP)).
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the NIMH, and 
inspection by local and regulatory authorities, including the FDA.
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) and clinical laboratory data will be entered into Yale REDCap, a 21 
CFR Part 11-compliant data capture system provided by Yale University. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate.
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For neuroimaging data, we perform many steps to ensure data quality in our imaging center 
including daily phantom studies to test temporal stability, SNR, ghosting measures, and 
contrast levels. The MR techs perform daily stability tests, and scripts automatically upload 
the data, analyze the above measures, and send an alert if any measures are outside the 
acceptable range. During subject scanning, we have a real-time motion correction algorithm 
that provides feedback on subject motion compliance. Subjects can be provided with verbal 
feedback to try to decrease motion if it is too high or specific runs can be repeated if the 
motion is too high. Following these steps, a number of other QC steps are taken during 
analysis as described above (including motion censoring) for those subjects that remained 
still enough to produce useable data.
Rigor: Scientific rigor for the proposed study is established in the following manner: (a) 
experimental design follows state-of-the-art study guidelines; (b) safety, efficacy, and 
neuroimaging data collection is based on well-validated protocols (see below for quality 
assurance), and the same protocol will be used for all subjects; (c) we consider important 
biological variables, such as sex, and strictly follow inclusion and exclusion criteria; (d) all 
results will be compared to well-validated, previously published results; and finally, (e) 
connectome predictors of suicidal ideation generated via CPM will be based on a 10-fold cross- 
validated prediction of constructs—from the standpoint of scientific rigor, cross-validation is a 
more conservative way to infer the presence of a brain-behavior relationship than correlation. 
All results will be corrected for multiple comparisons using the false discovery rate.
Replication: The ultimate replication is a study wherein a model is built in one population and 
validated in another. To encourage replication of this work, we (1) will make the clinical trial 
protocol available, (2) disseminate outcomes as indicated on ClinicalTrials.gov, and (3) will 
make available all of our neuroimaging data, software, and models. We are hopeful that the 
clinical results and connectome predictors identified from the current study will be inform the 
design of a larger trial in suicidal youth, consistent with the aims of the RFA.
Please see also sections 10.1.6 Safety Monitoring and 10.1.7 Clinical Monitoring above
10.1.9 Data Handling and Record Keeping
Private identifiable information will be collected (name, date of birth, age, telephone number, 
address, medical and psychiatric history, diagnoses, laboratory tests, and psychiatric rating 
scores) but will be kept confidential and will not be divulged in any publication emanating 
from this work. The urine toxicology results will not be kept and, as an NIH-funded study, 
this trial is covered by a Certificate of Confidentiality. Risks to subject confidentiality will be 
minimized by adopting suitable data storage procedures. All data for each subject will be 
identified by numerical ID. The master list of subject IDs and names will be stored in a 
locked file at a separate location. Once data are collected and entered, hard copies of the 
testing protocols and clinical notes will be stored in a locked filing cabinet. All research data 
and the clinical information containing PHI are stored separately in locked file cabinets.
Permission and assent forms are stored in yet another location. Throughout these procedures, 
all reasonable precautions are taken to minimize linking any PHI to the research data. All 
computers are password protected and furnished with firewalls and anti-spy and anti-virus 
software in accordance with the general guidelines of the Yale Information Technology and 
HIPAA offices. All data will be stored on a secure server and cloud backup managed by the 
Yale ITS Office. Reports based on these data will not identify subjects by name. The 
database will be maintained within the existing data management system, providing a high
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degree of security and quality monitoring. Clinical data will be entered directly into RedCap 
from the source documents.
Access to Source Documents
Source documents include participant data and records that include but are not limited to the 
following: hospital or medical records, clinical and office charts, laboratory notes, 
memoranda, evaluation checklists, pharmacy dispensing records and records, MAR from 
infusion procedures, recorded data from automated instruments, laboratory values, subject 
files, structural and functional MRI images. Data will be collected electronically in the 
RedCap 21 CFR Part 11-compliant system whenever possible. Any paper source documents 
will be kept in binders located in rooms that are locked when not in use, and are only 
accessible to authorized, trained personnel.
Study Records
Study records include but are not limited to regulatory documents, protocols, permissions, 
assents, consenting checklists, case report forms, and subject medical records.
Retention of Records
Study documents will be retained for a minimum of 2 years after the formal discontinuation 
of clinical development of the study intervention. These documents will be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without 
the written consent of the sponsor, if applicable.
Data or Specimen Storage/Security
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data.
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study. Data recorded in 
the electronic case report form (eCRF) derived from source documents should be consistent 
with the data recorded on the source documents.
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) and clinical laboratory data will be entered into Yale REDCap, a 21 
CFR Part 11-compliant a data capture system provided by Yale University. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents.
Handling of Missing Data
We will make every reasonable effort to retain all available patients to preserve the integrity 
of the study data and to minimize possible bias due to the missing data points. We will 
minimize the loss of data by having clear data collection and performance standards to 
achieve highest data quality. We will monitor data collection to ensure quality standards are 
met, including targeted levels of data capture.
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We will undertake sensitivity analyses to assess the impact of the missing response data on 
our conclusions. We will perform single-step (e.g., missing values on the response variable 
replaced by predicted values from linear or generalized linear models of the longitudinal data 
over time) or multiple imputation and compare the performance of the imputed data results 
compared to complete case analyses. It is important to note that the linear mixed model 
method we propose to use is valid under the assumption that missing data is missing at 
random (MAR). Since it is not possible to test the MAR assumption and since for every 
MNAR model there is an equally well fitting MAR model, we believe that the only suitable 
approach is to perform sensitivity analyses according to different plausible scenarios for 
missing data and make sure the conclusions are consistent. If the results are not consistent 
depending on the assumptions for missing data we will report the conclusions based on each 
set of assumptions.
10.1.10
Protocol Deviations
A protocol deviation is any noncompliance with the clinical trial protocol, 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective 
actions are to be developed by the site and implemented promptly.
These practices are consistent with ICH GCP:
•
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3
•
5.1 Quality Assurance and Quality Control, section 5.1.1
•
5.20 Noncompliance, sections 5.20.1, and 5.20.2.
It is the responsibility of the site investigator to use continuous vigilance to identify and 
report deviations within 5 working days of identification of the protocol deviation. All 
deviations must be addressed in study source documents and reported Yale HRPP per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. All deviations will also be reported in summary format to the DSMB in the 
triannual reports and to the NIMH program officer in annual progress reports.
10.1.11
Publication and Data Sharing Policy
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations:
NIH Expectation
Study Action
The applicant will ensure that clinical trial under 
the award are registered and results information is 
submitted to ClinicalTrials.gov as outlined in the 
policy and according to the specific timelines 
stated in the policy
Michael Bloch, MD, MS (PI) in 
conjunction with the Yale Center for 
Clinical Investigation (YCCI), will 
be responsible for handling 
ClinicalTrials.gov requirements for 
this project.
We will register the trial prior to 
enrolling the first patient.
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Informed consent forms (ICFs) for the clinical trial 
will include a specific statement relating to posting 
of clinical trial information at ClinicalTrials.gov.
Per guidance from Title 
21CFR.50.25 (Part 50, Protection of 
Human Subjects, Subpart B, 
Informed Consent of Human 
Subjects), we will include the 
following statement in the ICF: “A 
description of this clinical trial will 
be available on www.clinical 
trials.gov, as required by US Law. 
This website will not include 
information that can identify you. At 
most, the Web site will include a 
summary of the results. You can 
search this Web site at any time.”
The recipient institution has an internal policy in 
place to ensure that clinical trials registration and 
results reporting occur in compliance with policy 
requirements.
Once a record is established, we will 
confirm accuracy of record content, 
resolve problems and maintain 
records including content update 
and modifications. We will also be 
responsible for aggregate results 
reporting and adverse event 
reporting at the conclusion of the 
project.
In addition, every attempt will be 
made to publish results in peer- 
reviewed journals. Data from this 
study may be requested from other 
researchers 5 years after the 
completion of the primary endpoint 
by contacting the PI.
Under the NIH Public Access Policy, the public 
deserves access to the published results of NIH 
funded research.
The PI will ensure that all peer- 
reviewed manuscripts relating to 
this work will be digitally archived 
with PubMed Central upon 
acceptance for publication.
10.1.12
Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership in conjunction with the appropriate conflict of interest 
review committee has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest.
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All investigators will follow the applicable conflict of interest policies. Yale University 
maintains an up-to-date, written, enforced policy on financial conflicts of interest that 
complies with the requirements of Title 42 C.F.R. Part 50, Subpart F. As part of Yale’s 
standard process, investigators are required to disclose, in writing, significant financial 
interests that relate to their research and other Yale responsibilities. In accordance with 
Yale’s COI policy, Yale’s Conflict of Interest Committee (or its designee) determines 
whether significant financial interests (SFIs) present financial conflicts of interest, and by 
what means such conflicts should be avoided or managed.
Dr. Michael Bloch (the Principal Investigator of this award) and Drs. Angeli Landeros, Todd 
Constable, Feng Dai, and Gerard Sanacora have submitted PHS-compliant conflict of interest 
disclosures to Yale’s Conflict of Interest Office. Yale’s COI Policy, posted at 
https://your.yale.edu/policies-procedures/other/yale-university-policy-conflict-interest, 
describes the specific processes and procedures that are in place to identity, address and 
report financial conflicts of interest.
10.2
Additional Considerations
Funding from 1R01MH125203 (PI Bloch)
10.3
Abbreviations
CADSS
Clinician-Administered Dissociative States Scale
CBT
Cognitive Behavioral Therapy
CDRS-R
Children’s Depression Rating Scale- Revised
CPM
Connective-based Predictive Modeling
C-SSRS
Columbia-Suicide Severity Rating Scale
DBP
Diastolic Blood Pressure
DHNK
Dehydronorketamine
ECG
Electrocardiogram
GCP
Good Clinical Practice
HCP
Human Connectome Project
HNK
Hydroxynorketamine
HR
Heart rate
HSP
Human Subjects Protection
ICH
International Conference for Harmonisation
IDS
Investigational Drug Service
MADRS
Montgomery Asberg Depression Rating Scale
MAR
Medication Administration record
MDD
Major Depressive Disorder
MRI
Magnetic Resonance Imaging
NMDA
N-methyl-D-aspartate receptor
NK
Norketamine
PHI
Protected Health Information
SBP
Systolic Blood Pressure
SOP
Standard Operating Procedures
Abbreviation
Explanation
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TORDIA
Treatment of Resistant Depression in Adolescents Trial
TRD
Treatment Resistant Depression
RDoC
Research Domain Criteria
RFA
Request for Applications
SSRI
Selective Serotonin Reuptake Inhibitor
10.4
Protocol Amendment History
Revision #
Version Date
0
09/04/2020
V1.2
09/14/2020
V1.3
09/15/2020
V1.4
10/27/2020
V2.0
03/05/21
V2.1
04/12/21
V2.2
02AUG2021
V2.3
01SEPT2021
V2.4
19OCT2021
V2.5
15NOV21
V3.0
18FEB22
V 4.4
30JAN2023
V 4.5
11SEPT2023
V 4.6
15APR2024
V 4.7
05SEPT2024
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ICF_001.pdf: 
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COMPOUND AUTHORIZATION FOR PARTICIPATION IN A RESEARCH STUDY 
YALE UNIVERSITY SCHOOL OF MEDICINE
Study Title: Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome Phenotypes 
of Intravenous Ketamine
Principal Investigator (the person who is responsible for this research): Michael Bloch, 
MD, MS, 230 S. Frontage Rd., New Haven, CT 06519
Phone Number: (203)745-9921
Research Study Summary:

We are asking you to join a research study.

The main purpose of the study is to find out if intravenous (IV) ketamine lowers suicidal 
thinking in teenagers who have hard to treat depression and a recent suicide event. A 
“suicide event” means either a suicide attempt, an emergency room visit for suicidal thinking, 
or moving to an inpatient unit for suicidality in the past 120 days.

We compare ketamine to an “active placebo” called midazolam. Midazolam is a different 
kind of medicine than ketamine. From now on, when we say “placebo”, we mean 
midazolam.

We are also testing if certain brain-based measures, gotten by functional MRIneuroimaging, 
can tell us whose symptoms will get better with ketamine. This research also looks at how 
ketamine impacts the body’s medical systems (liver function, kidney function, and bladder 
function) and how it impacts mental health symptoms in the 16 weeks after treatment.

Study procedures include:
o (1) clinical interviews and questionnaires,
o (2) four intravenous (IV) medication treatments (you will get either ketamine or the 
active placebo medicine (midazolam); you have a 50/50 chance of getting ketamine. 
Neither you nor the doctor will know which medicine you get),
o (3) if you get the active placebo medicine and you are still depressed or suicidalafter 
the four treatments, you may get four IV ketamine treatments thereafter,
o (4) three 1-hour visits where you will lay in an MRI while they rest or do some tasks, 
and
o (5) after the IV treatments, we give standard of care adolescent depression treatment 
for 16 weeks. This means medication management by a Child and Adolescent 
Psychiatrist and an 8-week course of cognitive behavioral therapy (CBT) by a Child 
and Adolescent therapist. If feasible, we would prefer that you come in person 
for CBT sessions, if clinically appropriate these sessions may be offered remotely 
via telehealth assessment.

Number of Visits: 24 visits are needed over 4 and a half months. If you get the placebo 
medicine first and want to get four ketamine treatments after that, the total number of visits 
goes up to 30 over 5 months.

Time per visit: There are a few different kinds of visits, which take different amounts of 
time. The visits at the start of the study take the longest, and then tend to get shorter later in 
the study.
1
Compound Authorization and Consent Form Template 
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o The first study day (the “baseline”) has lots of questions about mood and mental 
health, and an MRI. It happens on a day before the IV treatment starts and will take 
about 4 hours.
o The first and second IV treatment days will take about 5 hours each and are spaced 
two days apart. We do not schedule activities in between these days so that you can 
rest.
o The third and fourth IV treatment days are shorter, and take about 2.5 hours.
o During the 4-months after the four IV treatments (the “open phase”), weekly visits for 
CBT (8 weeks) and medication checks take about an hour.
o After the 8 weeks of CBT is over, weekly mood checks will take about 30 minutes and 
can happen over the phone. The monthly in-person mood and thinking/remembering 
questions will take about 1.5 - 2 hours.

Possible Risks: There are some risks from being in in this study. Ketamine and the placebo 
medicine (midazolam) are FDA approved for anesthesia but they are not FDA approved for 
depression or suicidal thinking in adults. The FDA considers ketamine to be an 
Investigational New Drug in this study. The doses used in this study are lower than what 
someone would get for anesthesia and the study team has used them before in teenagers 
with depression. But they do still carry risks when they are given. Some risks are mild and 
common, such as nausea, feeling sleepy, feeling “out of it” or other psychological 
symptoms, and changes in blood pressure, heart rate, or breathing. Other risks are more 
rare but serious, such as changes in heart rhythm, severe slowing of breathing, big changes 
in blood or eye pressure, or psychological reactions that go on for a longer time. The level of 
risk of giving repeated doses of ketamine over time is not known. Rare, but serious possible 
longer-term risks implied from animal studies include brain toxicity, cognitive or thinking 
problems, liver and bladder inflammation (swelling), and substance abuse or dependence. 
Other study risks include discomfort from blood draws and getting an IV, discomfort from 
answering sensitive mental health questions, and feeling confined or having anxiety during 
an MRI. It is also possible that mental health symptoms could get worse during the study. 
Feeling worse could be due to the natural ups and downs of the illness, being assigned to 
placebo treatment (although we limit this risk by the option to get ketamine treatment after 2 
weeks), or not having a therapeutic response to ketamine.

Possible Benefits: The study might also directly help you. Studies with adults show that 
ketamine improves depressive symptoms and suicidal thinking in some patients, usually for 
a short time, or several days. The placebo (midazolam) is also used to help anxiety in 
children and adults, but often has shorter lasting effects than ketamine. If you get midazolam 
at first, you will be offered ketamine treatment after if you still feel depressed or have suicidal 
thinking. During all parts of the trial, the increased time spent with a child psychiatrist and 
research staff may be helpful to you.

Other options: There are other choices available to you instead of this study. One other 
option is to continue your current mental health medications or therapy. Another option is to 
choose other depression treatments that are available from your doctor. There are multiple 
medicines and therapies that have been shown to help depression in teenagers. Another 
choice is to join a different pediatric depression study.
2
Compound Authorization and Consent Form Template 
(Biomedical) Version 3.4 22MAY2024
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#2000029003

Safety: Your safety is very important. If we think that you are in immediate danger ofhurting 
yourself or someone else, hospitalization is required. A hospitalization does not 
automatically mean that you cannot be in the study anymore. We will work with you, and 
your clinical teams to decide whether staying or leaving the study is in your best interest.

Agreeing to take part in this study is your choice. You can choose to participate, or you can 
choose not to. You can also change your mind at any time. Whatever choice you make, you 
will not lose access to your medical care or give up any legal rights or benefits.

If you are interested in learning more about the study, please continue reading, or have 
someone read to you, the rest of this document. Take as much time as you need before you 
make your decision. Ask the study staff questions about anything you do not understand. 
Once you understand the study, we will ask you if you wish agree to participate; if so, you 
will have to sign this form.
Why is this study being offered to me?
We are asking you to join a research study because you have hard to treat depression and 
recent suicidal thinking. Hard to treat depression means that you are still depressed after trying 
an antidepressant medicine. You also must have had serious suicidal thinking or action in the 
last 120 days. We are looking for 40-66 adolescents to be part of this research study.
Who is paying for the study?
The National Institutes of Mental Health (NIMH) is paying for this study. The NIMH research 
grant is R01MH125203.
Who is providing other support for the study?
None
What is the study about?
The main purpose of this research study is to find out if IV ketamine reduces suicidal thinking 
compared to an active placebo (a different medication, midazolam) in adolescents who have 
hard to treat depression and a recent “suicide event”. A “suicide event” can mean a suicide 
attempt. It can also mean an emergency room visit for suicidal thinking, or a move to an 
intensive outpatient or inpatient care for suicidality. “Recent” means within the last 120 days.
We are also testing whether certain brain-based measures, obtained by functional MRI brain 
imaging, can tell us who will feel better with ketamine. We also want to know how the brain 
changes with treatment. This research also looks at how ketamine impacts the body’s medical 
systems (liver function, kidney function, and bladder function) and how it impacts mental health 
symptoms in the 16 weeks after treatment. Ketamine has not been FDA approved for treating 
depression or suicidal thinking for patients of any age.
What are you asking me to do and how long will it take?
If you agree to join this study, this is what will happen:
Screening Visit:
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The purpose of the screening visit is for us to tell you about the study. We will tell you about the 
risks, benefits, and other options. This visit is also for the research team to get to know you to 
see if the study might be an appropriate fit. After you give your consent, we begin the main 
study screening procedures to see if you can be in the study. The study screening usually 
happens in a single visit and takes between 2 and 3 hours. The visit includes a clinical 
evaluation, a review of past treatments, a medical assessment, and a urine test for drug use 
and pregnancy. We will ask you sign a release of information so that we may talk to your mental 
health providers. We will establish a connection with them so that we can talk to each other 
throughout the study. We will also give you a doctor’s order to get lab tests after your visit.
Clinical Evaluation: This study is for adolescents (13 to 17 years old) who have hard to treat 
depression and recent suicidal thinking or action. Hard to treat depression means that you have 
a diagnosis of Major Depressive Disorder and are still depressed after trying an anti-depressant 
medicine. First, we will interview you to understand your mental health history. We will focus on 
depression and other disorders related to your condition. We will review your medical history, 
your current medications, and all other medication and behavioral treatments for depression that 
you have tried. If we find that you have hard to treat depression and had significant suicidal 
thinking or behavior within the last 120 days, we will go to the next step, which is the medical 
assessment.
Medical Assessment: The study doctor will perform a brief physical exam, including getting vital 
signs. We will give you a lab order to get an electrocardiogram (ECG) to trace the electrical 
activity of your heart. We will also give you a lab order for blood collection and urine collection, 
to check your health. Blood collection happens by venipuncture (entering a vein with a needle 
through the skin) and about 2 tablespoons of blood are needed. These are standard medical 
checks to make sure that you are healthy and eligible for the study. If any worrisome finding is 
seen in your blood work or ECG results, the primary study doctor or another doctor will contact 
you. They will tell you about the finding and discuss what they recommend from there. The 
decision to get additional medical exams or treatment would be completely up to you and your 
regular doctor. The investigators, the consulting doctor, and Yale University are not responsible 
for any exams or treatment that you get based on these findings.
Rating Scales: Trained research staff will ask you to complete rating scales about your feelings 
and behaviors. These rating scales are research-related. They will find out if you meet diagnosis 
and severity criteria for the study. To be eligible for this study, you must have had significant 
symptoms of depression and recent suicidal thinking. You will be asked to complete surveys 
which include questions about depression, thoughts of suicide, appetite and weight, quality of 
sleep, memory, energy level, and current feelings, etc. For some surveys the doctor will ask you 
the questions and for others you will use a tablet to read questions and give answers on your 
own. Study staff will be present at all times to assess safety.
Drug, Alcohol, and Pregnancy Testing: Female participants of childbearing potential will require 
pregnancy testing by a blood test before they can be in the study. Once you are in the study, 
you will have urine pregnancy tests during the treatment phase. Only you will be told the results. 
We will, of course, counsel you to seek appropriate healthcare and if you were found to be 
pregnant. A positive pregnancy test means that you cannot be in this study. If you are not 
comfortable with pregnancy testing, then we would recommend that you do not participate.
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The medicines used in this study pose a risk to an unborn baby if they are taken while pregnant. 
For this reason, sexual abstinence is strongly recommended. Contraceptive use is required for 
any heterosexually active participants during the treatment phase and for a certain time after 
that. For females, that time is 30 days after the last dose of study medication. For males, that 
time is 90 days after the last dose. Forms of contraception that we accept include: hormonal 
birth control being taken for at least 1 month before screening, intrauterine device, condom with 
spermicide (cream, spray, foam, gel, suppository, or polymer film), diaphragm with spermicide 
(with or without condom), cervical cap with spermicide (with or without condom), or vaginal 
sponge impregnated with spermicide used with a condom. Not having sex at all (sexual 
abstinence) is strongly recommended. Participants who practice total abstinence from sexual 
intercourse as their preferred lifestyle are not required to use additional contraception. Male 
participants are also asked to use a condom if their partner is pregnant and agree not to donate 
sperm during the study. Please tell your study doctor right away if you think you might be 
pregnant or are planning a pregnancy.
We will also need to ask you about current or past use of alcohol and illicit "street" drugs. We 
will require a urine toxicology screen on the screening day and at other times during the study. If 
you decide not to join the study, this drug testing information will be destroyed. If you are using 
drugs now or have a history of drug dependence, you will not be able to participate in this study. 
However, if you choose not to share, we must keep this information confidential. If you are 
uncomfortable with drug testing or talking about drug use, then we would recommend that you 
do not join this study. Throughout the study, if you are in immediate danger of hurting yourself or 
someone else, we will refer you to get an emergency evaluation.
Baseline (Study Day 0, Visit 1)
Once screening is complete (including review of lab results), we will know if you are eligible for 
the study. If eligible, you will be enrolled in the study and we will schedule the baseline visit. We 
ask you, and your outpatient psychiatrist to avoid making any medication changes. This means 
not changing the medicine type or the dose until the follow-up phase of the study. The baseline 
visit occurs on a Monday and lasts about 4 hours.
Rating Scales and Questionnaires: You will come to the Child Study Center to complete the 
baseline clinical assessments. Questionnaires are about both mood and cognition, which refers 
to how someone thinks and remembers. We expect the questionnaires and cognitive testing to 
take about 2 hours.
Safety Planning: You will meet with the study therapist. You will work together to create your 
safety plan. This includes identifying triggers, coping skills, and people to call if there is a crisis. 
We will include phone numbers for the study staff, including a 24-hour phone number for a study 
clinician. We will ask you to keep copies of the plan in places that are easy to find in your home. 
We will review and update the plan throughout the study.
MRI neuroimaging: After the questions, a member of the research team will bring you to the 
Magnetic Resonance Research Center (MRRC). They will stay with you for the entire scan. 
There, you will review safety procedures with study staff, including walking through a metal
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detector. Part of your body will be passed into a long, narrow tube – the MRI scanner – which is 
open at both ends. You will lie on your back in the scanner.
The MRI machine is very loud. You will be given ear plugs, and headphones will be placed over 
your ears to dampen out the sounds of the machine (the MR system). You may have a clip 
placed on your finger to monitor your pulse, and a belt placed across your abdomen to monitor 
breathing patterns. Your head will be cradled in pillows and a special holder before being moved 
into the MR magnet in order to help you keep still throughout the study. The researchers 
operating the MR system will be able to see you, and you will be able to talk with them while in 
the magnet. You will be able to see out into the room via a mirror prism. When the study starts, 
we will begin taking images of your brain. When an image is being taken, the machine will make 
a short burst of noise. You will be required to lie as still as possible. You will be inside the 
scanner for 1 hour. For some portion of this time, while we perform scans of the function of your 
brain, you will participate in computer tasks in which you will look at a screen inside the scanner, 
listen to information presented through headphones (loud enough to hear despite the earplugs), 
or both. For some tasks, you will press buttons in response to the task. For other portions of the 
time in the scanner, you will not need to do any task.
MRI tasks include:
1.
Card guessing task: You will be shown a card on a screen and will have to guess whether the 
number on the other side of the card is less than or greater than five. The card will then be 
flipped over and you will be told if you guessed correctly via feedback on the screen.
2.
N-back task: You will be asked to watch a set of pictures (or words) and push a button if a 
new picture (or word) is the same as the previous item (1-back condition) or as the item that 
came two items before (2-back condition).
3.
Response inhibition task: You will see items on the screen and either respond (go trial) or not 
respond (no-go trial), depending on the presented item.
4.
Understanding mental states task: You will be asked to infer the perspective of others, either 
by looking at photographs of their eyes and labeling the emotions of the person in the picture, 
or by responding to questions that require you to interpret social “hints” in vignettes.
5.
Perception: You will be asked to passively watch images on a screen or listen to sounds 
through headphones, which could include flashing checkerboards, movie clips, beeps and 
tones, blank screens, etc.
6.
Resting state run: You will be asked to stay still with his or her eyes open during the resting 
runs. There is no task involved.
Phase A1: Double Blind Phase (doctors and participants do not know which medicine you 
are assigned) (IV Treatments on Days 1, 3, 8, 10 Visits 2 – 6 and Post-Treatment (Day 11,
Visit 7)
Once enrolled, you will be scheduled to receive four IV treatments over a 2-week period. You 
will get either ketamine (the study drug) or midazolam (the active placebo). IV treatments occur 
on Tuesdays and Thursdays. The first treatment will be on Visit 2 (Day 1). The Yale 
Investigational Drug Service will decide which medicine you get. Neither you nor the study 
doctors and nurses will know which treatment was assigned during these first 2 weeks. In an 
emergency, we can find out right away which medicine you got. All IV treatments will happen at 
the Interventional Psychiatry Service (IPS) at Yale Psychiatric Hospital.
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We ask you to follow American Society of Anesthesiologists eating guidelines the night before 
the treatments. These rules allow milk or a “light meal” 6 hours before the treatment and clear 
liquids up to 2 hours before. One hour before the IV treatment, catheters (small plastic tubes) 
will be placed in your arm or hand. These are used to give the IV treatment and to collect 
samples of blood (approximately 2 tablespoons total). On the first treatment day (Day 1, Visit 2), 
two IV’s will be placed to make bloodwork collection easier. On the other IV treatment days only 
one IV will be placed. The blood samples are only used for research. They will be used to 
measure the way that ketamine is broken down in the body. Before each treatment, you will be 
asked a series of questions by a trained research staff member who is supervised by a licensed 
professional. The questions are about your depression symptoms, and other psychiatric 
conditions or physical symptoms. You will get an ECG before the first IV treatment, and a rapid 
urine drug screen and urine pregnancy test (if applicable) before the first and third treatments.
Before the second IV treatment (Day 3, Visit 4), you will have your second brain imaging 
session. The brain imaging tasks are the same as the ones you did at baseline. The scanning 
session will take less than 1 hour. For the day in between the first and second treatments, we 
will not ask you to come in, but will check in with you by phone. On the phone, we will ask about 
mood and any physical symptoms (estimated phone time of 20 minutes).
Once questionnaires and medical checks are finished (estimated to take 30 minutes to 1 hour), 
we will start the IV treatment. The medication (ketamine or placebo) will be given through the IV 
catheter in your arm or hand, which takes 40 minutes. Afterward, the study doctor will ask you 
questions to check how you are feeling. Your vital signs will be monitored for two hours after 
the IV treatment. A doctor who has extra training to handle medical emergencies (Advanced 
Cardiovascular Life Support certification), a trained research nurse, and a psychiatrist will be 
present at all times during the treatment and recovery. You will come back on Day 11 (Visit 7), 
which is the day after the last IV treatment. This in-person visit includes an in depth assessment 
of mood, thinking, and remembering. It will take about 2 hours. After the rating scales are 
finished on Day 11, the study doctor will contact the pharmacy to ask which medicine you have 
been getting. If you were getting the active placebo (midazolam) and your mental health 
symptoms have not gotten significantly better, we will discuss with you the option for you to get 
four ketamine IV treatments, starting the next week.
The first IV treatment visit will take about 5 hours. It is longer than the others because of blood 
draws after the IV treatment. The second treatment visit will take about 4 hours. It is longer 
because of the brain imaging session. The treatment visits after that will take about 3 hours.
Another responsible adult must be available to take you home from this visit. You should not 
drive for 24 hours following the procedure. The in-person follow-up visit on Day 11 will take 
about 2 hours.
Phase A2: Open Phase IV Ketamine Treatments (doctors and participants know that you 
are getting ketamine)—this phase is only available if you received the active placebo in the 
first phase (A1) and did not get significant symptom improvement. (IV Treatment on Days 15, 
17, 22, 24 Visits 8 – 12 and Post-Treatment Day 25, Visit 13).
In the first phase of the study (A1), you will get either ketamine or the active placebo 
(midazolam). So that we can offer active ketamine treatment to all participants who still have 
severe symptoms, at the end of the first 2 weeks, we will find out which medicine you got. If you
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got midazolam and still have severe symptoms, we will offer you the choice to now get 4 
ketamine treatments. If you decide to do this, the study procedures are identical to the ones 
described in Phase A1. That includes additional blood tests on the first IV treatment day (Day
15) and a brain imaging session before the second IV treatment (Day 17). The four open IV 
ketamine treatments will be followed by an in-person assessment on Day 25 (Visit 13).
If you got ketamine during the first 2 weeks, you will go directly to Phase B. If you got 
midazolam in the first 2 weeks and your symptoms got much better, you will also go directly to 
Phase B. There are no additional ketamine treatments for these groups.
Table 1. Study Outline for First Phases (A1 and A2)
D1
D3
D8
D10
D11
Screening Baseline 
(D0)
(D15)
(D17)
(D22)
(D24)
(D25)
IV Treatment
X
X
X
X
Physical Exam
X
ECG
X
X
Blood Draw
X
X
Urine Tests
X
X
X
Brain imaging
X
X
Symptom 
Questionnaires
X
X
X
X
X
X
X
Cognitive Testing 
(assesses 
thinking and 
remembering)
X
X
Estimated 
Total time
2-3
hours
4
hours
5 hours 4 hours
3 hours
3 hours
2 hours
Phase B: Open Phase Follow-up and Standard of Care Depression Treatment 
(Visits 8 – 24 for participants proceeding directly from Phase A1) 
(Visits 14 – 30 for participants proceeding from Phase A2)
After finishing the IV treatments, we provide you with standard of care depression treatment 
through the study. We used the guidelines of the American Academy of Child and Adolescent 
Psychiatry to design the treatment. You will get medication management visits with a Child and 
Adolescent Psychiatrist. You will also get an 8-week course of CBT with a trained therapist. In 
this phase, you will have weekly mood check-ins and monthly in-depth mood and cognitive 
assessments with our research staff. If feasible, we would prefer that you come in person 
for CBT sessions, if clinically appropriate these sessions may be offered remotely via 
telehealth assessment.
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The study team works to group study procedures with the standard of care depression 
treatment to make visits more convenient. In the first 8 weeks of follow-up, visits include about 
30 minutes of symptom questionnaires, a 15-minute med management visit, and a 45-minute 
CBT session (total visit is about 1-1.5 hours). Every fourth week, there is a more in-depth 
assessment of mood, thinking, and remembering, that you must come in for. This is instead of 
the basic mood symptom questionnaires. These visits will take about 2.5 hours.
If there is a pandemic or public-health related reason that you can’t come in person, we may 
have these visits by telehealth.
For the last 8 weeks of the follow-up phase, the course of CBT will have ended. Then, the brief 
mood questionnaires can happen over the phone (taking about 30 minutes). The only required 
in person visits will be for the last two monthly in-depth mood and cognitive assessments.
Table 2. Study Outline for Second Phase (Follow-up)
Study Day
CBT
Medication 
Management
Brief mood 
question- 
aires
Mood and 
Cognitive 
Testing
Blood 
and 
Urine 
Labs
Location
Estimate 
d Time
D17
(D31)
X
X
X
In 
person/Te 
lepsychiat 
ry
1.5
hours
D24
(D38)
X
X
X
In 
person/Te 
lepsychiat 
ry
1.5
hours
D31
(D45)
X
X
X
In 
person/Te 
lepsychiat 
ry
1.5
hours
D38
(D52)
X
X
X
In 
person/Te 
lepsychiat 
ry
2.5
hours
D45
(D59)
X
X
X
In 
person/Te 
lepsychiat 
ry
1.5
hours
D52
(D66)
X
X
X
In 
person/Te
lepsychiat 
ry
1.5
hours
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D59
(D73)
X
X
X
In 
person/Te 
lepsychiat 
ry
1.5
hours
D66
(D80)
X
X
X
X
In 
person/Te 
lepsychiat 
ry
2.5
hours
D73
(D87)
X
Telepsych 
iatry
30
minutes
D80
(D94)
X
Telepsych 
iatry
30
minutes
D87
(D101)
X
Telepsych 
iatry
30
minutes
D94
(D108)
X
X
In person
2 hours
D101
(D115)
X
Telepsych 
iatry
30
minutes
D108
(D122)
X
Telepsych 
iatry
30
minutes
D115
(D129)
X
Telepsych 
iatry
30
minutes
D122
(D136)
X
X
X
In person
2 hours
D126
(D140)
Discharge Visit
In person
1 hour
Discharge from the study
If you are still very depressed or at increased suicide risk at the end of the study, the study will 
help make referrals. Referrals could include other outpatient mental health doctors, intensive 
outpatient programs, or inpatient psychiatric hospitals. The study staff may continue close 
monitoring of you if your symptoms put you at elevated risk until the referrals are in place.
What are the risks and discomforts of participating?
(A) Risks of Ketamine and Midazolam
The experimental (study) drug in this study, ketamine, is a medicine approved by the FDA 
to be used as an anesthetic in children and adults. An anesthetic is a medicine used to block
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sensations or pain, and to make people drowsy or sedated during surgery. Ketamine is not 
FDA approved to treat depression or suicidal thinking in adults or children. All of the risks of 
ketamine are not fully known. The dose of ketamine used in this study is lower than the dose 
typically used for anesthesia. You will be told that it is possible for people to abuse ketamine. 
It is unclear whether exposure to ketamine in the laboratory can result in recreational 
ketamine use or abuse. If you are concerned about this possibility, you should not join this 
study.
The active placebo drug, midazolam, is a medication that is approved by the FDA as a 
sedative for both children and adults. It is a benzodiazepine used commonly in pediatric 
dentistry and conscious sedation. “Conscious sedation” means ways to use medicines to 
relax people or decrease pain without putting them fully to sleep. It is often given more quickly 
and at higher doses than in the current study. Midazolam is not FDA approved for depression 
treatment or suicidal thinking in adults or children. We do not expect it to improve depression 
symptoms or suicidality. If used often, midazolam also has the potential for physical 
dependence and abuse.
Now we will describe the potential effects of ketamine or midazolam that you may or may 
not experience. Both midazolam and ketamine are medicines that are broken down quickly 
by the body. Side effects are not typical after 30 to 60 minutes after getting the medicine. 
Our research group has significant experience giving ketamine and midazolam to 
adolescents with depression.
The most common short-term side effects of these medications are:
1.
Elevated blood pressure, breathing rate, heart rate, and sweating
2.
Local pain at injection site and temporary rash
3.
A variety of temporary psychological symptoms including, but not limited to anxiety, 
sadness, disorientation or confusion, decreased concentration, decreased pain, 
feeling high, feeling detached from surroundings, flashbacks, hallucinations (hearing 
or seeing things that are not really there), dream-like sensations, changes in the way 
colors or sounds are perceived, changed bodily sensations (e.g. floating), and 
psychotic symptoms.
4.
Many people also experience sleepiness, sedation, or blurred vision
5.
Nausea, vomiting, hiccups: the risks of vomiting will be minimized if you do not eat 
anything on the morning of the IV treatments. If you still get nauseous, we can give 
an anti-nausea medicine called ondansetron. If given for nausea, 4mg of 
ondansetron is given by mouth. The dose can be repeated one more time for a total 
amount of 8mg. There may be side effects from taking ondansetron and we will tell 
you about those.
6.
Headache
Less common short-term side effects of these medications are:
1.
Respiratory depression or slowed breathing
2.
Enhanced muscle tone causing shakiness and jerking movements
Rare but serious possible short-term risks or side effects of these medications are:
1.
Changes in heart rhythm
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2.
Severe slowing down or stopping of breathing (apnea)
3.
Elevations in intraocular pressure (eye pressure) that could lead to vision problems
4.
Recurrences of psychological side effects such as hallucinations, disorientation, or 
anxiety up to 24 hours after the dose administration.
5.
Allergic reactions are possible. Serious allergic reactions can belife-threatening
6.
Elevation in blood pressure that could result in stroke, heart problems, anddeath
7.
Drop in blood pressure
We believe that the risks of serious adverse heart or breathing events are low because we 
have chosen low doses for this study. In any case, airway equipment and qualified medical 
personnel will be readily available.
Rare but serious possible longer-term risks of these medications are:
1.
Neurotoxicity: risk is larger in young children (less than 3 years old) and is thought to 
relate to high doses or long exposures. However, the exact dose or number of 
exposures that can cause these problems in humans is unknown. High amounts of 
ketamine given to rats caused damage to different parts of the brain. It is not known 
whether this finding in rats will happen in humans, but the ketamine doses given to you 
will be lower than the amounts given to the rats in the animal study.
2.
Adverse effects on cognition (thinking and remembering): The added effect of 
repeated ketamine treatments is unknown. People who have taken ketamine 
many times (mostly people who are abusing ketamine for recreational purposes) 
have structural and functional brain changes that are associated with cognitive 
problems. We are uncertain if this will occur with the four ketamine doses 
proposed in this study. We will be carefully following your cognitive function during 
this study with monthly neurocognitive testing.
3.
Liver and bladder inflammation: Bladder and liver inflammation have been related to 
the repeated use of ketamine (mostly in people who are abusing ketamine). We are 
uncertain if this will occur with the four ketamine doses proposed in this study,however 
we will be monitoring liver, kidney, and bladder health at 2 months and 4 months into 
the study.
4.
Substance abuse/dependence: If at any point after completing this study you 
become aware that you are having a desire to use or abuse ketamine or 
midazolam, you should contact us right away. We will refer you to an appropriate 
treatment facility if necessary. In our experience doing research with these 
medicines, we are unaware of people abusing ketamine as a result of being in a 
study.
You will be evaluated by a clinical member of the research staff before leaving the IV treatment 
visits. This is to ensure that all clinically significant medication effects have gone away and that 
it is safe to leave the research site. Before arriving, please arrange how you will be transported 
back home. You should not drive to avoid any difficulties with lingering sleepiness. Some people 
have reported mildly decreased concentration or a ‘hangover’ on the day after receiving these 
medications, or more vivid dreams.
People with a history of mental health problems may be more likely to have an unpleasant 
experience when taking these medicines. So, please tell us as much as you can about your past 
and present mental health difficulties during screening.
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We also take a number of precautions to help reduce the chance of having an unpleasant 
response to the study medications and to reduce the severity of any potential lingering effects. 
These precautions include:
1) A research clinician will be there throughout the study visit to offer support. They can also 
help spell out the progress of the treatment day in case the medicine makes you feel confused. 
A research doctor will also be available.
2) If you experience psychological distress, diazepam may be given. Diazepam is a medicine 
that helps to quickly reduce anxiety. If used for anxiety, 5mg of diazepam is given by mouth one 
time.
3) We will ask you to stay at the treatment site for at least two hours after the behavioral effects 
of the study medications are expected to wear off. Please see study schedule for the details of 
each IV treatment day.
4) We will review the treatment day with you to explore any feelings and reactions to the session 
before leaving.
5) We will ask you to contact us at any time if any unpleasant effects occur.
6) We will ask you not to engage in demanding work on the day after the treatment sessions.
7) If you have any medication effects that last longer than expected, such as drowsiness, we will 
terminate the remaining test days. We will work with you and you until these side effects have 
resolved.
8) If your mental health significantly worsens, you will be referred to the Yale-New Haven 
Hospital Psychiatric Emergency Room for further evaluation and treatment. No adult patients 
getting ketamine for depression in research studies have needed psychiatric hospitalization 
because of side-effects of ketamine or midazolam given during the study. If you are determined 
to be an acute danger to yourself or others, psychiatric hospitalization would be required.
9) This study is designed to evaluate the anti-depressant, anti-suicidal, and safety profile of the 
study medicines in the 16 weeks after the last dose. We will have frequent contact with you over 
those 16 weeks post-treatment. Please see Table 1 for the contact schedule during the 
treatment phase. See Table 2 for the contact schedule during the 16-week post-treatment 
phase.
(B) Risks of Neuroimaging (MRI) studies
Magnetic resonance imaging (MRI) is a technique that uses magnetism and radio waves, not x- 
rays, to take pictures and measure chemicals of different parts of the body. The FDA has set 
guidelines for magnet strength and exposure to radio waves. We carefully observe those 
guidelines.
You will be watched closely throughout the MRI study. Some people may feel uncomfortable or 
anxious. If this happens to you, you may ask to stop the study at any time, and we will take you 
out of the MRI scanner. On rare occasions, some people might feel dizzy, get an upset 
stomach, have a metallic taste, or feel tingling sensations or muscle twitches. These sensations 
usually go away quickly, but you should tell the research staff if you have them.
There are some risks with an MRI study for certain people. If you have a pacemaker or some 
metal objects inside your body, you may not be in this portion of the study because the strong 
magnets in the MRI scanner might harm you. Another risk is the possibility of metal objects 
being pulled into the magnet and hitting you. To reduce this risk, we require that all people
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involved with the study remove all metal from their clothing and all metal objects from their 
pockets. We also ask all people involved with the study to walk through a detector designed to 
detect metal objects. It is important to know that no metal can be brought into the magnet room 
at any time. Also, once you are in the magnet, the door to the room will be closed so that no 
one from outside accidentally goes near the magnet. It is also necessary to know whether you 
have a tattoo or a self-tattoo, and where the tattoo is located. You will be instructed to inform 
the research team if you feel pain, burning, or an uncomfortable sensation at the tattoo site.
We want you to read and answer very carefully the questions on the MRI Safety Questionnaire 
related to your personal safety. Take a moment now to be sure that you have read the MRI 
Safety Questionnaire. Please be sure to tell us any information you think might be important.
This MRI study is for research purposes only and is not in any way a healthcare exam. The 
scans performed in this study are not designed to find abnormalities. The principal investigator, 
the lab, the MRI technologist, and the Magnetic Resonance Research Center are not qualified 
to interpret the MRI scans and are not responsible for providing a healthcare evaluation of the 
images. If a worrisome finding is seen on your scan, a radiologist or another physician will be 
asked to review the relevant images. Based on his or her recommendation (if any), the principal 
investigator or consulting physician will contact you. They will inform you of the finding regarding 
your exam, and recommend that you seek medical advice as a precautionary measure. The 
decision for additional examination or treatment would lie only with you and your physician. The 
investigators, the consulting physician, the Magnetic Resonance Research Center, and Yale 
University are not responsible for any exam or treatment that you gets based on these findings. 
The images collected in this study are not a healthcare MRI exam and, for that reason, they will 
not be made available for healthcare purposes.
If you are unable to get an MRI or feel very uncomfortable getting an MRI, please let us know. 
You may still be able to do the treatment parts of the study if you meet all of the other study 
criteria.
(C) Risk of Blood Drawing/IV placement: This study requires drawing blood and the placement 
of an IV needle into your arm in order to deliver the study medicines. These procedures may 
cause pain, bruising, lightheadedness, fainting, and, on rare occasions, infection. These risks 
will be minimized by using trained personnel who will draw blood and insert IV needles under 
sterile conditions. A total of 5 tablespoons of blood be drawn over the first 2 weeks. That 
includes 2tbsp at baseline and 3tbsp on the first IV treatment day (Day 1). If you go on to get 
ketamine treatment after at first being assigned to placebo, another 3tbsp will be drawn on the 
first day of the ketamine series (Day 15). We collect labs two more times during the 4-month 
open phase (Phase B). We collect 2tbsp at the half-way point and 2tbsp at the end.
(D) Risk of Questionnaires: As part of the study, you will be asked to complete questionnaires 
about your feelings and behaviors. It is possible that you may find these questionnaires to be 
upsetting. However, these questions have been used in research before and a negative 
reaction has been uncommon. A trained researcher will be asking these questions under the 
supervision of a study doctor. You do not have to answer any questions that make you feel 
uncomfortable.
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(E) Risk of Worsening Symptoms: There is a risk that you may experience an increase in 
depression symptoms or suicidal thinking. This could be due to the natural course of the illness 
or being given the placebo during the first 2 weeks. It could also be because of a poor response 
to ketamine treatment. You will be asked not to change any of your medicines during the first 
2 weeks of the study, there will be frequent follow-up by the study team. Additionally, the 
standard of care treatment for a child or adolescent who insufficiently responds to initial 
antidepressant therapy is to try another antidepressant or add an additional medication. By 
participating in this trial, you would be delaying the standard of care change in your medication 
by 2-4 weeks. If you feel that your symptoms are getting worse, you will be evaluated by a 
clinic psychiatrist. You will be provided treatment if appropriate, in collaboration with your 
outpatient mental health provider(s). Referrals may be given if a higher level of care (such as 
an intensive outpatient program) is recommended. If you are in immediate danger of hurting 
yourself or someone else, hospitalization is required. Being hospitalized does not automatically 
mean that you must leave the study. We will work with you and the hospital team to decide 
whether staying or leaving the study is in your best interest. If new medicines are needed to 
treat the worsening symptoms, you should know that this decision will not affect your eligibility 
to participate in future studies. It also will not affect your chance to get treatment at the Yale 
Child Study Center or Yale New Haven Hospital, or to get treatment on a private basis from a 
referring doctor. Everyone in the study will be given wallet-sized cards, which provide contact 
information. The cards will identify the HIC number of the study, the study PI (Michael Bloch, 
MD, MS 203-745-9921), and the Yale Investigational Drug service phone number (203-688- 
4872). They will also have telephone contact numbers for research support staff.
(F) Risk of time commitment: The first two weeks of the study are busy. It is likely that it will be 
hard to be at school full-time while getting the experimental treatments. If you get placebo at 
first, then ketamine after, the next two weeks are busy also. Not being at school full-time 
everyday can impact school performance. The study team can provide doctor’s notes for school 
or another commitment to explain why you were absent. We can also suggest that your school 
allow re-arranging assignments or modifying the workload during this part of the study.
(G) Risk of Remote Assessments: Like online shopping, videoconferencing technology 
has some privacy and security risks. It is possible that information could be intercepted 
by unauthorized people (hacked) or otherwise shared by accident. Thisrisk can’t be 
completely eliminated, however Yale has approved the use of an encrypted version of 
zoom for videoconferencing sessions because the appointments take place over a 
secure encrypted network. We want to make sure you are aware of this.
Video sessions can be conducted using a smart phone, tablet or personal computer 
enabled with a camera/microphone and internet connection. You should use your home 
computer or personal device, and not a shared or work device, and use a home 
(private) Wi-Fi network, and not free (public) Wi-Fi for your internet connection. To use 
zoom, an e-mail will be sent to you including the instructions for how to log-in. When 
meeting with the team remotely for study-related activities, you should be in a private 
space.
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There is limited experience with ketamine in the treatment of teenage depression. 
Therefore, the study may involve risks and side effects that we cannot predict or foresee.
How will I know about new risks or important information about the study?
We will tell you if we learn any new information that could change your mind about you taking 
part in this study.
How can the study possibly benefit me?
The study has the potential to directly benefit you. Studies with adults show that ketamine 
improves depressive symptoms and suicidal thinking in some patients. This is usually for a short 
time, or several days. Midazolam (the placebo) is used to reduce anxiety in children and adults. 
Midazolam typically has shorter lasting effects than ketamine (lasts for minutes to hours). Even 
if you get midazolam in the first phase, you will have the option to get open ketamine treatment 
afterward if you still have significant depression or suicidal thinking. During all parts of the trial, 
you may get some benefit from increased contact with a child psychiatrist and research staff.
Through this study you will also receive a thorough medical and mental health evaluation.
How can the study possibly benefit other people?
The benefits to science and other people may include a better understanding and treatment of 
depression and suicidality in teenagers. Your involvement may also help us better understand 
how brain function links to treatment outcomes with these medications.
Are there any costs to participation?
If you join this study, you will not have to pay for any services, supplies, study procedures, or 
care that are provided for this research only. “Research only” means that it is NOT part of your 
routine medical care. However, there may be additional costs to you.  These can include costs 
of transportation and the time to come to the study visits. You or your health insurance must pay 
for services, supplies, procedures, and care that are part of your routine medical care. You will 
be responsible for any co-payments required by your insurance.
Will I be paid for participation?
To try to offset costs related to your travel and time, you will be paid in the following way: 
Completing the 2-week double-blind phase: $40
If applicable: completing the 2-week open ketamine phase: $40
Open Phase:
Completing all 4 visits and rating scales in Month 1: $80 
Completing all 4 visits and ratings scales in Month 2: $80 
Completing all 4 visits and rating scales in Month 3: $80 
Completing all 5 visits and rating scales in Month 4: $80
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You are responsible for paying state, federal, or other taxes for the payments you receive for 
being in this study. Taxes are not withheld from your payments.
We will use a Bank of America pre-paid debit card to provide the payment for taking part in the 
study. We will have to share your name, address, and telephone number with Bank of America 
for ePayments. You will receive a card in the mail with the first payment. You will need to 
activate the card over the phone. Each additional payment will be automatically added to your 
card.
What are my choices if I decide not to take part in this study? 
Instead of joining this study, you have some other choices. 
You could:

Get treatment without being in a study. Other options involve continuing your current 
medicines or therapy. The study doctor will discuss these with you. You do not have to 
join this study to be treated for depression. There are multiple medicines and behavioral 
therapies that have been shown to be effective for pediatric depression. Examples of 
medicines include fluoxetine, sertraline and other selective-serotonin reuptake inhibitors. 
Examples of psychotherapy include cognitive behavior therapy. Electroconvulsive 
therapy is FDA approved for severe adolescent depression and can be appropriate.

Take part in another study.

Receive comfort care only, without any treatment for your disease.
How will you keep my data safe and private?
We will keep information we collect about you confidential. We will share it with others if you 
agree to it or when we have to do it because U.S. or State law requires it. For example, we will 
tell somebody if we learn that someone is hurting a child or an older person.
Any study records that identify you and the study parental permission form and assent form 
signed by you will be locked in a file cabinet in the Yale Child Study Center. They will be made 
available only to the researchers on this study. Any electronic study information will be stored on 
a password-protected computer. When we publish the results of the research or talk about it in 
conferences, we will not use your name. If we want to use your name, we would ask you for 
your permission.
We understand that information about you obtained in connection with your health is personal. 
We are committed to protecting the privacy of that information. If you decide to be in this study, 
we will obtain information that identifies you and your personal health information. This may 
include information that might directly identify you, such as your name, date of birth, address, 
and telephone number. This information will be de-identified at the earliest reasonable time after 
we receive it. That means that we will replace your identifying information with a code that does 
not directly identify you. The principal investigator will keep a link that identifies you to your 
coded information. This link will be kept secure and available only to the members of the 
research team that need it. Any information that can identify you will remain confidential. All 
study materials will be kept in locked storage cabinets and password protected computers in
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locked rooms. The research team will only give this coded information to others to carry out this 
research study. The link to your personal information will be kept for 2 years after the study is 
over. After the that time, the link will be destroyed, and the data will become anonymous. The 
data will be kept in this anonymous form for 7 years after completion of the study and then will 
be destroyed.
What information will you collect about me in this study?
The information we are asking to use and share is called “Protected Health Information (PHI).” It 
is protected by a federal law called the Privacy Rule of the Health Insurance Portability and 
Accountability Act (HIPAA). In general, we cannot use or share your health information for 
research without your permission. If you want, we can give you more information about the Privacy 
Rule. Also, if you have any questions about the Privacy Rule and your rights, you can speak to 
Yale Privacy Officer at 203-432-5919.
The specific information about you and your health that we will collect, use, and share includes:
• Research study records.
• Medical and laboratory records of only those services provided in connection with this 
Study.
• The entire research record and any medical records held by Yale New Haven Hospital or 
Yale Medicine created between the date of signed consent and the end of your 
participation in the research study.
• Records about phone calls made as part of this research
• Records about your study visits.
• Information obtained during this research regarding

Physical exams.

Laboratory, x-ray, neuroimaging results, and other test results.

Diaries and questionnaires.

The diagnosis and treatment of a mental health condition.

Use of illegal drugs or the study of illegal behavior.

Records about any study drug you received.
How will you use and share my information?
We will use your information to conduct the study described in this consent form. 
We may share your information with:
•
The U.S. Department of Health and Human Services (DHHS) agencies (for example, 
NIMH).
•
Representatives from Yale University, the Yale Human Research Protection Program and 
the Institutional Review Board, who are responsible for ensuring research compliance. The 
Institutional Review Board is the committee that reviews, approves, and monitors research 
on human participants. These individuals are required to keep all information confidential.
•
The FDA. This is done so that the FDA can review information about ketamine for use in 
adolescents with depression and suicidality, which is not currently an FDA-approved use 
of this medicine. The information may also be used to meet the reporting requirements of 
drug regulatory agencies.
•
Health care providers who provide services to you in connection with this study.
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•
Laboratories and other individuals and organizations that analyze your health information 
in connection with this study, according to the study plan.
•
The study’s Principal Investigator.
•
Co-Investigators and other investigators.
•
Study Coordinator and Members of the Research Team.
•
Data and Safety Monitoring Boards and others authorized to monitor the conduct of the 
Study.
We will do our best to make sure your information stays private. But, if we share information with 
people who do not have to follow the Privacy Rule, your information will no longer be protected 
by the Privacy Rule. Let us know if you have questions about this. However, to better protect your 
health information, agreements are in place with these individuals and/or companies that require 
that they keep your information confidential.
If you decide to join this research study and you are a female, you will be asked to have a 
pregnancy test before starting this study. Only you will be told the results. If you are pregnant, 
we will advise you to get care for your pregnancy and to get the support of a medical 
professional. Females under the age of 13 with a positive pregnancy test require a report to the 
Department of Children and Families, however this study only includes adolescents 13 or older.
Certification of Confidentiality (CoC)
We will also be asking you for urine samples, which we will test for drugs of abuse. This 
research is covered by a Certificate of Confidentiality (CoC) from the National Institutes of 
Health. The CoC protects the researchers from being forced, even under a court order or 
subpoena, to release research information that could identify you.
Information protected by this CoC cannot be shared with anyone else who is not connected with 
the research except in the cases below.

One exception is if there is a federal, state, or local law that requires us to disclose 
information. Examples include reporting child or elder abuse, certain communicable 
diseases, or when we believe you may harm yourself or someone else. If we find that 
you are experiencing abuse, we will give you a list of additional resources and referral 
options for trauma treatment.

Another exception is if you have consented to us sharing the information. Signing this 
permission form means that you agree to the information sharing we describe. This 
includes releasing data to a clinician involved in your medical or mental health treatment. 
It also includes the release of your de-identified data to a public data repository. If you 
want your research information released to an insurer, medical care provider, or any 
other person not connected with the research, you must provide consent to allow the 
researchers to release it.

A third exception is if it is used for other scientific research, as allowed by federal 
regulations that protect research participants.
This research is sponsored by the Department of Health and Human Services (DHHS) through 
the NIMH. The CoC cannot be used to refuse a request for information from staff from the NIMH 
and other DHHS agencies that is needed for auditing or program evaluation. Researchers must 
also submit any information that must be disclosed to meet FDA requirements.
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Even with the CoC, you and your family members must still continue to actively protect your 
own privacy. If you voluntarily give your written consent for anyone to receive information about 
your participation, then we may not use the CoC to withhold this information.
Data Sharing for Future Research
We may also share de-identified information about you with other researchers for future 
research. “De-identified information” means that all personal information about research 
participants such as name, address, and phone number is removed. It is replaced with a code 
number so that there is no information that can directly identify you. We will not ask you for any 
additional permission. Once de-identified information or biospecimens could be used for future 
research studies or given to another investigator for future research studies, we will not need 
additional informed consent from you.
De-identified data from this study will be submitted to the NIMH Data Archive (NDA) at the NIH. 
The NDA is a large data repository that allows researchers studying mental illness and healthy 
cognition to collect and share de-identified information with each other. A data repository is a 
large database where information from many studies is stored and managed. During and after 
the study, the researchers will send de-identified information about your health and behavior to 
the NDA. Other researchers across the world may then obtain access to your de-identified study 
data for research purposes. Sharing de-identified study data helps researchers learn new and 
important things about mental health more quickly than before.
Every researcher (and the institutions where they work) who requests the deidentified study 
data must promise to keep the data safe. They also must promise not to try to learn your 
identity. Experts at the NIH who know how to keep your data safe will review each request 
carefully to reduce privacy risks. Sharing your study data does have some risks, although these 
risks are rare. The study data could be accidentally shared with an unauthorized person who 
may attempt to learn your identity. The study researchers will make every attempt to protect 
your identity.
You may not benefit directly from allowing your data to be shared with NDA. The study data 
provided to NDA may help researchers around the world learn more about mental health and 
how to help others with mental health disorders. NIMH will also report to Congress and on its 
website about the different studies using NDA data. You will not be contacted directly about the 
study data you contributed to NDA.
You may decide now or later that you do not want your study data to be added to the NDA. You 
can still participate in this research study even if you decide that you do not want your data to be 
added to the NDA. If you know now that you do not want your data in the NDA, please tell the 
study researcher before leaving the clinic today. If you decide any time after today that you do 
not want your data to be added to the NDA, call or email the study staff, and they will tell NDA to 
stop sharing your study data. Once your data is part of the NDA, the study researchers cannot 
take back the study data that was shared before they were notified that you changed your mind. 
If you would like more information about NDA, this is available on-line at http://nda.nih.gov.
Why must I sign this document?
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By signing this form, you will allow researchers to use and disclose your information described 
above for this research study. This is to be sure that the information related to this research is 
available to all parties who may need it for research purposes. You always have the right to review 
and copy your health information in your medical record.
However, the first part of this study is a double blind treatment study. That means that you, and 
the study staff are not supposed to know which medicine you are getting. If you sign this 
permission form, you will not be allowed to look at or copy your study related information until 
after we see which medicine you got. This will happen at the end of the first two weeks of the 
study (i.e. after the four IV treatments are completed).
What if I change my mind?
The authorization to use and disclose your health information collected during your participation 
in this study will never expire. However, you may withdraw or take away your permission at any 
time. You may withdraw your permission by telling the study staff or by writing to Michael Bloch, 
MD, MS, 230 S. Frontage Rd at the Yale University, New Haven, CT 06519.
If you withdraw your permission, you will not be able to stay in this study. But, the care you get 
from your doctor outside of this study will not change. No new health information identifying you 
will be gathered after the date you withdraw your permission. Information that has already been 
collected may still be used and given to others until the end of the research study. This policy is 
to ensure the integrity of the study and/or study oversight.
Who will pay for treatment if I am injured or become ill due to participation in the study?
If you are injured while enrolled in the study, seek treatment and contact the study doctor as 
soon as you are able.
Yale School of Medicine and Yale-New Haven Hospital do not provide funds for the treatment of 
research- related injury. If you are injured as a result of your participation in this study, treatment 
will be provided. You or your insurance carrier will be expected to pay the costs of this 
treatment. No additional financial compensation for injury or lost wages is available.
You do not give up any of your legal rights by signing this form.
What if I want to refuse or end my participation before the study is over?
Taking part in this study is your choice. You can choose to give permission, or you can choose 
not to give permission. You also can change your mind at any time. Whatever choice you 
make, you will not lose access to your medical care or give up any legal rights or benefits.
We would still treat you with standard therapy or, at your request, refer you to a clinic or doctor 
who can offer this treatment. Not participating or withdrawing later will not harm your 
relationship with your own doctors or with this institution.
To withdraw from the study, you can call a member of the research team at any time and tell 
them that you no longer want you to take part.
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The researchers may withdraw you from participating in the research if necessary. There are 
several reasons that a researcher may need to withdrawal you from the study. You could have a 
poor response to treatment or develop a serious side effect(s). You could be withdrawn if you do 
not follow study instructions or if you change doses of the other medicines that you are taking.
You would also be withdrawn if the study is closed for safety reasons.
Withdrawing from the study will involve no penalty or loss of benefits to which you are otherwise 
entitled. If you choose not to participate or withdraws it will not harm your relationship with your 
doctors, Yale Child Study Center, or Yale New Haven Hospital. We would still treat you with 
standard therapy or, at your request, refer you to a clinic or doctor who can offer this treatment.
What will happen with my data if I stop participating?
You may withdraw or take away permission to use and disclose your health information at any 
time. You do this by telling the study staff or by writing to the study doctor Michael Bloch, MD, 
MS at Yale University 230 South Frontage Rd. New Haven, CT 06519. If you withdraw your 
permission, you will not be able to stay enrolled in this study.
When you withdraw your permission, no new health information identifying you will be gathered 
after that date. Information that has already been gathered may still be used and given to others 
until the end of the research study. This policy is to insure the integrity of the study and/or study 
oversight.
Who should I contact if I have questions?
Please feel free to ask about anything you don't understand.
If you have questions later or if you have a research-related problem, you can call the Principal 
Investigator, Michael Bloch, MD, MS, at 203-745-9921
If you have questions about your rights as a research participant, or you have complaints about 
this research, you call the Yale Institutional Review Boards at (203) 785-4688 or email 
hrpp@yale.edu.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
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Permission Quiz:
1.
In the first 2 weeks of the study, I will get …
☐
1 IV treatment
☐ 4 IV treatments
☐ 100 IV treatments
2.
Is ketamine approved by the FDA to treat depression or suicidal thinking?
☐
Yes
☐ No
3.
In the first two weeks of the study, who will know if I am getting ketamine or the active 
placebo (midazolam)?
☐The Study Doctor (Dr. Bloch)
☐Me
☐None of the above
4.
I may experience some side effects from the study medicines, such as:
Nausea
Increased heart rate
Sweating
Feeling sleepy
All of the above
5.
If I get the active placebo medicine (midazolam) in the first 2 weeks of 
the trial, but am still very depressed I will:
Get more midazolam treatments
Be offered ketamine treatment
Be asked to leave the study
6.
I can stop participating in this trial …
Only if Dr. Bloch says it’s OK
☐ Anytime I wish to stop
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Authorization and Permission
Your signature below indicates that you have read this consent document and that you agree to 
be in this study.
We will give you a copy of this form.
Participant Printed Name
Participant Signature
Person Obtaining Permission 
Printed Name
Person Obtaining Permission 
Signature
Date
Opt-Out: Please write your initials if you are unable or feel uncomfortable doing these parts of 
the study.
 
Brain imaging parts of the study.
 
 De-identified data shared in the NIMH Data Archive
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