Conditions: Major Depressive Disorder
Keywords: Treatment-resistant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
This study will test the use of ketamine for treatment of depression in adolescents that have not responded to other treatments. We will also examine neurobiological mechanisms of treatment.

Detailed description:
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. 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 at 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.

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. The specific aims of this preliminary study are as follows:

Aim #1: To determine the efficacy of repeated-dose subanesthetic IV ketamine among adolescent patients with 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.

Aim #2: To explore durability of antidepressant response to repeated dose of IV ketamine in a 4-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.

Aim #3: To study the neurobiological mechanisms of response to ketamine. We will examine relevant biological systems using several different brain imaging indices and measures of intracellular functioning from peripheral blood.

Arms:
arm 1: Intravenous ketamine 0.5 mg/kg over 40 minutes will be given 6 times over 2 weeks.

Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
 
 
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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This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
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 


Clinical Research Protocol 
 
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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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This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
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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CONFIDENTIAL 
This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
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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CONFIDENTIAL 
This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
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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symptoms with an n-methyl-d-aspartate antagonist in ect-resistant major 
depression. Prog Neuropsychopharmacol Biol Psychiatry. 35, 1155-1159. 
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Collins, K. A., Mathew, S. J., Charney, D. S., & Iosifescu, D. V., 2012. Rapid and 
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resistant major depression. Biol Psychiatry. 
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Perry, E. B., Jr., Cramer, J. A., Cho, H. S., Petrakis, I. L., Karper, L. P., Genovese, A., 
O'Donnell, E., Krystal, J. H., & D'Souza, D. C., 2007. Psychiatric safety of 
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253-260. 
Poznanski, E. O., Freman L.N. Mokros H.B., 1985. Children's depression rating scale-
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Scheidegger, M., Walter, M., Lehmann, M., Metzger, C., Grimm, S., Boeker, H., 
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Sinner, B., & Graf, B. M., 2008. Ketamine. Handb Exp Pharmacol313-333. 
Snaith, R.P., Hamilton, M., Morley, S., Humayan, A., Hargreaves, D., & Trigwell, P., 
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Tanti, J. F., Ceppo, F., Jager, J., & Berthou, F., 2013. Implication of inflammatory 
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This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
Wolkowitz, O. M., Mellon, S. H., Epel, E. S., Lin, J., Reus, V. I., Rosser, R., Burke, H., 
Compagnone, M., Nelson, J. C., Dhabhar, F. S., & Blackburn, E. H., 2012. 
Resting leukocyte telomerase activity is elevated in major depression and 
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Zarate, C. A., Jr., Mathews, D. C., & Furey, M. L., 2013. Human biomarkers of rapid 
antidepressant effects. Biol Psychiatry. 73, 1142-1155. 
Zarate, C. A., Jr., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, 
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Psychiatry. 63, 856-864. 
 
 
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 

ICF_000.pdf: 
Adult Participant Consent Form
CTSI 22225
Initials __________    Date __________
Version 3, dated 06/19/17
Page 1 of 11
Adult Participant Consent Form
Study Title:
Open-Label Intravenous Subanesthetic Ketamine For Adolescents With 
Treatment-Resistant Depression
Study #:
CTSI 22225
Study Doctor:
Kathryn Cullen, MD
University of Minnesota - Division of Child and Adolescent Psychiatry
2450 Riverside Ave., F256/2B, Minneapolis, MN  55454
Telephone Number: (612) 273-9711
After Office Hours:
(612) 382-7052
You are invited to enroll in a research study that will use a drug called ketamine as a potential 
antidepressant treatment. Before agreeing to participate in this study, it is important that you 
read this consent form. This form may contain words that you may not understand.  Please ask 
one of the study team members to explain any information that is not clear. You may take as 
much time as you wish to make up your mind about whether or not you would like to participate.  
You may take home an unsigned copy of this consent form to think about or discuss with family 
or friends before making your decision.
This study is being conducted by Dr. Kathryn Cullen and her colleagues in the Department of 
Psychiatry at the University of Minnesota (UMN). It is funded by the Clinical and Translational 
Science Institute at UMN.  We hope to enroll about 20 people aged 12-18 years at the 
University of Minnesota.
Why is this study being done?
This study will try to learn if a drug called ketamine can be used to help adolescents with 
treatment-resistant depression.  Ketamine is investigational in this study, which means it is not 
approved in the United States for adolescent treatment-resistant depression by the U.S. Food 
and Drug Administration (FDA).
How long will the study last?
Participation in this study may last up to 9 weeks, and we may also contact you after 6 months 
for a brief follow-up interview. 
What is involved in the study?
The following information describes what will happen if you agree to participate in the study. 
We will ask you to participate in a clinical assessment, including a physical exam if you have not 
had one within 30 days. We will ask questions about your medical and psychiatric history, and 
ask you to complete questionnaires about your symptoms, including any thoughts of hurting 
QUORUM REVIEW
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INSTITUTIONAL
REVIEW BOARD


Adult Participant Consent Form
CTSI 22225
Initials __________    Date __________
Version 3, dated 06/19/17
Page 2 of 11
yourself or others. We also test the urine for the presence of certain drugs. The study doctor or 
study staff will tell you if the drug test results are positive. The results of the drug test must be 
negative in order for you to be in the study.
Due to unknown risks and potential harm to an unborn fetus, we will not include anyone who is 
pregnant in the study. Females who can have children will be asked to give a urine sample for a 
pregnancy test. The study doctor or study staff will tell you if the pregnancy test results are 
positive. The results of the pregnancy testing must be negative to participate in the study.
We will ask you to have Magnetic Resonance Images (MRI) of the brain. This will take place on 
a 3 Tesla MRI scanner at the Center for Magnetic Resonance Research (CMRR) at the 
University of Minnesota. This involves lying quietly inside the center of a large doughnut-shaped 
magnet. To help you keep still during the MRI, we will place foam pillows around your head. We 
will perform several different kinds of scans, including scans while you are at rest and scans 
during an "emotion task", during which you will look at pictures/words and decide whether they 
are positive or negative. 
The entire MRI procedure will take about 2 hours. We will do this before and after the 2-week 
ketamine dosing. We will ask you to provide your own transportation to the CMRR. If you are 
admitted to the inpatient mental health unit on the day of the scan, you will need a pass written 
by your regular physician to allow you to leave the hospital to complete this visit. If either you or 
your regular doctor do not feel comfortable with having you go on a pass for this MRI visit, this 
part of the study does not need to happen.
The ketamine infusions take place at University of Minnesota Masonic Children's Hospital in the 
Journey Clinic. You will complete several questionnaires about how you are feeling, and these 
are repeated throughout the session. Then we will place a tube, or IV (intravenous—directly into 
the vein) catheter, in your non-dominant arm to administer the ketamine at a dose of 0.5 mg/kg. 
The dose is based on your weight. We will measure heart rate and other vital signs (blood 
pressure, breathing rate and oxygen saturation) throughout the visit. The entire infusion will last 
40 minutes. You will stay another 2 hours after the infusion to be monitored for comfort and 
safety. The ketamine infusions will follow a Monday, Wednesday, Friday schedule for a total of 6 
infusions over 2 weeks. 
Participants will undergo a blood draw (20 mL, or about a tablespoon) three times in the study, 
once before and once after the first ketamine infusion, and once after the last infusion. The 
blood samples will be sent to the Mayo Clinic in the laboratory of Susannah Tye, Ph.D. for 
analysis.
At two visits during the study (at the beginning of the study and after the last infusion), you will 
be asked to take a “dot pattern expectancy” task, which will measure your ability to follow visual 
cues using simple dot patterns.
We will re-assess your depression after the 6 doses of ketamine. 

In the event you no longer wish to participate, you will be referred back to your regular 
physician for treatment. If you did not have established care for depression we will refer 
you to an appropriate provider. We will provide recommendations as to level of care (for 
example, inpatient vs. outpatient, time to next visit if outpatient). If inpatient care is 
needed, we will work with you to facilitate this. If safety is an immediate concern, we will 
escort you to the emergency room, which is located one floor below the research facility 
where your interviews will take place. We will also possibly share the study information 
QUORUM REVIEW
APPROVED
INSTITUTIONAL
REVIEW BOARD


Adult Participant Consent Form
CTSI 22225
Initials __________    Date __________
Version 3, dated 06/19/17
Page 3 of 11
with your treating physician. If you would like us to do this, we will ask you to sign a 
release of information to allow us to contact your treating physician and share the 
information and our recommendations.

If you wish to continue the study, you will participate in 6 weekly follow-up visits for a 
brief interview and to complete questionnaires about how you are feeling. If depression 
returns before the sixth visit, you will exit the study at that time. Procedures for 
transitioning you to an ongoing provider will then be identical to those outlined above.

We will also contact you after 6 months from the last day of your participation in the 
above activities in order to arrange a brief (approximately 30 minute) interview, either in 
person or by video conference, to assess your progression during the intervening time 
period. This encounter will be similar to the follow-up visits in content and duration.
Any urine samples taken during the study will be used for the testing described above, and then 
discarded when the results are available. There are no plans to store these urine samples.
Your blood samples will be identified only with your study code number.
All biological samples will be destroyed at the end of the study.  Be aware that if you change 
your mind about being in the study, your blood samples may or may not be withdrawn from the 
research, depending on the study center's policies. You can ask the study doctor or study staff if 
you have questions about this.
While you are in the study, you must:

Follow the instructions you are given.

Come to the study center for all visits with the study doctor or study staff.

Tell the study doctor or study staff about any changes in your health or the way you feel.

Tell the study doctor or study staff if you want to stop being in the study at any time.
What are the possible risks?
Effects of ketamine during infusion may include: 

feeling detached from surroundings 

reduced concentration 

feeling as if in a dream 

colors or sounds seeming brighter or duller than usual 

blurred vision 

decreased pain 

increased anxiety 

euphoria (feelings of extreme happiness) 

confusion 

hallucinations 

sweating 

increased blood pressure 

increased heart rate 

rash 

nausea 

vomiting 
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Ketamine at lower doses, such as those used in this study, may have side effects that are mild, 
and only last for a short period of time. These effects include:

memory impairment

dizziness

increased libido

gastrointestinal distress

increased thirst

headache

metallic taste

constipation
Some subjects have reported a "hangover" on the day after ketamine administration, and some 
report vivid dreams for a few days afterward.
At higher doses, ketamine can affect vital signs such as blood pressure and heart rate. We will 
monitor vital signs. Ketamine infusions will be administered with supervision in the Journey 
Clinic as a day procedure. Pulse, breathing rate, and blood pressure will be continually 
monitored. If a severe or unexpected adverse event occurs, you will be evaluated to determine 
the need for any of the following: stopping the ketamine, changing other drugs, or providing 
medical care.
Please tell the study doctor or study staff right away if you have any side effects.  Please tell 
them if you have any other problems with your health or the way you feel during the study, 
whether or not you think these problems are related to the study.
It is possible that receiving ketamine may change how your regular medications, vaccines, or 
supplements work.  It is very important that you tell the study doctor about any medications, 
supplements, or vaccines before you take them during the study.
You may be given medications during and after the ketamine infusions to help treat or prevent 
side effects. You should ask the study doctor or study staff about the risks of these medications.
Sometimes people have allergic reactions to drugs. If you have a very bad allergic reaction, you 
could die.  Some things that happen during an allergic reaction that could be a sign or symptom 
of a life-threatening allergic reaction (anaphylaxis) are:

a rash

a fast pulse

sweating

a feeling of dread

swelling around the eyes and mouth

swelling of the throat

wheezing

having a hard time breathing

a sudden drop in blood pressure (making you feel dizzy or lightheaded)

inability to breathe without assistance
You should get medical help and contact the study doctor or study staff if you have any of these 
or any other side effects during the study.
There are risks associated with use of the high field MRI system. 
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
Claustrophobia. Some people experience claustrophobia (fear of confined spaces) while 
inside the scanner. Use the squeeze bulb to let us know immediately if you are 
experiencing claustrophobia, and we will terminate the scan.

Magnetic pull of metal objects. Objects with magnetic properties can be pulled into the 
magnet. Also, an MRI could be very dangerous if you have certain objects or devices 
implanted in your body, such as a pacemaker, insulin pump, ear implant, joint 
replacement, permanent dentures, piercings, or shrapnel.  You must tell the study doctor 
or study staff about any objects that you know are implanted or embedded in your body.

Energy from the scanner can cause heating or nerve stimulation. Another risk is 
presented by the energy waves used in the scanner. The power of the energy waves is 
well below the strength needed to heat the tissue in your body and cause harm, but any 
metal in contact with your skin could heat up. This is why you will be asked to remove all 
jewelry. If you have metal on your body that cannot be removed, we will review this with 
you carefully, and it may be that you will not be able to participate in the study. It is also 
possible that the scanner will cause peripheral nerve stimulation (stimulation of the 
nerves or muscles). If you feel any tingling or unusual sensations during the scan, or 
muscle contractions, use the squeeze bulb to alert the researcher immediately. 

Scanner noise. The noise generated by the operation of the scanner during a study is 
loud enough to cause hearing damage if you do not wear hearing protection, which we 
will provide. If, even with the hearing protection we give you, you find the noise from the 
scanner to be uncomfortable or painful, you should ask the scanner operator to stop the 
scan immediately. 

Unknown long-term risks. In addition, there is a risk of unknown effects related to 
participation in 3 Tesla MRI research. Long-term effects of exposure to high magnetic 
fields are unknown. 

Short-term symptoms. Short term, most people experience no ill effects from the strong 
magnetic field, but some people report dizziness, mild nausea, headache, a metallic 
taste in their mouth, or sensations of flashing lights. These symptoms, if present, 
become less intense shortly after leaving the magnet. If any sensations experienced 
during participation cause discomfort or pain, notify the researcher right away and your 
scan will stop and you will be taken out of the magnetic field. 

Risks related to pregnancy. The risks of exposure to high magnetic fields are unknown 
for fetuses. Therefore, we will not include anyone in the study who is pregnant, as 
measured by a urine pregnancy test. 

Potential for discovery of brain abnormalities. It is possible that the MRI scan would 
reveal unknown and unlooked for abnormalities in your brain. We routinely have each 
scan sent to a radiologist (a doctor who specializes in looking at these images), and if 
there are abnormalities we will let you know of these results. We will provide your regular 
physician with a copy of these images if you would like. 
The risks of drawing blood and putting an I.V. catheter in your arm include dizziness, pain, 
bruising, or infection at the site of the needle stick. Infections happen rarely.
In addition, problems you could have from I.V. administration of ketamine directly into your vein 
include:

irritation of the vein; your skin near the vein could become warm, swell, hurt, or get red

damage to your vein

damage to the skin or tissue around the injection site
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
too much of the ketamine may be given to you

increase or decrease in electrolyte levels (the amount of certain salts and other 
chemicals in your blood), causing health problems

a blood clot or an air bubble could form, which could block a blood vessel in another 
part of your body
Some of these problems could be very serious.
Over time, getting a lot of injections can cause a vein to become hard or scar, which can make it 
difficult to put a needle into the vein to give you a shot or take blood.
If you are pregnant or nursing a child while receiving ketamine, there may be risks to your 
unborn baby or nursing child.  Some drugs cause premature (early) birth or birth defects.  
Nobody knows what all of these risks are right now.
If you are a woman who can have children, the study doctor or study staff will talk to you about 
birth control you must use during the study.
If you think you are pregnant during the study, you must tell the study doctor or study staff 
immediately. Women who become pregnant during the study will have to leave the study.
Some of the questions you will be asked in the study questionnaires may make you feel 
uncomfortable or upset. Please tell the study doctor or study staff if you feel uncomfortable or 
upset while answering the study questionnaires. You do not have to answer any question that 
makes you uncomfortable or upset.
There is a risk of loss of confidentiality of your information.  You will read more about the 
protection of your information later in this form.  Please ask the study doctor or study staff if you 
would like to know more about how your information will be protected while you are in this study.
There may be other unknown side effects that could occur, which include your depression 
getting worse.
Ask the study doctor if you have questions about the signs or symptoms of any side effects that 
you read about in this consent form.
Are there any potential benefits?
With ketamine, it is possible that you may experience a reduction in depressive symptoms and 
improvement in social and family functioning. However, this is not guaranteed and there may be 
no direct benefit to you from being in the study. The knowledge gained from this study may 
benefit others in the future.
What other options are there?
You do not have to be in this study to get help for your treatment-resistant depression. You can 
choose to not participate in this study. You can continue to work with your current provider to 
manage depression.
You should discuss your alternatives to participating in this research with the study doctor or 
study staff. In addition, you may discuss your options with your regular health care provider.
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What are the costs?
Participation in this study will be at no cost to you. 
Will I get paid?
You will be compensated up to $220 for your participation at different time points: $40 for the 
initial visit, $20 for the post infusion clinical visit, $40 after each MRI assessment (total of 2), $20 
for the 6 month visit, and $10 for each of the weekly follow-up visits (up to 6). There will be no 
reimbursement for the ketamine infusion visits. If you start, but do not finish the study, monetary 
compensation will be pro-rated according to each completed visit.
In addition to study payment, you will also be reimbursed for parking at the study center, up to a 
total of $126 for the entire study.
What will happen if there is a research-related injury?
In the event that this research activity results in an injury, treatment will be available, including 
first aid, emergency treatment and follow-up care as needed. Care for such injuries will be billed 
in the ordinary manner to you or your insurance company. If you think you have suffered a 
research related injury let the study doctor or study staff know right away.
You do not give up any of your legal rights by signing this form.
Be aware that your health care payer/insurer might not cover the costs of study-related injuries 
or illnesses.
Will medical information be kept private?
The records of this study will be kept private. In any publications or presentations, you will not 
be identified by name or other recognizable way on any records, results or publications relating 
to the study. Your medical records, as they relate to the research study, may be reviewed by the 
U.S. Food and Drug Administration, CMRR personnel, other regulatory authorities, and Quorum 
Review (a group of people who review research studies to protect the rights and welfare of 
research participants) to check trial data and procedures and ensure that the information is 
accurate. 
Any information obtained in connection with this study that can be identified with you will remain 
confidential and will be disclosed only with your permission.  However, mental health 
professionals are mandated reporters, which means that we are obliged to report alleged or 
probable abuse, as well as known abuse. If there are any concerns about maltreatment, they 
will be reported in accordance to the law. If you tell us that someone (including yourself) is in 
danger of serious harm, we may need to obtain outside assistance. 
Only researchers associated with this study and other authorized personnel will have access to 
the records; research records will be kept in a locked file. In any sort of report we might publish, 
we will not include any information that will make it possible to identify you. 
Your protected health information created or received for the purposes of this study is protected 
under the federal law known as HIPAA. This means that we must keep your medical information 
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private and confidential to the greatest extent possible. Your protected health information 
includes contact information or any identifying information. You will be asked to review and sign 
a separate HIPAA authorization form concerning the use of this information. 
To these extents, confidentiality is not absolute.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
Incidental Findings
The images or pictures created during this study are for research purposes only and are not 
intended to provide health care to you. However, if the results from the magnetic resonance 
imaging show something unusual in the pictures, a Radiologist trained in reading the pictures 
will look at them. The Radiologist would not receive any personal information except your age 
and pertinent medical history collected as part of the research. There will be no charge to you 
for having the Radiologist look at your pictures. The investigator in charge of this study will 
contact you if the recommendation of the Radiologist is to further investigate the unusual results 
of the pictures with your own physician. However, further medical follow up is not a part of this 
study and the study does not have funds set aside for this purpose. Therefore, if the results do 
show something unusual, any medical follow up cost will be your responsibility and/or the 
responsibility of your health insurance carrier.
What are your rights as a research subject?
Your decision to take part in this study is voluntary.  You have the right to decide not to 
participate.  Should you agree to participate in this research, you may change your mind at any 
time and withdraw yourself from the study. A decision not to participate will not harm your 
relationship with the study doctors and the study staff, nor will it affect your regular treatment in 
any way. Deciding not to be in this study or changing your mind later will not result in any 
penalty to you, and you won't lose any benefits except for benefits having to do with the study.
The study doctor may withdraw you from the study without your consent at any time if: he or she 
believes it is in your best interest (for example, if your condition is worsening, and a treatment 
option outside of the study is available that would be better for you); you significantly fail to 
follow study directions and procedures; or if there are unexpected or serious side effects.
If you stop being in the study early, the study doctor or study staff may ask you some questions 
about being in the study.  The study doctor or study staff may ask you to participate in some 
procedures or tests to help you leave the study safely and/or to collect more information for the 
study.  If you leave the study, the study doctor and study staff will still be able to use your 
information that they have already collected.
What if new information becomes available about the study?
The study doctors will notify you if there are new findings that might affect your willingness to 
continue to be in the study, or that could affect your health either during or after the study.
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Who can you call if you have questions about the study? 
In the event of an emergency, dial 911 immediately.
If you require emergency care, be sure to tell the emergency care provider about your 
participation in this study.  Contact the study doctor or study staff as soon as possible.
You can ask questions about the study at any time.  You can call the study doctor or study staff 
at any time if you have any concerns or complaints.  You should call the study doctor or study 
staff at the phone number listed on page 1 of this form if you have questions about the study 
procedures, study costs (if any), study payment (if any), or if you get hurt or sick during the 
study.
Quorum Review reviewed this study.  Quorum Review is a group of people who review research 
studies to protect the rights and welfare of research participants.  Review by Quorum Review 
does not mean that the study is without risks.  If you have questions about your rights as a 
research participant, if you are not able to resolve your concerns with the study doctor or study 
staff, if you have a complaint, or if you have general questions about what it means to be in a 
research study, you can call Quorum Review or visit the Quorum Review website at 
www.quorumreview.com.
Quorum Review is located in Seattle, Washington.
Office hours are 8:00 AM to 5:00 PM Pacific Time, Monday through Friday.
Ask to speak with a Research Participant Liaison at 888-776-9115 (toll free).
You will be given a signed copy of this form to keep for your records.
Permission to Videotape
We are asking your permission to videotape certain portions of the study during visits and 
ketamine infusions. You do not have to let the study doctor or study staff videotape you if you 
don't want to. You can still be in the study if you do not want to be videotaped. You can ask the 
study doctor or study staff questions about it before you decide if you want to let them videotape 
you.
If you agree to be videotaped, the videotape will be used by individuals directly involved in the 
study for research purposes in order to ensure the reliability of the diagnoses and assessments.
Videotapes may also be presented to individuals such as medical students and residents for 
educational purposes. (We will not provide your name.)
The videotapes will show your whole body. It is possible that people who see the videotapes will 
recognize you.
If you change your mind later, tell the study doctor or study staff.  Be aware that any videotape 
taken before you changed your mind may still be used and shared as described in this form.
You will indicate your choice about being videotaped at the end of this form.
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Permission to Share Data Outside the Study
The data that you provide is valuable and could be useful for other studies of adolescent health 
problems. When individuals provide consent to be in a research study, they are consenting for 
their information to be used only for the purpose of that study. The data cannot be combined 
with data from other studies. Investigators who focus on clinical samples do not always have 
easy access to comparison groups. Therefore, we request your consent to use your data in the 
context of other studies where Dr. Cullen is a co-investigator. We need to know if this is okay 
with you. If you agree to have your data shared across studies, your data will be grouped with 
that of other study participants for comparison with groups from other studies (for example, 
other groups of people with depression or other conditions, other healthy groups, groups of 
different ages). Data to be shared may include results from any of the tests that are described 
above in the study procedures. We will not share your name, address, or other contact 
information. 
You will indicate your choice regarding data sharing at the end of this form.
Permission for Future Re-Contact
The study team wants to know if you will allow the members of the study team to contact you in 
the future to request information about your progress, and possibly to request further 
participation in an expanded portion of this study. Allowing the study team to contact you again 
does not obligate you to join any study or take part in any activities. If you do not want to allow 
this contact, you can still be in the study. If you agree now, you can change your mind at any 
time.
You will indicate your choice regarding future re-contact at the end of this form.
Statement of Consent
I have read the above information.  I have asked questions and have received answers.  I 
voluntarily consent to participate in the study.
By signing this form, I do not give up any of my legal rights.  I will get a signed copy of this 
consent form.
Permission to Videotape: Please initial one line regarding videotaping of study visits as 
described above:
_____ I agree to allow portions of the visits to be videotaped for research purposes.
_____ I do not agree to be videotaped. I can still be in the study.
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Permission for Data-Sharing: Please initial one line regarding data-sharing as described 
above.
_____ I agree to have my data shared with other studies where Dr. Cullen is a co-investigator.  I 
may withdraw this consent to share data at any time in the future by contacting Dr. 
Cullen at (612)-273-9711.
_____ I do not agree to have my data shared with other studies. I can still be in the study.
Permission for Future Re-Contact: Please initial one line regarding your choice to be 
contacted in the future as described above.
_____ I agree to be re-contacted.
_____ I do not agree to be re-contacted. I can still be in the study.
Printed Name of Participant
Signature of Participant
Date
I attest that the individual providing consent had enough time to consider this information, had 
an opportunity to ask questions, and voluntarily agreed to participation in this study.
Printed Name of Person Explaining Consent
Signature of Person Explaining Consent
Date
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