Conditions: Major Depressive Disorder Anxiety Disorder
Keywords: Ketamine Depression Major Depressive Disorder Anxiety School refusal Suicide Generalized Anxiety Suicidal Ideation
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 17
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the tolerability and short-term efficacy of a single ketamine infusion for the treatment of adolescents with 1) medication-refractory major depressive disorder (MDD) and/or 2) medication-refractory anxiety disorders (social anxiety disorder, panic disorder, generalized anxiety disorder and/or separation anxiety disorder).

Detailed description:
We will conduct a crossover trial in which as many as 36 adolescents (18 with MDD and 18 with anxiety disorders) will be given a single infusion of ketamine (study drug) or midazolam (active control). MDD symptoms and anxiety symptoms will be monitored over a two-week period. If applicable, comorbid school refusal symptoms will also be monitored over a two-week period for both cohorts. A 2-week washout period will be required between infusion doses. Our primary outcomes will be 1) improvement in MDD symptoms (measured by Montgomery-Asberg Depression Rating Scale, revised (MADRS) score) 1 day after infusion, for the cohort of subjects enrolled in the MDD arm of this trial and 2) improvement in the anxiety symptoms (measured by the Multimodal Anxiety Scale for Children (MASC) acute physical symptoms subscale) for the cohort of subjects enrolled in the anxiety disorders arm of the trial.

Arms:
arm 1: Participants were randomly be assigned to receive a dose of 0.5 mg/kg of Ketamine (administered intravenously over 40 minutes with a maximum total dose allowed in this study will be 50mg). arm 2: Participants were randomly assigned to receive a dose of 0.045mg/kg of Midazolam (administered Intravenously over 40 minutes with a the maximum total dose allowed in this study of 4.5mg),

Interventions: intervention 1: Ketamine intervention 2: Midazolam
Intervention descriptions: intervention 1: A single dose of 0.5mg/kg of Ketamine will be administered Intravenously during 40 minutes in the Hospital Research Unit of YNHH. The subject will be monitored continuously during the procedure, and every hour for three hours after the infusion. intervention 2: A single dose of 0.045mg/kg of Midazolam will be administered intravenously during 40 minutes in the Hospital Research Unit of YNHH. The subject will be monitored continuously during the procedure, and every hour for three hours after the infusion.

Protocol document:
Prot_SAP_000.pdf: 
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YALE UNIVERSITY
                                  HUMAN INVESTIGATION COMMITTEE
Application to Involve Pediatric Human Subjects in Biomedical Research
100 FR17 (2013-1)
DATE STAMPED-RECEIVED
PROTOCOL NUMBER
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: 
Efficacy of Rapid-Acting NMDA Antagonist for Treatment of Adolescent Treatment Refractory Major 
Depressive Disorder and Anxiety Disorders
Principal Investigator:
Michael H. Bloch, MD
Yale Academic Appointment:
Assistant Professor in the Yale Child Study Center
Department: Yale Child Study Center
Campus Address: 
Yale Child Study Center, 230 South Frontage Rd., New Haven, CT 06510
Campus Phone: 203-745-9921
Fax: 203-785-7611
Pager: 
E-mail: Michael.bloch@yale.edu
Protocol Correspondent Name & Address (if different than PI):
Angeli Landeros-Weisenberger, MD, 230 South Frontage Rd., New Haven, CT 06520 SHM-I-371
Campus Phone: 203-737-4809
Fax: 203-737-5104
E-mail: angeli.landeros@yale.edu
Business Manager:
Campus Phone:
Fax :
E-mail:
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)           
 NA
Yale Academic Appointment:
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail: 
Please refer to the HIC website for application 
instructions and information required to 
complete this application.  The Instructions are 
available at http://www.yale.edu/hrpp/forms-
templates/biomedical.html 
Submit the original application and one (1) 
copy of all materials including relevant 
sections of the grant which funds this project 
(if applicable) to the HIC.  
HIC OFFICE USE ONLY


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Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research. 
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
  Yes
X  No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
  Yes
X No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as con-investigators on a protocol with a 
Yale University Principal Investigator must also have a current financial disclosure form on file 
with the University’s Conflict of Interest Office. If this has not been done, the individual(s) 
should follow this link to the COI Office Website to complete the form:  
http://www.yale.edu/coi/  
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
 
a. Internal Location[s] of the Study:
 Magnetic Resonance Research Center 
 Yale University PET Center
     (MR-TAC)   
 YCCI/Church Street Research Unit (CSRU)
 Yale Cancer Center/Smilow
 YCCI/Hospital Research Unit (2)
 Yale Cancer Center/Clinical Trials Office        
 YCCI/Keck Laboratories
 Yale-New Haven Hospital
Yale-New Haven Hospital/Saint Raphael Campus


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 Cancer Data Repository/Tumor Registry
 Specify Other Yale Location:
Yale Child Study Center
b. External Location[s]:
 APT Foundation, Inc.
 
 Haskins Laboratories
 Connecticut Mental Health Center
 
 John B. Pierce Laboratory, Inc.
 Clinical Neuroscience Research Unit (CNRU)  
 Veterans Affairs Hospital, West Haven
 Other Locations, Specify: 
             
 International Research Site (Specify 
location(s)):
c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date: 
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found at 
 http://radiology.yale.edu/research/ClinTrials.aspx
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities.  3 years
3. Research Type/Phase: (Check all that apply)
a. Study Type
    
 Single Center Study
    
 Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes 
No 
    
 Coordinating Center/Data Management
    
 Other: 
b. Study Phase
 N/A
    
 Pilot
 Phase I
 Phase II
 Phase III
 Phase IV
    
 Other (Specify): Efficacy trial
4.  Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more 
    than one category may apply to your research protocol. Definitions for the following can be found  
    in the instructions section 4c:
    
 Clinical Research: Patient-Oriented
    
 Clinical Research: Outcomes and 
    
 Clinical Research: Epidemiologic and Behavioral                 Health Services
    
 Translational Research #1 (“Bench-to-Bedside”)
    
 Interdisciplinary Research


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 Translational Research #2 (“Bedside-to-Community”) 
 Community-Based Research
5.   Is this study a clinical trial? Yes 
No 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of 
humans to one or more health-related interventions to evaluate the effects on health outcomes.” 
Health-related interventions include any intervention used to modify a biomedical or health-
related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, 
dietary interventions, and process-of-care changes). Health outcomes include any biomedical or 
health-related measures obtained in patients or participants, including pharmacokinetic 
measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and 
compound authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx  or 
 contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes 
 No
7. Will this study have a billable service? A Billable Service is defined as a service or procedure 
that will be ordered, performed or result in charging in EPIC for individuals who are enrolled in 
a clinical research study, regardless if the charge is intended to be paid by the subject/their 
insurance or the research study.
Yes 
 No
If you answered "yes", this study will need to be set up in OnCore Support.
Contact Thomas.debski@yale.edu. 
8. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes _X__ No ___  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform?
Yes – members of the Yale Pediatric Sedation team are credentialed to give all study drugs 
outlined in this protocol.
 
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
No


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c. Will a novel approach using existing equipment be applied?
No
 
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
 
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that 
apply.
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).  
PI 
Title of Grant
Name of Funding Source 
Funding
Funding Mechanism
Jennifer B 
Dwyer, MD, 
PhD
Efficacy of Rapid-
Acting NMDA 
Antagonist for 
Treatment of 
Adolescent 
Depression
AACAP Pilot Award
  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify:
Jennifer B 
Dwyer, MD, 
PhD
Efficacy of Rapid-
Acting NMDA 
Antagonist for 
Treatment of 
Adolescent 
Depression
Yale Child Study Center 
Internal Award 
  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify:
Amalia Londono 
Tobon, M.D.
Ketamine for 
Prolonged School 
Refusal in 
Adolescents: A 
Pilot Study
Yale Child Study Center 
Internal Award
  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify: 


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Jennifer B 
Dwyer, MD, PhD
Efficacy of Rapid-
Acting NMDA 
Antagonist for 
Treatment of 
Adolescent 
Depression
Thrasher Research 
Foundation: Early Career 
Award 
  Federal
  State
  Non 
Profit
  Industry
  Other 
For Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  
Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify: 
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided.
Send IRB Review Fee Invoice To:
Name:
Company:
Address:
2. Research Team:  List all members of the research team. Indicate under the affiliation 
column whether the investigators or study personnel are part of the Yale faculty or staff, or 
part of the faculty or staff from a collaborating institution, or are not formally affiliated with 
any institution. ALL members of the research team MUST complete Human Subject 
Protection Training (HSPT) and Health Insurance Portability and Accountability Act 
(HIPAA) Training before they may be listed on the protocol.  See NOTE below.
Name
Affiliation: Yale/Other 
Institution (Identify) 
NetID
Principal Investigator 
Michael Bloch, MD
Yale Child Study Center
Mhb32
Role: Co-investigator
Gerard Sanacora, MD, PhD
Yale Dept of Psychiatry
Gs59
Role: Co-investigator
Jennifer Dwyer, MD, PhD
Yale Child Study Center
Jd775
Role: Co-investigator
Angeli Landeros-Weisenberger, MD
Yale Child Study Center
Al495
Role: Co-investigator
Hilary Blumberg, MD
Yale Dept of Psychiatry
Hb62
Role:  Co investigator
Wendy Silverman, Ph.D.
Yale Child Study Center
Wks9
Role:  Co investigator
      Eli Lebowitz, Ph.D.
Yale Child Study Center
Er132
Role:  Co investigator
      Amalia Londono Tobon, MD
Yale Child Study Center 
Al868
Role: Study Personnel
John Giuliano, MD
Yale Dept of Pediatrics
Jsg22
Role: Study Personnel
Edward Vincent Faustino, MD, MPH
Yale Dept of Pediatrics
Evf5
Role: Study Personnel
Susan Quatrano
Yale Dept of Psychiatry
Ss438
Role: Study Personnel
Linda Spencer
Yale Dept of Psychiatry
Las78
Role: Study Personnel
Jennifer Johnston
Yale Dept of Psychiatry
Jj434
Role: Study Personnel
Judah Weathers
Yale Dept of Psychiatry
Jdw49
Role: Study Personnel
Jessica Johnson, BS
Yale Child Study Center
Jaj62


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NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed.
Role: Study Personnel
Baris Olten
Yale Child Study Center
BO222
Role: Study Personnel
Shilpa Telang
Yale Child Study Center
SB2528


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SECTION IV:
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the
      research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’
      rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the
      study or any change and I will obtain continuing approval of this study prior to the expiration date     
      of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to
      participants.

I am in compliance with the requirements set by the University and qualify to serve as the
      principal investigator of this project or have acquired the appropriate approval from the 
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at
      Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a
smooth transfer of investigator responsibilities.
_____
 
PI Name (PRINT) and Signature
Date


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As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the 
      necessary resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of
      human subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions
      Prior to initiating the study or revision and will obtain continuing approval prior to the expiration
      of any approval period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated 
      problems involving risk to participants. 

I am in compliance with the requirements set forth by the University and qualify to serve as
      the faculty advisor of this project.
___________
______
_____
    Advisor Name (PRINT) and Signature
Date
___________
______
_____
    Advisor Name (PRINT) and Signature
Date


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Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
 Yes (provide a description of that interest in a separate letter addressed to the HIC.)
 No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC.)
No
I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
conduct this trial appropriately.
   ____________________________
   Chair Name (PRINT) and Signature  
    
 Date
   _________________________________
   Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and had the support of the hospital 
for this research project.
  ______________________________________
    YNHH HSPA  Name (PRINT) and Signature       
Date
For HIC Use Only
Date Approved
Human Investigation Committee Signature


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SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
The purpose of this study is to determine the tolerability and short-term efficacy of a single 
ketamine infusion for the treatment of adolescents with 1) medication-refractory major 
depressive disorder (MDD) and/or 2) medication-refractory anxiety disorders (social anxiety 
disorder, panic disorder, generalized anxiety disorder and/or separation anxiety disorder). We 
will conduct a crossover trial in which as many as 36 adolescents (18 with MDD and 18 with 
anxiety disorders) will be given a single infusion of ketamine (study drug) or midazolam (active 
control).  MDD symptoms and anxiety symptoms will be monitored over a two-week period.  If 
applicable, comorbid school refusal symptoms will also be monitored over a two-week period for 
both cohorts.  A 2-week washout period will be required between infusion doses.  Our primary 
outcomes will be 1) improvement in MDD symptoms (measured by Montgomery-Asberg 
Depression Rating Scale, revised (MADRS) score) 1 day after infusion, for the cohort of subjects 
enrolled in the MDD arm of this trial and 2) improvement in the anxiety symptoms (measured by 
the Multimodal Anxiety Scale for Children (MASC) acute physical symptoms subscale) for the 
cohort of subjects enrolled in the anxiety disorders arm of the trial.  As secondary outcomes, we 
are also proposing to (1) more comprehensively assess suicidal ideation as an additional 
efficacy outcome in the trial, (2) measure ketamine’s effects on symptom constructs associated 
with suicidal ideation or behavior, including anxiety, anhedonia and hopelessness (3-8), (3) 
examine ketamine’s effects on school-refusal behavior (SRB) that is associated with anxiety 
and depression and (4) examine ketamine’s effects on frontal neural systems associated with 
suicidal ideation and behavior as well as anxiety using functional magnetic resonance imaging 
(fMRI) and a behavioral task that has previously demonstrated findings associated with 
suicide attempts in adolescents with mood disorders (9).
2.   Background: Describe the background information that led to the plan for this project. Provide
      references to support the expectation of obtaining useful scientific data. 
Major Depressive Disorder (MDD):
      MDD is a significant pediatric health problem with a point prevalence of up to 8% and a 
lifetime prevalence approaching 25% by the end of adolescence (10-13). Adolescent MDD is 
associated with significant comorbidity including poor social and scholastic functioning, early 
pregnancy, and increased risk of physical illness and substance abuse (14-16). It is also linked 
with significant mortality, with an increased risk for suicide (the 3rd leading cause of death in 15-
24 year olds) (10, 17). Treatment can be difficult, with 40% of patients failing to achieve 
remission from SSRIs (18). Of that SSRI-resistant population, nearly half remain depressed 
despite switching medications and adding psychotherapy (19, 20). Of those that do improve, 1 in 
4 relapse within a year (21). 
Anxiety Disorders:
Pediatric anxiety disorders (e.g. generalized anxiety disorder, social anxiety disorder, 
separation anxiety disorder and panic disorder) are some of the most prevalent psychiatric 
conditions in children and adolescents(22, 23).  It is estimated that 15–20% of youth suffer from 
these disorders(22, 23). When not treated successfully, anxiety disorders are associated with 
significant short- and long-term impairment and tremendous societal costs (24-26).  Childhood 
anxiety disorders are often precursors to additional subsequent anxiety disorders, major 
depression, substance abuse and suicide attempts (27, 28).  Cognitive-behavior therapy and 


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selective serotonin reuptake inhibitors have emerged as the most effective treatments for 
pediatric anxiety disorders.  The Childhood Anxiety Multimodal Study (CAMS) demonstrated 
that both CBT and SSRIs were highly effective for childhood anxiety disorders and their 
combination was superior to each individual therapy (29).  However, it is estimated that roughly 
have of children with anxiety disorders fail to achieve remission with available first-line 
treatment (30).   Severe anxiety in childhood is associated with increased risk of depression, 
school refusal, substance abuse, suicide and reduced quality of life (31).   Although first-line 
treatments are quite effective in pediatric anxiety additional treatments to benefit those children 
and adolescents who fail to benefit from these first-line treatments are urgently needed as other 
evidence-based treatment options are lacking.
Ketamine
       Evidence implicates the glutamate system in the pathophysiology of depression and anxiety. 
Ketamine, an NMDA receptor antagonist, has been demonstrated in multiple controlled clinical 
studies to have rapidly acting antidepressant, anti-anxiety and anti-suicidal effects (32-37) (see 
preliminary data section). In adult studies, ketamine has a robust average effect size of >1.2 and 
an number needed to treat (NNT) of only 2.3 in the medication-refractory depressed population 
(1). While ketamine improves a range of depressive symptoms in adults, it notably reduces 
anhedonia (38), a symptom associated with poor therapeutic response in adolescent MDD (39). 
Ketamine also specifically reduces suicidality in adults (40), a dimension of adolescent MDD 
that is resistant to, or perhaps even increased, by SSRIs (41, 42). Similarly, several controlled 
studies in adults have suggested ketamine may be effective in reducing OCD and PTSD 
symptoms as well as comorbid anxiety symptoms in subjects with primary MDD.  While the 
glutamate system continues to mature in adolescence (43), preclinical data suggests that 
ketamine reverses depressive phenotypes in adolescent rats (44). Due to its success in treating 
adult MDD, ketamine has started to be used for treatment-refractory affective disorders in 
adolescence in the community (45), despite having no prospective evidence available to guide 
clinicians.  Similarly, we know of no controlled trials examining the effects of ketamine on 
anxiety disorders in children or adolescents. 
We propose to conduct a study to explore the efficacy and time course of action of 
intravenous ketamine in the treatment of adolescent treatment-refractory 1) MDD and/or 2) 
anxiety disorders (generalized anxiety disorder, social anxiety disorder, panic disorder and 
separation anxiety)  
Secondary Outcomes
As secondary outcomes we will examine the effects of ketamine on (1) suicidal ideation 
and related constructs associated with suicidal behavior; (2) frontal systems involved in 
emotional face processing using fMRI that have been associated with depression, suicidal 
behavior and anxiety and (3) school refusal behaviors.
Suicidal Ideation and Related Constructs
We are proposing a more thorough assessment of ketamine’s effect on suicidal ideation 
and related constructs in order to provide data on whether ketamine has similar anti-suicidal 
properties in adolescents as has been demonstrated in adults. Throughout the trial we will 
regularly monitor the subjects. We will also examine ketamine’s effects on biological markers of 
depressive, anxiety and suicidal behavior on neurocognitive testing.  Specifically, we will 
examine ketamine’s effects (compared to midazolam) in the both cohorts 24-hours after infusion 
on at least three neuropsychological tasks (46) (47); (1) Depression Implicit Association Tasks, 
(2) Anxiety Implicit Association Task, (3) Suicide Implicit Association Tasks (48), (4) Self 


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Injurious Implicit Association Tasks.  Stronger implicit association between death/suicide and 
self on the Death/Suicide IAT has been associated with not only previous history of suicide 
attempts but also future attempts.  
Emotional Face Processing on fMRI
To investigate the brain changes that underlie ketamine’s effects, we also propose to 
examine the effects of ketamine on responses within a frontal system during performance of an 
implicit emotional face processing task. Previous fMRI research using emotional face processing 
tasks has shown that it is affected by ketamine treatment and sensitive to differences between 
depressed and non-depressed adolescents and depressed adolescents with and without past 
suicide attempt history (9, 49-52). Emotional face processing tasks have also been demonstrated 
to be affected by anxiety disorders (53-55).
School Refusal Behavior (SRB):
MDD and anxiety are commonly associated with comorbid school refusal behavior. Nearly 5 
to 10% of school aged children and adolescents have excessive SRB (56, 57).  Long-term 
consequences of SRB include increased risk of substance abuse, suicide attempt, risky sexual 
behavior, and school dropout (58-60). Furthermore, SRB has high societal cost in the billions 
with proximal costs associated with poor academic performance or attendance, future 
underemployment and increased risk of criminal prosecution (60). Once refusal of school begins, 
children tend to continue this behavior, and returning youth to school becomes extremely 
challenging for children, parents, schools, and clinicians.  
Although the population of children and adolescents with prolonged SRB is heterogeneous, 
up to 50% of these youth have comorbid anxiety and depression (61-63).  Children with SRB 
and comorbid anxiety and depressive symptoms tend to refuse school primarily to avoid school-
related stimuli that provoke a sense of general negative affectivity and/or to escape from aversive 
social or evaluative situations at school (64, 65).  The longer the avoidance of school-related 
stimuli persists, the more difficult SRB become to treat and the greater the psychiatric, social and 
academic consequences. The SRB intervention literature is limited. A recent review of 
psychosocial interventions, predominantly cognitive behavior therapy (CBT) for SRB, identified 
only 8 small randomized controlled and quasi-experimental trials involving 435 participants.  
Results from this meta-analysis demonstrated that psychosocial interventions significantly 
increased attendance but did not significantly decrease anxiety in SRB (66).  Other studies have 
examined medications including tricyclic antidepressants (TCAs) (67-70), serotonin reuptake 
inhibitors (71) (72, 73), and benzodiazepines (72), for SRB school refusal behavior in children 
and have reported inconsistent effects. Other than imipramine no medication, has shown 
significant benefit for school refusal in any randomized, controlled trial (67-70).  Even when 
beneficial, antidepressant medications (e.g. TCAs, SSRIs) even when beneficial, take several 
weeks to reach full effects in improving anxiety and depression. 
PRELIMINARY DATA: 
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 


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blocks the entry of calcium. 
Ketamine has a wide therapeutic window and has been used safely in Pediatrics for over 40 years 
for sedation prior to medical procedures and dentistry (74, 75). 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 there are no prospective studies of 
ketamine in pediatric psychiatric populations, the recently published retrospective report of 
ketamine use in pediatric bipolar depression did not describe any serious safety problems or 
adverse events associated with its use (45). Yale University has been safely using ketamine in 
research studies with adult psychiatric patients for over 20 years (32).
Major Depressive Disorder
A placebo-controlled study completed here at Yale first demonstrated the surprising finding that 
a single dose of ketamine (0.5 mg/kg, intravenously) had rapid antidepressant effects in 
depressed patients (33). In these subjects, 
ketamine infusion produced mild 
psychotomimetic symptoms and euphoria that 
dissipated within 120 minutes, while the 
antidepressant effects of ketamine infusion 
emerged over the first 180 minutes and persisted 
over 72 hours (33). Fifty percent of depressed 
patients receiving ketamine were treatment 
responders at Day 3 compared to 12.5% in the 
placebo infusion group (33). Another recent 
double-blind study performed at NIMH 
confirmed the rapid antidepressant effects of 
ketamine (34). In this second study, 72% of 
ketamine infused patients responded to 
treatment compared to no treatment responders 
in the placebo group (34).  Since these initial 
studies at Yale, multiple controlled clinical 
studies have demonstrated that ketamine yields 
rapid antidepressant effect in unipolar and 
bipolar depression (33, 34, 76-78) (Figure 1) 
with an average effect size of 1.2 and a number 
needed to treat of only 2.3 (1).  Ketamine’s anti-
depressant effects peak 1-3 days following 
infusion.  Ketamine’s antidepressant effect is 
observed long after ketamine has been 
metabolized and excreted by the body and after 
ketamine’s sedative and dissociative effects have dissipated.  
In order to provide proof of “target engagement” as pilot data for a larger, more definitive NIH-
funded clinical trial examining ketamine’s suicide preventive properties, we also plan to examine 
ketamine’s effects on a frontal neural system associated with suicidal ideation and behavior. 
Specifically, abnormalities involving emotional processing neural circuitry are hypothesized to 
be particularly important in the development of adolescent suicidal behavior. Previous structural 
Figure 1: A) Ketamine improves depressive symptoms 
in saline –controlled IV trials (dashed grey line), and in 
all pooled trials (solid black lines, including intranasal 
ketamine and midazolam controls) B). Ketamine induces 
an antidepressant response in a significant proportion of 
subjects. Adapted with permission (1)


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and functional neuroimaging studies have demonstrated abnormalities in a frontal neural system 
thought to contribute to suicidal ideation and behavior. These abnormalities  include increased  
responses in anterior paralimbic cortex and amygdala to negative emotional stimuli that are 
hypothesized to underlie negative affect and anxiety, and decreased  responses in more rostral 
and dorsal prefrontal cortex and striatal regions, including responses to positive stimuli that are 
hypothesized to increase anhedonia, and decreases in regions subserving impulse regulation (79). 
The interplay between neural circuits mediating emotional processing and impulsivity is central 
to our working model of adolescent suicidal behavior (79). We will specifically examine 
ketamine’s effects on fMRI measures during an emotion face processing paradigm. Similar 
methods have previously elicited frontal neural system differences between adolescents and 
young adults who have made suicide attempts and who have suicidal ideation, from those 
without (9, 80, 81). Previous fMRI studies demonstrated elevated responses to faces depicting 
negative emotions in MDD subjects within paralimbic orbitofrontal, anterior cingulate and 
insular cortices and amygdala, and hypoactivation to happy faces within dorsal and rostral 
prefrontal cortex and striatal regions (50-52). In previous fMRI studies of depressed adolescents, 
the responses to negative emotional stimuli were shown to be higher in those with a previous 
history of suicide attempts than those without (9). A previous open-trial of 20 adults with 
treatment-refractory depression demonstrated normalization of blunted neural responses to happy 
faces 24-hours after ketamine infusion in subjects whose depressive symptoms responded to 
ketamine (49). With the current proposal, we plan to extend upon this previous work by 
examining with fMRI the changes in neural system responses with ketamine treatment and 
associated changes in suicide ideation and related constructs.
Due to its success in treating adult MDD and suicidal ideation, ketamine is now in use for 
treatment-refractory adolescents (45), despite having no data from controlled clinical trials to 
support this practice. Thus, carefully monitored prospective studies measuring ketamine’s effects 
on suicidal ideation and constructs associated with suicide attempts, such as anxiety, anhedonia, 
hopelessness and depression, are urgently needed.
Anxiety Disorders
Strong evidence also implicates the glutamate system in the pathophysiology of anxiety (82-86).  
The results of several clinical studies suggest that ketamine may also have significant anxiolytic 
effects in addition to antidepressant effects.  As discussed earlier, ketamine has a robust average 
effect size of >1.2 in reducing depressive symptoms and an NNT of only 2.3 in the medication 
refractory adults with major depressive disorder (90). Randomized controlled trials of ketamine 
for depressed adult patients demonstrated a significant reduction in comorbid anxiety symptoms, 
with a similar effect size of 1.4 (91, 92). Moderator studies in adults with depression have also 
demonstrated that adults with an anxious depression sub-type have an increased initial response 
to ketamine and longer time to relapse (93, 94).  Adults with anxious depression relapsed 
significantly later than those with non-anxious depression (median ± SE = 19.0 ± 17.9 vs 1.0 ± 
0.0 days to relapse, respectively; χ² = 9.30; P = .002) (93, 94).  Ketamine has also been shown to 
reduce anxiety in adult patients with PTSD (95, 96) and OCD (97, 98). We also have recently 
completed a randomized, saline-controlled crossover study of ketamine in 18 adults with social 
anxiety disorder.  Ketamine demonstrated a significant reduction in the CGI-I score at 1 day 
following infusion compared to saline (paired t-test t=2.78, p=0.015). Eleven of 18 subjects 
receiving ketamine were rated as minimally improved or better on the CGI 1-day following 
infusion compared to 2 of 17 receiving saline. 


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3.   Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to distinguish 
between standard of care vs. research procedures when applicable, and include any flowcharts of 
visits specifying their individual times and lengths. Describe the setting in which the research 
will take place.
Overview:
This is a double-blind, active control crossover study of 36 adolescents (13-17 years old) 
with treatment-refractory 1)  MDD and/or 2) anxiety (social anxiety disorder, generalized 
anxiety disorder, panic disorder and/or separation anxiety disorder). Subjects will be assigned to 
the MDD treatment arm and/or the anxiety disorder treatment arm based on whether they meet 
inclusion criteria for each treatment arm (or both treatment arms).  Subjects will receive similar 
symptom ratings regardless of which treatment arm(s) they are assigned.    
Each subject will receive one infusion of ketamine (the study drug) and one infusion of 
midazolam (an active control agent). Due to the difficulty in blinding ketamine’s acute effects 
and the high rate of placebo responses in depression and anxiety research, use of an active 
control is considered essential in establishing efficacy. There will be a 2-week period in between 
infusions in order to balance a potentially acceptable washout period with the risks of forbidding 
medication changes during the protocol. As shown in figure 1A, in adults, the antidepressant 
effects of ketamine typically subside by 7 days, and thus a 2-week period in between infusions is 
expected to be adequate. The study investigators, subjects, their parents, and research staff will 
be blinded to the infusion order. Infusion order will be determined by the Yale Investigational 
Drug Service, assigned in a balanced manner, and kept strictly confidential until the time of 
unblinding. Following each infusion, plasma ketamine metabolites and D-serine levels will be 
measured at 4 time points (last at 230 minutes post-infusion) and the participant’s 1) MDD 
and/or 2) anxiety symptoms will be assessed for 2 weeks.  Comorbid SRB (if applicable) will 
also be assessed for two weeks for participants in each of the cohorts.  These psychiatric 
assessments will be conducted by a rater unaware of the clinical and side effect ratings on 
infusion day. Additionally, a separate rater will conduct side effect and psychotomimetic ratings 
for ketamine and midazolam throughout the study in order to reduce the risk of unblinding due to 
the psychometric and physiologic side effects associated with ketamine. 
In addition, we will be performing Dr. Blumberg’s paradigm for fMRI at baseline (before 
the first infusion) and 24 hours after each infusion to examine ketamine’s effect on the frontal 
system during an emotional face processing task. 
Screening/Baseline (Visit 1):
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. 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 
enroll, the patient and his/her parent/guardian 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 


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(MINI-KID) (99).  Additionally, the participant and his/her parent/guardian will complete 
clinical ratings related to the participant’s 1) MDD symptoms and/or anxiety symptoms 2) 
symptoms of other commonly comorbid psychiatric conditions including school refusal 
behaviors. A medical assessment including vital signs, physical exam, baseline serum labs, urine 
drug screen, and urine pregnancy test will be completed prior to enrollment. The clinical 
assessment will take approximately 2 hours and the imaging will take about 1 hour and a half.
Assessments and Ratings (Table 1 provides a detailed assessment schedule)
a. Medical Assessments: Vital signs, physical exam, and clinical laboratory tests (i.e. 
CBC with differential, complete metabolic panel (CMP) (including electrolytes, LFTs, BUN, 
creatinine and glucose), TFTs, and routine urinalysis) will be completed. A total of 30 cc of 
blood will be drawn via venipuncture at this visit. In addition, an EKG will be performed and 
read in order to rule out any cardiac abnormalities. 
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 consent 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 consent, without having to declare specific reasons. According 
to CT state statutes for mandatory reporting, pregnancy in females less than age of 13 years, 
will be reported to parent(s) and to the State of Connecticut Department of Children and Family 
Services (DCF). Confidentiality with regard to pregnancy test results will be maintained for 
females > 13 years.  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 
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 
consent, without having to declare specific reasons. 
Drug use information (in the adolescent > 13 years of age) 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. 
b. Psychiatric Assessments: Ratings will be conducted by trained research staff. A detailed
description of the most common assessments included but not limited to, is listed below. The 
timing of the clinical assessments is depicted in Table 1 (located at the end of this Research 
Plan).
All Subjects:


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1)
Children’s Depression Rating Scale, Revised (CDRS-R): a standardized rating scale that assesses 
depression severity in children and adolescents (100)Montgomery-Asberg Depression Rating Scale 
(MADRS): a standardized rating scale that assesses depression severity in children and adolescents 
(101)
2)
Columbia-Pleasure Scale for Children (CPS) (102): a standardized rating scale to assess anhedonia 
(103)Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP): a rating scale 
designed to detect increased behavioral activation and suicidality (104)
3)
Clinical Global Impressions (CGI): a widely used instrument used to assess overall severity of illness 
and symptom improvement on 1-7 point scales (105)
4)
Multidimensional Anxiety Scale for Children (MASC): a multidimensional assessment of anxiety in 
children and adolescents (3)
5)
Pediatric Anxiety Rating Scale (PARS): s a clinician-rated measure of anxiety severity in children and 
adolescents (106)
6)
Clinician-Administered Dissociative States Scale (CADSS): self and interviewer administered items 
that evaluate dissociative symptoms (107)
7)
Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID): structured 
clinical interview evaluating psychiatric disorders (99)Beck Suicidal Ideation Scale (SSI-5): 
instrument to assess suicidal ideation(108) 
8)
Beck Hopelessness Scale (BHS): instrument to assess hopelessness(109)
9)
Childhood Trauma Questionnaire (CTQ): a self-report screening measure for maltreatment histories 
in children (110)
10) Social Networks Interview (ASSIS):a brief measure of social supports (111)
11) Friendship Questionnaire
12) Visual Analog Scale (112) for Anxiety and Mood Symptoms
13) Affective Reactivity Index Self-report (ARI-S) (113)
14) Columbia-Suicide Severity Rating Scale (C-SSRS): assessment of suicidal ideation and behavior in 
clinical and research settings (114)Anxiety Disorders Interview Schedule (ADIS-IV): parent and child 
semi structured interview to assessment anxiety disorders (100)
School Refusal Measures
15) School Refusal Assessment Scale- Revised (SRAS-R): child and parental questionnaire to evaluate 
etiology of school refusal behavior (115)
16) Hours attending school questionnaire: hours per day of child attending school and expected hours of 
school attendance
c.
 MRI Data Acquisition: Subjects will be scanned on three different time points:  1) at 
Baseline, 2) 24 hours after the first infusion and 3) 24 hours after the second infusion. All scanning 
will be performed on a 3-Tesla Siemens Trio MR scanner. High resolution, 3-dimensional 
Magnetization Prepared Rapid Acquisition Gradient Echo T1-weighted sagittal structural images will 
be acquired: TR=1500ms, TE=2.83ms, FOV=256x256mm, matrix=256x256, slice thickness= 1.0mm 
no gap, 160 slices. FMRI will be acquired in alignment with the anterior commissure-posterior 
commissure plane with a single-shot echo planar imaging sequence: TR=2000ms, TE=25ms, 
matrix=64x64, FOV=240x240mm2, 40 3-mm slices no gap. FMRI data will be acquired while 
subjects perform the attention bias to treat task and the event-related emotional face processing task 
explained below, and if time permits two 5-minute resting runs. DTI data will be acquired in 
alignment with the fMRI data. Diffusion sensitizing gradients will be applied along 32 non-collinear 
directions with b-value=1000sec/mm2, together with an acquisition without diffusion weighting: b-
value=0; TR=7400msec; TE=115msec; matrix=128x128; FOV=256mmx256mm and 40 3mm slices 
without gap. Youth participants will be asked not to drink any alcohol or use any other non-
prescribed medications that could change brain function within 24 hours of the MRI scanning 
session. He/she will also be asked not to drink caffeinated beverages (coffee, tea, cola drinks) or 
smoke cigarettes the morning of the MRI scanning session. 


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Event-Related Emotional Face Processing Task: In brief, subjects will view Ekman faces depicting 
neutral, negative and positive emotional expressions. Subjects will make a female/male button press 
determination (reaction time/accuracy recorded) for stimuli on-screen for 2sec, separated by 4, 8 or 
12sec of cross-hair fixation: images of 5 men/5 women, each individual exhibiting all 3 expressions, 
30 faces/run, 4 runs. Stimulus order is varied to control for sequential dependencies and 
counterbalanced within and across runs for expression, sex, identity and interstimulus interval.
Neuropsychological Testing: Subjects will perform various neuropsychological tests (46).  
Subjects will perform four tests, (1) Suicide Implicit Association Tasks, (2) Depression Implicit 
Association Tasks, and (3) Self Injurious Implicit Association Tasks and (4) the Anxiety 
Implicit Association Task.  These tests will be administered first at Baseline, 24 hours after each 
infusion, and Day 7 and 14 after each infusion.  The IAT are brief computer-administered tests 
that use people’s reaction times when classifying semantic stimuli to measure the automatic 
mental associations they hold about various topics, in this case, life and death/suicide (48) (47).
Infusion (Visit 2 &10 – Day 0 & Day 14): Subjects who, in the opinion of the principal 
investigator, are eligible to continue with the protocol procedures (after the results of the 
screening/baseline measures and diagnostics are considered) will present to the Hospital 
Research Unit (2) at Yale New Haven Hospital (YNHH) for the first infusion. 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, two IV’s 
will be placed and the patient will complete a screening interview with the Conscious Sedation 
physician. The participant’s vital signs will be taken and they will receive a physical exam, EKG, 
rapid urine drug screen, and urine pregnancy test (if applicable). They will additionally complete 
a series of clinical ratings (see Table 1). 5cc of blood will be collected off of the non-infusion IV 
to measure pre-infusion ketamine metabolites and D-serine levels. One hour later, 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 100kg). Ketamine and midazolam administrations will be 
performed on the HRU in the presence of a physician from the Pediatric Sedation Service, with 
access to airway and rescue equipment. The participant’s vital signs will be monitored every 
hour for three hours following the infusion. 5cc blood collections off of the non-infusion iv will 
take place at 40 minutes (end of the infusion), 80 minutes, 110 minutes, and 230 minutes, post-
infusion for analysis of ketamine metabolites and D-serine concentrations. The psychotomimetic 
side effects of ketamine or midazolam, and the mental status of the participant will also be 
monitored every hour for three hours following the infusion. In addition to the physician from 
the Pediatric Sedation service, a research nurse and psychiatrist will be present at all times during 
the procedure and recovery. This visit will take approximately 7-8 hours because the participant 
will receive the infusion as well as assessments and blood collection before and after the 
infusion. The total amount of blood collected on the infusion day will be 35cc (ranging from 
0.77cc/kg for a 45kg adolescent (average weight of a 13-year-old girl or boy) to 0.53cc/kg 
(average weight of a 17-year-old boy)), all collected from the non-infusion IV to minimize 
discomfort. Fourteen days will separate the first and second infusions. 
Ketamine has been used safely in pediatrics for over 40 years for conscious sedation and 
dentistry (75), however it does have significant risks.  The most common side effects when 
ketamine is infused at the current rate and dose in adult studies are (1) increased blood pressure, 


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respiratory rate, pulse, (2) pain/rash at the injection site, (3) temporary psychiatric symptoms 
including, but not limited to, disorientation, anxiety, dysphoria, flashbacks, hallucinations, and 
psychotic-like symptoms (which occur less frequently in younger patients (75)). These reactions 
are typically self-limited and occur in ~12% of adults given higher doses of ketamine than 
proposed in this study (116). The most serious side effects are (1) increased intraocular pressure, 
(2) allergic reaction, (3) laryngospasm, (4) elevated blood pressure resulting in stroke, heart 
attack, or death, and (5) substance abuse, all of which are rare (74, 75). These risks will be 
mitigated by providing comprehensive monitoring in the HRU during and 3 hours following the 
infusion, supervised by the YPCS Service with access to airway equipment. Ketamine has been 
studied in over 10,000 psychiatric patients in more than 100 separate studies. Our institution has 
had experience using ketamine safely in research studies involving adult psychiatric patients for 
the last 20 years. The Yale Pediatric Sedation Service uses ketamine in children and adolescents 
on a daily basis. This dose of ketamine is considered subanesthetic in both adults and children 
(74), and thus we expect minimal cardiorespiratory and neurologic side effects. Case report level 
data suggests a favorable side effect profile for intranasal ketamine for adolescents with 
refractory disorders (45). However, if side effects do not dissipate we will additionally offer 
patients hospitalization at Yale Psychiatric Hospital, Adolescent Unit for psychiatric side effects 
or YNHH for medical side effects. 
Midazolam, the active control in this study, similarly has a robust history of use in pediatric 
sedation and dentistry (117-123). Also similar to ketamine, the dose proposed in the current 
study (0.045mg/kg over 40 minutes) is lower and slower than doses used in most pediatric 
sedation procedures (0.05 – 0.1mg/kg over 2 minutes)(122, 124). The most common side effects 
related to midazolam infusions are hiccups, nausea, vomiting, coughing, headache, and 
drowsiness. In doses higher than those involved in the proposed study, serious cardiorespiratory 
adverse events have occurred after administration of midazolam, including respiratory 
depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac 
arrest. In younger children, these higher doses have been associated with a risk for paradoxical 
disinhibition. Midazolam, like ketamine, has a short half-life, and important adverse events 
related either drug are not observed after 30 minutes following drug administration (74). The 
Yale Pediatric Sedation team has vast experience with this medication given its common usage, 
and will be present during the infusion and until the patient has reached an appropriate state of 
recovery. While the risks of serious adverse cardiorespiratory events are low given the dose 
chosen for this study, airway equipment and qualified physician personnel will be readily 
available. 
Midazolam is the most appropriate control for ketamine in the proposed study, as the 
psychotomimetic effects of ketamine make it extremely difficult to blind when compared to 
saline (1). Specifically, the typically mild dizziness, nausea and dissociative effects on ketamine 
functionally un-blind subjects and investigators.  As such, more recent ketamine studies have 
used midazolam as a control.  Using an appropriate active control in this efficacy trial is critical 
to establishing genuine clinical efficacy for ketamine (and not just treatment expectancy or 
subject performance bias) before designing a larger trial, exposing more adolescents to this novel 
therapeutic intervention. 
Outpatient Follow-up: In-person (Visits 3, 7, 9 & 11, 15, 17 – Days 1, 7, 14 & 15, 21, 28)
Subjects will return to the Yale Child Study Center for follow-up in person visits to monitor their 
symptoms of depression and/or anxiety and physical health. During these visits, the participant 


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will complete a series of clinical ratings (see Table 1) to be conducted by a trained research staff 
member. Additionally, on Day 1 and 15 (visit 3 and 11), the psychotomimetic side effects of 
ketamine will be assessed; this assessment will be conducted by a separate rater than the clinical 
ratings.  Imaging will be done and neuropsychological batteries will be applied (see Table 1) 
which will add about 1 to 2 more hour to those assessment days. All of the outpatient study 
follow-up visits will take approximately 1-2 hours.
Outpatient Follow-up: Telephone (Visits 4-6, 8 & 12-14, 16 – Days 2, 3, 5, 10 & 16, 17, 19, 
24)
Each subject will schedule follow-up telephone calls with a member of the research staff to 
monitor his/her MDD symptoms and anxiety symptoms along with his/her comorbid school 
refusal symptoms (if applicable).  During these telephone calls, participants will complete a 
series of clinical ratings (see Table 1) conducted by a trained research staff member. These 
telephone calls will take approximately 1 hour.
Discharge from the Study: In the event that a subject is judged to remain significantly 
depressed, anxious, presents with worsening school refusal behavior and/or is at an 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. Participants who have completed the trial 
must have a CDRS score of less than 50 to be discharged from the study.
 


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Table 1: Overall Study Assessment Schedule 
 
-60m
0-40m
60m
80m
110m
120m
180m
230m
INTERVENTION
Infusion
x
MEDICAL ASSESSMENT
Physical Exam
x
x
EKG
x
Blood Tests:
Medical Screening Labs
x
Metabolites
x
x
x
x
x
Urine Tests:
Urine pregnancy test
x
x
Urine drug screen
x
x
CLINICAL RATINGS
MDD Cohort
C-SSRS
x
x
x
x
x
x
x
x
x
CDRS-R
x
x
x
x
x
SSI-5
x
x
x
x
x
x
SRB Cohort
ADIS-IV
x
x
x
x
x
x
Attendance
x
x
x
x
x
x
x
x
x
SRAS-R
x
x
x
x
x
x
x
x
x
All participants
MINI-KID/K-SADS
x
ASSIS
x
CTQ
x
Friendship
x
x
x
x
BHS
x
x
x
x
x
x
RCADS
x
x
x
x
x
x
x
x
x
TEASAP
x
x
x
x
x
x
x
x
MASC
x
x
x
x
x
x
VAS Anxiety
x
x
x
x
x
x
x
x
x
x
x
x
VAS Mood
x
x
x
x
x
x
x
x
x
x
x
x
MADRS
x
x
x
x
x
x
x
x
x
x
x
x
CADSS
x
x
x
x
x
x
x
CGI
x
x
x
x
x
CPS
x
x
x
x
x
x
x
x
x
ARI-S
x
x
x
x
x
IMAGING
Development 
Questionnaire
x
MFTQ
x
Edinburgh Handedness
x
WASI Vocab
x
WASI Matrix
x
Family History
x
MRI Safety Questionnaire
x
x
MRI Data Sheet
x
x
ER1 and ER2
x
x
fMRI Practice Test
x
x
YMRS
x
x
WASH-U-KSADS
x
x
PANAS-SF
x
x
DERS
x
x
ERS
x
x
BISII 
x
x
NEUROPSYCH TESTING
IAT 
x
x
x
x
x
Day 5 
and 
Day 
5+14 
(Day 19)
Day 14 
(see 2nd 
inf) Day 
14+14 
(Day 28)
Day 7 
and 
Day 
7+14 
(Day 21)
Day 10 
and 
Day 
10+14 
(Day 24)
Day 1 
and   
Day 
1+14 
(Day 15)
Day 2 
and 
Day 
2+14 
(Day 16)
Day 3 
and 
Day 
3+14 
(Day 17)
SCREENING
Day 0 - First Infusion (Ketamine or Midazolam)        
and                                         
Day 0+14 - Second Infusion (Ketamine or Midazolam) 


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Table 1: Assessment and Procedure Schedule for Trial Examining Ketamine’s Effects on Suicidal 
Ideation in Adolescent Depression and Anxiety Symptoms. Medical Assessment: Electrocardiogram 
(EKG).  Ratings Scales: Suicide Severity Rating Scale (C-SSRS)(114); Children’s Depression Rating Scale, 
Revised (CDRS-R)(100); Beck Suicidal Ideation Scale (SSI-5)(108); Anxiety Disorders Interview Schedule 
(ADIS-IV)(100) ; School Refusal Assessment Scale, Revised (SRAS-R)(125); Mini International 
Neuropsychiatric Interview for Children and Adolescents (MINI-KID 15/K-SADS)(99); Social Networks 
Interview (ASSIS)(99, 111); Childhood Trauma Questionnaire (CTQ)(110); Beck Hopelessness Scale 
(BHS)(109, 126); Revised Child Anxiety and Depression Scale (RCADS) (127); Treatment-Emergent 
Activation and Suicidality Assessment Profile (TEASAP)(104); Multidimensional Anxiety Scale for Children 
(MASC)(128); Visual Analog Scale (112, 129); Montgomery-Asberg Depression Rating Scale 
(MADRS)(101); Clinician-Administered Dissociative States Scale (CADSS)(107);  Clinical Global 
Impressions (CGI)(105); Columbia-Pleasure Scale for Children (CPS)(44); Affective Reactivity Index (ARI-
S) (113); Implicit Association Tasks (IAT) (47, 48). Assessments at 60 and 120 minutes on infusion days will 
be conducted by a non-blinded study physician.  We will additionally include the recommended self-report 
measures of sexual orientation and gender for all screened study subjects at baseline assessment.  
4.  Genetic Testing   
N/A 
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which material will 
be received
iii. the types of information about the donor/individual contributors that will be 
entered into a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the 
identifiers that connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials 
5. Subject Population: Provide a detailed description of the types of human subjects who 
will be recruited into this study.
Recruitment: Adolescents ages 13-17 years with medication-refractory MDD and/or treatment-
refractory anxiety disorders will be recruited for this study.  As many as 36 adolescents (18 with 
MDD and 18 with anxiety disorders) will be recruited through the Yale Child Study Center.   
The YCSC serves a large population of children with both MDD and anxiety disorders and has 
forged relationships with local schools for referrals of children and adolescents with MDD and 


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Anxiety to the clinics.   We will additionally employ letters to child mental health clinicians, 
educational lectures on adolescent MDD and anxiety disorders at mental health centers, and 
outreach to adolescent MDD and anxiety disorders researchers in the Boston-New York City 
area. Averages weights of subjects are anticipated to be 45-54kg for females 13-17 years old and 
45-65kg for males 13-17 years old.  
6. Subject Classification: Check off all classifications of subjects that will be targeted for 
enrollment in the research project. Will subjects who may require additional safeguards 
or other considerations be enrolled in the study? If so, identify the population of subjects 
requiring special safeguards and provide a justification for their involvement.
 Children
 Healthy 
Fetal material, placenta, or dead fetus
 Non-English Speaking
 Prisoners
 Economically disadvantaged persons
 Decisionally Impaired
 Employees
 Pregnant women and/or fetuses
 Yale Students 
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see HIC Application Instructions section VII #2 for 
further requirements)
For adolescents, we will obtain consent from their parent (legal guardian) before enrolling them 
in the study. We will also require childhood assent for participation. A simple quiz testing the 
understanding of the protocol and important elements of informed consent is in place at the end 
of the consent form. 
For females of child bearing potential we will conduct a urine pregnancy test prior to enrollment 
in the study. If the pregnancy test is positive, we will refer people to appropriate treatment and 
will exclude them from participation in the trial until completion of their pregnancy. For sexually 
active females, we will provide contraceptive counseling and refer them for contraceptive 
treatment if indicated. The acceptable methods of contraception will include oral birth control 
pills (OTCs), IUD, transdermal preparations, parenteral preparations, barrier contraceptive 
methods (i.e. condoms and diaphragm) and abstinence. As noted above, 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 consent 
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 consent, 
without having to declare specific reasons. Pregnancy testing will be repeated on the day of both 
infusions.
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion 
or    exclusion? 
Inclusion Criteria for MDD Cohort:
1) Meet DSM-5 criteria for Major Depressive Disorder by structured interview (MINI-KID).
2) Children’s Depression Rating Scale, Revised CDRS-R score 
40 at screening
≥


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3) Failure to achieve remission with at least 1 adequate prior antidepressant trial (e.g. SSRI, 
SNRI, or TCA), meaning at least 8 weeks at therapeutic dosing, including at least 4 weeks of 
stable dosing.  
Inclusion Criteria for Anxiety Cohort:
1) Meet DSM-5 criteria for any of the following anxiety disorders: Social Anxiety Disorders, 
Generalized Anxiety Disorder, Separation Anxiety Disorder and/or Panic Disorder by 
structured interview (MINI-KID)
2) ADIS Clinical Severity Rating ≥4 (moderately severe) for any of the 4 included anxiety 
disorders
3)  Failure to achieve remission with at least 1 adequate prior anxiolytic medication trial (e.g. 
SSRI, SNRI, or TCA), meaning at least 8 weeks at therapeutic dosing, including at least 4 
weeks of stable dosing.
4) Failure to achieve remission with previous CBT or subject declines current CBT therapy. 
Inclusion Criteria for ALL:
1) Male or female ages 13-17 years
2) Stable psychiatric medications and doses for the month prior to enrollment. Subjects may 
continue to engage in any ongoing psychotherapy. 
3) Medically and neurologically healthy on the basis of physical examination and medical 
history. 
4) Parents able to provide written informed consent and adolescents must additionally provide 
assent.
Exclusion Criteria: 
1) Current inpatient hospitalization or active suicidal ideation requiring referral for inpatient 
hospitalization for safety. 
2) History of psychotic disorder or manic episode diagnosed by MINI-KID
3) History of substance dependence diagnosis by MINI-KID (excluding tobacco) or positive 
urine toxicology. 
4) Intellectual disability (IQ<70) per medical history
5) Pregnancy (urine pregnancy tests on the day of scans for menstruating girls).
6) Inability to provide written informed consent according to the Yale Human Investigation 
Committee (HIC) guidelines in English.
7) Safety contraindication to MRI scanning (for MRI portions of study only):
a) History of significant medical illness, particularly illness associated with possible changes in 
cerebral tissue or cerebrovascular. 
b) History of neurologic abnormality, including significant head trauma (defined by loss of 
consciousness of ≥5-minutes duration), seizure disorder, cerebrovascular or neoplastic lesion, or 
neurodegenerative disorder. 
c) Contraindication to MRI scanning, e.g. presence of a ferromagnetic object, including orthodontic 
braces, or claustrophobia. All participants will be screened for metal objects by the same methods 
used for routine clinical MRI scanning.
8. How will eligibility be determined, and by whom? 
After an initial telephone contact to rule out obvious exclusions from the study protocol, 
potential participants will be scheduled for a screening visit at the Yale Child Study Center. A 


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member of our research team will discuss all aspects of this research: its purpose, the procedures 
that will be performed, any/all risks of the procedures, possible benefits, and possible alternative 
treatments. All patients will also be informed of the standard of care for children with MDD 
and/or anxiety disorders. The standard of care for MDD is initial treatment with an SSRI, which 
may be augmented with the addition of psychotherapy. The standard of care for anxiety disorders 
including Generalized Anxiety Disorder, Social Anxiety Disorders, Separation Anxiety Disorder 
and Panic disorder is evidence-based psychotherapy (e.g. CBT) and pharmacologic interventions 
(e.g. SSRI, SNRI, TCA).  The research team will discuss the inclusion and exclusion criteria for 
each arm of the study. To be included in the MDD arm of this study, adolescents must have 1) 
failed their first treatment with an antidepressant medication (e.g. SSRI, SNRI, TCA or other 
accepted FDA-approved medications for MDD and 2) have a diagnosis of MDD by DSM-5 
criteria and (3) have a CDRS-R score > 40.  To be included in the Anxiety Disorders arm of this 
study, adolescents must have 1) failed pharmacologic  treatment with an antidepressant 
medication  (e.g. SSRI, SNRI, TCA),(2) been offered or failed a trial of CBT for anxiety; (3) 
Meet DSM-5 Criteria for Generalized Anxiety Disorder, Social Anxiety Disorders, Separation 
Anxiety Disorder and/or Panic disorder  4) have at least moderately severe anxiety disorders 
symptoms as measured by ADIS CSR ≥4, If they agree to enroll in the study, they will sign the 
consent forms and undergo a standard clinical evaluation consisting of psychiatric history, 
physical, laboratory and mental status exams with one of the study doctors. The participant will 
also receive a clinical diagnostic interview using the MINI-KID, in addition to the baseline rating 
described in Table 1. A medical assessment including vital signs, physical exam, and urine drug 
screen and pregnancy test will be completed prior to enrollment.  
Participants will be enrolled if 1) they have a clinical diagnosis of MDD, meeting DSM-V 
criteria, defined as having at least 2 weeks of depressed mood or loss of interest/pleasure, in 
addition to 4 or more of the following symptoms: change in sleep, loss of interest in daily 
activities, inappropriate guilt, decreased energy, change in concentration, change in appetite, 
psychomotor symptoms, or recurrent thoughts of death and a CDRS-R score > 40 and/or 2) if 
they have clinical diagnosis of the following anxiety disorders (Generalized Anxiety Disorder, 
Social Anxiety Disorder, Separation Anxiety Disorder or Panic disorder). As a secondary 
outcome subjects with severe SRB defined by >25% of absenteeism from school one month 
prior to initiation of study will also be followed if the meet the inclusion criteria with symptoms 
of MDD or Anxiety disorders.
Participants will be excluded from the study if they present with active suicidal ideation, a 
history of serious medical or neurological illness, current psychoactive substance dependence, 
mental disorders due to identified medical conditions, or non-psychotic disorder. Participants 
will also be excluded if they manifest signs of major medical or neurological illness on 
examination or as detected by laboratory studies. The routine laboratory studies will include a 
CMP (including LFT’s), TFTs, CBC w/ diff, urinalysis, urine toxicology, EKG, and medical 
history, and a urine pregnancy test for females. Care will be taken to exclude pregnant women. 
Female participants will have a serum pregnancy test prior to receiving any treatment or testing 
in the study and will be informed of the importance of not becoming pregnant during the study. 
Participants will be excluded if they are judged to be so clinically unstable that participation in 
the study might represent a significant clinical risk or are unwilling to stay on a stable medication 
regimen for the length of this study. 
After lab results are received and if the patient remains eligible as indicated by meeting the 
inclusion criteria, the patient will be called in order to schedule their first infusion. In the case of 
abnormal test results, the proper referrals will be made to ensure the patients receive the 


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appropriate clinical care. 
Eligibility will be determined by the PI and co-investigators based on the study inclusion 
criteria (above). 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
Ketamine administration: Ketamine is a medication approved by the Food and Drug 
Administration to be used as an anesthetic in both children and adults. It is a dissociative 
anesthetic that has been used in humans since the late 1960's. Despite extensive experience there 
is no clear evidence of long-term toxicity associated with ketamine administration. However, the 
acute behavioral side effects of this medication warrant particular attention. Krystal et al, 
administered ketamine to healthy subjects at the West Haven VAMC(32). The study showed that 
ketamine produces dose-related effects at sub-anesthetic effects in healthy subjects. At 0.1 mg/kg 
administered over 40 minutes, the low dose in the VA protocol, ketamine produced little more 
than a tingling in the extremities and a "little buzzing in the head". At 0.5 mg/kg, the VA study’s 
high dose, and the dose proposed in this protocol, ketamine transiently elicited both the positive 
and negative symptoms of schizophrenia, dissociative symptoms, attentional impairments, a 
preferential impairment in delayed over immediate recall, increased perseverative errors on the 
Wisconsin card sort test, and decreased verbal fluency. In the sub-anesthetic dose utilized in this 
study, perceptual changes dissipate within 10-20 minutes following the termination of ketamine 
infusion. Ketamine also increased prolactin and cortisol, while blunting a test day decline in 
plasma HVA. Ketamine increased systolic and diastolic blood pressure by approximately 10-15 
mm Hg, without a clear effect on pulse. Ketamine did not produce gross disorientation, as 
evidenced by complete absence of an effect on the MMSE and the successful completion of all 
categories on the Wisconsin card sort test. There have been no medical complications of 
ketamine administration to date. Out of the 18 adult subjects administered ketamine 0.5 mg/kg 
over 40 minutes, 8 complained of blurred vision and two subjects vomited. Both the individuals 
who vomited were noted to have horizontal nystagmus. In this study, the absolute dose of 
ketamine is not to exceed 50mg, corresponding to a weight of 100kg. There have not been 
adverse psychological reactions in any of the healthy adult subjects. In the Yale Pediatric 
Sedation Team’s experience, there have not been serious after-effects reported in follow-up 
phone calls after sedation with ketamine for medical purposes, although one family reported that 
their child had “weird dreams” the night following the procedure. There is no doubt that 
ketamine has clear and, in some cases, dramatic effects upon cognitive function. Some people 
find these effects pleasant or interesting and others find these effects frightening. In prior studies, 
all subjects have been thoroughly prepared for possible ketamine response prior to testing and 
debriefed at the end of each test day. As a result, only two subjects terminated their participation 
in either study prematurely. No subject has had adverse or lingering responses to ketamine 
following a test day. Also, none of the subjects experienced "flashbacks" to their ketamine 
experiences following a test day. These findings are very consistent with the earlier work of 
Domino and his colleagues. Thus, ketamine appears to be safe and, despite the intensity of its 
short-term behavioral effects, well tolerated. The extent to which the effects of ketamine are 
perceived as unpleasant is context dependent and can be reduced by preparing individuals in 
advance for the possible responses to ketamine. The response to ketamine appears to be reduced 
by a number of medications, including benzodiazepines and antipsychotic agents.


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Since 1989, Yale researchers have administered ketamine to over 140 healthy subjects, 30 
recovering alcohol patients and 20 patients with major depression. Adverse effects in response 
to ketamine infusion have been mild and transient, with no evidence of any clinically 
significant adverse side effects. We have reported 8 adverse events associated with ketamine 
administration to the Institutional Review Boards of Yale and/or the West Haven VA since 
October of 2000. None was considered serious and all resolved shortly after discontinuation of 
the ketamine infusion or within two weeks of the ketamine test day. Adverse events included 
nausea and vomiting, sedation, hypotension, insomnia and nightmares, headaches, visual and 
somatosensory perceptual alterations, strong paranoid feelings, and anxiety. 
None of the patients or healthy subjects studied to date has had any long-term adverse 
consequences as a result of ketamine administration. This impression is supported by follow-up 
data up to 2 years on 132 healthy subjects participating in ketamine studies at Yale University 
and at Washington University at St. Louis (unpublished data). We examined follow-up 
assessments collected in a sub-sample of 132 healthy subjects who returned for subsequent 
testing over a duration of 1 week to 2 years. These subjects completed a similar battery of 
assessments when they reappeared as they completed in their earlier testing. In this analysis, no 
significant changes occurred in any measure between their initial and follow-up assessment.
In a previous study where ketamine was administered to depressed subjects there were adverse 
effects, though none were severe and none persisted beyond 110 minutes. Conversely, there was 
a significant transient improvement of depressive symptoms. 
Additional risks of ketamine must be considered in the pediatric population, particularly in light 
of earlier studies with antidepressants in which pediatric patients experienced side effects/risks 
that adults did not. While ketamine specifically reduces suicidality in adults (40, 130) 
antidepressant medications have been associated with increased suicidal ideation in pediatric but 
not adult populations (42). In order to minimize the risk of increased suicidality in this study, 
subjects will (1) be excluded for active suicidal ideation at baseline, (2) undergo regular 
psychiatric assessments of suicidality and (3) have direct access to a child psychiatrist 
throughout the study.  Additionally, any subject with significant psychiatric side effects will be 
offered hospitalization at one of Yale’s inpatient psychiatric units.
As ketamine can be abused outside of its medical purpose, the risk of any potential addictive 
properties must also be considered. Ketamine has been used in the pediatric population for years, 
and the rates of ketamine addiction in the United States remain very low (131). The ketamine 
infusion protocol in this trial is given slowly at a low dose (smaller than what is used in 
anesthesia) to minimize psychotomimetic effects (the high) associated with it. Adult studies have 
not reported problems with addiction following this ketamine protocol (102). The potential risk 
of abuse will be mitigated by excluding subjects with a history of substance use disorder.  
Additionally, subjects and their parents will be warned about abuse potential in all consent/assent 
documents.
Midazolam administration: Midazolam, the active control in this study, is a medication that is 
approved by the Food and Drug Administration as a sedative for both children and adults. It is a 
benzodiazepine with a short half-life that is used commonly in pediatric sedation and dentistry 
(117-123) and it is frequently administered rapidly at higher doses than proposed in the current 
study (we propose 0.045mg/kg over 40 minutes versus sedation dosing of 0.05 – 0.1mg/kg over 
2 minutes (122, 124)). In this study, the total midazolam dose is not to exceed 4.5mg, 
corresponding to a weight of 100kg. The most common side effects related to midazolam 


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infusions are hiccups, nausea, vomiting, coughing, headache, and drowsiness. In doses higher 
than those involved in the proposed study, serious cardiorespiratory adverse events have 
occurred after administration of midazolam, including respiratory depression, airway obstruction, 
oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest. In younger children, these 
higher doses have been associated with a risk for paradoxical disinhibition or agitation. 
Midazolam, like ketamine, has a short half-life, and important adverse events related either drug 
are not observed after 30 minutes following drug administration (74). The Yale Pediatric 
Sedation team has vast experience with this medication given its common usage, and will be 
present during the infusion and until the patient has reached an appropriate state of recovery, as 
is done for all pediatric sedation procedures at YNHH. While the risks of serious adverse 
cardiorespiratory events are low given the dose chosen for this study, airway equipment and 
qualified physician personnel will be readily available. The reversal medication, flumazenil, will 
also be available, which can rapidly abort the effects of midazolam should any untoward effects 
occur. 
All benzodiazepines have the potential for physical and psychological dependence after 
prolonged use. The single infusion and low dose proposed in this study would not be expected to 
result in any physiologic dependence. Benzodiazepines as a class are also at risk to be abused for 
recreational use outside of medical purposes. The addictive potential of midazolam will be 
mitigated by using a low dose and a slow infusion paradigm. Midazolam is used very frequently 
in the pediatric setting, and is not thought to be associated with precipitating subsequent 
benzodiazepine abuse. The risks will further be mitigated by screening out adolescent subjects 
with concurrent substance use disorders. Subjects will also be warned about the abuse potential 
in all consent/assent documents. 
Blood drawing/intravenous placement: Bruising or thrombosis can occur with placement of 
the intravenous line. A total of 110cc will be drawn over 4 weeks (30cc at baseline, 35cc on first 
infusion day (Day 0), 5cc on Day 1, 35cc on second infusion (Day 14), and 5cc on Day 15), 
which equates to 1.5cc/kg – 2.2cc/kg (based on average weights of 13-17yo adolescents). 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. 
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 complete them.
Clinical Deterioration: There is a risk that a participant may experience of depression and/or 
anxiety symptoms or school refusal if applicable due to the natural course of the illness or poor 
response to ketamine administration. Because subjects will be asked to refrain from changing 
any psychotropic medication over the course of the study, clinical progress will be monitored 
closely with frequent CDRS-R and MADRS, and/or PARS and school attendance questionnaire, 
as well as ratings and frequent contact with clinic personnel. The following are criteria for 
evaluation and possible pharmacological and/or non-pharmacological treatments: (1) an increase 
of 25% in CDRS-R score at any time over the course of treatment (lasting beyond acute 
administration studies), (2) new-onset of suicidal ideation or an increase in passive 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 


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referrals are provided and available to the study participant. Participants who have completed the 
trial must have a CDRS score of less than 50 to be discharged from the study.
Magnetic Resonance Imaging: MRI is considered to be among the safest ways to examine the 
human body. The United States Food and Drug Administration (FDA) has set guidelines for magnet 
strength and exposure to radiowaves, and we carefully observe those guidelines. Subjects will be 
watched closely throughout the study. Some youths may feel uncomfortable or even anxious during 
the MRI. If this happens to a subject, the subject may ask to stop the study at any time and we will 
take the subject out of the MR scanner. On rare occasions, some people might feel dizzy, get an upset 
stomach, have a metallic taste in their mouth or feel tingling sensations or muscle twitches. These 
sensations usually go away quickly but subjects will be encouraged to tell the research staff if the 
subject experiences such sensations. MRI poses some risks for certain people. If the subject has some 
metal object(s) inside his or her body, the subject may not be in this study because the strong 
magnets in the MR scanner might harm him or her. Another risk is a metallic object flying through 
the air toward the magnet and hitting subjects. To reduce this risk, we require that all people involved 
with the study remove all metal from their clothing and all metal objects from their pockets. Nothing 
metal can be brought into the magnet room at any time. Also, once subjects are in the magnet, the 
door to the room is closed so that no one from outside inadvertently approaches the magnet. To 
minimize this risk, the participant will walk through a ferromagnetic detector to ensure he/she does 
not have any metal objects on his/her body.
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized. 
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 dose allowed in this 
study will be 50mg, corresponding to a weight of 100kg. The most common side effects of 
ketamine are (1) Elevated blood pressure (relatively common, but dose-dependent) breathing rate 
and pulse rate, (2) Local pain at injection site and temporary rash (rare) and (3) A variety of 
temporary psychological symptoms including, but not limited to anxiety, sadness, disorientation, 
insomnia, flashbacks, hallucinations, and psychotic-like symptoms.  These types of reactions 
have occurred in approximately 12% of patients given higher doses of ketamine when used for 
anesthesia.  These symptoms usually last no more than a few hours.  The most serious possible 
side effects of ketamine use are (1) Substance abuse/dependence, (2) Elevations in intraocular 
pressure that could lead to vision problems, (3) Allergic reaction and (4) Elevation in blood 
pressure that could result in stroke, heart problems and death.  All the serious possible side 
effects of ketamine are rare.  In order to minimize these risks for research subjects, vital signs 
will be monitored regularly throughout and for the first hour following the ketamine infusion.  A 
physician from the Yale Pediatric Sedation Service who is credentialed by YNHH for the 
administration of ketamine will be present for all infusions, with access to rescue equipment. 
Subjects will be monitored for at least 3 hours following ketamine infusion by Dr. Bloch. A 
study doctor 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, the site of infusion. 
All participants will be asked not to engage in demanding work for the first 3 days after the 
ketamine infusion. However, for those with school refusal, they continue with their regular 
school schedule.  If participants develop psychiatric symptoms, we may admit them to the 


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hospital. Hospitalization may be involuntary if patients are in danger of harming themselves or 
others. 
The consent 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. 
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 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. A research doctor will also be available. The physician would be informed 
in case of any alarming changes in the patient’s physical or mental state. The research nurse will 
also offer support and provide consistent “reality testing” for individuals experiencing confusion 
or transient psychosis. 
Intravenous and oral diazepam will be kept available to control markedly distressing behavioral 
effects of ketamine, should they emerge.
All participants will be asked to contact us at any time if any unpleasant effects occur. All 
participants will be given wallet-sized cards, which provide contact information. The cards will 
identify the Yale Human Investigation Committee number for the study, the study PI (Michael 
Bloch, MD (203) 745-9921, Yale Investigational Drug Service phone number, regular hours and 
telephone numbers of their study physician and research support staff (Angeli Landeros-
Weisenberger (203) 737-4809), should unpleasant effects occur after the subject has left the 
testing facility. All participants are contacted 1, 2, 3, 5, 7, 10, 14, days after each infusion for 
safety reasons. In addition, participants will be contacted 1, 2, 3, 5, 7, 10, and 14 days after each 
infusion to administer symptom ratings. 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.  
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 (122). The maximum total dose allowed in this study will be 
4.5mg, corresponding to a weight of 100kg. The most common side effects related to midazolam 
infusions are hiccoughs, nausea, vomiting, coughing, headache, and drowsiness. In younger 
children, higher midazolam doses have also been associated with a risk for paradoxical 
disinhibition or agitation. 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 (74). The most serious possible adverse reactions 
associated with midazolam, which are associated with higher doses than proposed in the study 
include: (1) substance abuse/dependence, (2) anaphylaxis or other allergic reaction, (3) 
respiratory depression or arrest, (4) decreases in blood pressure resulting in end organ damage or 
death. The serious side effects associated with midazolam are rare. In order to minimize the risk 
of these side effects, subjects will be medically screened prior to enrollment in the study, vitals 
will be monitored regularly throughout the infusions (with continuous pulse oximetry), and 
regularly for the hour following the infusion. To additionally minimize the risks associated with 
midazolam, a physician from the Yale Pediatric Sedation service will pre-screen subjects and 


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will be present for the duration of the infusion, with access to airway equipment (although we 
believe that the likelihood of a serious event at the dose proposed in this study is low). There will 
also be access to flumazenil, a reversal agent that rapidly terminates that action of midazolam. 
The Yale Pediatric Sedation team is credentialed to administer these medications at YNHH and 
have vast experience with midazolam given its common usage, and their consultation has been 
integral to designing the monitoring parameters detailed herein. Subjects will be monitored for at 
least 3 hours following ketamine infusion by Dr. Bloch. A study doctor 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, the site of infusion. 
All participants will be asked to contact us at any time if any unpleasant effects occur. All 
participants will be given wallet-sized cards, which provide contact information. The cards will 
identify the Yale Human Investigation Committee number for the study, the study PI (Michael 
Bloch, MD (203) 745-9921, Yale Investigational Drug Service phone number, and regular hours 
and telephone numbers of their study physician and research support staff (Angeli Landeros-
Weisenberger, MD (203) 737-5104), should unpleasant effects occur after the subject has left the 
testing facility. All participants are contacted 1, 2, 3, 5, 7, 10, 14, days after each infusion for 
safety reasons. In addition, participants will be contacted 1, 2, 3, 5, 7, 10, and 14 days after each 
infusion to administer symptom ratings. 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.  
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.  
During the infusion days, blood draws will occur off of the non-infusing iv in order to prevent 
the discomfort of repeated needle sticks. The total amount of blood to be collected in this study is 
110cc over 4 weeks (30cc screening + 35cc first infusion day (Day 0) + 5cc on Day 1 + 35cc 
second infusion day (Day 14) + 5cc on Day 15). This amount ranges from 2.4cc/kg for a 45kg 
adolescent to 1.7cc/kg for a 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. 
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.
Clinical deterioration: If a participant shows significant worsening of symptoms, he or she will 
be removed from the study and evaluated for clinically appropriate pharmacological and non-
pharmacological treatments by a clinic psychiatrist and followed until successful contact with a 
community provider is made. 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 


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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 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. Participants who have completed the trial must have a CDRS score of less than 
50 to be discharged from the study.
Magnetic Resonance Imaging: In addition to what was stated above, the following steps will be 
taken to minimize potential risks associated with MRI data collection: 
1) Claustrophobia 
The subjects can be given the option to acclimate to MR imaging by using the mock scanner. In the 
scanner, subjects will have a mirror with which to view console and room. There will be constant 
assessment as to how subject is feeling via console speaker. Subjects can have a member of the 
research team sit in scan room during the study. We will talk with the subject, assess their condition, 
and ask whether or not they would like to continue. Subjects will be encouraged to relax, will be 
reassured that they are safe, and we will ask them to use the mirror, music or have someone in the 
room with them. They will be taken out of the scanner and their scanning terminated if they do not 
want to continue. 
2) Hearing damage due to loud noises produced by the scanner 
Hearing damage will be minimized by ear plugs and headphones. The ear plugs and headphones are 
estimated to each reduce noise by approximately 35 db at the sound frequencies generated by the 
scanner. We will evaluate the fit of the ear plugs and the headphone. This is usually very successful 
in dampening noise. The subject will be taken out of the scanner and their scanning terminated if 
they do not want to continue. 
3) Dizziness 
Dizziness will be minimized by sliding the subject slowly into and out of the scanner (dizziness 
occurs mainly when sliding in and out of scanner). Subjects will be informed the best approach to 
minimize dizziness is not to clasp one’s hands together and not to cross one’s legs during scanning. 
We will tell the subjects they might have dizziness as we position them into the scanner but that it 
subsides after they are in position. If the dizziness continues, we will take the subject out of the 
scanner and have them lie supine on the scanner bed until the dizziness passes. Their scanning will 
be terminated if they do not want to continue. 
This MR study is for research purposes only and is not in any way a clinical scan to diagnose 
diseases for subjects. The scans in this study are not designed for diagnosis. The research team,
the MR technologist, and the Magnetic Resonance Research Center are not qualified to interpret the 
MR scans and cannot give the subject, the subject’s parents and/or guardians, or their doctor a 
diagnostic evaluation of the images. If we see something on a subject’s scan that might be medically 
significant, we will ask a radiologist or another physician to review the relevant images. If that 
person recommends that a subject should seek medical advice, then the primary investigator or 
consulting physician will contact the subject’s parent and/or guardian, about the situation, and 
recommend that the family seeks medical advice as a precautionary measure. At that point, the 
decision to seek advice or treatment is completely up to the parent/guardian, and their child’s doctor. 
If the child’s doctor wants to pursue additional MR images, the research scans from this study will 
not be available, and new scans that are appropriate for medical diagnosis will need to be done. 
While there are no known risks associated with MRI and pregnancy it is standard clinical practice to 
avoid MRI scans in pregnancy when possible and therefore there is not a large pool of data. Given 
this, pregnant subjects will be excluded from study. Scanning is performed on the campus of the Yale 


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Medical Center so that emergency medical intervention is available in the event of an adverse event.
Dr. Blumberg has extensive experience in performing scans with young people particularly including 
those with anxiety and associated problems. Minimizing head movement is critical especially when 
scanning children and adolescents. We are careful both to comfortably stabilize head position for the 
subject with use of foam padding and velcro straps, and to be sure at least one staff member whom 
the subject has gotten to know during the interview process stays during scanning to support the 
subject through the scanning session and to provide reminders about remaining still, which has 
helped keep the motion in our data minimal. This has been further enhanced by the outstanding 
technical staff members at the MRRC, who have many years of experience in clinical research 
studies and are highly supportive and skilled in working with our research subjects. In over Dr. 
Blumberg’s 16 years of MRI research at the MRRC, it has been rare that we need to remove a subject 
from the scanner due to anxiety. However, if this issue should arise we have the ability to utilize the 
mock scanner that is in a room down the hall from the scanner and resembles an actual scanner.
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make the final 
determination of the risk to subjects.) For more information, see the Instructions, page 24.
a. 
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
We judge this study to be moderate risk, but with the possibility of direct benefit 
to the pediatric patient.
b.
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study? 
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
20 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, 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 control 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.
c.
Copy and paste, and then tailor an appropriate Data and Safety Monitoring Plan 
from  http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal/moderate risk


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iii. High risk
1. Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency, which must be 
conducted at a minimum of every 6 months (including when reapproval of the protocol is 
sought).  During the review process, the principal investigator will evaluate whether the study 
should continue unchanged, require modification/amendment, or close to enrollment. Either the 
principal investigator or the IRB have the authority to stop or suspend the study, or require 
modifications.
2. The risks associated with the current study are deemed greater than minimal for the 
following reasons: (choose those that apply)
1. We do not view the risks associated with the ketamine and midazolam infusions as 
minimal risks.
2. Given the established safety and validity of the current ketamine dosing from our prior 
work in adults, as well as the frequent use of both ketamine and midazolam at higher 
doses in pediatric populations, we do not view the proposed studies as high risk.
Although we have assessed the proposed study as one of greater than minimal risk, the potential 
exists for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it 
is not possible to predict with certainty the absolute risk in any given individual or in advance of 
first-hand experience with the proposed study methods. Therefore, we provide a plan for 
monitoring the data and safety of the proposed study as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design by the principal investigator (Dr. Michael Bloch) according to the 
following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe 
5. Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:


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In addition to grading the adverse event, the PI will determine whether the adverse event meets 
the criteria for a Serious Adverse Event (SAE).  An adverse event is considered serious if it 
results in any of the following outcomes:
1. Death;
2. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization; 
3. A persistent or significant disability or incapacity; 
4. A congenital anomaly or birth defect; OR
5. Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria for an 
SAE.  It is important for the PI to consider the grade of the event as well as its “seriousness” 
when determining whether reporting to the IRB is necessary.
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
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 consent 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.  Please note that adverse events are 
reportable to the IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the 
appropriate forms found on the website. All related events involving risk but not meeting the 
prompt reporting requirements described in IRB Policy 710 should 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.  In lieu of a summary of external events, a current DSMB report can be 
submitted for research studies that are subject to oversight by a DSMB (or other monitoring 
entity that is monitoring the study on behalf of an industry sponsor).


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7. Plan for reporting adverse events to co-investigators on the study, as appropriate the 
protocol’s research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study 
sponsors, funding and regulatory agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified (choose those that apply):
X All Co-Investigators listed on the protocol.
X Food and Drug Administration
The principal investigator (Dr. Michael Bloch) will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and 
severity of the adverse events and determine if modifications to the protocol or consent form are 
required.
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
12. Statistical Considerations: Describe the statistical analyses that support the study design. 
MDD Arm: Controlled studies of ketamine (both saline and midazolam controls) in adult MDD 
report effect sizes of 1.5 (34, 132). If of similar efficacy in adolescents, a sample size of 18 would 
have power greater than 0.8 to detect a difference from midazolam (α=0.05) for an effect size≥1.0. 
For the primary outcome, paired t-tests will compare MADRS score at 1 day following infusion 
between midazolam and ketamine. Scores of the other rating scales and time course will be 
assessed as secondary measures. It is quite possible that the benefits of ketamine will be smaller 
in adolescent depression compared to adult depression. Therefore, even if the results of our 
primary analysis are not statistically significant, we would consider having 6 of 18 patients 
exhibiting a response to ketamine (but not midazolam) during the first week following infusion as 
sufficient evidence towards conducting a more definitive trial. Treatment response for the MDD 
cohort is defined as 40% reduction in CDRS-R scores anytime in the first three days following 
infusion. 
Anxiety Arm:  Controlled studies of ketamine (saline controls) in adult MDD assessing anxiety as 
a secondary outcome have reported effect sizes of 1.4 at day 1.  Similarly, controlled studies of 
adults with OCD and PTSD both reported an ES≈0.9 at day 1 following infusion (96, 98). By 
comparison, in our adult social anxiety trial we observed an ES≈0.8 at day-1 following infusion 
on the CGI.  Given a sample size of 18 adolescents we would have power greater than 0.8 to detect 
a difference from midazolam (α=0.05) for an effect size≥1.0.  For the primary outcome, paired t-
tests will compare MASC physical symptom subscale score at 1 day following infusion between 
midazolam and ketamine. Scores of the other rating scales and time course will be assessed as 
secondary measures. It is quite possible that the benefits of ketamine will be smaller in adolescent 
anxiety compared to previous adult trials. We would define treatment response as a CGI≤3 and a 


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greater than 35% improvement in the MASC physical symptoms subscale at any time point during 
the first 7 days following infusion.  The MASC physical symptoms was chosen as the primary 
outcome for the anxiety disorders arm of this trial because (1) we believe the physical symptoms 
of anxiety may change within a short time frame (e.g. 1 -day) whereas the behavioral symptoms 
of anxiety (avoidance, performance fears, social anxiety symptoms, fear of humiliation/rejection 
symptoms) are less likely to be detectable over short time periods.
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, PLACEBOS AND DEVICES
A.  DRUGS and BIOLOGICS
1. Identification of Drug or Biologic: What is (are) the name(s) of the drug(s) or
biologic(s) being used? Identify whether FDA approval has been granted and for what indication(s). 
Ketamine (Ketalar) has USDA approval as the sole anesthetic agent for diagnostic and surgical 
procedures that do not require skeletal muscle relaxation. The drug is also indicated for the induction 
of anesthesia prior to the administration Dr. Bloch holds a therapeutic license for administering 
controlled substances.
Midazolam HCl (Versed) 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. As with ketamine, Dr. Bloch holds a therapeutic license for 
administering controlled substances.
All protocols which utilize a drug or biologic not approved by, but regulated by, the FDA must 
provide the following information:  N/A
What is the Investigational New Drug (IND) number assigned by the FDA? 
Who holds the IND? 
All protocols which utilize a radiotracer not approved by, but regulated by the FDA must provide 
the IND number: _______________
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________
For all investigational radiotracers, attach a copy of the RDRC/RSC application ( for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission
Alternatively, an exemption from IND filing requirements may be sought for a clinical
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and
 an exemption is being sought, review the following categories and complete the category that applies


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 (and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be
exempt from IND regulations if all of the following are yes:
2. The intention of the investigation is NOT to report to the FDA as a well-controlled study in support
     of a new indication for use or to be used to support any other significant change in the labeling for
     the drug.  
 Yes  
 No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and
      the intention of the investigation is NOT to support a significant change in the advertising for the
      product. 
 Yes  
 No
3. The investigation does NOT involve a route of administration or dosage level or use in populations
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)   
      associated with the use of the drug product. 
 Yes  
 No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)   
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56). 
 Yes  
 No
4. The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. 
 Yes  
 No
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one or
more of the following (check all that apply):
 Blood grouping serum
 Reagent red blood cells 
 Anti-human globulin
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the
diagnosis made by another, medically established, diagnostic product or procedure; and
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60
Exempt Category 4
 A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND.
5. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might influence 
risks. If this is the first time this drug is being administered to humans, include relevant data on animal 
models. 
Ketamine: Ketamine has a wide margin of safety, and is usually given in doses of 1mg/kg – 


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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 (see Preliminary Data).  
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 (133). 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 
(133). 5) Neurological: enhanced skeletal-muscular tone resulting in tonic clonic movements 
have rarely been observed with acute administration. 6) General: Anaphylaxis, local pain at 
injection site and transient rash have been described at the case report level. 7) 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 (133). 
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. 8) 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.
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: 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, 


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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, oversedation; 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 single infusion 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. Source: a) Identify the source of the drug or biologic to be used. 
Ketamine (Ketalar) and midazolam (Versed) will be obtained from the YNHH Research Pharmacy
b) Is the drug provided free of charge? 
 Yes  
 No
    If yes, by whom? 
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity. 
Ketalar is chemically designated d,l – 2- (0-chlorophenyl)-2-(methylamino) cyclohexanone 
hydrochloride. It is formulated as a slightly acidic (pH 3.5-5.5) sterile solution for intravenous or 
intramuscular injection in concentrations containing he equivalent of either 10, 50, or 100 mg 
ketamine base per milliliter and contains not more than 0.1 mg/mL Phemerol®  (benzethonium 
chloride) added as a preservative. The 10mg/mL solution has been made isotonic with sodium 
chloride. The medication will be obtained and stored at the YNHH research pharmacy, and will be 
picked up by investigators on the morning of infusion.
Midazolam is chemically designated as HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo 
[1,5-a] [1,4] benzodiazepine hydrochloride. It is formulated as a slightly acidic sterile solution for 
intravenous injection. It is available in both preservative and preservative-free preparations, and is 
available in 1mg/mL and 5mg/mL preparations. The medication will be obtained and stored at the 
YNHH research pharmacy, and will be picked up by investigators the morning of the infusion.
Check applicable Investigational Drug Service utilized:
     
  YNHH IDS                                                                       
   Yale Cancer Center 
     
  CMHC Pharmacy                                                           
    West Haven VA


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  PET Center       
    None
     
  Other:                              
                                                                             
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.  
  
5. Use of Placebo: 
 Not applicable to this research project
Provide a justification which addresses the following:
a.   Describe the safety and efficacy of other available therapies (if any). Standard treatments for 
depression and anxiety in adolescents include SSRIs, SNRIs, and psychotherapy. Nearly 40% of 
pediatric patients fail to respond to these first line pharmacotherapies and of those non-responders, 
nearly half remain depressed and anxious after switching medications and adding psychotherapy. 
Even when effective these medications take several weeks to take clinical effect, leaving a 
vulnerable period between the initiation of treatment and the start of resolution of symptoms of 
anxiety and depression. Importantly, these medications carry a black box warning for Pediatric 
patients as they are associated with a small, but significant increase in suicidality. Psychotherapy 
does not carry any specific medical or psychiatric risks, and subjects enrolled in the study are 
permitted to continue to engage in psychotherapy if they have already been doing so. They are also 
permitted to stay on their current pharmacotherapies during the 4-week trial, but are not allowed to 
make medication changes. 
b.   State the maximum total length of time a participant may receive placebo while on the study. 
One dose of IV midazolam will be given. However, the protocol will require 2 weeks in between 
each infusion. During this time the participant would not be receiving any additional treatments 
(they may remain on any current therapy (daily medications, psychotherapy, etc.)). 
c.   Address the greatest potential harm that may come to a participant as a result of not receiving    
  
   effective therapy (immediate or delayed onset.) 
Symptoms of MDD, anxiety and common comorbid symptoms may not improve or even worsen 
depending on the clinical course of illness.  Subjects have the option of withdrawing from the 
research protocol at any point if their symptoms worsen.  Additionally, inpatient hospitalization 
resources are available to the investigator if subject’s symptoms worsen to the point of requiring 
inpatient hospitalization as part of the protocol.
d.   Describe the procedures that are in place to safeguard participants receiving placebo. 
As stated in the “Minimize Risk” section under “Clinical Deterioration above, if a participant 
shows significant worsening of symptoms, he or she will be evaluated for clinically appropriate 
pharmacological and non-pharmacological treatments by a clinic psychiatrist and followed 
until successful contact with a community provider is made. The crossover design also ensures 
that all subjects will receive the active medication within the month of the study protocol. 
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 Yale, or to 
receive treatment on a private basis from a referring clinician. 
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?


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 Yes  
 No See HIC Application Instructions to view controlled substance listings. 
If yes, is the use of the controlled substance considered:
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
 Non Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical studies 
or other non-therapeutic purposes.
 
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended? 
 Yes  If yes, describe the conditions under which continued access to study drug(s) may 
apply as well as conditions for termination of such access. 
                   
 No    If no, explain why this is acceptable.
This study is designed to determine the short-term safety and benefit of ketamine as a 
rapidly acting antidepressant and anxiolytic in adolescents. Further studies will be needed to 
carefully assess the safety and efficacy of a longer-term treatment course with this medication. 
B.  DEVICES - N/A
SECTION VII: RECRUITMENT/CONSENT/ ASSENT 
1. Targeted Enrollment: Give the number of subjects: 18
a.
  targeted for enrollment at Yale for this protocol: 18
b.    If this is a multi-site study, give the total number of subjects targeted across all 
sites_N/A__ 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will 
be used.
 Flyers
 Internet/Web Postings
 Radio
 Posters
 Mass E-mail Solicitation
 Telephone
 Letter
 
 Departmental/Center Website
 Television
 Medical Record Review
 Departmental/Center Research Boards
 Newspaper
 Departmental/Center Newsletters
 Web-Based Clinical Trial Registries
 YCCI Recruitment Database
 Clinicaltrials.gov Registry (do not send materials to HIC)
 Other (describe):
3.  Recruitment Procedures:
a.
Describe how potential subjects will be identified. Subjects will be identified 
through their response to the contact number on the clinicaltrials.gov listing, 
flyers, internet ads, or postings on the departmental website/YCCI recruitment 
database. We will also reach out to local child mental health providers in the 
area, who may tell their patients about this study.  


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b. Describe how potential subjects are contacted.  Potential subjects interested in 
the trial will initiate first contact with the study recruitment coordinator or 
another member of the research team.
c.
Who is recruiting potential subjects?   The study investigator and listed 
research staff will be recruiting potential subjects.
4. Screening Procedures:
 A. Will email or telephone correspondence be used to screen potential subjects for eligibility 
prior to the potential subject coming to the research office? 
 Yes  
 No
B. If yes, identify any health information and check off any of the following HIPAA 
identifiers to be collected and retained by the research team during this screening process. 
 
HEALTH INFORMATION TO BE COLLECTED:
HIPAA identifiers: 
 Names 
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000. 
  Telephone numbers
 Fax numbers 
 E-mail addresses
 Social Security numbers 
 Medical record numbers
 Health plan beneficiary numbers 
 Account numbers 
  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older 
 Certificate/license numbers 
 Vehicle identifiers and serial numbers, including license plate numbers 
 Device identifiers and serial numbers 
 Web Universal Resource Locators (URLs) 
 Internet Protocol (IP) address numbers 
 Biometric identifiers, including finger and voice prints 
 Full face photographic images and any comparable images 
 Any other unique identifying numbers, characteristics, or codes 
5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
 No


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6. Request for waiver of HIPAA authorization (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: For entire study: ______ For recruitment purposes only: __x____
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;
i. We are requesting a waiver of HIPAA authorization for recruitment 
purposes only. Subjects will be initially recruited through word of mouth, 
clinicaltrials.gov, physician referrals, and Internet ads. We will need to use PHI 
such as name, telephone number and email addresses to schedule initial screening 
interviews. It would be impractical to coordinate initial subject enrollment and 
recruitment without this data. 
ii. Signed authorization is impractical because initial screening of patients 
recruited through advertisements or referral may occur over the telephone or email. 
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer.
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure 
of protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
 Compound Consent and Authorization form
 HIPAA Research Authorization Form
 
8. Consent Personnel: List the names of all members of the research team who will be 
obtaining consent/assent. Jennifer Dwyer, MD, PhD, Amalia Londono Tobon, MD, 
Angeli Landeros-Weisenberger MD, Michael H. Bloch MD, MS; Jessica Johnson BS.
9.
Process of Consent/Assent: Describe the setting and conditions under which 
consent/assent will be obtained, including parental permission or surrogate permission and 
the steps taken to ensure subjects’ independent decision-making. 


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Subjects will be minors (ages 13-17) and the consents will be obtained from the parent 
(guardians). We will also obtain assent from minors participating in our trial. Trained 
research study staff or the principle investigator will review the consent documents verbally 
with both the parent and child. Assent will be signed in the presence of the child’s 
parent/guardian.
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how 
the personnel obtaining consent will assess the potential subject’s ability and capacity to 
consent to the research being proposed. 
Subjects will be minors (ages 13-17) and the consents will be obtained from the parent 
(guardians). We will also obtain assent from minors participating in our trial. Trained 
research study staff or the principle investigator will review the consent documents 
verbally with both the parent and child. Assent will be signed in the presence of the 
child’s parent/guardian. A brief questionnaire will be used to assess their basic 
understanding of our protocol – random order, need for regular visits, and risks of 
ketamine. If for any reason, it becomes clear that either the parent or child cannot 
comprehend trial design or procedures they will not be enrolled in this study. 
 
11.
Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the 
same format that they will be given to subjects. 
Compound Authorization and Parental Permission Form and adolescent assent form (ages 
13-17). 
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent 
materials must be submitted for approval prior to use. 
This protocol will not involve Non-English speaking subjects due to an inability to 
adequately translate the consent materials and clinical rating and the investigator and study 
staff’s non-fluency in languages other than English.
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed 
consent, or a full waiver of consent, depending on the study.  If you will request either a 
waiver of consent, or a waiver of signed consent for this study, complete the appropriate 
section below.  
 
 Not Requesting a consent waiver 
 
 Requesting a waiver of signed consent
       
 Requesting a full waiver of consent
   
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)


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 Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research activity pose greater than minimal risk? 
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity. 
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
B. Full waiver of consent: (No consent from subjects will be obtained.) 
 Requesting a waiver of consent for Recruitment/Screening only 
a. Does the research activity pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity 
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:


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a. Does the research pose greater than minimal risk to subjects?  
 Yes  If you answered 
yes, stop. A waiver cannot be granted.  
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
 Confidentiality & Security of Data:
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?   
       
b.    How will the research data be collected, recorded and stored? 
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard   
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other
d.    What methods and procedures will be used to safeguard the confidentiality and security of    
 the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study?
Do all portable devices contain encryption software? 
 Yes   
 No
e.    What will be done with the data when the research is completed? Are there plans to destroy  
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If no, 
describe how the data and/or identifiers will be secured.
f.   Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-
identified data) 
g.   If appropriate, has a Certificate of Confidentiality been obtained? 
h.  Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported. 
(a) 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 be place in the research study record.
A Certificate of Confidentiality has been obtained by the investigator to protect all sensitive 
information connected with this study.
(b) 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 


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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 
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.
(c) Above 
(d) 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.
 (e) 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. 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 his Department 
Chair and Faculty Advisor to ensure that proper and continued protection of individually 
identifiable information and protected health information continues. 
After a period of five years these files will be destroyed by ITS approved methods or de-identified 
to protect subject confidentiality. 
(f)  In addition to the study investigators, co-investigators, and study staff, members of HIC and 
the study sponsor may have access to the study data. 
(g) A Certificate of Confidentiality has been obtained to protect the drug toxicology results. Where 
possible, information will be destroyed that may link the subject to illicit drug use. Since a YNHH 
chart will need to be created for these subjects by virtue of their visit to the site, there is a concern 
that these results could be traced back to the subject. Subjects who test positive on the toxicology test 
will not be able to participate in this protocol. Subjects will be encouraged to seek treatment for their 
substance use, as appropriate.
(h)  Yes. Evidence of child abuse or situations in which the subject is deemed a danger to self or 
 others will be reported.  
         SECTION IX: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.) 
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 suggest that adolescent 
subjects may receive a significant benefit. Given the crossover design, all subjects will be 
exposed to the potentially beneficial intervention. The potential benefits to society of these 
investigations are considerable. Depression and anxiety continue to be a major public health 


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problem with tragic cost to the individual, the family, and the community. The present study may 
improve our understanding of depression, anxiety and SRB by providing a pharmacologic 
rationale for developing novel treatments. 
Midazolam arm: While the active control 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 schedule contact with Child Psychiatry on 
Days 1 (in person), 2, 3, 5, 7 (in person), 10, and 14 (in person) after the infusion, and will 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.
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.     Alternatives: What other alternatives are available to the study subjects outside of the research?
The subject and his/her parent/guardian may discuss other non-research treatments for MDD 
and/or anxiety and/or SRB with their practitioner or continue with their current stand of care. 
Other treatment alternatives include: change to another class of antidepressants (e.g. selective 
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs). Monoamine 
uptake inhibitors (MAOIs), psychotherapy (e.g. cognitive behavioral therapy, insight-oriented 
psychotherapy). 
 
2. 
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation. 
Subjects will be paid $375 if they complete all scheduled visits. 
If they leave the study early, they will be compensated $10 for each completed in-person study 
visit (6 total), $5 for each telephone study assessment (8 total). Additionally, participants will be 
paid $25 for each of the infusion days (2 total). Subjects will be paid $50 for each MRI and $25 
for each neuropsychological assessment (Baseline and 24 hours after each infusions) (3 Total 
each.). 
Participants will receive an additional $75 if they complete all assessments for SRB.
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.   
The study drug and all medical treatment in this research study will be provided free of charge. 
There will be no charges for study visits. Costs of the participant are thus limited to the cost of 
transportation to and from the study appointments and their time spent participating in the study.
 
  


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4.
In Case of Injury: This section is required for any research involving more than minimal risk.
a.     Will medical treatment be available if research-related injury occurs? 
If a physical injury or illness occurs as a direct result of participation in this study, study 
physicians and nursing personnel will provide emergency medical care and ensure that research 
participants receive prompt evaluation and medical treatment as necessary. In severe cases this 
may involve a transfer to Yale-New Haven Hospital emergency room. The cost of treatment for 
any such injury or illness will not be paid for through the study and will be the responsibility of 
the research participant.
b. Where and from whom may treatment be obtained? 
In the event of a significant medical emergency the participant will be treated at Yale New 
Haven Hospital (the location of the infusion). Should there be adverse psychiatric effects as a 
result of the study they will receive inpatient treatment by going through the Yale New Haven 
Hospital Psychiatric Emergency Room.  The cost of treatment for any such injury or illness will 
not be paid for through the study and will be the responsibility of the research participant.
c.     Are there any limits to the treatment being provided? 
In the unlikely event that any psychiatric care more intensive than regular clinic visits is required 
as a direct result of participation in this study, study personnel will provide emergent care and 
stabilization. If longer-term psychiatric care is required, beyond what is normally provided by a 
research clinic, then study personnel will provide referrals and otherwise endeavor to assist 
participants in arranging such care. 
d.     Who will pay for this treatment? 
The cost of treatment for any such injury or illness will not be paid for through the study and will 
be the responsibility of the research participant.  These costs include emergency care for side-
effects of ketamine and psychiatric treatment for worsening of depression and anxiety symptoms 
that may occur during the course of the trial.
Participants do not give up any of their legal rights by signing the consent forms. 
e.     How will the medical treatment be accessed by subjects? 
As part of the study protocol, participants will be systematically asked about any adverse events 
they experience and their depressive symptom severity by study personnel. They will also be 
instructed to inform study personnel if they believe they have suffered an adverse event or 
worsening of their depressive symptoms as a result of the protocol. 


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References
1.
Turner H JE, Bloch MH. Meta-Analysis: Ketamine Response in Depressive Disorders. In 
preparation. 2015.
2.
Williams DK, Thrush CR, Armitage TL, Owen RR, Hudson TJ, Thapa P. The Effect of 
Guideline Implementation Strategies on Akathisia Outcomes in Schizophrenia. Journal of 
Applied Research. 2003;3(4):470-82.
3.
March JS, Parker JD, Sullivan K, Stallings P, Conners CK. The Multidimensional 
Anxiety Scale for Children (MASC): factor structure, reliability, and validity. Journal of the 
American Academy of Child and Adolescent Psychiatry. 1997;36(4):554-65.
4.
Breton JJ, Labelle R, Berthiaume C, Royer C, St-Georges M, Ricard D, et al. Protective 
factors against depression and suicidal behaviour in adolescence. Canadian journal of psychiatry 
Revue canadienne de psychiatrie. 2015;60(2 Suppl 1):S5-S15.
5.
Consoli A, Cohen D, Bodeau N, Guile JM, Mirkovic B, Knafo A, et al. Risk and 
Protective Factors for Suicidality at 6-Month Follow-up in Adolescent Inpatients Who 
Attempted Suicide: An Exploratory Model. Canadian journal of psychiatry Revue canadienne de 
psychiatrie. 2015;60(2 Suppl 1):S27-36.
6.
Isometsa E. Suicidal behaviour in mood disorders--who, when, and why? Canadian 
journal of psychiatry Revue canadienne de psychiatrie. 2014;59(3):120-30.
7.
Perlis RH, Fraguas R, Fava M, Trivedi MH, Luther JF, Wisniewski SR, et al. Prevalence 
and clinical correlates of irritability in major depressive disorder: a preliminary report from the 
Sequenced Treatment Alternatives to Relieve Depression study. The Journal of clinical 
psychiatry. 2005;66(2):159-66; quiz 47, 273-4.
8.
Woosley JA, Lichstein KL, Taylor DJ, Riedel BW, Bush AJ. Hopelessness mediates the 
relation between insomnia and suicidal ideation. Journal of clinical sleep medicine : JCSM : 
official publication of the American Academy of Sleep Medicine. 2014;10(11):1223-30.
9.
Pan LA, Hassel S, Segreti AM, Nau SA, Brent DA, Phillips ML. Differential patterns of 
activity and functional connectivity in emotion processing neural circuitry to angry and happy 
faces in adolescents with and without suicide attempt. Psychological medicine. 
2013;43(10):2129-42.
10.
Williams SB, O'Connor EA, Eder M, Whitlock EP. Screening for child and adolescent 
depression in primary care settings: a systematic evidence review for the US Preventive Services 
Task Force. Pediatrics. 2009;123(4):e716-35.
11.
Costello EJ, Foley DL, Angold A. 10-year research update review: the epidemiology of 
child and adolescent psychiatric disorders: II. Developmental epidemiology. Journal of the 
American Academy of Child and Adolescent Psychiatry. 2006;45(1):8-25.
12.
Richmond TK, Rosen DS. The treatment of adolescent depression in the era of the black 
box warning. Current opinion in pediatrics. 2005;17(4):466-72.
13.
Kessler RC, Avenevoli S, Ries Merikangas K. Mood disorders in children and 
adolescents: an epidemiologic perspective. Biological psychiatry. 2001;49(12):1002-14.
14.
Weissman MM, Wolk S, Goldstein RB, Moreau D, Adams P, Greenwald S, et al. 
Depressed adolescents grown up. Jama. 1999;281(18):1707-13.
15.
Fergusson DM, Woodward LJ. Mental health, educational, and social role outcomes of 
adolescents with depression. Archives of general psychiatry. 2002;59(3):225-31.
16.
Keenan-Miller D, Hammen CL, Brennan PA. Health outcomes related to early adolescent 
depression. The Journal of adolescent health : official publication of the Society for Adolescent 
Medicine. 2007;41(3):256-62.
17.
Shaffer D, Gould MS, Fisher P, Trautman P, Moreau D, Kleinman M, et al. Psychiatric 
diagnosis in child and adolescent suicide. Archives of general psychiatry. 1996;53(4):339-48.


APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
HIC# 1506016041 
Page 53 of 59
18.
Kennard BD, Silva SG, Tonev S, Rohde P, Hughes JL, Vitiello B, et al. Remission and 
recovery in the Treatment for Adolescents with Depression Study (TADS): acute and long-term 
outcomes. Journal of the American Academy of Child and Adolescent Psychiatry. 
2009;48(2):186-95.
19.
Brent D, Emslie G, Clarke G, Wagner KD, Asarnow JR, Keller M, et al. Switching to 
another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with 
SSRI-resistant depression: the TORDIA randomized controlled trial. Jama. 2008;299(8):901-13.
20.
Emslie GJ, Mayes T, Porta G, Vitiello B, Clarke G, Wagner KD, et al. Treatment of 
Resistant Depression in Adolescents (TORDIA): week 24 outcomes. The American journal of 
psychiatry. 2010;167(7):782-91.
21.
Vitiello B, Emslie G, Clarke G, Wagner KD, Asarnow JR, Keller MB, et al. Long-term 
outcome of adolescent depression initially resistant to selective serotonin reuptake inhibitor 
treatment: a follow-up study of the TORDIA sample. The Journal of clinical psychiatry. 
2011;72(3):388-96.
22.
Costello EJ, Egger HL, Angold A. The developmental epidemiology of anxiety disorders: 
phenomenology, prevalence, and comorbidity. Child and adolescent psychiatric clinics of North 
America. 2005;14(4):631-48, vii.
23.
Copeland WE, Angold A, Shanahan L, Costello EJ. Longitudinal patterns of anxiety from 
childhood to adulthood: the Great Smoky Mountains Study. Journal of the American Academy 
of Child and Adolescent Psychiatry. 2014;53(1):21-33.
24.
Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt ER, Davidson JR, et al. 
The economic burden of anxiety disorders in the 1990s. The Journal of clinical psychiatry. 
1999;60(7):427-35.
25.
Towe-Goodman NR, Franz L, Copeland W, Angold A, Egger H. Perceived family impact 
of preschool anxiety disorders. Journal of the American Academy of Child and Adolescent 
Psychiatry. 2014;53(4):437-46.
26.
Shanahan L, Copeland WE, Angold A, Bondy CL, Costello EJ. Sleep problems predict 
and are predicted by generalized anxiety/depression and oppositional defiant disorder. Journal of 
the American Academy of Child and Adolescent Psychiatry. 2014;53(5):550-8.
27.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime 
prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity 
Survey Replication. Archives of general psychiatry. 2005;62(6):593-602.
28.
Wittchen HU, Stein MB, Kessler RC. Social fears and social phobia in a community 
sample of adolescents and young adults: prevalence, risk factors and co-morbidity. Psychological 
medicine. 1999;29(2):309-23.
29.
Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT, et al. 
Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 
2008;359(26):2753-66.
30.
Silverman WK, Pina AA, Viswesvaran C. Evidence-based psychosocial treatments for 
phobic and anxiety disorders in children and adolescents. J Clin Child Adolesc Psychol. 
2008;37(1):105-30.
31.
Strawn JR, Welge JA, Wehry AM, Keeshin B, Rynn MA. Efficacy and tolerability of 
antidepressants in pediatric anxiety disorders: a systematic review and meta-analysis. Depress 
Anxiety. 2015;32(3):149-57.
32.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. 
Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. 
Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of general 
psychiatry. 1994;51(3):199-214.


APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
HIC# 1506016041 
Page 54 of 59
33.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. 
Antidepressant effects of ketamine in depressed patients. Biological psychiatry. 2000;47(4):351-
4.
34.
Zarate CA, Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A 
randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. 
Archives of general psychiatry. 2006;63(8):856-64.
35.
Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. 
Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site 
randomized controlled trial. The American journal of psychiatry. 2013;170(10):1134-42.
36.
Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A 
randomized controlled trial of intranasal ketamine in major depressive disorder. Biological 
psychiatry. 2014;76(12):970-6.
37.
Niciu MJ, Ionescu DF, Richards EM, Zarate CA, Jr. Glutamate and its receptors in the 
pathophysiology and treatment of major depressive disorder. Journal of neural transmission 
(Vienna, Austria : 1996). 2014;121(8):907-24.
38.
Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA. Anti-anhedonic 
effect of ketamine and its neural correlates in treatment-resistant bipolar depression. 
Translational psychiatry. 2014;4:e469.
39.
McMakin DL, Olino TM, Porta G, Dietz LJ, Emslie G, Clarke G, et al. Anhedonia 
predicts poorer recovery among youth with selective serotonin reuptake inhibitor treatment-
resistant depression. Journal of the American Academy of Child and Adolescent Psychiatry. 
2012;51(4):404-11.
40.
Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, et 
al. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in 
depression and anxiety. Journal of psychiatric research. 2014;58:161-6.
41.
Asarnow JR, Porta G, Spirito A, Emslie G, Clarke G, Wagner KD, et al. Suicide attempts 
and nonsuicidal self-injury in the treatment of resistant depression in adolescents: findings from 
the TORDIA study. Journal of the American Academy of Child and Adolescent Psychiatry. 
2011;50(8):772-81.
42.
Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with 
antidepressant drugs. Archives of general psychiatry. 2006;63(3):332-9.
43.
Catts VS, Fung SJ, Long LE, Joshi D, Vercammen A, Allen KM, et al. Rethinking 
schizophrenia in the context of normal neurodevelopment. Frontiers in cellular neuroscience. 
2013;7:60.
44.
Parise EM, Alcantara LF, Warren BL, Wright KN, Hadad R, Sial OK, et al. Repeated 
ketamine exposure induces an enduring resilient phenotype in adolescent and adult rats. 
Biological psychiatry. 2013;74(10):750-9.
45.
Papolos DF, Teicher MH, Faedda GL, Murphy P, Mattis S. Clinical experience using 
intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype. Journal 
of affective disorders. 2013;147(1-3):431-6.
46.
Lynch D, Eliatamby C, Anderson A. Pipothiazine palmitate in the management of 
aggressive mentally handicapped patients. The British Journal of Psychiatry. 1985;146:525-9.
47.
Greenwald AG, McGhee DE, Schwartz JL. Measuring individual differences in implicit 
cognition: the implicit association test. J Pers Soc Psychol. 1998;74(6):1464-80.
48.
Nock MK, Park JM, Finn CT, Deliberto TL, Dour HJ, Banaji MR. Measuring the suicidal 
mind: implicit cognition predicts suicidal behavior. Psychological science. 2010;21(4):511-7.
49.
Murrough JW, Collins KA, Fields J, DeWilde KE, Phillips ML, Mathew SJ, et al. 
Regulation of neural responses to emotion perception by ketamine in individuals with treatment-
resistant major depressive disorder. Translational psychiatry. 2015;5:e509.


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APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
HIC# 1506016041 
Page 55 of 59
50.
Diener C, Kuehner C, Brusniak W, Ubl B, Wessa M, Flor H. A meta-analysis of 
neurofunctional imaging studies of emotion and cognition in major depression. NeuroImage. 
2012;61(3):677-85.
51.
Groenewold NA, Opmeer EM, de Jonge P, Aleman A, Costafreda SG. Emotional valence 
modulates brain functional abnormalities in depression: evidence from a meta-analysis of fMRI 
studies. Neuroscience and biobehavioral reviews. 2013;37(2):152-63.
52.
Hamilton JP, Etkin A, Furman DJ, Lemus MG, Johnson RF, Gotlib IH. Functional 
neuroimaging of major depressive disorder: a meta-analysis and new integration of base line 
activation and neural response data. The American journal of psychiatry. 2012;169(7):693-703.
53.
Gentili C, Cristea IA, Angstadt M, Klumpp H, Tozzi L, Phan KL, et al. Beyond 
emotions: A meta-analysis of neural response within face processing system in social anxiety. 
Exp Biol Med (Maywood). 2016;241(3):225-37.
54.
Pine DS. Affective neuroscience and the development of social anxiety disorder. 
Psychiatr Clin North Am. 2001;24(4):689-705.
55.
Staugaard SR, Rosenberg NK. Processing of emotional faces in social phobia. Ment Illn. 
2011;3(1):e5.
56.
Gottfried MA. Excused versus unexcused: How student absences in elementary school 
affect academic achievement. Educational Evaluation and Policy Analysis. 2009;31(4):392-415.
57.
Henry KL, Huizinga DH. School-related risk and protective factors associated with 
truancy among urban youth placed at risk. The Journal of Primary Prevention. 2007;28(6):505-
19.
58.
Almeida MdCC, Aquino EM, Barros APd. School trajectory and teenage pregnancy in 
three Brazilian state capitals. Cadernos de saúde pública. 2006;22(7):1397-409.
59.
Henry KL, Huizinga DH. Truancy’s effect on the onset of drug use among urban 
adolescents placed at risk. Journal of Adolescent Health. 2007;40(4):358. e9-. e17.
60.
Kaufman P, Alt MN, Chapman CD. Dropout Rates in the United States, 2000. Statistical 
Analysis Report: ERIC; 2001.
61.
Berg I. Absence from school and mental health. The British Journal of Psychiatry. 
1992;161(2):154-66.
62.
Bernstein GA. Comorbidity and severity of anxiety and depressive disorders in a clinic 
sample. Journal of the American Academy of Child & Adolescent Psychiatry. 1991;30(1):43-50.
63.
Bernstein GA, Garfinkel BD. School phobia: The overlap of affective and anxiety 
disorders. Journal of the American Academy of Child Psychiatry. 1986;25(2):235-41.
64.
Egger HL, Costello JE, Angold A. School refusal and psychiatric disorders: A 
community study. Journal of the American Academy of Child & Adolescent Psychiatry. 
2003;42(7):797-807.
65.
Kearney CA. Confirmatory factor analysis of the School Refusal Assessment Scale-
Revised: Child and parent versions. Journal of Psychopathology and Behavioral Assessment. 
2006;28(3):139-44.
66.
Maynard BR, Heyne D, Brendel KE, Bulanda JJ, Thompson AM, Pigott TD. Treatment 
for School Refusal Among Children and Adolescents A Systematic Review and Meta-Analysis. 
Research on Social Work Practice. 2015:1049731515598619.
67.
Berney T, Kolvin I, Bhate S, Garside R, Jeans J, Kay B, et al. School phobia: a 
therapeutic trial with clomipramine and short-term outcome. The British Journal of Psychiatry. 
1981;138(2):110-8.
68.
Bernstein GA, Borchardt CM, Perwien AR, Crosby RD, Kushner MG, Thuras PD, et al. 
Imipramine plus cognitive-behavioral therapy in the treatment of school refusal. Journal of the 
American Academy of Child & Adolescent Psychiatry. 2000;39(3):276-83.


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APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
HIC# 1506016041 
Page 56 of 59
69.
Bernstein GA, Garfinkel BD, Borchardt CM. Comparative studies of pharmacotherapy 
for school refusal. Journal of the American Academy of Child & Adolescent Psychiatry. 
1990;29(5):773-81.
70.
Gittelman-Klein R, Klein DF. Controlled imipramine treatment of school phobia. 
Archives of general psychiatry. 1971;25(3):204-7.
71.
Padala PR, Madison J, Monnahan M, Marcil W, Price P, Ramaswamy S, et al. 
Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and 
domestic abuse in women. International Clinical Psychopharmacology. 2006;21(5):275-80.
72.
King NJ, Bernstein GA. School refusal in children and adolescents: A review of the past 
10 years. Journal of the American academy of child & adolescent psychiatry. 2001;40(2):197-
205.
73.
Wu X, Liu F, Cai H, Huang L, Li Y, Mo Z, et al. Cognitive behaviour therapy combined 
fluoxetine treatment superior to cognitive behaviour therapy alone for school refusal. 
International Journal of Pharmacology. 2013;9(3):197-203.
74.
Green SM, Krauss B. Clinical practice guideline for emergency department ketamine 
dissociative sedation in children. Annals of emergency medicine. 2004;44(5):460-71.
75.
Dolansky G, Shah A, Mosdossy G, Rieder M. What is the evidence for the safety and 
efficacy of using ketamine in children? Paediatrics & child health. 2008;13(4):307-8.
76.
Maeng S, Zarate CA, Jr. The role of glutamate in mood disorders: results from the 
ketamine in major depression study and the presumed cellular mechanism underlying its 
antidepressant effects. Curr Psychiatry Rep. 2007;9(6):467-74.
77.
Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, et al. The 
antidepressant effect of ketamine is not associated with changes in occipital amino acid 
neurotransmitter content as measured by [(1)H]-MRS. Psychiatry research. 2011;191(2):122-7.
78.
Murrough JW, Perez AM, Mathew SJ, Charney DS. A case of sustained remission 
following an acute course of ketamine in treatment-resistant depression. The Journal of clinical 
psychiatry. 2011;72(3):414-5.
79.
Cox Lippard ET, Johnston JA, Blumberg HP. Neurobiological risk factors for suicide: 
insights from brain imaging. American journal of preventive medicine. 2014;47(3 Suppl 
2):S152-62.
80.
Pan LA, Batezati-Alves SC, Almeida JR, Segreti A, Akkal D, Hassel S, et al. Dissociable 
patterns of neural activity during response inhibition in depressed adolescents with and without 
suicidal behavior. Journal of the American Academy of Child and Adolescent Psychiatry. 
2011;50(6):602-11 e3.
81.
Jollant F, Lawrence NS, Giampietro V, Brammer MJ, Fullana MA, Drapier D, et al. 
Orbitofrontal cortex response to angry faces in men with histories of suicide attempts. The 
American journal of psychiatry. 2008;165(6):740-8.
82.
Johnson HS, Inderbitzen-Nolan HM, Schapman AM. A comparison between socially 
anxious and depressive symptomatology in youth: A focus on perceived family environment. 
Journal of Anxiety Disorders. 2005;19(4):423-42.
83.
Phan KL, Fitzgerald DA, Cortese BM, Seraji-Bozorgzad N, Tancer ME, Moore GJ. 
Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla. Neuroreport. 
2005;16(2):183-6.
84.
Pollack MH, Jensen JE, Simon NM, Kaufman RE, Renshaw PF. High-field MRS study 
of GABA, glutamate and glutamine in social anxiety disorder: response to treatment with 
levetiracetam. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 
2008;32(3):739-43.
85.
Walker DL, Davis M. The role of amygdala glutamate receptors in fear learning, fear-
potentiated startle, and extinction. Pharmacology Biochemistry and Behavior. 2002;71(3):379-
92.


APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
HIC# 1506016041 
Page 57 of 59
86.
Linden A-M, Johnson B, Peters S, Shannon H, Tian M, Wang Y, et al. Increased anxiety-
related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor. 
Neuropharmacology. 2002;43(2):251-9.
87.
Maeng S, Zarate Jr CA. The role of glutamate in mood disorders: results from the 
ketamine in major depression study and the presumed cellular mechanism underlying its 
antidepressant effects. Current psychiatry reports. 2007;9(6):467-74.
88.
Niciu MJ, Ionescu DF, Richards EM, Zarate Jr CA. Glutamate and its receptors in the 
pathophysiology and treatment of major depressive disorder. Journal of Neural Transmission. 
2014;121(8):907-24.
89.
Williams WS, Gerald. Stress, Anxiety, and Depression and the Role of Glutamate 
Neurotransmission.  Anxiety Disorders2015. p. 389.
90.
Turner H, Jakubovski E, Bloch M. Meta-Analysis: Ketamine Response in Depressive 
Disorders. In preparation. 2015.
91.
Salvadore G, Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA, et al. 
Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological 
biomarker that predicts rapid antidepressant response to ketamine. Biological psychiatry. 
2009;65(4):289-95.
92.
Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A 
randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. 
Archives of general psychiatry. 2006;63(8):856-64.
93.
Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Slonena EE, Vande Voort JL, et 
al. Effect of baseline anxious depression on initial and sustained antidepressant response to 
ketamine. The Journal of clinical psychiatry. 2014;75(9):e932-8.
94.
Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Zarate CA, Jr. A single infusion 
of ketamine improves depression scores in patients with anxious bipolar depression. Bipolar 
Disord. 2015;17(4):438-43.
95.
Donoghue AC, Roback MG, Cullen KR. Remission From Behavioral Dysregulation in a 
Child With PTSD After Receiving Procedural Ketamine. Pediatrics. 2015;136(3):e694-e6.
96.
Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, et al. Efficacy of 
intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized 
clinical trial. JAMA psychiatry. 2014;71(6):681-8.
97.
Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E, Leckman 
JF, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biological 
psychiatry. 2012;72(11):964-70.
98.
Rodriguez CI, Kegeles LS, Levinson A, Feng T, Marcus SM, Vermes D, et al. 
Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-
concept. Neuropsychopharmacology. 2013;38(12):2475-83.
99.
Sheehan DV, Sheehan KH, Shytle RD, Janavs J, Bannon Y, Rogers JE, et al. Reliability 
and validity of the Mini International Neuropsychiatric Interview for Children and Adolescents 
(MINI-KID). The Journal of clinical psychiatry. 2010;71(3):313-26.
100.
Mayes TL, Bernstein IH, Haley CL, Kennard BD, Emslie GJ. Psychometric properties of 
the Children's Depression Rating Scale-Revised in adolescents. Journal of child and adolescent 
psychopharmacology. 2010;20(6):513-6.
101.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. 
The British journal of psychiatry : the journal of mental science. 1979;134:382-9.
102.
Cho HS, D'Souza DC, Gueorguieva R, Perry EB, Madonick S, Karper LP, et al. Absence 
of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. 
Psychopharmacology. 2005;179(1):136-43.
103.
Kazdin AE. Evaluation of the Pleasure Scale in the assessment of anhedonia in children. 
Journal of the American Academy of Child and Adolescent Psychiatry. 1989;28(3):364-72.


APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
HIC# 1506016041 
Page 58 of 59
104.
Reid JM, Storch EA, Murphy TK, Bodzin D, Mutch PJ, Lehmkuhl H, et al. Development 
and Psychometric Evaluation of the Treatment-Emergent Activation and Suicidality Assessment 
Profile. Child & youth care forum. 2010;39(2):113-24.
105.
Busner J, Targum SD. The clinical global impressions scale: applying a research tool in 
clinical practice. Psychiatry (Edgmont (Pa : Township)). 2007;4(7):28-37.
106.
The Pediatric Anxiety Rating Scale (PARS): development and psychometric properties. 
Journal of the American Academy of Child and Adolescent Psychiatry. 2002;41(9):1061-9.
107.
Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, et al. 
Measurement of dissociative states with the Clinician-Administered Dissociative States Scale 
(CADSS). Journal of traumatic stress. 1998;11(1):125-36.
108.
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: 
psychometric properties. Journal of consulting and clinical psychology. 1988;56(6):893-7.
109.
Beck AT, Weissman A, Lester D, Trexler L. The measurement of pessimism: the 
hopelessness scale. Journal of consulting and clinical psychology. 1974;42(6):861-5.
110.
Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, et al. 
Development and validation of a brief screening version of the Childhood Trauma 
Questionnaire. Child abuse & neglect. 2003;27(2):169-90.
111.
Kaufman J. Depressive disorders in maltreated children. Journal of the American 
Academy of Child and Adolescent Psychiatry. 1991;30(2):257-65.
112.
Rezayat AA, Hebrani P, Behdani F, Salaran M, Marvast MN. Comparison the 
effectiveness of aripiprazole and risperidone for the treatment of acute bipolar mania. Journal of 
Research in Medical Sciences. 2014;19(8):733-8.
113.
Stringaris A, Goodman R, Ferdinando S, Razdan V, Muhrer E, Leibenluft E, et al. The 
Affective Reactivity Index: a concise irritability scale for clinical and research settings. Journal 
of Child Psychology and Psychiatry. 2012;53(11):1109-17.
114.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. The American journal of psychiatry. 
2011;168(12):1266-77.
115.
Kearney CA, Silverman WK. Measuring the function of school refusal behavior: The 
School Refusal Assessment Scale. Journal of Clinical Child Psychology. 1993;22(1):85-96.
116.
Bergman SA. Ketamine: review of its pharmacology and its use in pediatric anesthesia. 
Anesthesia progress. 1999;46(1):10-20.
117.
Parker RI, Mahan RA, Giugliano D, Parker MM. Efficacy and safety of intravenous 
midazolam and ketamine as sedation for therapeutic and diagnostic procedures in children. 
Pediatrics. 1997;99(3):427-31.
118.
Lourenco-Matharu L, Ashley PF, Furness S. Sedation of children undergoing dental 
treatment. The Cochrane database of systematic reviews. 2012;3:CD003877.
119.
Roback MG, Wathen JE, Bajaj L, Bothner JP. Adverse events associated with procedural 
sedation and analgesia in a pediatric emergency department: a comparison of common parenteral 
drugs. Academic emergency medicine : official journal of the Society for Academic Emergency 
Medicine. 2005;12(6):508-13.
120.
Everitt I, Younge P, Barnett P. Paediatric sedation in emergency department: what is our 
practice? Emergency medicine (Fremantle, WA). 2002;14(1):62-6.
121.
Sacchetti A, Stander E, Ferguson N, Maniar G, Valko P. Pediatric Procedural Sedation in 
the Community Emergency Department: results from the ProSCED registry. Pediatric 
emergency care. 2007;23(4):218-22.
122.
Verhage J, Mulder CJ, Willekens FL. Intravenous midazolam sedation in pediatric 
diagnostic upper digestive endoscopy. A prospective study in a general hospital. Romanian 
journal of gastroenterology. 2003;12(4):273-6.


APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
APPROVED BY THE YALE UNIVERSITY IRB 9/13/2017 VALID THROUGH 9/15/2018
HIC# 1506016041 
Page 59 of 59
123.
Rosen DA, Rosen KR. Intravenous conscious sedation with midazolam in paediatric 
patients. International journal of clinical practice. 1998;52(1):46-50.
124.
Hegenbarth MA. Preparing for pediatric emergencies: drugs to consider. Pediatrics. 
2008;121(2):433-43.
125.
Kearney CA. An interdisciplinary model of school absenteeism in youth to inform 
professional practice and public policy. Educational Psychology Review. 2008;20(3):257-82.
126.
Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a 
behavior rating scale for the assessment of treatment effects. American journal of mental 
deficiency. 1985;89(5):485-91.
127.
Chorpita BF, Yim L, Moffitt C, Umemoto LA, Francis SE. Assessment of symptoms of 
DSM-IV anxiety and depression in children: A revised child anxiety and depression scale. 
Behaviour research and therapy. 2000;38(8):835-55.
128.
Shafer A. Meta-analysis of the brief psychiatric rating scale factor structure. 
Psychological assessment. 2005;17(3):324-35.
129.
Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med. 
1969;62(10):989-93.
130.
DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et 
al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate 
antagonist in patients with treatment-resistant major depressive disorder. The Journal of clinical 
psychiatry. 2010;71(12):1605-11.
131.
Johnston LD OMP, Bachman JG, Schulenberg JE. Monitoring the Future national results 
on adolescent drug use: Overview of key findings, 2011. Ann Arbor: Institute for Social 
Research, The University of Michigan. 2012.
132.
Salvadore G, Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA, Jr., et al. 
Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological 
biomarker that predicts rapid antidepressant response to ketamine. Biological psychiatry. 
2009;65(4):289-95.
133.
Green SM, Rothrock SG, Harris T, Hopkins GA, Garrett W, Sherwin T. Intravenous 
ketamine for pediatric sedation in the emergency department: safety profile with 156 cases. 
Academic emergency medicine : official journal of the Society for Academic Emergency 
Medicine. 1998;5(10):971-6.