Open-Label Intravenous Subanesthetic Ketamine for Adolescents With Treatment-Resistant Depression
Phase: PHASE2
Conditions: Major Depressive Disorder
Sponsor: University of Minnesota

 
 
 
 
 
OPEN-LABEL INTRAVENOUS SUBANESTHETIC KETAMINE 
FOR ADOLESCENTS WITH TREATMENT-RESISTANT 
DEPRESSION 
 
 
 
Regulatory Sponsor: 
Kathryn R. Cullen, MD 
Department of Psychiatry 
University of Minnesota 
 
Funding Sponsor: 
Clinical Translational Science Institute 
Study Product: 
Ketamine hydrochloride 
Protocol Number: 
CTSI 22225 
IND Number: 
IND exemption 
 
Version Date: 
 
        July 10, 2017 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the University of Minnesota.  
No part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study sponsor. 

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Table of Contents 
STUDY SUMMARY .................................................................................................................................................... 1 
1 
INTRODUCTION ............................................................................................................................................... 2 
1.1 
BACKGROUND .............................................................................................................................................. 2 
1.2 
INVESTIGATIONAL AGENT............................................................................................................................. 2 
1.3 
PRECLINICAL DATA ...................................................................................................................................... 3 
1.4 
CLINICAL DATA TO DATE ............................................................................................................................. 3 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ....................................................................................................... 5 
2 
STUDY OBJECTIVES ...................................................................................................................................... 6 
3 
STUDY DESIGN ................................................................................................................................................ 6 
3.1 
GENERAL DESIGN ........................................................................................................................................ 6 
3.2 
PRIMARY STUDY ENDPOINTS ...................................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ................................................................................................................. 7 
3.4 
PRIMARY SAFETY ENDPOINTS ..................................................................................................................... 7 
4 
SUBJECT SELECTION AND WITHDRAWAL............................................................................................. 8 
4.1 
INCLUSION CRITERIA .................................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA .................................................................................................................................. 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING .................................................................................................. 9 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .......................................................................................................... 10 
5 
STUDY DRUG ................................................................................................................................................. 10 
5.1 
DESCRIPTION ............................................................................................................................................. 10 
5.2 
TREATMENT REGIMEN ............................................................................................................................... 11 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................... 11 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ............................................................................ 11 
5.5 
SUBJECT COMPLIANCE MONITORING ........................................................................................................ 11 
5.6 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................ 11 
5.7 
PACKAGING ................................................................................................................................................ 12 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................................ 12 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................... 12 
6 
STUDY PROCEDURES ................................................................................................................................. 13 
6.1 
VISIT 1 – BASELINE ASSESSMENT ............................................................................................................. 13 
6.2 
VISIT 2 – MRI SCAN ................................................................................................................................... 13 
6.3 
VISIT 3 – FIRST KETAMINE INFUSION ......................................................................................................... 14 
6.4 
VISITS 4-8 – 5 SUBSEQUENT KETAMINE INFUSIONS .................................................................................. 15 
6.5 
VISIT 9 – SECOND BRAIN MRI AND BLOOD DRAW ..................................................................................... 15 
6.6 
VISITS 10-13 – FOLLOW-UP PERIOD ......................................................................................................... 16 
6.7 
SCHEDULE OF EVENTS TABLE ................................................................................................................... 16 
7 
STATISTICAL PLAN ...................................................................................................................................... 17 
7.1 
SAMPLE SIZE DETERMINATION .................................................................................................................. 17 
7.2 
SUBJECT POPULATION(S) FOR ANALYSIS ................................................................................................. 17 
7.3 
STATISTICAL METHODS ............................................................................................................................. 17 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 18 
8.1 
DEFINITIONS ............................................................................................................................................... 18 
8.2 
RECORDING OF ADVERSE EVENTS............................................................................................................ 20 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................ 21 
8.4 
UNBLINDING PROCEDURES........................................................................................................................ 22 
8.5 
STOPPING RULES ...................................................................................................................................... 22 

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8.6 
DATA AND SAFETY MONITORING / AUDITING ............................................................................................ 22 
9 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 23 
9.1 
CONFIDENTIALITY ....................................................................................................................................... 23 
9.2 
SOURCE DOCUMENTS ............................................................................................................................... 23 
9.3 
CASE REPORT FORMS ............................................................................................................................... 24 
9.4 
RECORDS RETENTION ............................................................................................................................... 24 
10 
ETHICAL CONSIDERATIONS ..................................................................................................................... 24 
11 
STUDY FINANCES ......................................................................................................................................... 25 
11.1 
FUNDING SOURCE...................................................................................................................................... 25 
11.2 
CONFLICT OF INTEREST ............................................................................................................................. 25 
11.3 
SUBJECT STIPENDS OR PAYMENTS ........................................................................................................... 25 
12 
PUBLICATION PLAN .................................................................................................................................... 25 
13 
REFERENCES ................................................................................................................................................ 26 
14 
LIST OF REFERENCE DOCUMENTS ........................................................................................................ 29 
 

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List of Abbreviations 
 
 
3T 
 
3 Tesla 
AE 
 
Adverse Event 
ATHF  
Antidepressant Treatment History Form 
BDI-II  
Beck Depression Inventory 
BPRS  
Brief Psychiatric Rating Scale 
CADSS 
Clinician-Administered Dissociative States Scale 
CC 
 
Cubic Centimeters 
CDRS-R 
Children’s Depression Rating Scale - Revised 
CFR 
 
Code of Federal Regulations 
CGI 
 
Clinical Global Impressions 
CMRR  
Center for Magnetic Resonance Research 
CRF 
 
Case Report Form 
CSSRS 
Columbia Suicide Severity Rating Scale 
CSSRS-SLV Columbia Suicide Severity Rating Scale – Since Last Visit 
CTSI  
Clinical and Translational Science Institute  
DSMB  
Data and Safety Monitoring Board 
DSMP  
Data and Safety Monitoring Plan 
DPX  
Dot Pattern Expectancy task 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICH 
 
International Conference on Harmonisation 
IDS 
 
Investigational Drug Services 
IRB 
 
Institutional Review Board 
IV 
 
Intravenous 
KG 
 
Kilogram 
K-SADS-PL Kiddie Schedule of Affective Disorders and Schizophrenia -Present and Lifetime 
LPS 
 
Lipopolysaccharide 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD  
Major-Depressive Disorder 
MEG  
Magnetoencephalography 
MG 
 
Milligram 
ML 
 
Milliliter 
MMC  
Mayo Mail Code 
MRI 
 
Magnetic Resonance Imaging 
MRS  
Magnetic Resonance Spectroscopy 
NOS  
Not Otherwise Specified 
PBS 
 
Phosphate Buffered Saline 
PET 
 
Positron Emission Tomography 
PHA  
Phytohemagglutinin 
PHI 
 
Protected Health Information 
PI 
 
Principal Investigator 
POMS-A 
Profile of Mood States – Adolescent 
REPA  
Report of External Professional Activities 

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SAE 
 
Serious Adverse Event 
SHAPS 
Snaith-Hamilton Pleasure Scale 
TRD  
Treatment-Resistant Depression 
TEPS  
Temporal Experience of Pleasure Scale 
UTox  
Urine Toxicology Screen 
VA 
 
Veterans’ Affairs 
WASI  
Weschler Abbreviated Scale of Intelligence 

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Study Summary 
Title 
Open-label intravenous subanesthetic ketamine for adolescents 
with treatment-resistant depression 
Protocol Number 
CTSI 22225 
Phase 
2 
Methodology 
Single group open-label pilot study 
Study Duration 
2 years 
Study Center(s) 
University of Minnesota  
Objectives 
To determine the efficacy of repeated-dose subanesthetic IV 
ketamine among adolescent patients with treatment resistant 
depression.  
Number of 
Subjects 
20 
Diagnosis and 
Main Inclusion 
Criteria 
Male and female adolescents aged 12 to 18 with the presence of 
recurrent major depressive disorder without psychotic features. 
Study Product, 
Dose, Route, 
Regimen 
IV infusions of 0.5mg/kg of Ketamine hydrochloride over a 40-
minute infusion period. Participants will receive a total of 6 doses 
over a 2-week period.  
Duration of 
administration 
2 weeks  
Reference therapy 
Not applicable.   
Statistical 
Methodology 
The maximum effect of the ketamine infusions on symptoms for 
each participant will be assessed by conducting paired t tests 
between the lowest score from the post-treatment assessments 
and the baseline symptoms levels.  
 
The time to relapse for each participant will be calculated and an 
average relapse time for the group will be reported. 
 
Exploratory analysis will be done on changes in brain function, 
connectivity and chemistry, as well as in peripheral blood 
biomarkers.  
 

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1 Introduction 
This document is a protocol for a human research study. This study will be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonisation guidelines), applicable government 
regulations and Institutional research policies and procedures.  
1.1 Background 
 
Depression frequently emerges during adolescence and is associated with severe 
outcomes. Current interventions do not lead to remission for many adolescents. 
Treatment-resistant depression (TRD) in adolescence is an ominous prognostic 
indicator for a lifetime of suffering and increased risk for suicide. Efforts should be 
directed toward novel interventions that could alter this perilous course. Theoretically, 
restoration of healthy development during this critical window would substantially 
improve outcomes over the lifespan. 
 
Ketamine is a noncompetitive, high-affinity antagonist of the N-methyl-D-aspartate type 
glutamate receptor that has long been used for induction and maintenance of 
anesthesia in children and adults, and recently has been investigated for its rapid 
antidepressant effects.  
 
No results from any studies examining effectiveness of either single-dose or serial-dose 
ketamine have yet been published in adolescents with TRD. Because of the ongoing 
neurodevelopment in adolescence, which is thought to confer enhanced neuroplasticity, 
it is possible that adolescents with TRD could show greater responses and more 
sustained remission than adults with TRD. The biological mechanisms of depression 
impacted by ketamine are only now being uncovered in adults (Zarate et al., 2013). 
Characterization of the neural mechanisms underlying ketamine response or non-
response in adolescents with TRD will represent a significant advance. 
 
1.2 Investigational Agent 
 
The effects of ketamine are mediated by N-methyl-D-aspartate, opioid, muscarinic and 
different voltage-gated receptors. It has hypnotic, analgesic and amnesic effects (Sinner 
& Graf, 2008). Ketamine is water and lipid soluble, which allows it to be administered in 
different ways (intramuscularly, intravenously, intranasally, rectally and orally) and 
distributes widely throughout the body including crossing the blood brain barrier. It has a 
molecular weight of 274.4M, its chemical formula is C13H16ClNO, and its melting point 
is between 258°C and 261°C (Sinner & Graf, 2008).  The IV dose used for anesthesia 
ranges between 1 to 4.5 mg/kg (Elia & Tramer, 2005; Sinner & Graf, 2008). The median 
dose for analgesia is 0.4 mg/kg (Elia & Tramer, 2005), similar to that used for 
depression. Dose reported in the drug abuse literature is typically 1/8 g usually taken 
intranasally.  Metabolism of ketamine is primary hepatic and it is excreted in the urine; 
metabolism half-life is 2.5-3 hours (Sinner & Graf, 2008).  

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1.3 Preclinical Data 
 
Despite the fact that depression frequently emerges during adolescence (Kessler & 
Walters, 1998) and that many adolescents do not respond to treatment (March et al., 
2004), ketamine has not yet been tested in adolescents. However, recent research 
using animal models of depression has suggested that repeated doses of ketamine 
alleviated depressive behaviors in both adolescent and adult rats (Parise et al., 2013). 
Due to the enhanced neuroplasticity associated with the developing brain, adolescents 
with TRD may show greater and more sustained response to ketamine than adults with 
TRD.  
 
1.4 Clinical Data to Date 
 
Randomized, double-blind, saline-controlled trials in adults with TRD have 
demonstrated that a single, subanesthetic infusion of intravenous (IV) ketamine at 0.5 
mg/kg over 40 minutes can produce a rapid (within 2 hours) antidepressant response 
(Ibrahim et al., 2011; Zarate et al., 2006). Recent evidence suggests that serial doses of 
ketamine may be even more effective and may lead to more prolonged remission (aan 
het Rot et al., 2010; Murrough et al., 2012). Our current research with using serial 
dosing of IV ketamine among adult veterans with TRD over a 2-week period has shown 
promising results, with a response rate of 92% among the 12 participants to date.  
 
Our motivation to test the efficacy of IV ketamine in adolescents with TRD stems in part 
from our encouraging experience testing repeated-dose IV ketamine in adult veterans 
with TRD (PI Lim) at the Veterans’ Affairs (VA) Medical Center in Minneapolis (Shiroma, 
Journal of Affective Disorders 2013, in press). Patients receive 6 infusions of IV 
ketamine 0.5mg.kg over 60 minutes, with infusion visits occurring 3 times weekly for 2 
weeks with no “wash-out” period. So far, as indicated below, a 90% cumulative 
response rate has been observed. The duration of response (i.e. time to relapse) has 
been considerably longer than other studies (i.e. 2-3 weeks (Murrough et al., 2013)). At 
4 weeks, 50% of the patients in our study have still not relapsed. Ten adults have 
completed treatment to date. 

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With its rapid onset of action, ketamine provides an ideal tool for the study of 
biomarkers in major depressive disorder (MDD). Prior studies have used neuroimaging, 
including functional magnetic resonance imaging (fMRI) (Scheidegger et al., 2012), 
positron emission tomography (PET) (Carlson et al., 2013), and 
magnetoencephalography (MEG) (Salvadore et al., 2009; Salvadore et al., 2010), and 
proton magnetic resonance spectroscopy (proton MRS) (Salvadore et al., 2012) in 
ketamine trials to further elucidate the underlying biological mechanisms of MDD. We 
have been developing tools for examining neural circuitry in adolescents with MDD 
(Cullen et al., 2009; Cullen et al., 2010) which we plan to apply in the proposed study to 
examine neural mechanisms of ketamine action. 
 
Another avenue for understanding the mechanisms of response to ketamine in TRD is 
to examine the cellular mechanisms associated with stress and resilience. MDD and 
other mental illnesses provide significant stress on an individual, and research has 
shown that there are deleterious neurobiological effects that result from chronic stress. 
Allostatic overload occurs in certain chronic medical disorders that are associated with 
chronic stress such as mood disorders (Brietzke et al., 2011). Allostatic overload leads 
to compromised resilience, rendering the organism more vulnerable to disease 
(Karatsoreos & McEwen, 2011). Evidence suggests that there is a correlation between 
enhanced cellular aging, as seen by reduced telomerase activity and telomerase length, 
and TRD (Wolkowitz et al., 2012) and it is hypothesized that allostatic overload is the 
driving factor. Insulin signaling and cytokine responses are two key cellular pathways 
that are chronically altered through the process of allostatic overload over time (Tanti et 
al., 2013). We hypothesize that the rapid effects of ketamine to reverse depression 
symptoms may occur via reversal of these systems. Through experimental procedures 
including white blood cell challenge, we hope to identify how these key cellular 
adaptations are associated with disease severity and treatment response to ketamine. 
 
 

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1.5 Dose Rationale and Risk/Benefits 
 
Subjects will receive an IV infusion of 0.5 mg/Kg of ketamine hydrochloride over 40 
minutes. The dose is based on antidepressant effects of patients with major depression 
reported in previous studies (Ibrahim et al., 2011; Zarate et al., 2006). The dose of 
ketamine will be determined by actual body weight. 
 
The IV dose used for anesthesia ranges between 1 to 4.5 mg/kg (Elia & Tramer, 2005; 
Sinner & Graf, 2008). The median dose for analgesia is 0.4 mg/kg (Elia & Tramer, 
2005), similar to that used for depression. The dose reported in the drug abuse 
literature is typically 1/8 g usually taken intranasally (see graphic below).  
 
 
 
       
 
 
 
 
 
 
 
 
 
As a laboratory agent, ketamine has several desirable qualities. It has a short-half life; it 
is relatively easy to administer; it does not usually cause cardiovascular or respiratory 
depression and it has been well-studied in clinical settings (Reich & Silvay, 1989). 
Recent literature supports the safety of using ketamine as an ideal anesthetic for 
children emergency room settings because of its positive safety profile including lack of 
respiratory suppression (Dolansky et al., 2008).  In the lower doses used for 
antidepressant treatment reported in the literature, short-term side effects are very 
infrequent, mild, and transient (Carpenter, 1999; Lahti et al., 2001). These side effects 
include perceptual and mood changes and impairment in memory, attention and 
abstract reasoning, euphoria, elevations in blood pressure, dizziness, and increased 
libido, as well as gastrointestinal distress, increased thirst, headache, metallic taste, and 
constipation (Reich & Silvay, 1989). In the long-term, subanesthetic doses yielded no 
reports of emotional or psychological problems, cognitive deficits, medical or 
neurological problems, cravings for ketamine, use outside the research setting, unusual 
perceptions, sluggishness, flashbacks or paranoid thoughts (Perry et al., 2007). These 
findings further document the lack of long-term effects previously reported with 
anesthetic doses of ketamine (Moretti et al., 1984) and support the FDA-approved drug 
insert about the safety of ketamine:  
 
"Ketamine has a wide margin of safety; several instances of unintentional administration 
of overdoses of ketamine (up to ten times that usually required) have been followed by 
prolonged but complete recovery”.  
  
0 
0.2 
0.4 
0.6 
1.0 
0.8 
  1.2 
1.4 
 
 
 
 
 
Depression 
Analgesia 
Abuse 
Anesthesia (IV) 
Ketamine Dose (mg/kg) 

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2 Study Objectives 
 
Primary Objective:   
To determine the efficacy of repeated-dose subanesthetic IV ketamine among 
adolescent patients with treatment resistant depression (TRD). Hypothesis: Based on 
previous results in adults with TRD, we predict that response rates will improve over the 
course of six treatments of ketamine. 
 
Secondary Objectives: 
To explore the durability of antidepressant response to repeated dose of IV ketamine in 
a 6-week observational period. Hypothesis:  Based on the inherent neuroplasticity in 
adolescence due to ongoing neurodevelopment, adolescents may show a more durable 
clinical response than has been seen in adults. 
To study the neurobiological mechanisms of response to ketamine. We will explore how 
clinical improvement relates to change in brain function, brain connectivity, brain 
chemistry, and in peripheral blood biomarkers of neuroplasticity and cellular resilience. 
 
3 Study Design 
3.1 General Design 
 
This is a single-group (n=20) open-label pilot study of 6 doses of IV ketamine, 3 doses 
per week over a 2-week period, followed by a 4-week post-treatment observational 
period. Symptom levels will be assessed prior to infusion, directly after infusion, 1 and 2 
hours after infusion. We will also assess symptoms weekly for 6 weeks after the last 
ketamine infusion. A study goal is to identify neurobiological biomarkers of treatment 
response using neuroimaging and blood studies.  
 
3.2 Primary Study Endpoints 
The primary outcome measure is response status as defined by  Children’s Depression 
Rating Scale (CDRS) (Poznanski, 1985)Responders will be defined as having a 
significant reduction in their CDRS score (≥50%) whereas non-responders will be 
defined as subjects whose scores do not show such a significant reduction or whose 
score increase. The percent change will be calculated by the formula below (Tao, 
2009): 
 
 
(Baseline CDRS – Exit CDRS) / (Baseline CDRS – 17) 
 
Baseline CDRS: CDRS score obtained on Visit 1 – Baseline Assessment (Section 6.1) 
Exit CDRS: the latest CDRS score obtained on Visit 10 - Clinical Assessment (Section 
6.6) or Visit 11-16 – Follow-up Period (Section 6.7) 

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3.3 Secondary Study Endpoints 
 
1. Montgomery-Åsberg Depression Rating Scale (MADRS) (Montgomery & Asberg, 
1979) score of ≥50%. The MADRS has been used in most previous ketamine studies in 
adults and is designed to be sensitive to change. Although it has not been validated in 
adolescents, it has been used in several previous treatment studies of adolescent 
depression (Berard et al., 2006; von Knorring et al., 2006). 
2. The Clinician-Administered Dissociative States Scale (CADSS) (Bremner et al., 1998) 
3. The Profile of Mood States-Adolescent Version (POMS-A) (Terry et al., 1999) 
4. The Beck Depression Inventory-II (Beck, 1988) which has been validated for 
adolescents (Osman et al., 2004) 
5. The four-item positive symptom subscale of the Brief Psychiatric Rating Scale 
(BPRS) (Overall, 1962) consisting of suspiciousness, hallucinations, unusual thought 
content, and conceptual disorganization.  
6. Relapse will be defined as a CDRS score ≥50% of the pre-ketamine baseline. The 
onset of relapse will be calculated as the day halfway between the date of relapse and 
the previous date of response.  
7. Biological endpoints will include MRI-based measures and blood-based measures of 
neuroplasticity. 
8. The Clinical Global Impressions Scale (CGI) (Guy, 1976) 
9. The Dot Pattern Expectancy task (2017) The DPX-task is a neurocognitive task that 
measures an aspect of goal representation known as context processing using pairs of 
simple dot patterns. In this task, there are four types of trials, and we refer to the trial 
type using letters: A means valid target, B means invalid target; X means valid cue, Y 
means invalid cue. Most of the trials are "target trials" (AX); in these types of trials a 
valid cue (A versus B) is followed by a valid probe (X versus Y). The 3 other trial types 
are "Non-target trials" in which either a valid cue is followed by an invalid probe (AY) or 
an invalid cue is followed by either a valid probe (BX) or invalid probe (BY). Participants 
are required to make one response for target trials, and another response for non-target 
trials. The nature of the cue (valid or invalid) provides the "context" for responding on a 
given trial. The intent of having the majority of trials as "target trials" (AX)  is to 
encourage participants to "expect" a valid probe to follow a valid cue. A consequence of 
this manipulation is that participants develop a prepotency to respond with "target" 
responses on trials for which valid cues are presented, regardless of whether the trials 
were of the target (AX) or non-target (AY) type. Non-target cues provide the context that 
a non-target response will be required, regardless of the nature of the probe (valid or 
invalid). The expectancy manipulation is designed to increase AY error rates. On BX 
trials, participants with normal context processing must maintain the cue in order to 
inhibit the prepotency to respond to valid probes with a target response. Compared with 
controls, persons with impaired context processing may be expected to make more BX 
errors, whereas the AY condition is more difficult for people with intact context 
processing. (Jones, Sponheim & MacDonald 2010; MacDonald, III, Carter, Flory, Ferrel 
& Manuch, 2007; MacDonald et al, 2005).  
3.4 Primary Safety Endpoints 
 

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Primary safety endpoints will consist of vital signs (blood pressure, pulse, oxygen 
saturation, and respiratory rate), measured every 15 minutes during the administration 
of ketamine and every 30 minutes in the ensuing 2 hours, and the Clinician-
Administered Dissociative States Scale (CADSS) (Bremner et al., 1998).  
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
Patients will be eligible to participate in the study if all of the following conditions exist: 
 
1) 
Willing and able to provide informed consent and assent. 
2) 
Male and female adolescents aged 12 to 18 years. 
3) 
Presence of recurrent MDD confirmed by the K-SADS-PL (Kaufman et al., 1997). 
4) 
Current depression severity measured by the Children’s Depression Rating Scale 
(CDRS) (Poznanski, 1985) raw score greater than or equal to 36 at screening and 
the day ketamine is due to be received for the first time.  
5) 
Current depressive episode resistant to treatment, defined as failure to achieve 
remission (elimination of symptoms and restoration of pre-morbid psychosocial 
functioning) from at least 2 antidepressant trials. Systematic evaluation of previous 
antidepressant trials will be assessed by using the Antidepressant Treatment History 
Form (Sackeim, 2001).   
6) 
If present, current antidepressant medication treatment must be dose stable for 
at least 2 months prior to beginning the study*  
7) 
Participants should have a medical history and physical examination in the 30 
days prior to initiating the ketamine infusions. 
4.2 Exclusion Criteria 
Patients will be excluded from participation in the study if any of the following conditions 
exist: 
 
1. Inability to speak English 
 
2. A history of Mental Retardation or Autism Spectrum Disorder 
 
3. Current or lifetime diagnosis of schizophrenia, schizoaffective disorder, psychosis 
not otherwise specified (NOS). 
 
4. Diagnosis of seizures or other neurological disorders.  
 
5. Comorbid diagnosis of substance abuse or dependence within 6 months of 
assessment. 

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6. Clinically unstable medical illness. 
7. Current use of barbiturates, narcotics, or non-benzodiazepine hypnotics at doses 
higher than Zolpidem 10 mg or equivalent for insomnia. 
8. For females:  pregnancy. 
9. Inability to undergo an MRI scan. 
10.  A Family History notable for having at least one first-degree relative with 
schizophrenia, schizoaffective disorder, psychosis not otherwise specified (NOS). 
 
* If there has been a recent discontinuation of a medication, we will require lapses of 
time before study entry as follows: Antidepressants (excluding Fluoxetine) – 2 weeks; 
Fluoxetine – 4 weeks; Mood Stabilizers – 2 weeks; Antipsychotics – 2 weeks; 
Stimulants – 1 week. 
4.3 Subject Recruitment and Screening 
 
Adolescents with treatment resistant depression who have been admitted to the 
adolescent mental health inpatient unit, who present to the University of Minnesota 
Psychiatry Adolescent Mood Clinic, or who are referred from outside clinicians, and who 
meet inclusion and exclusion criteria for the study, will be invited to participate.  
 
Prior to enrollment, project staff selected to recruit for this study will screen review 
records from the hospital and clinical services noted above to determine potentially 
eligible adolescent participants. If an adolescent appears to meet basic criteria for the 
study (appropriate age and diagnosis), staff will then check the consent for treatment 
form in the patient’s chart. If parents indicated on that form their willingness to have their 
child’s medical records used in research, study staff will then contact the current treating 
provider to determine whether the provider feels it would be appropriate to invite this 
participant into the study. If so, the provider will request written permission of the 
adolescent and/or the parent for the study staff to contact them regarding the study. The 
study staff will then contact the parents by phone or in person to inform them about the 
purpose and activities of the current study.  
 
We anticipate that some families will hear about our study through word of mouth or by 
searching on ClinicalTrials.gov. We will post information about the study in the 
community using flyers and online posting boards. 
 
If after hearing about the study from study staff patients/families are interested in 
participating, the study staff will then conduct a screening form to ensure eligibility. If 
parents are interested and the adolescent is eligible, the first study visit will be 
scheduled. Informed consent will be obtained at the time of the first study visit.  
 

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4.4 Early Withdrawal of Subjects 
 
When and How to Withdraw Subjects 
A subject may be withdrawn from the study prior to expected completion for the 
following reasons:  
• Participant experiences adverse side effects to the ketamine treatments that are 
intolerable to the adolescent or the parent. 
• Participant fails to adhere to protocol requirements 
• Participant or participant’s parent(s) withdraw consent 
 
If a subject exits the study for any reason (withdrawal, non-response, or relapse), he or 
she will continue his or her pre-study regimens and consult with his or her psychiatrist 
about the next step in treatment.  
 
Data Collection and Follow-up for Withdrawn Subjects 
For all participants, we will request permission during the consent process to collect 
naturalistic follow-up data through in person visit to clinic or video conference 6 months 
after the 6-week study period.  
 
The naturalistic follow-up encounter will be as follows: 
 
We will ask permission to contact the family to inquire about the participant. Subjects 
will be determined lost to follow-up if they do not respond to 4 e-mails to the primary e-
mail address of parent(s) or 4 phone calls to their primary number or to their next-of-kin, 
or to a certified letter.   
 
During the follow up in person visit to clinic or video conference subject will be asked to 
provide: 
a) A narrative interval history including following elements 
a. Changes in medications and their effects 
b. Therapies or other treatments they have undergone and their effects 
c. Evolution of their symptoms during the interval 
d. Any hospitalizations including cause and outcome 
e. Any suicide attempts including precipitating factor (if any) and outcome 
 
b) Participate in a clinical interview in order for clinician to complete an 
assessment using CDRS-R, CADSS, CGI, and MADRS. 
c) Complete the BDI-II, Profile of Mood States – Adolescent, SHAPS and TEPS  
5 Study Drug  
5.1 Description 
Study solutions of ketamine will be prepared as a liquid in 50mL IV bag, with 0.9% 
saline and a dose of ketamine that equal 0.5mg/kg of the subject’s actual body weight, 
dissolved into the saline. 

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5.2 Treatment Regimen 
 
At each of the ketamine treatment visits, subjects will receive an IV infusion of 0.5mg/Kg 
of ketamine hydrochloride over 40 minutes. To ease IV placement, we will use emla 
cream, or if necessary, J tip (a needle-free injector that uses compressed air to propel 
lidocaine beneath the skin’s surface, numbing the area). The dose of ketamine will be 
determined by  body weight. 
 
 
Each participant will undergo a total of 6 ketamine infusions over a 2-week period (on a 
Monday, Wednesday, Friday schedule).  
 
For this pilot study we do not include a placebo in the design. After confirming the 
feasibility of recruiting adolescents with TRD to a ketamine study and showing 
preliminary evidence of efficacy and mechanism, a future step will be to conduct a 
randomized placebo controlled trial. 
 
Patients will continue with current antidepressant treatment throughout the study. Based 
on our experience in current research at the VA Medical Center using serial ketamine 
dosing, patients have shown positive results while continuing their current 
antidepressant treatment. 
5.3 Method for Assigning Subjects to Treatment Groups 
 
Not applicable. There is only one treatment group.  
5.4 Preparation and Administration of Study Drug 
The IV ketamine study medication will be prepared in the Investigational Pharmacy and 
administered by the nursing staff in the Journey Clinic. 
5.5 Subject Compliance Monitoring 
 
Since the study medication is administered in an infusion unit, compliance with study 
medication will be measured by whether participants present to infusion visits and 
cooperate with all procedures of IV ketamine administration. To be compliant with other 
aspects of the study, participants will be required to attend two MRI scans, six ketamine 
treatment visits and six weekly follow-up visits. The follow up visits may take place in 
person or, for subjects who do not reside within convenient travel distance to 
Minneapolis, via phone or video conference. Study staff will monitor whether the 
participant is attending these visits. If a participant is not compliant with study 
procedures, his/her participation in the study will be terminated.  
5.6 Prior and Concomitant Therapy 
 

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If present, current antidepressant treatment (pharmacological, augmenting agents, and 
non-pharmacological) must be dose stable for at least 2 months prior to beginning the 
study.  Patients will continue with current antidepressant treatment throughout the 
study. Based on our experience in current research at the VA Medical Center using 
serial ketamine dosing (Shiroma 2013), patients have shown positive results while 
continuing their current antidepressant treatment.  
 
5.7 Packaging 
Commercially available ketamine hydrochloride will be purchased 10 mL vials of 
50mg/mL ketamine.  Cartons of study drug vials will be purchased to ensure sufficient 
drug is available for at least five subjects at a time.  
 
5.8 Blinding of Study Drug 
 
Not applicable.  
5.9 Receiving, Storage, Dispensing and Return 
 
 
 
 
Receipt and Storage of Drug Supplies  
The local site pharmacist will purchase and store the commercially available 
study drug. Ketamine must be stored between 20 and 25 degrees Celsius, and 
protected from light. Ketamine vials will be stored in carton until time of use.  
 
Dispensing of Study Drug 
The local site pharmacist will dispense the study drug, which will be openly 
labeled for investigational use only. Regular study drug reconciliation will be 
performed to document drug assigned, drug consumed, and drug remaining. This 
reconciliation will be logged on the drug reconciliation form, and signed and 
dated by the study team.  
 
Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, 
drug consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be 
investigated, resolved, and documented prior to return or destruction of unused 
study drug.  Drug destroyed on site will be documented in the study files. 

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6 Study Procedures 
6.1 Visit 1 – Baseline assessment 
As a first step, informed consent will be obtained from the parents/guardians of the 
adolescent and assent will be obtained from the adolescent by authorized members of 
the study team. If the adolescent is able to provide consent legally, such consent will be 
obtained from him/her. We will attempt to obtain consent from both parents except 
where it is not possible (e.g. death of a parent, parent does not have custody) or it is 
prohibitive to do so (e.g. parent lives in another state, parent is unavailable during 
reasonable business hours). 
 
Demographic information will be obtained from the adolescent and the 
parent(s)/guardian(s) using “Ketamine Demographics Form”. 
  
The adolescent and the parent(s)/guardian(s) will participate in a semi-structured 
diagnostic interview (the Kiddie Schedule for Affective Disorders and Schizophrenia, 
parent and lifetime version – K-SADS-PL). During this interview, a complete psychiatric 
history will be obtained for each participant. We will systematically evaluate the history 
of previous antidepressant trials using the Antidepressant Treatment History Form 
(Sackeim, 2001). Adolescent participants will complete a self-report Beck-Depression 
Inventory-II to assess depression severity as well as Snait-Hamilton Pleasure Scale 
(SHAPS) and Temporal Experience of Pleasure Scale (TEPS) to assess anhedonia 
severity. The clinician will complete a Children’s Depression Rating Scale-Revised, a 
clinical interview with both adolescent and parent/guardian (separately), to assess 
depression severity. Clinicians will also complete the Columbia Suicide Severity Rating 
Scale (CSSRS), Brief Psychiatric Rating Scale (BPRS) and Montgomery-Åsberg 
Depression Rating Scale (MADRS). Additionally, the clinician will also administer the 
two subset version of the WASI to estimate intelligence. Finally, the participant will be 
asked to complete DPX-task. If participants meet inclusion criteria they will be 
scheduled for the subsequent procedures. For participants that have not had a medical 
history and physical examination completed within the past 30 days, this will be 
completed at the end of the baseline visit by one of the medical doctors on the research 
team. 
6.2 Visit 2 – MRI scan 
Participants will be undergo an MRI scan before the first ketamine treatment and after 
the last ketamine treatment using a Siemens Prisma 3 Tesla scanner located in the 
University of Minnesota Center for Magnetic Resonance Research (CMRR). Before the 
scan, the parent/guardian will be asked to complete an MRI safety screening form for 
their child and the adolescent will be asked to provide a urine sample, which will be 
used to test for the presence of illicit drugs and (for females) pregnancy. If either result 
is positive, the participant will not be able to continue with the study. The scanning 
protocol will consist of two functional MRI scans (one during rest and one during an 
emotion task), a high-resolution T1-weighted anatomical image, and a diffusion tensor 
imaging sequence. Participants will be transported to the CMRR by their parents. If the 
participant is on the inpatient service, the treating physician will write a pass to allow the 

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family to take the patient for several hours to complete the scanning. If the study 
physician and/or the family do not feel that a pass would be appropriate due to safety 
concerns, the MRI visit will be waived. 
6.3 Visit 3 – First ketamine infusion 
 
On the day of each infusion, participants will arrive at the University of Minnesota 
Masonic Children’s Hospital - Journey Clinic infusion center. Adolescent participants 
who are currently inpatient on the adolescent psychiatric ward will be escorted to the 
Journey clinic by hospital staff (four floors up the elevator). Adolescent participants who 
are outpatient will arrive at the Journey Clinic with their parent or guardian. An 
indwelling catheter will be placed in the non-dominant arm for ketamine administration 
and for two blood draws at the first infusion visit.  
 
At this visit, directly before the ketamine infusion, participants will have 20 cc of blood 
drawn into heparinized tubes. They will have a second blood draw two hours after the 
infusion is complete. The blood samples will be sent to Dr. Susannah Tye at the Mayo 
Clinic for analysis. 
 
Subjects will receive IV infusion of 0.5 mg/Kg of ketamine hydrochloride over 40 
minutes. Digital pulse oximetry, respiratory rate, heart rate and blood pressure will be 
recorded every 15 minutes throughout the infusion, beginning 15 minutes before 
infusion. Vital signs will be monitored for at least 2 hours post infusion, to be assured 
there are no lingering side effects before leaving the unit.  
 
Prior to infusion, participants will be asked to complete the BDI-II, SHAPS, TEPS and 
POMS-A, and a trained member of research staff will complete the Clinical Global 
Impressions Scale (CGI) (Guy, 1976), BPRS+, MADRS, CADSS.  At the end of the 
infusion and 1 hour post infusion, participants will be asked to complete SHAPS, TEPS 
and POMS-A, and a trained member of research staff will complete BPRS+ and 
CADSS. At 2 hours post infusion, participants will be asked to complete the BDI-II, 
MADRS, SHAPS, TEPS and POMS-A, and a trained member of research staff will 
complete the Clinical Global Impressions Scale (CGI) (Guy, 1976), BPRS+, MADRS, 
CADSS. 
 
If adolescent reports experiencing nausea or vomits during the infusion or the 
subsequent 2-hour observation period, the PI will evaluate the adolescent’s reported 
symptoms and determine if (a) P.R.N. Ondansetron is indicated at that time (0.15mg/kg, 
up to 8mg), and (b) pre-treatment with IV Ondansetron for control of nausea is 
warranted for the subsequent infusions. 
 
Participants will be asked about any adverse events (AE) and concomitant medications 
at each visit.  
 
To be discharged from the infusion unit, the adolescent must meet the following 
discharge criteria: 

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1)      Stable vital signs  
2)      Pain is under control 
3)      A return to the level of consciousness that is similar to the baseline for that patient 
4)      Adequate head control and muscle strength to maintain a patent airway 
5)      Nausea and/or vomiting is not present 
6)      The patient is adequately hydrated.  
 
After each infusion, adolescents will either return to the inpatient unit escorted by 
hospital staff, or if they are outpatient, will return home escorted by their parent(s).  
Participants (and parents if outpatient, or hospital staff if inpatient) will receive written 
discharge instructions regarding rare but serious side effects from ketamine and several 
measures to improve recovery at home. 
6.4 Visits 4-8 – 5 subsequent ketamine infusions 
Participants will undergo a total of six ketamine infusions within a 2-week period (on a 
Monday-Wednesday-Friday schedule). The 5 subsequent treatments will be conducted 
in the same way the first treatment was conducted (please see section 6.3 for details), 
except the blood draw only occurs before the first and after the last infusion. 
  
After the conclusion of the 6th ketamine infusion (after participants has past the “2 hour 
post infusion” time point during the 6th clinic visit). Participants will again have 20cc of 
blood drawn by venipuncture, which will be handled in the same way as other blood 
draws (see section 6.3 for further details). 
 
If adolescent has experienced nausea or vomited during any prior infusion and PI has 
determined that pre-treatment with IV Ondansetron is appropriate for management of 
adolescent’s nausea symptoms, adolescent will receive IV Ondansetron at a dose of 
0.15 mg /kg (up to 8 mg) via the same IV port established for infusion of ketamine 
immediately before the administration of ketamine.  
6.5 Visit 9 – Second brain MRI  
Within 1 week of the last ketamine infusion, participants will undergo another brain MRI 
identical to the previous one (please see section 6.2 for more details).  
 
6.6 Visit 10 – Clinical assessment and blood draw 
Also within one week of the last ketamine infusion, participants will come to the 
Ambulatory Research Center or participate in a phone or video conference for clinical 
evaluation to assess their clinical response to the ketamine infusions. At this visit, the 
following assessments will be completed to determine response to treatment: Columbia 
Suicide Severity Rating Scale – Since Last Visit (CSSRS-SLV), Montgomery-Asberg 
Depression Rating Scale (MADRS), Clinician-Administered Dissociative States Scale 
(CADSS), Profile of Mood States-Adolescent Version (POMS-A), Snaith-Hamilton 
Pleasure Scale (SHAPS), Temporal Experience of Pleasure Scale (TEPS), Beck 
Depression Inventory-II (BDI-II), Clinical Global Impression (CGI), and Brief Psychiatric 
Rating Scale (BPRS). Also, the clinician will complete a Children’s Depression Rating 

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Scale-Revised, a clinical interview with both adolescent and parent/guardian 
(separately), to assess depression severity. The participant will also be asked to 
perform the DPX-task. 
6.7 Visits 11-16 – Follow-up period 
All participants will be asked to speak with the research team  for weekly follow-up visits 
for 6 weeks. Participants will continue to take medications as prescribed by their doctor. 
At each of these visits, participants will be asked about any medication changes and will 
complete the same assessments as administered in visit 10 (MADRS, CADSS, POMS-
A, SHAPS, TEPS, BDI-II, CGI, CDRS and BPRS).  
 
All participants will be asked to participate in the 6 weekly follow-up visits, regardless of 
response. 
 
6.8 Schedule of Events Table 
 
*The Monday, Wednesday, Friday schedule does not have to start on a Monday, it can 
start on a Wednesday or Friday, but treatments will always occur on these days and the 
total time will always be 2 weeks. 
 
Consent 
Interview  
Questionnaires 
in-person 
MRI 
Blood draw 
Ketamine infusion  
Initial visit 
X 
X 
X 
 
 
 
Within a 
week from 
first visit 
 
 
 
X 
 
X 
 
Week 1 
*Monday 
 
 
 
 
 
X 
Week 1 
Wednesday 
 
 
 
 
 
X 
Week 1 
Friday 
 
 
 
 
 
X 
Week 2 
Monday 
 
 
 
 
 
X 
Week 2 
Wednesday 
 
 
 
 
 
X 
Week 2 
Friday 
 
 
 
 
 
X 
Within a 
week from 
last infusion 
 
X 
X 
X 
X 
 
Follow-Up 
Week 1 
 
 
X 
 
 
 
Follow-Up 
Week 2 
 
 
X 
 
 
 
Follow-Up 
Week 3 
 
 
X 
 
 
 
Follow-Up 
Week 4 
 
 
X 
 
 
 
Follow-Up 
Week 5 
 
 
X 
 
 
 
Follow-Up 
Week 6 
 
 
X 
 
 
 

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7 Statistical Plan 
7.1 Sample Size Determination 
In view of the lack of any reports on ketamine in adolescent depression, the study 
sample was based on published studies in adult depression.  
7.2 Subject Population(s) for Analysis 
 
Data from each participant who completes the six ketamine treatments will be subjected 
to the primary study analysis. We will conduct secondary analyses on all participants 
who received at least one dose of treatment. 
7.3 Statistical Methods 
 
In the following analyses, primary outcome measures will include the “per protocol” 
population. The secondary measures will include the “intent to treat” population. 
 
Primary analysis: Paired t tests will be conducted between the lowest score from the 
post-treatment assessments and the baseline symptom levels to assess the maximum 
effect of ketamine infusion on symptoms for each person.  
 
Secondary Analyses:   
1. We will calculate the time to relapse for each participant. 
2. Biological Mechanisms: 
a. Neuroimaging data: Paired t tests will be conducted to evaluate pre- and 
post ketamine treatment changes in measures of brain functional 
activation, connectivity, white matter microstructure and brain metabolite 
concentrations. These preliminary data will be used to identify responsive 
measures and estimate sample sizes that would be needed to use these 
measures as endpoints in future studies.  
b. Bimolecular studies to examine mechanisms of cellular resilience (insulin 
challenge, cytokine testing, gene expression) will be conducted to 
evaluate change in these pathways before and after ketamine. Analyses 
will be conducted by Dr. Susannah Tye at Mayo Clinic. Peripheral blood 
mononuclear cells (PBMCs) will be isolated from whole blood and divided 
into two groups. The first group will not receive any treatment. RNA will be 
extracted and whole genome microarray will be performed using illumina's 
genome-wide gene expression arrays. Differential pre- versus post-
ketamine mRNA levels will be quantified and bioinformatics pathway 
analysis will be used to identify key differences in molecular responses to 
ketamine. A second subset of PBMCs will be cultured and cryopreserved. 
Once all samples are collected cells will be immortalized to ensure 
sufficient tissue availability. The following two separate analyses will then 
be performed: 

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i. Group 1 PBMCs will be stimulated with insulin and intracellular Akt, 
mTOR, and GSK3 gene and protein levels will be quantified 
following 0, 5, 15, and 30 minutes of stimulation. This signaling 
pathway is implicated in mediating the antidepressant response to 
ketamine. Western blot and rtPCR techniques will be used to 
quantify protein and gene expression, respectively; 
ii. Group 2 PBMCs will be immortalized and undergo inflammatory 
challenge via stimulation with phytohemagglutinin. Levels of 
cytokines and kynurenines will be measured in the culture medium 
1, 3 and 24 hours post-stimulation. ELISA kits will be used to 
quantify proinflammatory cytokine levels. 
Outcomes of each assay will be correlated with patient response profile. 
All tissue will be destroyed upon completion of the study. 
 
Interim Analysis: The above analyses will be conducted on data from the first ten 
subjects to ensure that there is preliminary support for the proposed hypotheses. 
8 Safety and Adverse Events 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops 
or worsens in severity during the course of the study. Intercurrent illnesses or 
injuries will be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event 
is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs a hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, 
but are clearly of major clinical significance.   They may jeopardize the subject, and 
may require intervention to prevent one of the other serious outcomes noted 
above.  For example, drug overdose or abuse, a seizure that did not result in in-

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patient hospitalization, or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be 
regarded as non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of the 
study treatment follow-up.  For this study, the study treatment follow-up is defined 
as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition will be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event will also be 
recorded and documented as an adverse event.  
 
Post-Study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the investigator will instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.   
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for an adverse 
event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 

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reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
8.2 Recording of Adverse Events 
 
Adverse Event Recording 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events will be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results will be recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up to 
determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
 
SAE Recording 
A Serious Adverse Event (SAE) form must be completed by the investigator or study 
team member within 24 hours of finding out about the event. The investigator must 
determine causality and confirm the severity of the event in the SAE form.  The 
sponsor-investigator will keep a copy of this SAE form on file at the study site.   
 
At the time of the initial report, the following information should be provided: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was 
discontinued 
• The reason why the event is 
classified as serious 
• Investigator assessment of the 
association between the event 
and study treatment 
 
Within the following 48 hours, the investigator must provide further information on the 
serious adverse event in the form of a written narrative.  This should include a copy of 
the completed Serious Adverse Event form, and any other diagnostic information that 

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will assist the understanding of the event.  Significant new information of ongoing 
serious adverse events should be provided promptly to the sponsor-investigator. 
 
8.3 Reporting of Serious Adverse Events 
 
IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be 
submitted to the IRB within 10 working days if it falls under the UPIRTSO 
guidelines.  Copies of each report and documentation of IRB notification and 
receipt will be kept in the regulatory binder. 
 
Any other event not defined as an SAE, yet unanticipated, related and increases 
risk to subjects must be reported to the IRB within 10 working days, as defined in 
the IRB’s UPIRTSO guidelines.  
 
FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission 
of any unexpected fatal or life-threatening experience associated with the use of 
the drug as soon as possible but no later than 7 calendar days from the 
sponsor’s original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found 
to fit the criteria for reporting, the study sponsor will submit the adverse event in a 
written report to the FDA as soon as possible, but no later than 15 calendar days 
from the time the determination is made. 
 
Summary Table of Reporting Requirements 
 
 
 
 
 
Agency 
Criteria for 
Reporting 
Timeframe 
Form to Use  
Submission 
address/fax 
numbers  
U of MN 
IRB 
SAE: fatal, life-
threatening or 
serious, 
unexpected, at 
least possibly 
related  
10 working 
days 
UMCC SAE 
 
 
UPIRTSO 
For all 
unanticipated 
events that 
10 working 
days 
IRB’s UPIRTSO 
form 
MMC 820 

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increase risk to 
subjects or 
others 
FDA 
SAE: fatal, life-
threatening, 
unexpected, at 
least possible 
related 
7 calendar days  FDA prefers 
MedWatch 
3500a Form but 
alternative 
formats are 
acceptable (e.g. 
summary letter) 
Fax: 1 (800) FDA - 
0178 
SAE: serious, 
unexpected, at 
least possibly 
related 
15 calendar 
days 
 
 
8.4 Unblinding Procedures 
 
Not applicable.  
8.5 Stopping Rules  
 
The study will be stopped if new results either from our study or from other studies arise 
suggesting that the risks of the study medication significantly outweigh the benefit. 
8.6 Data and Safety Monitoring / Auditing 
 
Medical Monitoring 
The Principal Investigator will oversee the safety of the study at the University of 
Minnesota site. This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above.  Medical monitoring will include a regular 
assessment of the number and type of serious adverse events. 
 
Study Monitoring Plan 
Independent monitoring of the clinical protocol will be conducted periodically (i.e., at a 
minimum of annually) by qualified staff of the UMN CTSI in accordance with the 
monitoring plan. 
 
This study will be monitored according to FDA/GCP guidelines. The investigator will 
allocate adequate time for such monitoring activities. The Investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer is given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
Internal Data and Safety Monitoring Board 

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An internal independent, 3-person panel of physicians and researchers will conduct a 
reassessment of the risks and benefits to study participants.  This panel will review all 
adverse events for severity and frequency. Dr. Gail Bernstein, M.D., Dr. Jeff Wozniak, 
Ph.D., and Dr. Sanjiv Kurma, M.D. will review the safety of the study after the first five 
participants have completed at least the first infusion. The results of their review will be 
submitted to the IRB. Subsequent reviews will occur annually.  
 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents. Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 

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verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical trial. 
 
Data generated by the methods described in the protocol will be recorded in the 
subjects' medical records and/or study progress notes. Data may be transcribed legibly 
on CRFs supplied for each subject or directly inputted into an electronic system or any 
combination thereof. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF will be recorded.  All missing data will be explained. If a 
space on the CRF is left blank because the procedure was not done or the question 
was not asked, “N/D” will be written. If the item is not applicable to the individual case, 
“N/A” will be written. All entries will be printed legibly in black ink. If any entry error has 
been made, to correct such an error, a single straight line through the incorrect entry will 
be drawn and the correct data will be entered above it. All such changes will be initialed 
and dated. Errors will never be erased or whited out. For clarification of illegible or 
uncertain entries, the clarification will be printed above the item, then initialed and 
dated. 
9.4 Records Retention 
 
As applicable the Investigator-Sponsor will retain the specified records and reports until 
2 years after investigations under the IND have been discontinued and the FDA so 
notified. In addition, University policy states in part that researchers should maintain a 
file of all documents concerning the use of human subjects in research for 3 years from 
completion of IRB related work and 6 years for HIPAA. 
 
10 Ethical Considerations 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the sponsor-investigator 
before commencement of this study.   
 
All subjects for this study will be provided an assent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  Parents and/or guardians of the subject will be given a 
parent/guardian consent form that describes the study.  The consent and assent forms 

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will be submitted with the protocol for review and approval by the IRB for the study.  The 
formal assent of a subject and consent of the parent/guardian, using the IRB-approved 
consent and assent forms, must be obtained before that subject is submitted to any 
study procedure. The assent and consent forms must be signed by the subject and 
parent/guardian, respectively, and the investigator-designated research professional 
obtaining the consent. Although only one signature of one parent/guardian is required 
for this treatment study, the study team will attempt to obtain the signatures of both 
parents.  
11 Study Finances 
11.1 Funding Source 
 
The study is funded by the Clinical Science Translational Institute at the University of 
Minnesota, under the K to R Transition to Independence Award Program. 
11.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must refer to the Regents Policies on Individual Conflict of Interest Policy or Institutional 
Conflict of Interest Policy. These policies require University Faculty and staff to report 
external professional activities and business and significant financial interests related to 
his or her University activities by submitting a REPA (Report of External Professional 
Activities) at least once per year. Faculty and staff should also file a REPA when 
substantial changes in business or financial interests occur, when an activity that 
presents a potential conflict of interest is anticipated, or when submitting an application 
for research support or technology transfer, submitting research protocols to the IRB, or 
receiving financial contributions. All University of Minnesota investigators will follow the 
University conflict of interest policy. 
11.3 Subject Stipends or Payments 
 
Each child participant will be compensated up to $220 for completing the entire study: 
$40 for the baseline assessment, $20 for the clinical assessment after 6 infusions, $40 
for each MRI assessment (total of 2), $20 for the naturalistic follow up visit at 6 months 
and $10 for each of the weekly follow-up visits (up to 6). Participants will not be 
reimbursed for ketamine treatment visits. For participants who start but do not finish the 
study, monetary compensation will be pro-rated according to each completed visit. 
Parking will be reimbursed for each of the visits.  
12 Publication Plan 
 
Upon completion of the data collection, data analysis and interpretation of the results, 
the results of the study will be published in one or more peer-reviewed Psychiatry 
journal(s) by the investigators. 

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13 References 
 
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depression. Prog Neuropsychopharmacol Biol Psychiatry. 35, 1155-1159. 
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Wolkowitz, O. M., Mellon, S. H., Epel, E. S., Lin, J., Reus, V. I., Rosser, R., Burke, H., 
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14 List of Reference Documents 
 
The following study related documents will be maintained in the regulatory binder.  
 
• Parental consent form 
• Child assent 
• Consent form for adult participants (over age 18) 
• Addendum assent for female minors 
• Phone screen 
• Questionnaires/Rating Scales 
o ATHF  
Antidepressant Treatment History Form 
o BDI-II  
Beck Depression Inventory-II 
o BPRS  
Brief Psychiatric Rating Scale 
o CADSS 
Clinician-Administered Dissociative States Scale 
o CDRS  
Children’s Depression Rating Scale 
o CGI 
 
Clinical Global Impressions 
o CSSRS 
Columbia Suicide Severity Rating Scale 
o K-SADS-PL Kiddie-Schedule of Affective Disorders and Schizophrenia-Present 
and Lifetime 
o MADRS 
Montgomery-Asberg Depression Rating Scale 
o POMS-A 
Profile of Mood States – Adolescent 
o SHAPS 
Snaith-Hamilton Pleasure Scale 
o TEPS  
Temporal Experience of Pleasure Scale 
o WASI  
Weschler Abbreviated Scale of Intelligence 
o DPX task 
Dot Pattern Expectancy task 
 
• Data Monitoring Plan 
• Ketamine hydrochloride package insert