Clinical trial NCT04091971
Conditions: Major Depressive Disorder
Sponsor: New York State Psychiatric Institute
Start date: 2020-10-09; Completion date: 2022-05-01
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Depression is the leading cause of disability globally (1, 2). One-third to one-half of patients suffering from major depressive disorder (MDD) do not achieve remission even after multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic medication that at subanesthetic doses leads to rapid antidepressant and anti-suicidal ideation effects in hours, rather than weeks, following administration. Despite these promising findings, a key limitation of ketamine treatment is that it only yields an antidepressant response in approximately 50% of those treated. The goal of this project is to A) elucidate ketamine's mechanism of action and B) identify biomarkers predicting treatment outcome to ketamine which could be used to match patients to treatment based on the likelihood of effectiveness at the individual level. Data from animal models suggests that ketamine acts by enhancing the connections between neurons through a process known as synaptic plasticity (4-7), and that these biological changes are responsible for the sustained behavioral effects of ketamine (8). A newly available tool allows us to image the density of these synaptic connections in the living brain using PET (positron emission tomography) imaging with a radiotracer called \[11C\]UCB-J, which is a marker of synaptic density. We propose to directly quantify synaptic density in depressed patients before and after a course of ketamine, to examine changes in density following treatment. In exploratory analyses, we will examine synaptic density as a mediator of the sustained antidepressant effects of ketamine and as a predictor of treatment outcome. To study these questions, we will quantify synaptic density using PET imaging before and after a course of 4 sequential intravenous infusions of ketamine administered over a two week period. Study participation involves an inpatient stay of approximately three weeks at the New York State Psychiatric Institute at no cost.

Detailed description:
Depression is the leading cause of disability globally (1, 2). One-third to one-half of patients suffering from major depressive disorder (MDD) do not achieve remission even after multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic and non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. Recent randomized trials demonstrate that subanesthetic doses of ketamine lead to rapid antidepressant and antisuicidal ideation effects in individuals with MDD and bipolar depression (reviewed in (9)). In contrast to current FDA-approved antidepressants, ketamine exerts antidepressant effects in hours, rather than weeks, following administration. Despite these promising findings, a key limitation of ketamine treatment is that it only yields an antidepressant response in approximately 50% of those treated. In addition, ketamine's clinical utility is limited by its acute dissociative side effects, a one to two-week duration of action as monotherapy, its addictive potential, and long term safety concerns related to cognition and interstitial cystitis (9-11). Given the profound benefit of ketamine for some individuals yet these key limitations, developing a precision medicine research strategy for ketamine's antidepressant effects could be of tremendous scientific and clinical benefit, in order to A) elucidate ketamine's mechanism of action, to advance the development of safer alternative agents and B) identify biomarkers predicting treatment outcome to ketamine, which could be used to match patients to treatment based on the likelihood of effectiveness at the individual level.

There is evidence of brain atrophy in depression: gray matter volume is reduced in the prefrontal cortex (PFC) and in the hippocampus (HC) in depressed individuals (12). Postmortem studies in depression show low expression of several genes related to synaptic function and decreased synapse number in the dorsolateral PFC (13). Chronic stress, a risk factor for depression, precipitates neuronal atrophy and dendritic spine loss in HC and PFC (14, 15). Preclinical work in rodents suggests that ketamine may exert antidepressant effects by reversing neuronal atrophy, specifically through the formation of new dendritic spine synapses in the brain. In rodents, ketamine induces rapid synaptogenesis via stimulation of mechanistic target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF), leading to a reversal of chronic, stress-induced neuronal atrophy (4-7).

A recently developed research tool enables examination of synaptic density in vivo in humans. \[11C\]UCB-J is a PET radiotracer that is specific for synaptic vesicle glycoprotein 2A (SV2A) (16, 17), providing a quantitative measure of synaptic density in vivo in the brain in humans. A recent PET imaging pilot study identified low \[11C\]UCB-J binding in the PFC of individuals with current MDD as compared to healthy volunteers, providing early evidence that this synaptic density biomarker may quantify a disease-relevant process in depression (18). Furthermore, PET imaging with \[11C\]UCB-J displays outstanding test-retest reliability, with absolute test-retest variability of only 4-5% in brain regions of interest in this study (19), making it an outstanding tool for longitudinal studies of the effects of treatment interventions. We therefore propose to directly quantify synaptic density in depressed patients to investigate whether it is increased by treatment with ketamine in a regionally-specific manner. Moreover, we will examine synaptic density as a mediator of the sustained antidepressant effects of ketamine and as a predictor of treatment outcome. We will quantify synaptic density using PET imaging before and after a course of 4 sequential intravenous infusions of ketamine administered over a two-week period. Study participation involves an inpatient stay of approximately three weeks at the New York State Psychiatric Institute at no cost.

Arms: arm 1: Subjects will undergo 4 sequential intravenous infusions of ketamine administered over a two week period.
Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: Subjects will undergo 4 sequential intravenous infusions of ketamine administered over a two week period.

Ketamine is administered at a dose of 0.5mg/kg intravenously as a slow continuous infusion over approximately 40 minutes, with 4 sequential infusions over an approximately two week period (two infusions per week for two weeks).

Protocol documents:
Prot_SAP_003.pdf: 
Cover Sheet 
 
Protocol Name: Ketamine Treatment Eﬀects on Synap7c Plas7city in Depression 
 
Protocol NCT Number: NCT04091971 
 
Date: September 15, 2022 


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Miller, Jeffrey
Page 1 of 41
Protocol Title:
Examining the effects of ketamine 
treatment on synaptic plasticity in 
depression using PET imaging
Protocol Number:
7847
First Approval:
12/31/2019
Expiration Date:
09/22/2022
Version Date:
09/15/2022
Research Area:  
Molecular Imaging & Neuropathology
Division:  
Molecular Imaging and Neuropathology
Contact Principal Investigator:
Jeffrey Miller, MD
Email: jm2233@columbia.edu
Telephone: 646-774-7613
Co-Investigator(s):
Michael Grunebaum, MD
j john mann
Research Chief:
J John Mann, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am submitting an annual continuation without modifications 
Department & Unaffiliated Personnel
Department
What Department does the PI belong to?
MIND
Within the department, what Center or group are you affiliated with, if any? 
N/A
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New 
York State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.
N/A


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Miller, Jeffrey
Page 4 of 41
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Arterial Line
   Collection of Biological Specimens
   Internet-based Data Collection or Transmission
   Medication Trial
   MRI
   Neuropsychological Evaluation
   Off-label Use of Drug or Device
   PET/SPECT Scan
   Psychiatric Assessment
   Use of Investigational Drug or Device
Population
Indicate which of the following populations will be included in this research
   Adults
   Adults over 50
   Inpatients
Research Support/Funding
Will an existing internal account be used to support the project?
No
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
Funding Source #1
Is the PI of the grant/contract the same as the PI of the IRB protocol? 
Yes


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Miller, Jeffrey
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Select one of the following
The grant/contract is currently funded
Source of Funding
Foundation
Sponsor
Diane Goldberg Foundation
Select one of the following
Single Site
Business Office
CU
Does the grant/contract involve a subcontract?
No
Study Location
Indicate if the research is/will be conducted at any of the following
NYSPI
Other Columbia University Medical Center Facilities
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research
Lay Summary of Proposed Research
Depression is the leading cause of disability globally (1, 2). One-third to one-half of patients
suffering from major depressive disorder (MDD) do not achieve remission even after multiple
antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic medication that
at subanesthetic doses leads to rapid antidepressant and anti-suicidal ideation effects in hours,
rather than weeks, following administration. Despite these promising findings, a key limitation of
ketamine treatment is that it only yields an antidepressant response in approximately 50% of
those treated. The goal of this project is to A) elucidate ketamine’s mechanism of action and B)
identify biomarkers predicting treatment outcome to ketamine which could be used to match
patients to treatment based on the likelihood of effectiveness at the individual level. Data from
animal models suggests that ketamine acts by enhancing the connections between neurons
through a process known as synaptic plasticity (4-7), and that these biological changes are
responsible for the sustained behavioral effects of ketamine (8). A newly available tool allows us
to image the density of these synaptic connections in the living brain using PET imaging with a
radiotracer called [11C]UCB-J, which is a marker of synaptic density. We propose to directly
quantify synaptic density in depressed patients before and after a course of ketamine, to examine
changes in density following treatment. In exploratory analyses, we will examine synaptic density
as a mediator of the sustained antidepressant effects of ketamine and as a predictor of treatment


Protocol Summary Form
7847
Miller, Jeffrey
Page 6 of 41
outcome.   To study these questions, we will quantify synaptic density using PET imaging before 
and after a course of 4 sequential intravenous infusions of ketamine administered over a two-
week period.
   As a further enhancement to the specific goals of this project (A: elucidate ketamine’s 
mechanism of action; B: identify biomarkers predicting treatment outcome to ketamine), we 
propose to add non-invasive and cost-effective neurophysiological measures to the study protocol. 
Electroencephalogram (EEG) will be obtained at baseline and after ketamine treatment during two 
standard paradigms (at rest with eyes open/closed, loudness-dependent auditory evoked 
potentials [LDAEP]) that have shown 1) predictive utility for antidepressant treatment response 
and 2) sensitivity to ketamine administration.
Background, Significance and Rationale
Background, Significance and Rationale
            Depression is the leading cause of disability globally (1, 2). One-third to one-half of 
patients suffering from major depressive disorder (MDD) do not achieve remission even after 
multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic and 
non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. Recent 
randomized trials demonstrate that subanesthetic doses of ketamine lead to rapid antidepressant 
and anti-suicidal ideation effects in individuals with MDD and bipolar depression (reviewed in (9)). 
In contrast to current FDA-approved antidepressants, ketamine exerts antidepressant effects in 
hours, rather than weeks, following administration. Despite these promising findings, a key 
limitation of ketamine treatment is that it only yields an antidepressant response in approximately 
50% of those treated. In addition, ketamine’s clinical utility is limited by its acute dissociative side 
effects, a one to two-week duration of action as monotherapy, its addictive potential, and long-
term safety concerns related to cognition and interstitial cystitis (9-11). Given the profound benefit 
of ketamine for some individuals yet these key limitations, developing a precision medicine 
research strategy for ketamine’s antidepressant effects could be of tremendous scientific and 
clinical benefit, in order to A) elucidate ketamine’s mechanism of action, to advance the 
development of safer alternative agents and B) identify biomarkers predicting treatment outcome 
to ketamine, which could be used to match patients to treatment based on the likelihood of 
effectiveness at the individual level.
            There is evidence of brain atrophy in depression: gray matter volume is reduced in the 
prefrontal cortex (PFC) and in the hippocampus (HC) in depressed individuals (12). Postmortem 
studies in depression show low expression of several genes related to synaptic function and 
decreased synapse number in the dorsolateral PFC (13). Chronic stress, a risk factor for 
depression, precipitates neuronal atrophy and dendritic spine loss in HC and PFC (14, 15). Pre-
clinical work in rodents suggests that ketamine may exert antidepressant effects by reversing 
neuronal atrophy, specifically through the formation of new dendritic spine synapses in the brain. 
In rodents, ketamine induces rapid synaptogenesis via stimulation of mechanistic target of 
rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF), leading to a reversal of chronic, 
stress-induced neuronal atrophy (4-7).


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Miller, Jeffrey
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            A recently developed research tool enables examination of synaptic density in vivo in 
humans. [11C]UCB-J is a PET radiotracer that is specific for synaptic vesicle glycoprotein 2A 
(SV2A) (16, 17), providing a quantitative measure of synaptic density in vivo in the brain in 
humans.  A recent PET imaging pilot study identified low [11C]UCB-J binding in the PFC of 
individuals with current MDD as compared to healthy volunteers, providing early evidence that this 
synaptic density biomarker may quantify a disease-relevant process in depression (18). 
Furthermore, PET imaging with [11C]UCB-J displays outstanding test-retest reliability, with 
absolute test-retest variability of only 4-5% in brain regions of interest in this study (19), making it 
an outstanding tool for longitudinal studies of the effects of treatment interventions. We therefore 
propose to directly quantify synaptic density in depressed patients to investigate whether it is 
increased by treatment with ketamine in a regionally-specific manner.  Moreover, we will examine 
synaptic density as a mediator of the sustained antidepressant effects of ketamine and as a 
predictor of treatment outcome.   We will quantify synaptic density using PET imaging before and 
after a course of 4 sequential intravenous infusions of ketamine administered over a two-week 
period.
            Two oscillatory measures derived from resting EEG, midfrontal (anterior cingulate) theta 
and posterior (occipital-parietal) alpha, have been identified as putative EEG biomarkers of 
treatment outcome in depression (e.g., Pizzagalli et al., 2001, 2018; Smith et al., 2019; Tenke et 
al., 2011). Studies of ketamine in healthy participants and MDD patients also highlight the 
important role of these frontal and posterior regions. For example, ketamine administration in 
healthy participants increased activation in frontal brain regions (ACC, dlPFC, mPFC), including 
specific increases in ventral ACC theta activity and decreases at posterior regions (PCC, TPJ; 
McMillan et al., 2019; Mueller et al., 2019; see Curic et al., 2019). Studies of post-ketamine effects 
in MDD patients showed increases and normalization of dorsal-frontal PFC activity (Abdallah et 
al., 2017; Ionescu et al., 2019) and decreases of hyperactive bottom-up salience-related regions 
such as rACC and INS (Reed et al., 2019). Further, resting EEG studies of ketamine showed 
decreases in dominant (posterior-parietal) alpha oscillations and increases of slower (theta) and 
faster (gamma) oscillations, that is, increased frontal theta, decreased parietal-occipital alpha and 
global beta, and increases in global gamma (McMillan et al., 2019; Muthukumaraswamy et al., 
2015; Vlisides et al., 2018; Zacharias et al., 2019). 
            Data from animal models suggest that the LDAEP slope of the auditory N1/P2 amplitude 
(monotonic increase with increasing intensity) is indicative of serotonergic function (e.g., Hegerl et 
al., 1994, 2001), and several LDAEP studies reported a differential prediction of clinical response 
to serotonergic versus noradrenegric and placebo treatment (Gallinat et al., 2000; Lee et al., 2015; 
Mulert et al., 2002; Paige et al., 1994, 1995). Moreover, NMDA receptor blockade in monkeys 
blunted the LDAEP response, suggesting that the NMDA antagonist ketamine will likewise result 
in a blunted LDAEP response (i.e., shallower slope; Teichert, 2017). Use of the LDAEP in this 
project will increase knowledge regarding ERP studies of ketamine in humans, which revealed a 
general pattern of reduced cognitive ERPs (N2, P2, P3, MMN) but equivocal findings regarding 
ketamine-related increases and decreases in sensory ERPs (P50, P1, N1; Rosburg et al., 2016; 
Rosch et al., 2019; Schwertner et al., 2018).
            Brain connectivity studies related to ketamine in healthy humans showed decreased 
functional connectivity (FC) across frontal, parietal, insular, and occipital cortices, including 
decreased within-occipital alpha FC, and increases in delta and theta frontal-occipital FC as well 


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Miller, Jeffrey
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as low beta FC between frontal and precuneus/insula regions (Forsyth et al., 2019). After 
ketamine, MDD patients show decreased dlPFC-ACC connectivity as well as increased within-
frontal, PFC-PCC and DMN-Salience connectivity (Abdallah et al., 2017; Evans et al., 2018; 
Fleming et al., 2019). Related work with healthy humans during ketamine showed decreased FC 
across frontal, parietal, insular, and occipital cortices, including decreased within-occipital alpha 
FC, and increases in delta and theta frontal-occipital FC as well as low beta FC between frontal 
and precuneus/insula regions (Forsyth et al., 2019). Studies examining predictors of ketamine 
treatment response in MDD suggested that baseline and event-related lPFC-sgACC connectivity 
(Gartner et al., 2019), higher rostral ACC response to fearful faces (Salvadore et al., 2009) and 
higher post-ketamine gamma power was associated with better antidepressant treatment 
response in MDD subjects with lower baseline gamma (Nugent et al., 2019).
            Obtaining these EEG and ERP data will allow us to link relevant metrics to treatment 
response as well as to synaptic density. Specifically, changes in synaptic density should impact on 
functional connections between cortical regions (neuronal dynamics) and LDAEP component 
topographies (scalp or sensor-level radial current flow estimates; Tenke & Kayser, 2012) and 
tomographies (distributed inverses; Pascual-Marqui et al., 1994).
 
Specific Aims and Hypotheses
Specific Aims and Hypotheses
AIM 1: Quantify changes in regional synaptic density in response to intravenous ketamine. We 
hypothesize that administration of ketamine in individuals with MDD will induce new spine 
synapse formation and synaptic protein synthesis, reflected by increased synaptic density in 
mPFC and HC as quantified by changes in VT derived from PET imaging with [11C]UCB-J 
performed prior to and approximately 24 hours following a course of four ketamine infusions.
 
AIM 2: Evaluate the relationship between sustained improvement in depressive symptoms in 
response to intravenous ketamine and change in 11C-UCB-J binding. We hypothesize that the 
magnitude of the change in 11C-UCB-J VT in mPFC and HC in response to intravenous ketamine 
administration will correlate with clinical improvement on the Hamilton Depression Rating Scale 
from baseline to one week following the final ketamine infusion.
 
AIM 3: Examine whether baseline synaptic density in MDD-relevant brain regions as measured by 
PET imaging with [11C]UCB-J predicts the magnitude of sustained antidepressant effects of 
intravenous ketamine treatment. Hypothesis: lower pre-treatment [11C]UCB-J binding (VT) in 
mPFC and HC will predict greater improvement in depressive symptoms assessed one week 
following final ketamine infusion as assessed by the Hamilton Depression Rating Scale.  This aim 


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is based on the assumption that individuals with MDD who have particular deficits in this biological 
measure (regionally-specific synaptic density) will benefit most from an intervention that acts to 
restore such deficits.
 
 
AIM 4: Examine whether baseline EEG measures (midfrontal theta, posterior alpha, LDAEP slope) 
predict the magnitude of sustained antidepressant effects of intravenous ketamine treatment. 
Hypothesis: Greater rostral anterior cingulate cortex (rACC) theta, as identified via low resolution 
brain electromagnetic tomography (LORETA; e.g., Pizzagalli et al., 2001, 2018), greater posterior 
alpha as identified via scalp current source density (CSD; surface Laplacian) and frequency 
principal component analysis (fPCA; e.g., Tenke et al., 2011), and greater LDAEP will predict 
greater improvement in depressive symptoms assessed via the Hamilton Depression Rating Scale 
one week following final ketamine infusion. This aim is based on prior findings showing moderate 
predictive validity of these putative EEG biomarkers of treatment outcomes in depression (e.g., 
Pizzagalli et al., 2018; Tenke et al., 2011).
 
AIM 5: Examine whether pre/post ketamine treatment changes of EEG measures (midfrontal 
theta, posterior alpha, LDAEP slope) predict the magnitude of sustained antidepressant effects of 
intravenous ketamine treatment, and whether these changes are related to changes in synaptic 
density. Hypothesis: Ketamine treatment will reduce ERP amplitudes in general and LDAEP slope 
in particular; the extent of this reduction will be correlated with both reduction in depressive 
symptoms and increases in synaptic density. This aim is based on findings showing blunted 
LDAEP response after NMDA blockade (Teichart, 2017), which may be directly related to 
ketamine’s mechanism of action resulting in its antidepressant effects. 
 
Description of Subject Population
Sample #1
Specify subject population
Depressed adults with current MDD
Number of completers required to accomplish study aims
20
Projected number of subjects who will be enrolled to obtain required number of completers
40
Age range of subject population
18-55


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Gender, Racial and Ethnic Breakdown
Based on historical recruitment of depressed patients for research studies in our division, we 
expect the following gender and ethnic breakdown: Male (40%); Female (60%); White (67%); 
Black (24%); Hispanic (16%); Asian (9%).
Description of subject population
We will recruit unipolar depressed patients in a current major depressive episode.  We will attempt 
to recruit individuals who are unmedicated in the current episode, although this will not be required 
for study participation. Based on studies in our clinic, subjects come from the 5 boroughs of New 
York City and the nearby tri-state suburbs. 
Recruitment Procedures
Describe settings where recruitment will occur
Patients are recruited through advertisements and web-based recruitment tools, including 
Columbia's research study search engine, RecruitMe, clinician referrals, and the hospital inpatient 
and emergency services. These include the New York Presbyterian Hospital emergency room, 
referrals for inpatient and outpatient treatments from the community, a large network of referring 
doctors, the ECT service, the extensive outpatient depression clinics at NYSPI (e.g., Depression 
Evaluation Service and the Late Life Depression Center) and medical services.
How and by whom will subjects be approached and/or recruited? 
Subjects will complete a preliminary phone screening with a research coordinator under the 
Screening Protocol (PI IRB #6879R) to determine whether most inclusion/exclusion criteria 
(excluding medical screening) are met. For individuals in the emergency room or on an inpatient 
unit, this screening may be done in person by study staff, after permission is first obtained by a 
treating clinician not affiliated with the study to speak with our staff about possible research 
participation. If participants are screened and recruited through the Emergency Room, a treating 
clinician will give permission for the patient to be approached, and additionally, the treating 
clinician will ask the patient if they are open to speaking with research staff before screening by 
research staff occurs.
How will the study be advertised/publicized? 
Through local media, internet, mailings to clinicians, outreach to NYPH/NYSPI clinicians and other 
local emergency departments and clinical facilities.
Do you have ads/recruitment material requiring review at this time? 
Yes
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number


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04091971
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Participants will be screened through our division’s screening protocol:
IRB # 6879R: Molecular Imaging and Neuropathology Clinic Studies Initial Evaluation (PI: 
Elizabeth Sublette; formerly #5880R)
 
Participants will co-enroll in our division’s umbrella protocol:
IRB #4815: Biological and neurocognitive measures for genetic studies of psychiatric populations 
(PI: Elizabeth Sublette)
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Depressed adults with current MDD
Create or insert table to describe the inclusion criteria and methods to ascertain them
Inclusion
Method of Ascertainment
1. Unipolar, major depressive episode (MDE), 
with 17-item Hamilton Depression Rating 
Scale score ≥16. Patients may be psychiatric 
medication- free, or if currently taking 
psychiatric medication, not responding 
adequately as evidenced by current MDE.
1. DSM-5 criteria by SCID-5 administered by 
trained assessors; Medication history; Clinical 
evaluation; Hamilton Depression Rating Scale
 
2. 18-55 years old 
2. Interview
3. Female patients of child-bearing potential 
must be willing to use an acceptable form of 
birth control during study participation such as 
condoms, diaphragm, oral contraceptive pills. 
3. Interview
4. Must be enrolled in IRB #4815 (PI: 
Sublette) 
4. Interview
5. Able to provide informed consent
5. Interview.  For individuals who are initially 


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recruited as inpatients, an inpatient 
psychiatrist unaffiliated with the study will 
provide independent assessment of capacity.
6. Agrees to voluntary admission to an 
inpatient research unit at NYSPI for baseline 
PET/MR imaging, ketamine infusion, and 
repeat PET imaging
6. Interview
Create or insert table to describe the exclusion criteria and methods to ascertain them
EXCLUSION
METHOD OF ASCERTAINMENT
1. Unstable medical or neurological illness 
including: A) baseline hypertension 
(BP>140/90); B) significant history of 
cardiovascular illness; C) Platelet count < 
80,000 cells/uL; and D) Hemoglobin < 11 g/dL 
for females and < 12 g/dL for males
1. Medical history, laboratory testing, all 
through IRB #4815
2. Significant ECG abnormality (e.g., 
Ventricular tachycardia, evidence of 
myocardial ischemia, symptomatic 
bradycardia, unstable tachycardia, second 
degree (or greater) AV block). 
2. Baseline ECG
3. Pregnancy, currently lactating, or planning 
to conceive during the course of study 
participation.
3. History, baseline serum pregnancy test. 
Urine pregnancy tests will be repeated on the 
days of each MRI and PET scan, as well as 
one- to two-weeks after the second PET scan.
4. Diagnosis of bipolar disorder or current 
psychotic symptoms. 
4. Clinical assessment and baseline SCID-5
5. Current or past ketamine use disorder 
(lifetime); any drug or alcohol use 
disorder within past 6 months
5. Clinical assessment, SCID, urine drug 
screen. 
6. Inadequate understanding of English. 
6. Interview
7. Prior ineffective trial of or adverse reaction 
to ketamine.
7. Interview
8. A neurological disease or prior head trauma 
with evidence of cognitive impairment. 
Subjects who endorse a history of prior head 
trauma and score ≥ 1.5 standard deviations 
below the mean on the Trailmaking A&B will 
be excluded from study participation.
8. Clinical interview and medical history,
Trailmaking A & B as needed.
9. Metal implants or paramagnetic objects 
contained within the body (including heart 
pacemaker, shrapnel, or surgical prostheses) 
which may present a risk to the subject or 
9. Interview, MRI safety screening forms


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interfere with the MRI scan, according to the 
guidelines set forth in the following reference 
book commonly used by neuroradiologists: 
“Guide to MR procedures and metallic 
objects,” F.G. Shellock, Lippincott Williams 
and Wilkins NY 2001. Additionally transdermal 
patches will be removed during the MR study 
at the discretion of the investigator.
10. Current, past, or anticipated exposure to 
radiation, that may include: **
-being badged for radiation exposure in the 
workplace
-participation in nuclear medicine research 
protocols in the last year
10. Subjects will undergo a clinical interview 
during which they will be asked whether or not 
they have worked with radioactive substances 
or have been badged in the past. In addition, 
they are asked about any prior chemotherapy 
or radiation treatment and past research study 
participation involving radiation exposure.
11. Claustrophobia significant enough to 
interfere with MRI scanning 
11. Interview
12. Weight that exceeds 325 lbs or inability to 
fit into MRI scanner 
12. Weight and maximal body circumference 
(if necessary) as part of physical exam; visit to 
the MRI suite if necessary *** 
13. Individuals taking prescribed opioid 
medication, using opioids recreationally, or 
taking naltrexone at the time of enrollment
13. Interview 
 14. Daily use of: benzodiazepine, zolpidem 
(Ambien), zeleplon (Sonata), or eszopiclone 
(Lunesta) for ≥2 weeks at time of consent
 14. Interview
 15. Hearing loss (> 30 dB HL) or an ear 
asymmetry (> 10 dB)
 15. Determined using standard audiometric 
measures at 500, 1000, and 2000 Hz 
(audiogram)
** In case of previous exposure to radioactivity due to research studies, subjects will be eligible if 
all conditions listed below are fulfilled: 
1) For any research studies performed in the past year, the injected dose and dosimetry of the 
radiotracer are known; 
2) Except for research studies, the subject has no lifetime exposure to radiation in the workplace 
or in nuclear medicine procedures;
3) Adding the previous exposure to the expected exposure due to the current study will result in a 
yearly cumulative exposure lower than the limit defined by 21 CFR part 361.1 for research 
subjects (5 Rems for whole body, active blood-forming organs, lens of the eye, and gonads; 15 
Rems for other organs). 
*** In cases where there is a question about whether a participant's dimensions are compatible 
with the MRI scanner, a subject's circumference may be measured to determine if the subject's 
circumference is less than the MRI scanner limit, 200cm. The subject also may be brought to the 


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MRI center so that the MRI technologist can assess whether or not the subject will fit safely inside 
the MRI scanner. Metal screening and urine pregnancy testing will be done before this brief visit. 
Subjects who cannot safely enter the scanner will not be eligible to participate in the study. 
 
Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
No
Waiver of parental consent 
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB # 
6879R and 4815
Describe Study Consent Procedures
1. Possible participants will complete an initial phone screen with a research coordinator after 
providing verbal consent, through screening protocol #6879R.
2. Potentially eligible participants are scheduled for an evaluation and consent session.  There, 
participants are given a detailed verbal explanation of screening procedures by a research staff 
member. Participants then give written informed consent for screening procedures (under 
screening protocol #6879R).
3. If eligible, based on #6879R screening, participants will be asked to sign the consent form for 
IRB protocol #4815 (Biological and Neuropsychological Measures for Genetic Studies of 
Psychiatric Populations—PI: Sublette). Participants will then be given laboratory (blood draw) 
and psychiatric examinations, performed under protocol #4815.
4. Participants will also be given a detailed verbal explanation of this study by a research MD and 
then will give written informed consent, if they choose to participate in the study. Subjects who are 


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unable to come to NYSPI for multiple visits will complete consenting via NYSPI-approved remote
platforms including Webex, Zoom, or telephone. The commonest reason is that they live too far
away and may fly in or take a train a long distance to participate in the study. We want to be as
sure as possible they are both eligible and willing to participate before they travel a long way to
come to our center.
5. A Note to File will be added to the participant's charts that documents screening and study
consent discussions, signed by the consenter and dated on the day of the consent discussions.
6. Consent discussions will include informing participants of the option to reschedule if travel does
not seem safe and/or the study team may offer alternative transportation, such as Uber or Lyft.
7. There will be a consent procedure note that includes that there was a discussion of risk related
to COVID-19 during travel.
All screening and consenting procedures will be done remotely over a HIPAA-compliant
videoconferencing software (Webex or Zoom) or telephone. We will document consent for remote
clinical or research procedures, the consent discussion process will include discussion of the
technology HIPAA-compliant platforms to be used and any concerns the patient may have, such
as access to a private space in which to take calls, or accessibility—access at home to adequate
devices, cell signal, or wifi.
We will use REDCap with e-signature function enabled to obtain electronic documentation of
consent.
Indicate which of the following are employed as a part of screening or main study consent procedures
Consent Form
Information Sheet
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Grunebaum, Michael, MD
Lan, Martin, MD
mann, j john
Miller, Jeffrey, MD
Sublette, M, MD
Type in the name(s) not found in the above list
Independent Assessment of Capacity
You have indicated that your study involves subjects who MAY LACK capacity to consent.
Does this study require an independent assessment of capacity?


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No
Study Procedures
Describe the procedures required for this study
I attest to follow the COVID-19 Safety Guidelines for Columbia Psychiatry and NYSPI Re-Entry 
outlined in the NYSPI Director’s June 1st memo, which include but are not limited to:
Infection Control/PPE – Guidelines
Research participants will only come on-site if absolutely necessary for study procedures.
No volunteers/externs on-site during Stage 1.
Clinical research teams will screen their participants for COVID symptoms (night before 
and day of onsite visit, documenting this in the chart), and escort them in and out of the 
building.
COVID/COVID-like symptoms in participants will be reported to the IRB via PRISM as an 
SAE.
All inpatient participants will be tested for COVID and will be determined negative for 
COVID prior to admission on 5 South. Testing will occur either in the ER, through an 
outside private laboratory or via NKI. In the latter two cases, nasal swabbing may be 
performed at NYSPI by trained staff and sent to these laboratories.  Alternatively, COVID 
testing may be performed via saliva sample.  COVID testing will be repeated upon 
admission to the inpatient unit, and within 48 hours of discharge.
 
 
Personnel and Responsibilities:
1.    Medical history: MIND physician (covered under IRB #4815)
2.    Psychiatric Interview: physician or psychologist (covered under IRB #4815)
3.    Semi-structured  interview:       physician,      psychologist  or        research interviewer 
(covered under IRB #4815)
4.    Columbia PET Center staff (Elizabeth Greenstein MD, Jongho Kim MD, Akiva Mintz MD PhD) 
will be responsible for all aspects of the PET scans including PET tracer production under an 
IND held by the principal investigator. 
5.    The NYSPI MR Center, or in some cases other Columbia site with MR scanners, will be 
responsible for the conduct of MRI scans in this protocol. A MIND physician, psychologist, or 
research coordinator will accompany study participants to the MRI scan.
6.    Administration of ketamine: MIND physician with current BLS training


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7.    A radiologist designated to read MRI research scans from CUMC Radiology will generate a 
clinical report on MRI scans
8.    Open outpatient clinical treatment will be provided by MIND physicians.
9.   The following people will be involved in EEG collection and analysis: 
 
        Jurgen Kayser (Co-I): EEG collection/analysis 
        Lidia Y.X. Wong, M.A: Lab manager/EEG RA
        Tarik Bel-Bahar, Ph.D: Research Scientist with broad EEG expertise 
 
Procedures
1. Screening
a. We will recruit inpatients or outpatients with MDD in a major depressive episode. Referrals 
generally come from physicians, clinics, the NYPH Emergency Department, and ads in media 
including the internet.
b. Participant completes phone screen, approved under IRB #6879R (which may be done in-
person if in the emergency room or on an inpatient unit). If participant appears eligible based on 
the phone screen, they will be scheduled for a more in-depth screening visit under Screening 
Protocol (IRB #6879R) to determine whether inclusion/exclusion criteria (excluding medical 
screening) are met. Screening will occur via NYSPI-approved remote platforms including Webex, 
Zoom, or telephone.
 
c. Secure video/phone interviews: Under the procedures described in protocols #4815 and 
#6879R, consent forms for this protocol will be sent to the subject to be reviewed with an 
approved consenter at the end of the eligibility screening. Subjects will be asked to print the form 
prior to their eligibility screening.
 
d.  Secure video/phone interviews: Following the interview conducted under #6879R, the 
consenter will review the consent form for this protocol that was emailed to the subject. Consent 
forms will be signed electronically by the participant and the consenter in RedCap.
 
e. Secure video/phone interviews: Following the procedures detailed in protocol #4815, if the 
consenter determines that the potential subject has suffered a serious head injury a trailmaking 
test (TMT) will be sent to the subject. Research staff will administer the test over secure video as 
described fully in protocol #4815. 
 
f. For in-person screening procedures (which may be used with patients in the emergency room or 
on an inpatient unit), participant is given a detailed, verbal explanation of this study and IRB #4815 
and given a copy of both consent forms.


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g. Participant gives written informed consent to participate in IRB #4815 and this study.
h. Participant receives medical evaluation under IRB #4815. Genetics blood sample is also 
acquired under IRB #4815 (Biological and neuropsychological measures for genetic studies of 
psychiatric populations—PI: Sublette). 
i. An electrocardiogram will be performed to evaluate any cardiovascular contraindications to 
research procedures. 
j. Final eligibility is determined when results of laboratory tests acquired through IRB #4815 are 
obtained.
k. During the period between enrollment and the infusion, the treating physician will
assess the patient weekly in by phone, through secure video, or in person if these options are not 
available, through a clinical interview and a Clinical Global Impression (CGI) scale. If concerns are 
noted during a telephone or secure video contact, participants may be brought in for an in-person 
visit. If a participant has a CGI-I >5 at any time, the treating psychiatrist will assess whether it is 
safe to continue research participation and will discuss with the participant the possibility of 
discontinuing research procedures and initiating open clinical treatment.
If after enrollment a subject refuses inpatient admission that is deemed clinically necessary by the 
research team they will be withdrawn from research.
2. Prior Psychiatric Medication
a. For insomnia or anxiety, PRN diphenhydramine, hydroxyzine, zolpidem, or a
benzodiazepine will be permitted. The goal will be the equivalent of a maximum daily dose of 
lorazepam ≤2mg during the week leading to the first infusion. However, no zolpidem, eszopiclone, 
zaleplon, or benzodiazepine will be permitted during the 72 hours pre-infusion and during the 72 
hours prior to PET imaging. Subjects who at enrollment are taking a higher equivalent 
benzodiazepine dose will be tapered and converted to lorazepam during the pre-infusion week. 
Subjects who show signs of benzodiazepine withdrawal or who cannot tolerate the 24-hours 
without zolpidem, eszopiclone, zaleplon, or benzodiazepine will be withdrawn from the protocol.
b. Current psychiatric medications other than benzodiazepines or the above sleep medications will 
be maintained at a stable dose until post-infusion treatment. Minor dose adjustments may be 
made pre-infusion, such as to reduce side effects.
3. Actively Suicidal Patients
a. Patients with imminent (next few days) suicidal plan or intent will only be enrolled if they agree 
to acute inpatient hospitalization. The independent treatment team on the inpatient research unit 
must agree that study participation is clinically reasonable.
b. For patients who require hospitalization because of destabilization or suicidal risk,
admission to a NYSPI unit will be available. Hospitalized patients will be discharged from the 


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hospital when stable as judged by the inpatient staff and the treating psychiatrist as not being in 
imminent risk of harm to self/other.
c. A research psychiatrist will be available by telephone 24 hours a day, seven days a week. 
Patients requiring urgent admission will be brought to the NewYork Presbyterian/Columbia 
University Irving Medical Center Emergency Room by the study physician with security 
assistance, if needed. Non-emergent admissions will be arranged by the treating psychiatrist, if 
possible to 5 South or 4 Center. Patients who are deemed to require hospitalization, but who 
refuse hospitalization, will receive all necessary interventions such as contacting the local crisis 
team, family, or Emergency Medical Services.
 
4. Inpatient Phase.
a. To participate in the study, patients must agree to inpatient hospitalization at NYSPI (4 Center 
or 5 South units) throughout the period in which the following procedures occur: baseline 
neuroimaging (MRI and PET), ketamine infusions, and post-ketamine imaging (PET). Our goal will 
be for the admission to be as short as possible, but in general we anticipate that it may be on the 
order of 21 days, or more if clinically indicated. Patients will be evaluated by a research physician 
and the inpatient unit’s independent clinical team and will be discharged when assessed, 
according to standard practice, as safe for outpatient treatment in the research clinic. Patients who 
need to be kept involuntarily for safety reasons will be withdrawn from research and treated 
clinically.
5. Pre-Infusion Research Measures
a. Baseline clinical and neuropsychological ratings (See Figure 1, attached); may be performed as 
inpatient or outpatient. 
b. Baseline MRI imaging will take place at the New York State Psychiatric Institute on a GE 
SIGNA Premier 3T MRI Scanner, generally on a day prior to ketamine infusion, although it may 
take place after the ketamine infusion if scheduling constraints make this preferable.  MR imaging 
will include T1-weighted structural MRI of the brain for coregistration to PET and identification of 
regions of interest.  Resting-state functional MRI and diffusion weighted imaging acquisitions may 
be performed if time allows. MRI scanning time will not exceed 30 minutes. Scanning at NYSPI 
will occur on the GE Signa Premier 3T MRI system. A urine pregnancy test will be performed on 
women of child-bearing potential on the day of the MRI scan. Inpatients will be accompanied to 
the MRI Center by a research staff member (coordinator, psychologist or psychiatrist) who will 
remain in the MRI Center throughout the scan and bring them back to the inpatient unit at the 
completion of the scan. 
c. Before the MRI occurs, participants will have the option of visiting the MRI suite and entering a 
mock MRI scanner. The mock scanner is identical in size to an MRI scanner but cannot take 
pictures of the brain. Trying out the mock MRI scanner simulation gives participants an idea of 
what the MRI scan will be like and may reduce their anxiety about the scan.


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d. Baseline PET imaging will be performed at the Columbia PET Center prior to the first ketamine 
infusion, within one week prior to the first ketamine infusion; this could include scanning on the 
day of ketamine infusion itself prior to the infusion. PET imaging will be performed at the Columbia 
PET Center. SV2A will be quantified via PET with [11C]UCB-J, synthesized as previously 
described (17). Radiotracer synthesis will occur in the radioligand laboratory at the Columbia PET 
Center.  Baseline PET scanning will occur within one week prior to ketamine infusion. After 
acquisition of a low dose CT scan for attenuation correction, [11C]UCB-J will be injected as an 
intravenous bolus (≤740mBq), and PET data acquired on a Siemens mCT Biograph over 90 
minutes. A urine pregnancy test will be performed on women of child-bearing potential on the day 
of each PET scan. 
e. Blood Analysis: A radial artery catheter will be placed prior to PET imaging for concurrent blood 
sampling to measure arterial input function and unmetabolized plasma fraction of [11C]UCB-J 
using high-performance liquid chromatography. The radial artery catheter will be placed by a 
physician after completion of the Allen test and infiltration of the skin with 1% lidocaine. If a 
participant has a known allergy to lidocaine, an alternative local anesthetic may be used. Blood 
samples will be drawn using a combination of automated and/or manual blood sampling during the 
course of the PET scan.  No more than 100 ml of blood will be drawn for this purpose at each of 
the two PET scans. In the event that a radial artery catheter cannot be placed, we may place a 
second intravenous catheter and perform venous blood sampling instead of arterial blood 
sampling. 
f. After the scan is over, the participant exits the camera, the arterial and venous lines are 
removed, and discharge from the PET Center will be contingent upon clearance by the clinical and 
research staff. A member of the research team will accompany the participant back to the 
inpatient unit.
g. In the event that the subject needs to leave the scanner while scanning (e.g. to use the 
bathroom) we will perform an additional low dose CT transmission scan.
 
6. Ketamine Infusions.
a. Four Ketamine infusions will be administered over a two-week period with infusions occurring 
approximately on alternating days (such as Tues-Thurs) on each of two weeks; small variations to 
this schedule are allowed if necessitated by scheduling constraints. 
b. Patients will eat no food for 12 hours and drink no liquids for 4 hours before each infusion.  
Patients will be escorted by study staff to and from the Biological Studies Unit (BSU) at NYSPI, 
where the infusions will occur. 
c. No zolpidem or benzodiazepine will be permitted in the 24 hours prior to each ketamine 
infusion. We will monitor patients for signs of withdrawal, such as severe anxiety, diaphoresis, 
tachycardia (HR greater than 100), or hypertension (BP greater than 150/95).


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d. We exclude hypertension at screening. However, patients may be anxious at the ketamine 
procedure, which can transiently raise BP. We will check subjects’ BP approximately 1 hour pre-
ketamine, and if elevated, will have the patient do relaxation exercises.  If these are ineffective, 
the patient will be given amlodipine 5mg po.  We will allow start of the infusion with BP of 150/95 
or less.
e. Intravenous catheter will be placed by staff at the BSU or by a MIND physician or nurse, 
including Jayamole Kannamkuzhiyil. 
f. Dose: Patients will receive an intravenous infusion of saline solution with ketamine hydrochloride 
(0.5 mg/kg; Abbott Laboratories, North Chicago, IL) over the course of approximately 40 minutes 
in the BSU of NYSPI, with a study physician present at the beginning of the infusion and 
available throughout.
g. Vital Signs Monitoring: During study infusion(s), blood pressure, heart rate, and oxygen 
saturation will be monitored as follows:
i. -5 minutes
ii. 0 (start of infusion)
iii. Post start of infusion: 5, 10, 15, 20, 25, 30, 35, and 40 minutes (end of infusion)
iv. Post end of infusion: Blood pressure will continue to be obtained until there are two 
measurements at least 15 minutes apart that are within 10 mmHg of the baseline diastolic blood 
pressure or diastolic blood pressure is below 85. Oxygen saturation will continue to be obtained 
until there are two measurements at least 15 minutes apart that are within normal limits (02 
saturation of 94% or greater).
h. The research assistant will remain outside the patients room during the infusion, and will 
record vital signs. A study physician will be available at all times. After the subject is 
transferred back to their inpatient unit room, the blood pressure and heart rate will be obtained 
manually by the unit nursing staff.
i. Intervention for Hypertension: If the systolic blood pressure increases to ≥ 200 or diastolic blood 
pressure increases to ≥115 mmHg during the ketamine infusion, the infusion will be discontinued. 
The blood pressure will be monitored and if there is no decrease after 15 minutes, then we will 
initiate the following treatment interventions, consistent with our previous IRB-approved ketamine 
studies including IRB #6598:
1) One dose of sublingual nitroglycerine, 0.3 mg, will be administered.
2) If there is no response within 10 minutes, clonidine 0.1 mg po will be administered
every 30 minutes (total maximum dose 0.6 mg clonidine) until the desired blood
pressure is reached. Desired blood pressure is defined as within normal range or 10
mmHg of baseline diastolic reading.
3) If high blood pressure is symptomatic, i.e., blurred vision, headache, chest pain, the
subject will be transferred to the ER at New York Presbyterian Hospital. If they do not respond to 
the above treatment (1 and 2 above) then they will be transferred to the ER.
 
7. Post-infusion Neuroimaging:


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a. PET imaging with [11C]UCB-J, performed identically as described above, will be repeated as 
close to 24-48 hours following the 4th ketamine infusion as is possible with scheduling availability 
of the PET Center. If participants do not complete all four ketamine infusions for any reason 
(including adverse effects of ketamine, lack of clinical response and preference not to complete all 
sessions, etc), we may conduct repeat (post-ketamine) [11C]UCB-J PET scan after fewer 
ketamine administrations.
8. Post-Infusion Treatment:
Pharmacologic treatment will proceed as follows at the conclusion of post-infusion PET and MRI 
acquisition:
Study participants will receive six months of open clinical treatment in the form of:
a)    Continuation of inpatient treatment for as long as is clinically indicated, followed by
b)    Outpatient psychiatrist visits for medication management with a psychiatrist in MIND to complete a 
total of 6 months of psychiatric care inclusive of the inpatient stay.
 
9. Exploratory research assessments of mood, suicidality, and side effects (per Fig. 1) Research 
assessments will continue for a three-week continuation phase post-infusion. Continuation phase 
clinical appointments will be weekly for four weeks, then decreasing to at least monthly, as 
clinically indicated, for the remainder of the six months.
 
Research assessments may be performed using phone or secure video (Webex or Zoom) and 
using Internet-based encrypted systems including Redcap or Citrix, managed by The 
NYSPI/Columbia School of Public Health Data Coordination Center (DCC). 
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
Withdrawal from Study: A subject will be withdrawn from the study if:
a. Subject requests to be removed for any reason.
b. The PI judges that it is medically unwise for the subject to continue in the study. For example, if 
the subject is unable to comply with the study procedures.


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c. The subject is unable to tolerate the delay to treatment because of pronounced worsening of 
symptoms such as marked agitation or psychotic symptoms. Worsening of suicidal ideation will 
not automatically require discontinuation from research, as long as the team judges that the 
subject can be managed safely as an outpatient (e.g. they have no plan or intent), or they agree to 
inpatient treatment and the inpatient staff agrees that the patient may continue research 
participation. A CGI≥5 will trigger conversation with study PI regarding possible study 
discontinuation.
d. A rise in systolic blood pressure ≥ 200 mm Hg or diastolic blood pressure to ≥ 115 mm Hg 
during the infusion.
e. During infusion, if O2 saturation remains <94% with nasal canula oxygen, then subject will be 
withdrawn from research and treated clinically.
f. Other criteria for discontinuation will be appearance of psychosis, mania, severe
agitation, or other deterioration where the treating physician decides that research participation is 
unacceptable.
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
Sample
Collection Time Point
Total Collected per 
Participant
Blood
Baseline (through protocol 
4815): 43ml
 
Arterial blood sampling during 
PET scans, pre- and post-
ketamine infusion: ≤100ml x 2 
= ≤200 ml
Maximum blood drawn 
through both protocols 
collectively: ≤243ml
 
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Domain
Instrument
Time


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Informed consent
IRB-approved form
30-45 min
Diagnosis
SCID-5
120 min
Demographics
Division Baseline 
Demographic form (BDEMO)
30 min
Clinical State 
Hamilton Depression Rating 
Scale 24-Item (HDRS- 24) 
10 min
 
Beck Depression Inventory 
(BDI) 
10 min
 
Profile of Mood States 
(POMS)
10 min
 
Clinical Global Impressions 
(CGI)
1 min
 
Brief Psychiatric Rating 
Scale (BPRS) – 4 item 
positive symptom subscale 
5 min
Medication
Past and Current 
Medications List
10 min
 
Systematic Assessment for 
Treatment Emergent Events-
General Inquiry (SAFTEE-GI)
 
10 min
 
Clinician-Administered 
Dissociative States Scale 
(CADSS)
15 min
 
Brief Psychiatric Rating 
Scale (BPRS) – Positive 
Symptoms Subscale Only 
10 min
Biomarkers
Neuropsychological testing: 
Bushke, Stroop, Reaction 
Time, Computerized 
Continuous Performance Test 
(CPT; 5 minutes), 
Computerized A, Not B Timed 
Reasoning Task (5 minutes), 
Computerized Go-No Go Task 
(5 minutes), WAIS-IV Coding 
Subtest (3 minutes)
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45 min


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Please attach copies, unless standard instruments are used


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Off label and investigational use of drugs/devices
Choose from the following that will be applicable to your study
Drug
Select the number of drugs used in this study
2
Drug #1
Name of the drug
Ketamine
Manufacturer and other information
Multiple generic manufacturers.
Approval Status
No IND is required
Choose one of the following options
FDA conditions are met (see 'Rules')
Explain
This is a clinical study involving a marketed drug and the study meets all of the following
conditions:
1. It is not intended to be reported to the FDA in support of a new indication for use or to support
any other significant change in the labeling; and
2. It is not intended to support a significant change in the advertising for the product; and
3. It does not involve a route of administration or dosage level, use in a subject population, or
other factor that significantly increases the risks (or decreases the acceptability of the risks)
associated with the use of the product; and
4. It is conducted in compliance with the requirements for IRB review and informed consent [21
CFR parts 50 and 56 respectively]; and
5. It is conducted in compliance with the requirements concerning the promotion and sale of drugs
[21 CFR 312.7].
Drug #2
Name of the drug


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[11C]UCB-J
Manufacturer and other information
[11C]UCB-J will be synthesized in the radioligand lab of the Columbia PET Center.
Approval Status
IND is approved
IND#
146646
Who holds the IND/IND sponsor?
IND is held by PI/CU Investigator
Miller, Jeffrey, MD
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
Patients on an antidepressant regimen at enrollment will continue their current antidepressant 
regimen; there will be no delay to that ongoing treatment for those participants. The delay to 
inpatient admission will not exceed 3 weeks; if a participant needs a longer delay between 
consent and beginning treatment for logistical reasons, it will be determined by the study clinician 
on a case-by-case basis based on need for delay, clinical stability, and ability to comply with the 
plan for monitoring. This period allows the time required for processing lab samples, completion of 
baseline research measures, and scheduling inpatient admission, the infusion procedures in the 
BSU, PET, and MRI procedures. 
 
The delay to ketamine infusion will not exceed 4 weeks from the time of enrollment. 
 
Thus, for participants not on an antidepressant regimen at the time of enrollment, the delay to the 
inpatient milieu, which has a therapeutic component, will not exceed 3 weeks, and the delay to 
pharmacologic intervention of ketamine will not exceed 4 weeks.
Maximum duration of delay to standard care or treatment of known efficacy
For participants not already taking an antidepressant, open pharmacologic antidepressant 
treatment will begin as soon as post-ketamine PET scan is completed; this will not exceed 7 
weeks from the time of enrollment. 


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Treatment to be provided at the end of the study
Pharmacologic treatment will proceed as follows at the conclusion of post-infusion PET and MRI 
acquisition:
Study participants will receive six months of open clinical treatment in the form of:
a)    Continuation of inpatient treatment for as long as is clinically indicated, followed by
b)    Outpatient psychiatrist visits for medication management with a psychiatrist in MIND to complete a 
total of 6 months of psychiatric care inclusive of the inpatient stay.
Clinical Treatment Alternatives
Clinical treatment alternatives
Many treatments for MDD exist, such as numerous approved antidepressant medications, 
electroconvulsive therapy, and various evidence-based psychotherapies. 
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
1. PET Scan-Related Risks:
1A. Radiotracer 
1A. Radiation exposure (PET)
For [11C]UCB-J, the single scan injected dose limit is 740mBq or 20 mCi, yielding a cumulative 
protocol dose limit over two [11C]UCB-J PET scans of 1480 mBq or 40 mCi.  Single injection and 
annual exposures for all organs, as well as effective dose, are below limits set in 21CRF part 
361.1. The risk estimate is based on the subjects in the study population who are most sensitive 
to radiation exposure.
Radiation 
Dosimetry
 
 
740MBq 
dose
740MBq dose x 2
 
Organ
µSv/MBq
mSv
mSv


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Active Blood-forming 
Organs
Red 
marrow
0.71
0.525
1.1
Gonads
Ovaries
0.64
0.48
0.96
3 highest organs
Liver
19.9
14.73
29.5
 
Brain
17.4
12.88
25.8
 
Kidneys
12.6
9.32
18.6
Whole Body
5.328
3.94
7.9
Effective Dose + 2 low dose CT 
attenuations per PET scan
3.32
2.55
5.09
 
 
 
Ref: J Nucl Med 2016; 57:777–
784
 
 
 
Transmission Scan NOTE: We plan to do the scans on the mCT scanner where the attenuation 
correction is done with a low-dose CT and therefore there will be a small amount of radiation due 
to the CT. In the event that the subject needs to leave the scanner while scanning (e.g. to use the 
bathroom) we will perform an additional low dose CT transmission scan (maximum total exposure 
from four CT scans ~0.176 mSv). 
1B. Radiotracer physiological effects:
Consistent with previous work with [11C]UCB-J (17), we will limit injected mass to 10 micrograms. 
The safety of [11C]UCB-J at similar injected masses has been demonstrated in PET studies 
published in the literature, including 10 healthy volunteers and 3 individuals with epilepsy in this 
study (17); five of whom received repeat [11C]UCB-J injections and scans the same day (20).  
Another study performed PET imaging with [11C]UCB-J on 10 individuals with amnestic mild 
cognitive impairment and 11 individuals who were cognitively normal (21).  The risk of an 
idiosyncratic reaction is acknowledged in the consent form. A physician will be available at the 
time of each injection of the radiotracer. Any adverse reaction to the radioactive drug (radiation 
related or not) will be reported to the NYPSI IRB and the JRSC.
1C. Placement of Intra-arterial catheter 
Radial arterial catherization is needed for repeated arterial blood samples to construct tracer input 
curves. Complications resulting from such short-term catheterizations include bleeding, occlusion, 
clotting, or infection. 
The following paragraph appears in the subject consent forms as per the IRB website, with one 
phrase added [shown here in italics] for more clarity for participants with lack of mathematical 
skills: 


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“The placement of a catheter in your artery may cause discomfort. There is a very small chance of 
complications from this catheter such as bleeding, bruising, infection or blood clot. There is an 
extremely low risk (0.09%, or about 1 in a thousand) of cutting off circulation to your hand which 
could result in a need for surgical repair or, in rare instances, could result in the loss of use of part 
of or all of the hand. These complications are rare and usually occur in medically ill patients who 
have catheters in their wrists for several days. In contrast, the catheter will remain in your arm for 
about four hours for this study. If you have a history of a bleeding disorder or are taking certain 
medications that affect blood clotting, you will not be asked to participate in this study.”
The radial artery catheter is placed by an experienced physician. 
1D. Intravenous catheter (PET, ketamine infusion)
There is a small risk of infection and bleeding associated with intravenous catheters, which are 
prevented by proper techniques. Placement of IVs will be by a physician, nurse, or technician 
trained and certified in aseptic technique for catheter placement to minimize this risk.
1E. Blood Drawing (PET, screening)
The risks associated with drawing blood are slight discomfort and occasional bruising. The total 
volume drawn through enrollment in this study and co-enrollment in our area’s umbrella protocol, 
IRB #4815, is 243ml, which is less than the volume drawn during blood donation.  We exclude 
individuals who are anemic with a Hemoglobin value <11 g/dL for females or <12 g/dL for males.
1F. Discomfort during scanning (PET and MRI) 
It may be uncomfortable to lie motionless in the cameras (either PET or MRI) and it may cause 
some subjects to feel anxious. Our staff will be available to provide support, reduce anxiety, 
optimize the comfort of the subject and remove the subject from the scanner if requested. A 
benzodiazepine or antihistamine may be offered for the MRI scan for very anxious subjects. 
1G. Pregnancy (PET, MRI, Ketamine)
Studies involving radiation are contraindicated during pregnancy because of possible risk to the 
fetus. Patients must agree at the time of consent to use an effective form of birth control and to 
inform the treating psychiatrist in the event of pregnancy while in the study. Women of child-
bearing potential will have a serum pregnancy test administered as part of initial eligibility 
assessments, as well as urine pregnancy tests performed on the day of the PET and MRI scans 
prior to scanning, and within a day prior to each ketamine infusion. On the day of the PET 
scan, research staff will ask female participants whether they have had sex without birth control 
within two weeks of the PET scan. If they have, they will not be scanned that day. An additional 
urine pregnancy test will be administered one to two weeks after the second PET scan. The post-
PET pregnancy test can be completed at NYSPI or by a take home urine pregnancy test (test kit 
to be provided by the study team) with email the subject informing the research team of the 


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results. Subjects will not be charged for the pregnancy test. In addition, nursing mothers will also 
be excluded from the study. 
2. Side Effects of Intravenous Ketamine.
2A. Medical Risks related to Ketamine
Administration of sub-anesthetic doses of ketamine i.v., such as the 0.5 mg/kg dose to be used in 
this study, may induce a modest rise in blood pressure. We have administered sub-anesthetic 
doses of ketamine i.v. (0.5mg/kg over 40 minutes) in the setting of an IRB-approved MRI/MRS 
brain imaging protocol at this institution (IRB #5786, PI: J. Mann). The modest increases all 
peaked and largely resolved by 75 minutes, with vitals returning to near baseline. 
In addition, ketamine may produce nausea and vomiting.
Procedures for minimizing risks related to Ketamine infusion:
Any medical risks from increased blood pressure will be minimized through the careful screening 
of potential subjects. Subjects will be excluded for baseline hypertension or any history of 
cardiovascular illness. A BLS-certified physician who has been trained in the infusion procedure 
will be present during the procedure. Procedures for hypertension that occurs during the infusion 
are described above under Study Procedures. Nausea and vomiting will be treated supportively 
and, if severe, with anti-emetic agents; if necessary, administration of ketamine will be 
discontinued. Subject will be informed that they should be fasting (12 hours no food, 4 hours no 
liquids) prior to the ketamine infusion. 
2B. Psychiatric or Behavioral Risks Related to Ketamine
Ketamine is an FDA-approved dissociative anesthetic. Ketamine exposure at the sub-anesthetic 
dose to be used in this study can be associated with a moderate dissociative state, which is well 
tolerated in the majority of cases and is spontaneously reversible (22). There is extensive clinical 
experience with ketamine used at anesthetic doses, and no long-term detrimental effects of 
ketamine exposure have been reported. It is possible that ketamine administration will increase 
the risk of psychosis, even in normal subjects. Ketamine is a street drug of abuse. As such, it 
poses the risk that exposure during this study may predispose subjects to subsequent abuse of 
this drug. To minimize this risk, current drug or alcohol dependence or any history of ketamine 
abuse or dependence will be excluded. We will follow patients while they are receiving clinical 
treatment and review any evidence of abuse that may appear after the ketamine infusion. This 
dose of ketamine has been safely administered in similar settings to depressed patients with 
clinically significant suicidal ideation at least 23 times without any serious side effects (23, 24).
iv) Specific measures and precautions
The experiment will be carried out in the presence of at least one psychiatrist. In case of agitation, 
hyperarousal, or psychosis, the participant will be treated with benzodiazepine (lorazepam) or 
neuroleptics, as indicated.The risks of exposing subjects to a drug of abuse potential will be 
minimized by explaining this risk to prospective subjects, and by excluding from the study any 
subjects with documented or suspected current substance or alcohol dependence. 


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3. MRI Scan 
The MRI scanner uses a large magnet to take pictures of the brain and is not associated with any 
known medical risks, except for persons who have a heart pacemaker, or have metal in their body 
(e.g. shrapnel or surgical prostheses) which may be affected by the magnet. Patients will be 
asked to notify us if this is the case. There is also the risk of burns from medicinal patches during 
the MRI; therefore, subjects will be asked to remove any patches prior to the scanning session. 
Although there are no known risks associated with pregnancy, we will not scan someone who is 
known to be pregnant. Therefore, for women of childbearing potential, urine pregnancy testing will 
be conducted on the day of the MRI. Some people have reported sensations during the MRI scan, 
such as "tingling" or "twitching" (or, very rarely, a painful sensation), which are caused by changes 
in the magnetic field that can stimulate nerves in your body. If the subject experiences sensations 
and feels uncomfortable, the MR technologist will stop the scan immediately. Occasionally, some 
people experience nervousness or claustrophobic feelings due to the scanner's confined space. In 
our experience, no one has had sensations from the scanning that did not stop as soon as the 
scanning stopped. Except for pacemakers and some types of metallic implants, we know of no 
health hazard from the MRI scan. The MRI scan is not painful, but having to lie still in the enclosed 
space of the scanning table is uncomfortable for some people. 
Because this MRI scan is being performed for research purposes only, it may not show problems 
that would normally be found in a typical clinical MRI scan ordered by a doctor for a specific 
medical problem. The T1-weighted images acquired in this study, regardless of resolution of other 
image characteristics, do not, in general, yield adequate information for a clinical quality read. 
However, gross structural abnormalities such as the presence of mass effects or hydrocephalus 
will be examined and documented by an appropriately qualified radiologist. Upon request, results 
will be shared with research subjects or a physician designated by them. 
4. Electrocardiogram 
An electrocardiogram has no serious risks. On rare occasions a rash may develop where the 
electrodes are places which usually resolves without treatment. 
5. Interviews 
Interviews: Psychiatric interviews and neuropsychological testing can sometimes be
boring or stressful, but some people find talking to a physician or psychologist helpful. The 
interviewers will all be experienced personnel. The research team may request permission to 
record the interview for teaching purposes with audiotape and/or videotape. In this event, a 
separate consent process will occur for this. Subjects may choose to postpone or stop the 
interview at any time.
 6. EEG/ERP Tests
 
The procedures for measuring EEG are noninvasive and standard for clinical research in this area 
and represent no risk to subjects. Subjects may experience some discomfort when applying the 
electrode cap but this passes quickly. In our prior work, subjects have experienced little difficulty 


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doing resting EEG or LDAEP tasks. Testing procedures are designed to maximize the mental and 
physical comfort of the participants and represent no risk to them.
 
 7. COVID-19
 
There is a risk of being infected with COVID-19 while traveling to and from the medical center. In 
order to minimize the risk of travel we will instruct all subjects in the importance of social 
distancing and wearing a mask at all times during travel to and from NYSPI as well in NYSPI. On 
the day of the PET and MRI scans we will offer to pay for an Uber ride for subjects living in the 
extended New York metropolitan area. 
 
Describe procedures for minimizing risks
Procedures for minimizing risks are integrated into the risks section above.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
Personal information will be kept confidential and will not be released without the subject’s written 
permission except as described in this section or as required by law. The subject’s name or other 
identifying information will not be made known if the results of this study are published for 
scientific purposes. Clinical records, including the subject’s name and other personal identifying 
information, and research data will be kept in secure storage at the New York State Psychiatric 
Institute. Information in paper format will be kept in locked files. Electronic data, including MRI 
images, will be protected by a firewall (programming that makes it virtually impossible to access 
the data from outside the New York State Psychiatric Institute) and by restricting access within the 
New York State Psychiatric Institute through use of a password known only to authorized 
personnel. If information is transmitted electronically, it will be encrypted so that identifying 
information remains confidential. 
The subject’s information will only be available to study research staff and other authorized 
individuals, including those at the New York State Psychiatric Institute, New York State and 
federal regulatory agencies such as the Food and Drug Administration who may review records as 
part of routine audits. There are also legal advocacy organizations that have authority under New 
York State law to have access to otherwise confidential subject records, although they cannot 
disclose this information without the subject’s consent. 
The subject’s MRI will be interpreted and the results will be shared with the subject or physician 
who the subject may designate. The MRI report will be maintained as part of the clinical database 
at the Columbia Radiology MRI Center at the Neurological Institute along with the subject’s name 


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and will be accessible to clinicians at the New York State Psychiatric Institute. The subject’s 
psychiatric diagnosis will not be a part of the report. 
Data will be de-identified prior to publication in the scientific literature and presentation at scientific 
meetings, 
 
Data collected in this research study, including MRI and PET scans, measurements from blood 
samples drawn during the PET scan, and questionnaire answers, may be used in future studies, 
and may be shared with other investigators after being de-identified, including in scientific data 
banks.  There is a potential risk of loss of confidentiality from such data sharing, but this is 
extremely low as only de-identified data from this study may be shared. 
 
While we perform analyses of the blood samples that are drawn during the PET scan in this 
protocol, no biospecimens are banked/stored through this research study, and as such, no actual 
biospecimens from this research study will be shared with other investigators (though the results 
of blood assays may be shared as above).
 
All screening and consenting procedures will be done remotely over a HIPAA-compliant 
videoconferencing software (Webex or Zoom) or telephone. We will document consent 
electronically using Redcap. The consent discussion process will include discussion of the  
HIPAA-compliant, encrypted platforms to be used.  We will discuss any concerns the patient may 
have, such as access to a private space in which to take calls, or accessibility—access at home to 
adequate devices, cell signal, or wifi, and attempt to address these concerns to the best of our 
ability. 
Will the study be conducted under a certificate of confidentiality?
No
Direct Benefits to Subjects  
Direct Benefits to Subjects
This study was not designed for the direct benefit of participants.


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Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Participants who complete all neuroimaging assessments (baseline PET, baseline MRI, and post-
treatment PET) will be compensated $600.  Individuals who complete a subset of these 
procedures will be compensated  based on the components that they complete ($150 for each 
PET scan and $100 for each MRI).  
 
Payment procedures are initiated upon subjects’ completion of the study.  Payment is in the form 
of a check, usually received in the mail about 4-6 weeks after completion of the study procedures.
References
References
1.         Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJL, et al. (2013): 
Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden 
of Disease Study 2010. PLoS Med. 10:e1001547.
2.         WHO (2017): Depression and other common mental disorders: global health estimates. In: 
Organization. WH, editor. Geneva: World Health Organization, pp 1-24.
3.         McGrath PJ, Miller JM (2015): Pharmacological Management of Treatment-Resistant 
Unipolar Depression. In: Tasman A, Kay J, Lieberman JA, First MB, Riba MB, editors. Psychiatry, 
Fourth edition. ed: Wiley, pp 2311-2330.
4.         Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. (2010): mTOR-dependent 
synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science (New 
York, NY. 329:959-964.
5.         Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng P-f, et al. (2011): NMDA receptor 
blockade at rest triggers rapid behavioural antidepressant responses. Nature. 475:91-97.
6.         Ardalan M, Rafati AH, Nyengaard JR, Wegener G (2017): Rapid antidepressant effect of 
ketamine correlates with astroglial plasticity in the hippocampus. Br J Pharmacol. 174:483-492.


Protocol Summary Form
7847
Miller, Jeffrey
Page 36 of 41
7.         Duman CH, Duman RS (2015): Spine synapse remodeling in the pathophysiology and 
treatment of depression. Neurosci Lett. 601:20-29.
8.         Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. (2019): 
Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. 
Science (New York, NY. 364.
9.         WHO (2017): Depression. World Health Organization.
10.      Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB (2015): 
Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in 
Depression. Am J Psychiatry. 172:950-966.
11.      Caddy C, Amit BH, McCloud TL, Rendell JM, Furukawa TA, McShane R, et al. (2015): 
Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database 
Syst Rev.CD011612.
12.      Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, et al. (2017): 
A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA 
Psychiatry.
13.      Arnone D, Job D, Selvaraj S, Abe O, Amico F, Cheng Y, et al. (2016): Computational meta-
analysis of statistical parametric maps in major depression. Hum Brain Mapp. 37:1393-1404.
14.      Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. (2012): 
Decreased expression of synapse-related genes and loss of synapses in major depressive 
disorder. Nature medicine. 18:1413-1417.
15.      McEwen BS (1999): Stress and hippocampal plasticity. Annu Rev Neurosci. 22:105-122.
16.      Shansky RM, Morrison JH (2009): Stress-induced dendritic remodeling in the medial 
prefrontal cortex: effects of circuit, hormones and rest. Brain Res. 1293:108-113.
17.      Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al. (2016): Imaging 
synaptic density in the living human brain. Science translational medicine. 8:348ra396.
18.      Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, et al. (2016): 
Synthesis and Preclinical Evaluation of 11C-UCB-J as a PET Tracer for Imaging the Synaptic 
Vesicle Glycoprotein 2A in the Brain. J Nucl Med. 57:777-784.
19.      Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, et al. (2019): 
Lower synaptic density is associated with depression severity and network alterations. Nat 
Commun. 10:1529.
20.      Finnema SJ, Nabulsi NB, Mercier J, Lin SF, Chen MK, Matuskey D, et al. (2017): Kinetic 
evaluation and test-retest reproducibility of [(11)C]UCB-J, a novel radioligand for positron 


Protocol Summary Form
7847
Miller, Jeffrey
Page 37 of 41
emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow 
Metab.271678x17724947.
21.      Chen MK, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, et al. (2018): 
Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron 
Emission Tomographic Imaging. JAMA neurology. 75:1215-1224.
22.      Kudoh A, Takahira Y, Katagai H, Takazawa T (2002): Small-dose ketamine improves the 
postoperative state of depressed patients. Anesth Analg. 95:114-118, table of contents.
23.      DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et al. 
(2010): Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate 
antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 
71:1605-1611.
24.      Price RB, Nock MK, Charney DS, Mathew SJ (2009): Effects of intravenous ketamine on 
explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 
66:522-526.
25.      Abdallah, C.G., Averill, C.L., Salas, R., Averill, L.A., Baldwin, P.R., Krystal, J.H., Mathew, 
S.J., Mathalon, D.H., 2017. Prefrontal Connectivity and Glutamate Transmission: Relevance to 
Depression Pathophysiology and Ketamine Treatment. Biological psychiatry. Cognitive 
neuroscience and neuroimaging 2, 566-574.
26.      Curic, S., Leicht, G., Thiebes, S., Andreou, C., Polomac, N., Eichler, I.C., Eichler, L., 
Zollner, C., Gallinat, J., Steinmann, S., Mulert, C., 2019. Reduced auditory evoked gamma-band 
response and schizophrenia-like clinical symptoms under subanesthetic ketamine. 
Neuropsychopharmacology : official publication of the American College of 
Neuropsychopharmacology 44, 1239-1246.
27.      Curic, S., Leicht, G., Thiebes, S., Andreou, C., Polomac, N., Eichler, I.C., Eichler, L., 
Zollner, C., Gallinat, J., Steinmann, S., Mulert, C., 2019. Reduced auditory evoked gamma-band 
response and schizophrenia-like clinical symptoms under subanesthetic ketamine. 
Neuropsychopharmacology : official publication of the American College of 
Neuropsychopharmacology 44, 1239-1246.
28.      Evans, J.W., Szczepanik, J., Brutsche, N., Park, L.T., Nugent, A.C., Zarate, C.A., Jr., 2018. 
Default Mode Connectivity in Major Depressive Disorder Measured Up to 10 Days After Ketamine 
Administration. Biol Psychiatry 84, 582-590.
29.      Fleming, L.M., Javitt, D.C., Carter, C.S., Kantrowitz, J.T., Girgis, R.R., Kegeles, L.S., 
Ragland, J.D., Maddock, R.J., Lesh, T.A., Tanase, C., Robinson, J., Potter, W.Z., Carlson, M., 
Wall, M.M., Choo, T.H., Grinband, J., Lieberman, J., Krystal, J.H., Corlett, P.R., 2019. A 
multicenter study of ketamine effects on functional connectivity: Large scale network relationships, 
hubs and symptom mechanisms. NeuroImage. Clinical 22, 101739.


Protocol Summary Form
7847
Miller, Jeffrey
Page 38 of 41
30.      Forsyth, A., McMillan, R., Campbell, D., Malpas, G., Maxwell, E., Sleigh, J., Dukart, J., 
Hipp, J., Muthukumaraswamy, S.D., 2019. Modulation of simultaneously collected hemodynamic 
and electrophysiological functional connectivity by ketamine and midazolam. Human brain 
mapping.
31.      Gallinat, J., Bottlender, R., Juckel, G., Munke-Puchner, A., Stotz, G., Kuss, H.J., 
Mavrogiorgou, P., Hegerl, U., 2000. The loudness dependency of the auditory evoked N1/P2-
component as a predictor of the acute SSRI response in depression. Psychopharmacology 148, 
404-411.
32.      Gartner, M., Aust, S., Bajbouj, M., Fan, Y., Wingenfeld, K., Otte, C., Heuser-Collier, I., 
Boker, H., Hattenschwiler, J., Seifritz, E., Grimm, S., Scheidegger, M., 2019. Functional 
connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of 
ketamine. European neuropsychopharmacology : the journal of the European College of 
Neuropsychopharmacology 29, 501-508.
33.      Hegerl, U., Gallinat, J., Juckel, G., 2001. Event-related potentials. Do they reflect central 
serotonergic neurotransmission and do they predict clinical response to serotonin agonists? J 
Affect Disord 62, 93-100.
34.      Hegerl, U., Gallinat, J., Mrowinski, D., 1994. Intensity dependence of auditory evoked dipole 
source activity. Int J Psychophysiol 17, 1-13.
35.      Ionescu, D.F., Felicione, J.M., Gosai, A., Cusin, C., Shin, P., Shapero, B.G., Deckersbach, 
T., 2018. Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature. Harvard 
review of psychiatry 26, 320-339.
36.      Kayser, J., Tenke, C.E., 2003. Optimizing PCA methodology for ERP component 
identification and measurement: theoretical rationale and empirical evaluation. Clin Neurophysiol 
114, 2307-2325.
37.      Kayser, J., Tenke, C.E., 2015. Issues and considerations for using the scalp surface 
Laplacian in EEG/ERP research: A tutorial review. Int J Psychophysiol 97, 189-209.
37.      Kayser, J., Tenke, C.E., Abraham, K.S., Alschuler, D.M., Alvarenga, J.E., Skipper, J., 
Warner, V., Bruder, G.E., Weissman, M.M., 2016. Neuronal generator patterns at scalp elicited by 
lateralized aversive pictures reveal consecutive stages of motivated attention. NeuroImage 142, 
337-350.
38.      Lee, B.H., Park, Y.M., Lee, S.H., Shim, M., 2015. Prediction of long-term treatment 
response to selective serotonin reuptake inhibitors (SSRIs) using scalp and source loudness 
dependence of auditory evoked potentials (LDAEP) analysis in patients with major depressive 
disorder. International journal of molecular sciences 16, 6251-6265.


Protocol Summary Form
7847
Miller, Jeffrey
Page 39 of 41
39.      McMillan, R., Sumner, R., Forsyth, A., Campbell, D., Malpas, G., Maxwell, E., Deng, C., 
Hay, J., Ponton, R., Sundram, F., Muthukumaraswamy, S., 2019. Simultaneous EEG/fMRI 
recorded during ketamine infusion in patients with major depressive disorder. Progress in neuro-
psychopharmacology & biological psychiatry, 109838.
40.      Mueller, F., Musso, F., London, M., de Boer, P., Zacharias, N., Winterer, G., 2018. 
Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity 
in the default mode network, salience network, dorsal attention network and executive control 
network. NeuroImage. Clinical 19, 745-757.
41.      Mulert, C., Juckel, G., Augustin, H., Hegerl, U., 2002. Comparison between the analysis of 
the loudness dependency of the auditory N1/P2 component with LORETA and dipole source 
analysis in the prediction of treatment response to the selective serotonin reuptake inhibitor 
citalopram in major depression. Clin Neurophysiol 113, 1566-1572.
42.      Muthukumaraswamy, S.D., Shaw, A.D., Jackson, L.E., Hall, J., Moran, R., Saxena, N., 
2015. Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA 
and AMPA-Mediated Frontoparietal Connectivity in Humans. The Journal of neuroscience : the 
official journal of the Society for Neuroscience 35, 11694-11706.
43.      Paige, S.R., Fitzpatrick, D.F., Kline, J.P., Balogh, S.E., Hendricks, S.E., 1994. Event-related 
potential amplitude/intensity slopes predict response to antidepressants. Neuropsychobiology 30, 
197-201.
44.      Paige, S.R., Hendricks, S.E., Fitzpatrick, D.F., Balogh, S., Burke, W.J., 1995. 
Amplitude/intensity functions of auditory event-related potentials predict responsiveness to 
bupropion in major depressive disorder. Psychopharmacology bulletin 31, 243-248.
45.      Pascual-Marqui, R.D., Michel, C.M., Lehmann, D., 1994. Low resolution electromagnetic 
tomography: a new method for localizing electrical activity in the brain. Int J Psychophysiol 18, 49-
65.
46.      Pizzagalli, D., Pascual-Marqui, R.D., Nitschke, J.B., Oakes, T.R., Larson, C.L., 
Abercrombie, H.C., Schaefer, S.M., Koger, J.V., Benca, R.M., Davidson, R.J., 2001. Anterior 
cingulate activity as a predictor of degree of treatment response in major depression: evidence 
from brain electrical tomography analysis. The American journal of psychiatry 158, 405-415.
47.      Pizzagalli, D.A., Webb, C.A., Dillon, D.G., Tenke, C.E., Kayser, J., Goer, F., Fava, M., 
McGrath, P., Weissman, M., Parsey, R., Adams, P., Trombello, J., Cooper, C., Deldin, P., 
Oquendo, M.A., McInnis, M.G., Carmody, T., Bruder, G., Trivedi, M.H., 2018. Pretreatment Rostral 
Anterior Cingulate Cortex Theta Activity in Relation to Symptom Improvement in Depression: A 
Randomized Clinical Trial. JAMA Psychiatry 75, 547-554.
48.      Reed, J.L., Nugent, A.C., Furey, M.L., Szczepanik, J.E., Evans, J.W., Zarate, C.A., Jr., 


Protocol Summary Form
7847
Miller, Jeffrey
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2019. Effects of Ketamine on Brain Activity During Emotional Processing: Differential Findings in 
Depressed Versus Healthy Control Participants. Biological psychiatry. Cognitive neuroscience and 
neuroimaging 4, 610-618.
49.      Rosburg, T., Schmidt, A., 2018. Potential Mechanisms for the Ketamine-Induced Reduction 
of P3b Amplitudes. Frontiers in behavioral neuroscience 12, 308.
50.      Rosch, R.E., Auksztulewicz, R., Leung, P.D., Friston, K.J., Baldeweg, T., 2019. Selective 
Prefrontal Disinhibition in a Roving Auditory Oddball Paradigm Under N-Methyl-D-Aspartate 
Receptor Blockade. Biological psychiatry. Cognitive neuroscience and neuroimaging 4, 140-150.
51.      Salvadore, G., Cornwell, B.R., Colon-Rosario, V., Coppola, R., Grillon, C., Zarate, C.A., Jr., 
Manji, H.K., 2009. Increased anterior cingulate cortical activity in response to fearful faces: a 
neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol 
Psychiatry 65, 289-295.
52.      Schwertner, A., Zortea, M., Torres, F.V., Caumo, W., 2018. Effects of Subanesthetic 
Ketamine Administration on Visual and Auditory Event-Related Potentials (ERP) in Humans: A 
Systematic Review. Frontiers in behavioral neuroscience 12, 70.
53.      Smith, E.E., Tenke, C.E., Deldin, P.J., Trivedi, M.H., Weissman, M.M., Auerbach, R.P., 
Bruder, G.E., Pizzagalli, D.A., Kayser, J., 2019. Frontal theta and posterior alpha in resting EEG: 
A critical examination of convergent and discriminant validity. Psychophysiology, e13483.
54.      Teichert, T., 2017. Loudness- and time-dependence of auditory evoked potentials is blunted 
by the NMDA channel blocker MK-801. Psychiatry Res 256, 202-206.
55.      Tenke, C.E., Kayser, J., 2012. Generator localization by current source density (CSD): 
implications of volume conduction and field closure at intracranial and scalp resolutions. Clin 
Neurophysiol 123, 2328-2345.
56.      Tenke, C.E., Kayser, J., Manna, C.G., Fekri, S., Kroppmann, C.J., Schaller, J.D., Alschuler, 
D.M., Stewart, J.W., McGrath, P.J., Bruder, G.E., 2011. Current source density measures of 
electroencephalographic alpha predict antidepressant treatment response. Biol Psychiatry 70, 
388-394.
57.      Tenke, C.E., Kayser, J., Pechtel, P., Webb, C.A., Dillon, D.G., Goer, F., Murray, L., Deldin, 
P., Kurian, B.T., McGrath, P.J., Parsey, R., Trivedi, M., Fava, M., Weissman, M.M., McInnis, M., 
Abraham, K., J, E.A., Alschuler, D.M., Cooper, C., Pizzagalli, D.A., Bruder, G.E., 2017. 
Demonstrating test-retest reliability of electrophysiological measures for healthy adults in a 
multisite study of biomarkers of antidepressant treatment response. Psychophysiology 54, 34-50.
58.      Vlisides, P.E., Bel-Bahar, T., Nelson, A., Chilton, K., Smith, E., Janke, E., Tarnal, V., Picton, 
P., Harris, R.E., Mashour, G.A., 2018. Subanaesthetic ketamine and altered states of 
consciousness in humans. British journal of anaesthesia 121, 249-259.


Protocol Summary Form
7847
Miller, Jeffrey
Page 41 of 41
59.      Zacharias, N., Musso, F., Muller, F., Lammers, F., Saleh, A., London, M., de Boer, P., 
Winterer, G., 2020. Ketamine effects on default mode network activity and vigilance: A 
randomized, placebo-controlled crossover simultaneous fMRI/EEG study. Human brain mapping 
41, 107-119.
 
 
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Upload copy(ies) of unbolded Consent Form(s)
UCBJ Ketamine CF 9_7_21 clean.pdf
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Upload copy(ies) of unbolded Information Sheet(s)
Upload copy(ies) of bolded Information Sheet(s)
Upload copy(ies) of recruitment materials/ads to be reviewed
Ketamine UCB_J CUPP posting.pdf
Upload evidence of FDA IND approval(s)
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7847 HIPAA 9_3_19.pdf
Upload any additional documents that may be related to this study
7847_MRI_Findings_Letter_10_7_19.pdf
7847_MRI_No_Findings_Letter_9_7_21.pdf
7847.FB.CONT.appr.pend.aw.091421.pdf


Statistical Analysis Plan 
This is a pilot study examining the relationship between synaptic density quantified by 
PET imaging with [11C]UCB-J and clinical outcomes following treatment with ketamine 
infusions for depression.   
Primary aims will be assessed using linear mixed effects models.  All tests will be 
performed using two-sided alternatives with alpha=0.05.  For all analyses we will 
examine standard diagnostic plots to identify evidence of lack of model fit, presence of 
outliers or overly influential points, etc., and take appropriate remedies as indicated 
(e.g., review source data of outliers, transform data, etc.). 
As this is a pilot study, additional exploratory analyses will be conducted for hypothesis 
generating purposes.