Clinical trial NCT01944293
Conditions: Bipolar Disorder Major Depressive Episode Suicidal Ideation
Keywords: Ketamine Midazolam Bipolar Disorder Major Depressive Episode Suicidal Ideation Suicide Depression Treatment Ketamine Treatment
Sponsor: New York State Psychiatric Institute
Start date: 2013-09-01; Completion date: 2018-10-01
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to compare the effectiveness of two medications, Ketamine and Midazolam, for rapidly relieving suicidal thoughts in people suffering from bipolar depression.

The first drug, ketamine, is an experimental antidepressant that early studies have shown may quickly reduce suicidal thoughts, but we are not sure how well it may work. Midazolam, the comparison drug, is not thought to reduce depression or suicidal thoughts.

Detailed description:
Patients currently taking psychiatric medications may continue them during the study. However, if a patient is taking a benzodiazepine (such as Ativan, Klonopin, or Xanax), they will be able to take up to 2mg per day of Lorazepam during the week before the infusion, but none will be permitted in the 24 hours pre-infusion. Also, Zolpidem (Ambien) will not be permitted in the 24 hours pre-infusion. If a person chooses to participate, their dose of benzodiazepine may need to be reduced so that they can do without it during the 24 hours pre-infusion.

Participants are randomly assigned to receive a single dose of Ketamine (0.5 mg/kg) or Midazolam (0.02 mg/kg), which is given slowly, in a vein, over about 40 minutes. The study is "double-blind," meaning patients and study staff will not know which medication is in the infusion.

If a patient does not respond to the first infusion, and s/he received Midazolam, then s/he will be offered the option of a second infusion, this time with Ketamine (0.5 mg/kg). After the infusion(s), participants will have weekly research interviews for 6 weeks to monitor response.

After post-infusion research measures are completed, all subjects will receive open clinical treatment. During open clinical treatment, medication will be changed for those patients who don't respond or whose response is transient.

Participation in this study requires a brief inpatient stay, at no cost, at the New York State Psychiatric Institute (NYSPI).

Eligible participants enrolled in this study will be offered medication management visits at no cost for a total of up to 6 months combining inpatient and outpatient treatment. At the end of the 6 months of treatment patients will be referred for ongoing care.

Arms: arm 1: 0.5 mg/kg, I.V. (in the vein) arm 2: 0.02 mg/kg, I.V. (in the vein)
Interventions: intervention 1: Ketamine intervention 2: Midazolam
Intervention descriptions: intervention 1: Single dose of 0.5 mg/kg of Ketamine given intravenously (in the vein) over 40 minutes intervention 2: Single dose of 0.02 mg/kg of Midazolam given intravenously (in the vein) over 40 minutes

Protocol documents:
Prot_002.pdf: 
Signed copy on file at IRB 
 
             v. 11/15/13 
New York State Psychiatric Institute 
Institutional Review Board 
 
July 01, 2019  
 
To: 
 
Dr. Michael Grunebaum 
From:  
Dr. Edward Nunes, Co-Chair 
 
 
Dr. Agnes Whitaker, Co-Chair 
 
 
 
 
 
Subject: 
Approval Notice: Continuation expedited per 45CFR46.110(b)(1)(f)(8c) 
 
 
  
 
 
 
 
Your protocol # 6785 entitled: KETAMINE VS MIDAZOLAM IN BIPOLAR DEPRESSION (ADD-ON TO # 
6598) Protocol version date 07/01/2018 has been approved by the New York State Psychiatric 
Institute - Columbia University Department of Psychiatry Institutional Review Board from July 04, 
2019 to July 03, 2020.  
 
Consent requirements: 
     √  Not applicable: Data Analysis Only 
    45CFR46.116 (f)(3) waiver of consent  
      Signature by the person(s) obtaining consent is required to document the consent process 
      Documentation of an independent assessment of the participant’s capacity to consent is also 
required. 
Approved for recruitment of subjects who lack capacity to consent:  No  Yes    
 
 
Field Monitoring Requirements:  Routine Special: ___________________  
 
 
  Only copies of consent documents that are currently approved by the IRB may be used to obtain 
consent for participation in this study. 
  A progress report and application for continuing review is required 2 months prior to the 
expiration date of IRB approval. 
  Changes to this research may not be initiated without the review and approval of the IRB except 
when necessary to eliminate immediate hazards to participants.  
  All serious and/or unanticipated problems or events involving risks to subjects or others must be 
reported immediately to the IRB.  Please refer to the PI-IRB website at http://irb.nyspi.org for 
Adverse Event Reporting Procedures and additional reporting requirements.    
 
* Enrollment closed for bipolar population only. Recruitment of healthy controls continues. 
 
Cc: 
CU Business Office (NARSAD and Internal Acct GT002345) 
 
 
EN/AHW/alw 


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Protocol Title:
Ketamine in Bipolar Depression (Add-on to 
# 6598)
Protocol Number:
6785
First Approval:
07/31/2013
Expiration Date:
07/03/2020
Version Date:
07/01/2019
Clinic:
MIND Clinic
Contact Principal Investigator:
Michael Grunebaum, MD
Email: mfg14@columbia.edu
Telephone: 646-774-7573
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 
Division & Personnel
Division
What Division/Department does the PI belong to?
MIND
Within the division/department, what Center or group are you affiliated with, if any? 
None
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.
Outside Investigators: None
Consultant:


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Vivek K. Moitra, MD
Associate Clinical Professor of Anesthesiology
Associate Medical Director, Surgical ICU
Associate Program Director, Critical Care Medicine Fellowship
Division of Critical Care, Columbia University College of Physicians and Surgeons
Application for Continuation of Research
Status
Current Status of Study: 
All research interventions were completed. Only data analysis is ongoing.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
In the past year there was no further recruitment or enrollment of new subjects. The only study activity in 
the past year was secondary data analysis. We request the ACAR only for data analysis purposes. The study 
is closed to recruitment.
Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 
the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 
No


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Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?
Yes
Is the study covered by a certificate of confidentiality? 
No
Overall Progress
Approved sample size
14
Total number of participants enrolled to date
7
Number of participants who have completed the study to date 
7
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
No
Comments / additional information 
Sample Demographics
Specify population
Bipolar depression
Total number of participants enrolled from this population to date 
5
Specify population #2
Healthy volunteers
Total number of participants enrolled from this population to date 
2
Gender, Racial and Ethnic Breakdown 
Female: 3
Male: 4
Transgender male to female: 1
 
Non-Hispanic: 8
Hispanic: 0
 
White: 6
African American or Black: 1
Asian: 1
Summary of Current Year's Enrollment and Drop-out 
Number of participants who signed consent in the past year


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0
Did the investigator withdraw participants from the study? 
No
Did participants decide to discontinue study involvement? 
No
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Neuropsychological Evaluation
   Collection of Biological Specimens
   Medication Trial
   MRI
   Off-label Use of Drug or Device
   Somatic Treatment or Intervention
Population
Indicate which of the following populations will be included in this research
   Medically and Psychiatrically Healthy Subjects
   Adults
   Adults over 50
   Inpatients
Research Support/Funding
Will an existing internal account be used to support the project?
Yes
Describe internal account
The Nina S. Rahn account GT002345 
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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Select one of the following
The grant/contract is currently funded
Source of Funding
Foundation
Sponsor
NARSAD/BBRF
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
Enrollment was completed for this study in suicidal, bipolar, depressed patients to test random assignment 
to intravenous infusion of ketamine or midazolam control. We then enrolled 5 more subjects to collect pilot 
data from MRI scans done before and after the same ketamine infusion procedure that was done in the 
original randomized clinical trial. The primary aim is to gather pilot data exploring neuroimaging (MRI) 
correlates of the clinical effects of ketamine. We plan to enroll two healthy controls to evaluate whether 
differences in performance on the memory task during the MRI scans in the patient sample from pre- to 
post-infusion is associated with ketamine or simply due to practice effects.
Background, Significance and Rationale
Background, Significance and Rationale
There is a shortage of antidepressant options and an absence of antisuicidal treatments of demonstrable 
efficacy for depressed bipolar (BD) patients. Few double-blind randomized controlled trials (RCT) have 
examined suicidal behavior in bipolar samples. We are conducting an RCT of the glutamate antagonist 
ketamine versus midazolam control in suicidal, unipolar depressed patients (IRB 6598), which presented the 
opportunity for an add-on study in a bipolar depressed sample. Two RCTs by Zarate et al in 33 BD subjects, 
showed rapid reduction in depressive symptoms or suicidal thoughts after ketamine but not saline infusion 


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(1,2). We recently completed enrollment of the feasibility study of suicidal, depressed BD patients to extend 
our actively recruiting protocol to this clinically important population and to test ketamine infusion versus a 
more rigorous, active control medication (midazolam).
One double-blind, crossover RCT in 18 BD patients with treatment resistant depression on lithium or 
depakote maintenance compared antidepressant response after add-on ketamine versus saline infusion (1). 
Results showed markedly superior response to ketamine at 40 minutes post-infusion remaining significant 
until Day 3, but change in the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item did not 
differ by treatment (1). This group conducted a replication trial in an independent sample of 15 depressed 
BD patients and found similar antidepressant effects as well as reduction in the suicide items of the 
MADRS, Hamilton Depression Rating Scale (HDRS), and Beck Depression Inventory from 40 minutes to 
several days after ketamine but not saline infusion (2). Neither trial explicitly sought enrollment of suicidal 
patients, a key issue since pre-treatment suicidal ideation severity appears to be a moderator of treatment 
effect on suicidal ideation itself (3). Both studies used single scale items rather than a state of the art suicidal 
ideation rating instrument, such as the Beck Scale for Suicidal Ideation (SSI) (4). Saline control was used in 
both studies, which given ketamine's dissociative and psychotomimetic effects, may compromise blinding. 
Both trials were remarkable for a lack of adverse events and absence of a significant signal for ketamine-
induced mania, an obvious concern in this population (1, 2).
In unipolar Major Depressive Disorder (MDD), several studies found reduction of suicidal ideation in as 
little as 40 minutes after sub-anesthetic, intravenous (iv) ketamine infusion (5-9). Improvement in suicidal 
ideation lasted up to 4 hours, and up to 12 days with repeat infusions. A recent study added open ketamine 
infusion to emergency department patients’ current medication and/or psychosocial treatment and found 
improvement in suicidal ideation lasted for 10 days. We have replicated these antisuicidal results in an 
ongoing study of ketamine in depression: In N=6 patients who presented with HDRS suicide item score of 1 
or higher, all scored zero 24 hours post-ketamine. Two ketamine studies in MDD used a saline control, 
which is suboptimal due to ketamine’s dissociative and psychotomimetic side effects, and testing for 
adequacy of the blind was not reported.
Given the public health importance of suicidal behavior, lack of antisuicidal treatments for patients with BD 
who are at higher risk, and promising early results for ketamine, we propose to enroll 5 additional depressed 
BD patients with moderate to severe suicidal ideation. Subjects will undergo a 1-hour structural and 
functional MRI within 2 days before and 2 days after an open ketamine infusion following the same 
procedure is in the currently approved protocol, but without blinding or randomization.
Specific Aims and Hypotheses
Specific Aims and Hypotheses
PRIMARY AIM: The primary study aim will be to explore structural and functional MRI effects from 
before to after ketamine infusion in Bipolar Disorder during a major depressive episode with moderate to 
severe suicidal ideation. Unless contraindicated, patients will continue their current psychotropic 
medication. The goal will be to use pilot data for a neuroimaging grant application. Subjects will be 
administered the same clinical and neuropsychological assessments as in the currently approved protocol.
Exploratory AIM 1: Cognitive dysfunction is associated with suicide attempt (Keilp et al 2001). Therefore 
we will compare neurocognitive effects of ketamine vs. midazolam as in our R01-funded study. Our pilot 
data show that memory improvement correlates with reduction in suicidal ideation, even after adjusting for 


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depression improvement. We will explore this further by measuring performance on the Buschke Selective 
Reminding Task and other brief cognitive tests at baseline and post-infusion. 
Exploratory AIM 2: To assess suicidal ideation and behavior using the SSI and the Columbia-Suicide 
Severity Rating Scale (C-SSRS)(Posner et al 2011) during the initial 6 weeks of clinical follow-up after 
infusion.
Description of Subject Population
Sample #1
Specify subject population
Bipolar depression with moderate to severe suicidal ideation
Number of completers required to accomplish study aims
N=5
Projected number of subjects who will be enrolled to obtain required number of completers
10
Age range of subject population
18-65
Sample #2
Specify subject population
Healthy controls
Number of completers required to accomplish study aims
2
Projected number of subjects who will be enrolled to obtain required number of completers
4
Age range of subject population
18-65
Gender, Racial and Ethnic Breakdown
We expect the gender and ethnic breakdown to be consistent with the cumulative sample to date (N=16):
 
Male = 6 (37.5%)
Female = 10 (62.5%)
 
Hispanic = 1 (6%)
Non-Hispanic - 15 (94%)
 
White = 14 (88%)
Asian = 1 (6%)


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Mixed race = 1 (6%)
Description of subject population
Patients 
The goal is to recruit bipolar depressed patients with current Scale for Suicidal Ideation (SSI)
score of 4 or greater, to result in a sample with, overall, moderate to severe suicidal ideation.
Based on studies in our clinic, subjects come from the 5 boroughs of New York City and the
nearby tri-state suburbs.
 
Healthy Controls
The two healthy control subjects will not have any Axis I diagnosis (specific phobia acceptable), borderline 
personality disorder, or antisocial personality disorder.
Recruitment Procedures
Describe settings where recruitment will occur
Patients are recruited through advertisements, clinician referrals, and hospital clinic, inpatient and
emergency services.
How and by whom will subjects be approached and/or recruited? 
Subjects will be approached/recruited by study research assistants, psychologists and psychiatrists.
How will the study be advertised/publicized? 
Local media, internet, mailings to clinicians, outreach to the CPMC and other local emergency departments, 
clinical facilities, or relevant organizations. CUMC's research study search engine, RecruitMe, is one web-
based tool that will be used.
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
01944293
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
MIND umbrella protocol (IRB 4815) and screening protocol (IRB 5880R).


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Inclusion/Exclusion Criteria
Name the subject group/sub sample
Bipolar ketamine vs midazolam
Create or insert table to describe the inclusion criteria and methods to ascertain them
 1. Bipolar, major depressive episode, with 17-item 
HDRS score of 16 or greater. Patients may be 
psychiatric medication-free, or if on psychiatric 
medication, not responding adequately given 
current MDE with suicidal ideation (see 2).      
DSMIV criteria by 
SCID-I administered 
by trained assessors; 
medication history; 
clinical evaluation; 
HDRS. 
 2. Moderate to severe suicidal ideation as 
indicated by Beck Scale for Suicidal Ideation (SSI) 
score of 4 or greater.
SSI scale, clinical 
assessment.
 3. 18-65 years old
 Interview
 4. Patient must agree to voluntary admission to 
NYSPI inpatient research unit for infusion phase.
 Interview, informed 
consent.
 5. Female patients of child-bearing age must be 
willing to use an acceptable form of birth control 
during participation, such as condoms, diaphragm, 
oral contraceptive pills.
 Interview, informed 
consent.
 6. Must be co-enrolled in IRB#4815 (PI: 
Oquendo)
 Informed consent.
 7. Able to provide informed consent.
 Interview
 8. Subjects 61-65 years old must score 25 or 
higher on MMSE at screening.
 Mini Mental State 
Exam
Create or insert table to describe the exclusion criteria and methods to ascertain them
 1. Unstable medical or neurological illness including 
baseline hypertension (BP > 140/90) or significant 
history of cardiovascular illness.*
Baseline medical 
evaluation 
including blood 
pressure, heart 
rate, physical 
exam, routine 
labs, and 
electrocardiogram 
(ECG). 
 2. Significant ECG abnormality (e.g. ventricular 
tachycardia, evidence of ischemia, symptomatic 
bradycardia, unstable tachycardia, second degree or 
 Baseline ECG.


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greater AV block).
 3. Pregnancy/lactation.
 Baseline 
serum pregnancy 
test.
 4. Current psychotic symptoms.
 Clinical 
assessment and 
baseline SCID-I.
 5. Contraindication to any study treatment.
 Medical 
assessment and 
history.
 6. Current or past ketamine abuse or dependence; any 
drug or alcohol dependence within past 6 months; 
suicidality only due to binge substance use or 
withdrawal.
 Clinical 
assessment, 
SCID-I, urine 
drug screen.
 7. Inadequate understanding of English.
 Clinical 
assessment.
 8. Prior ineffective trial of or adverse reaction to 
ketamine or midazolam.
 Clinical 
assessment.
 9. Opiate use greater than total daily dose of 20mg 
oxycodone or equivalent during the 3 days pre-infusion.
 Clinical 
assessment and 
medical records.
 10. 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 Trail-making B 
will be excluded from study participation.
Clinical interview 
and 
medical history. 
Trail-making A & 
B, as needed.      
 11. 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
interfere with the MR 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 MRI study at the discretion of the 
investigator.
Interview, MRI 
Safety screening 
form
12. Claustrophobia significant enough to interfere with 
MRI scanning   
 Clinical interview
 13. Weight over 350 lbs or inability to fit into MRI 
scanner.
 Weight and 
maximal body 


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circumference (if 
necessary) as part 
of physical exam; 
visit to MRI suite 
if necessary.**
*HIV is not an exclusion if the subject’s depressive illness pre-dates HIV diagnosis, and the HIV is well-
controlled as indicated by: 1) Undetectable viral load (plasma HIV-1 RNA level < 50 copies/mL) to be 
confirmed by lab result provided by potential subject and/or discussion between study staff and subject’s 
HIV treatment provider; and 2) Potential subject has a normal finger-tapping test at screening evaluation.
**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, 55cm. The subject also may be brought to the 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 and will be provided with referrals.
Inclusion/Exclusion Criteria #2
Name the subject group/sub sample
Healthy Controls
Create or insert table to describe the inclusion criteria and methods to ascertain them 
 1. Absence of major psychiatric illness (specific 
phobia permissible), borderline personality 
disorder, and antisocial personality disorder.
 DSMIV criteria by SCID-
I and SCID-II 
administered by trained 
assessors; clinical 
evaluation.
 2. 18-65 years old.
 Interview
 3. Female subjects of child-bearing age must be 
willing to use an acceptable form of birth control 
during participation, such as condoms, 
diaphragm, oral contraceptive pills.
 Interview, informed 
consent.
4. Must be co-enrolled in IRB#4815 (PI: 
Sublette)
 Informed consent
 5. Able to provide informed consent.
 Interview
 6. Subjects 61-65 years old must score 25 or 
higher on MMSE at screening.
 Mini Mental State Exam
Create or insert table to describe the exclusion criteria and methods to ascertain them 
 1. Unstable medical or neurological illness including 
Baseline 


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baseline hypertension (BP ≥ 140/90) or significant history of 
cardiovascular illness.*
medical 
evaluation 
including 
blood 
pressure, 
heart rate, 
physical 
exam, and 
routine labs.
 2. Pregnancy/lactation.
 Baseline 
serum 
pregnancy 
test.
 3. Inadequate understanding of English.   
 Clinical 
assessment.
 4. A neurological disease or prior head trauma with evidence 
of cognitive impairment. Subjects who endorse a history of 
major head trauma and score 1.5 standard deviations below 
the mean on Trail-making B will be excluded from study 
participation.
 Clinical 
interview and 
medical 
history. Trail-
making A & 
B, as needed.
 5. 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 
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 MRI study at the discretion of the investigator.
 Interview, 
MRI Safety 
screening 
form
 6. Claustrophobia significant enough to interfere with MRI 
scanning
 Clinical 
interview
 7. Weight over 350 lbs or inability to fit into MRI scanner.
 Weight and 
maximal 
body 
circumferenc
e (if 
necessary) as 
part of 
physical 
exam; visit to 
MRI suite if 
necessary.**


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*HIV is not an exclusion if the HIV is well-controlled as indicated by: 1) Undetectable viral load (plasma 
HIV-1 RNA level < 50 copies/mL) to be confirmed by lab result provided by potential subject and/or 
discussion between study staff and subject’s HIV treatment provider; and 2) Potential subject has a normal 
finger-tapping test at screening evaluation.
**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, 55cm. The subject also may be brought to the 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 and will be provided with referrals.
 
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 # 
5880R, 4815
Describe Study Consent Procedures
a. Subject is given a detailed, verbal explanation of this study and IRB #5880R, 4815 and given a signed
copy of all consent forms.
b. Subject gives written informed consent to participate in IRB #5880R, 4815 and this study.
c. Subject receives medical evaluation under 4815 and this study. Genetics blood sample is under IRB
#4815 (Biological and neuropsychological measures for genetic studies of psychiatric
populations—PI: Oquendo).
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form


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   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
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?
No
Study Procedures
Describe the procedures required for this study
1. Screening
a. We will recruit inpatients or outpatients with bipolar disorder during a major depressive episode. We will 
also recruit two healthy control subjects who will not receive a ketamine infusion but who will only 
complete the two MRI scan procedures.
b. Subject completes phone screen, approved under IRB #5880R. If subject appears
eligible based on the phone screen, they will be scheduled for an in-person screening visit
under Screening Protocol IRB #5880R to determine whether inclusion/exclusion criteria
(excluding medical screening) are met.
c. Subject is given a detailed, verbal explanation of this study and IRB #4815.
d. Subject gives written informed consent to participate in IRB #4815 and this study and is given a copy of 
both signed consent forms.
e. Subject receives medical evaluation under IRB 4815 and this study. Genetics blood sample is under
IRB #4815 (Biological and neuropsychological measures for genetic studies of psychiatric
populations—PI: Oquendo).
f. During the period between enrollment and the infusion, the treating physician will
assess the patient weekly in person or by phone, including a Clinical Global Impression
(CGI) scale. If concerns are noted during a telephone contact, subjects will be brought in
for an in-person visit. If someone has a CGI-I >5 then a repeat CGI-I will be done within
3-4 days and if it remains >5 then the subject will be withdrawn; or 2) their CGI
Improvement score is six or seven on one occasion and the treating psychiatrist


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assesses that they cannot safely continue research participation. 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 . During the 72 hours before baseline MRI scans, PRN diphenhydramine, hydroxyzine, or quetiapine will 
be permitted for insomnia or anxiety. No zolpidem, benzodiazepine, or stimulant will be permitted during 
this time. Subjects who at enrollment are taking a benzodiazepine or stimulant will be tapered during the 
weeks between enrollment and the scan/infusion phase. We will monitor patients for signs of withdrawal, 
such as severe anxiety, diaphoresis, tachycardia
(HR greater than 100), or hypertension (BP greater than 140/90) and if such signs are
present, or subjects cannot tolerate the taper, then the taper will be extended, if possible, or if not then the 
subject will be withdrawn from the protocol. 
b. Current mood stabilizers, antipsychotic and antidepressant medications will be maintained at a stable dose 
during the 2 weeks prior to scanning/infusion. 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 as
inpatients. The independent inpatient treatment team must agree that study participation is clinically 
reasonable.
b. For patients who require hospitalization because of destabilization or suicidal risk, we will attempt to 
arrange admission to NYSPI. Hospitalized patients will be discharged from the 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 cellphone 24 hours a day, seven days a week.
Patients requiring urgent admission will be brought to the CUMC Emergency Dept. by the
study physician with security assistance, if needed. Non-emergent admissions will be
arranged by the treating psychiatrist, if possible to NYSPI. Patients who are
deemed to require hospitalization, but who refuse, will receive all necessary interventions such
as contacting the local crisis team, family, or Emergency Medical Services.
 
4. Pre-Infusion Research Measures
a. Baseline clinical and neuropsychological ratings (See Figure 2, attached).
b. Saliva Cortisol: We will measure salivary cortisol using Salivettes (Sarstedt, Germany) at the
following time-points for both the initial infusion and the optional open ketamine infusion:
Time-Sensitive (within 72 hours pre-infusion) and 24 HR Post-Infusion Day (i.e., Day 1
Follow-Up). The samples will be collected fasting and before the patient has taken any
medication that day. At each time point, patients will be asked to provide two samples, one immediately on 
waking in the morning and a second sample 30 minutes later. Samples will be processed in the Nathan Kline 
Institute laboratory of Thomas Cooper, M.A..
 
5. Inpatient Research Phase
a. To participate in the study, patients must agree to inpatient hospitalization at NYSPI
(4-Center or 5-South units) for the MRI scans and infusion. The duration of the inpatient study phase will be 
1-2 weeks. Our goal will be for the admission to be as short as possible, though participants will be offered 


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further inpatient treatment 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. Patients who need to be kept involuntarily for safety reasons will 
be withdrawn from research and treated clinically. 
b. We will attempt to schedule the study infusion as close as possible to the date of
enrollment, given time for screening lab results, inpatient admission and BSU and MRI 
scheduling. 
c. MRI/fMRI Scan:
MRI scans will be performed at the New York State Psychiatric Institute MRI facility. Subjects will receive 
an array of structural and functional MRI scans lasting 60 minutes at baseline, within 48 hours prior to 
ketamine infusion, and the scans will be repeated within 48 hours post-infusion. For the two healthy control 
subjects who will not receive a ketamine infusion, the two MRI scans will be separated by a period of 48 to 
96 hours. We will attempt to perform the follow-up MRI scanning session prior to initiating other treatments 
if possible. Structural scans will include T1-weighted images and DTI. Scans will include high-resolution 
imaging of the hippocampus. The procedure will be stopped if subjects exhibit significant distress.
Because this MRI scan is being performed for research purposes, 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 and T2* echoplanar 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, for the 
baseline MRI scan, 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. When there is evidence of a mass lesion, 
hydrocephalus or other significant abnormality, a qualified clinician will call the subject and then a letter 
will be sent, depending on the urgency, and at the discretion of the investigator and neuroradiologist. 
 
d. All patients will be NPO after midnight prior to study infusion and will be escorted by study
staff to and from the BSU where the infusion will occur.
e. For subjects currently taking psychiatric medication, we will give advance notice of infusion scheduling 
to anesthesiologist consultant, Dr. Moitra, to confirm his or a back-up anesthesiologist's availability for 
phone consultation during the infusion, if needed.
f. Pre-infusion blood level of BDNF will be measured by drawing a blood sample through
the iv site. This will be analyzed in the NKI lab of Tom Cooper. 
 
8. Ketamine Infusion
a. The infusion medication will be prepared by the NYSPI research pharmacy.
Patients will receive an open-label 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 continuous monitoring of the subject by a
study physician.
 
b. Vital Signs Monitoring: During study infusion(s), blood pressure, heart rate, respiratory
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)


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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. Respiratory rate and
oxygen saturation will continue to be obtained until there are two measurements at
least 15 minutes apart that are within normal limits (RR of 10 or greater; 0xygen
saturation of 94% or greater). Immediate post-infusion ratings, including suicidal ideation assessment, are 
done by the physician.
 
c. The physician and Research Assistant who remain in the patient’s room during the infusion
record the vital signs. After the subject is transferred back to their inpatient unit, the
blood pressure and heart rate will be obtained manually by the unit nursing staff.
 
d. 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:
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. If they do not respond to the above treatment (d.) then they will be 
transferred to the ER. 
 
e. Intervention for Decreased Oxygen Saturation or Respiratory Rate:
1) If 02 saturation is <94%, the patient will be given oxygen via nasal canula; then if 02
saturation returns to ≥94%, the infusion will be continued. If 02 saturation remains <94%
with nasal canula oxygen, then the infusion will be stopped, the anesthesiologist
called, and if necessary the patient will be transferred to the ER.
 
9. Post-Infusion Lab Tests
a. BDNF, ketamine and norketamine levels will be measured by drawing blood samples
with a blood-draw separate from the iv site. These will be analyzed in the NKI lab of Tom
Cooper.
b. Post-infusion saliva cortisol: Same procedure as Pre-Infusion (4b above).
 
10. Post-Infusion Treatment
a. After the post-infusion MRI scan and related research measures are completed, all patients will receive 
open clinical treatment. Patients will be offered a total of 6 months treatment including inpatient and 
outpatient phases. During open clinical treatment, medication will be changed for those patients who don't 
respond or whose response is transient.
b. Follow-up clinical research ratings will be done for the first 6 weeks of post-infusion treatment.
c. Continuation appointments will be weekly for six weeks, then decreasing to


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at least monthly, as clinically indicated, for the remainder of the six months.
d. In all follow-up treatments, psychiatrists will be available to patients between sessions for
consultations and emergencies (a research psychiatrist is on-call at all times). Thus, clinical
management will provide careful assessment of the patient's clinical condition to determine clinical
changes, safety, and the need for withdrawal from the protocol. Psychiatrists will evaluate mood,
suicidality, and treatment course to help determine if a patient's condition warrants removal from
the study. Independent, masters or PhD level, raters will systematically assess suicidal ideation
and/or behavior and depression weekly during the 6-week continuation phase for exploratory
analysis.
f. At the end of the 6 months of treatment patients will be referred for ongoing care.
 
11. Outcome Measures: See Figure 2, Schedule of Research Procedures and
Assessments (attached).
 
12. Safety Follow-up for Ketamine Abuse/Use:
a. At 3 and 6 months post-ketamine/midazolam, all patients we can contact will be evaluated to determine 
the absence of post-exposure ketamine use/abuse.
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
Criteria for Early Discontinuation
13. Withdrawal from Study: Subjects will be withdrawn from the study if:
a. They request it for any reason.
b. The PI judges that it is medically unwise to continue in the study, for example if the
subjects are unable to comply with the study procedures.
c. They are unable to tolerate the delay to treatment because of pronounced worsening
of symptoms such as marked agitation, mania, or psychotic symptoms. Worsening of suicidal ideation
will not automatically require discontinuation from research, since this is the primary study aim,
as long as the team judges that the patient 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.
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 oxygen saturation remains <94% with nasal canula oxygen or respiratory
rate <10, then patient will be withdrawn from research and treated clinically as described in
Section 8.e.
f. Inability to tolerate MRI scanning. 
g. 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.


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Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
 Patients
 Sample  Timepoint
 Total Collected Per Patient
 Blood
 Baseline
 Pre and Post-infusion
59 ml
32 ml total (64 ml if two
infusions)
 Saliva
 Pre-infusion (2 samples)
 Post-infusion (2 samples) 
 1ml per sample = Total 4 ml
 
Healthy Controls
 Sample
 Timepoint
 Total Collected Per Subject
 Blood
 Baseline screen
 59 ml
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Informed consent 
IRB approved form (30-45 min)
Diagnosis 
SCID I, II (1-2 hrs)
Demographics 
Division Baseline Demographic form (BDEMO) (30 min)
Clinical State 
24-item Hamilton Depression Rating Scale (HDRS) (15-20 min)
Beck Depression Inventory (BDI) (5 min)
Profile of Mood States (POMS) (10 min)
Global Assessment Score (GAS) (1 min)
Anxiety Visual Analog Scale (5 min)
Clinical Global Impressions (CGI) (1 min)
Young Mania Rating Scale (YMRS) (10 min) 
Suicidal Ideation and behavior 
Columbia Suicide History (CSH) and Lethality Rating Scale (LRS) (up to 20 min)
Beck Scale for Suicidal Ideation (SSI) (10 min)
Columbia Suicide Severity Rating Scale (C-SSRS) (10 min)
Beck Suicide Intent Scale (SIS) (10 min)
Brown Goodwin Aggression Inventory (BGAI) (up to 20 min)
Life Events 


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St. Paul Ramsey scale (SPR) (15 min)
Axis IV (5 min)
Medication 
Antidepressant Treatment History Form (ATHF) (20 min)
Systematic Assessment for Treatment Emergent Events-General Inquiry (SAFTEE) (10 min)
Clinician-Administered Dissociative States Scale (CADSS) (15 min)
Brief Psychiatric Rating Scale (BPRS) positive symptoms subscale only (10 min)
Biomarkers 
Saliva cortisol (10 min) 
Neuropsychological tests (60 min at Baseline and 60 min on Day 1 post-infusion):
      WAIS-III Vocabulary (pre-infusion only)
      WAIS-III Digit Symbol
      Letter and Category Fluency
      Buschke Selective Reminding Test
      Computerized Choice Reaction Time
      Computerized CPT
      Computerized Stroop Task
      Computerized A, Not B
      Computerized Go-No Go Task
      Computerized Fish/Face Task
      Cambridge Gambling Task
      Implicit Associations Task (Suicide version)
Please attach copies, unless standard instruments are used
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
1
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


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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].
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
Patients will continue their current psychiatric medication (as described in Procedures). The delay to 
inpatient admission will generally not exceed 2 weeks; if a subject needs a longer delay between consent 
and beginning treatment 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, MRI scans, and the infusion procedure in the BSU. We will attempt to minimize this delay. 
During this time the treating physician will contact the participant to assess their clinical condition weekly, 
either in person or via phone, including the Clinical Global Impressions (CGI) scale. If items of concern are 
noted during a telephone contact, the participant will be brought in for an in-person visit. If someone has a 
CGI-I >5 then a repeat CGI-I will be done within 3-4 days and if it remains >5 then the subject will be 
withdrawn from research and start clinical treatment. Additionally, if the team judges that this delay is not 
clinically acceptable or the participant does not agree to the delay, then the patient will be withdrawn from 
research.
Maximum duration of delay to standard care or treatment of known efficacy
 
For subjects not already taking medication for bipolar disorder, treatment with standard medication will 
begin on the day after the post-infusion MRI scan. This may add approximately 3-5 inpatient days to the 
delay described above, depending on MRI and infusion scheduling, since patients will usually be admitted 
to NYSPI a day or two before the baseline MRI scan. This delay may be slightly longer if a patient needs or 
wants to be admitted further in advance of the infusion. 
Treatment to be provided at the end of the study
Described in Procedures (Section 10) above.


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Clinical Treatment Alternatives
Clinical treatment alternatives
This is a pilot study to test feasibility and potential neural correlates of MRI scans before and after a sub-
anesthetic ketamine infusion in patients with bipolar depression and suicidal thoughts. Various treatments 
for bipolar depression exist, such as numerous approved antidepressant medications, ECT, and 
various psychotherapies. Relatively little is known about best practices for more suicidal depressed 
bipolar patients, or regarding the antidepressant mechanism of ketamine.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
Potential Risks to Subjects and Procedures for Minimizing Risks:
Risks associated with participation in this study are related to 1) side effects of ketamine; 2)
other medication related risks; 3) intravenous catheter; 4) blood drawing; 5) pregnancy; 6) MRI Scanning. 
We have experience with this ketamine dose in our ongoing trial in unipolar depression (IRB 6598). The 
latter study's consultant, Dr. Vivek Moitra, MD, Associate Clinical Professor of Anesthesiology, Associate 
Medical Director Surgical Intensive Care Unit, Associate Program Director, Critical Care Medicine 
Fellowship, Division of Critical Care, Columbia University College of Physicians and Surgeons, is 
experienced with ketamine and is a consultant on this study also.
 
1. Side effects of medications:
 
1.A. Side Effects of Intravenous Ketamine.
i) Medical Risks. 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 a brain imaging protocol 
at this institution (IRB #5786, PI: J. Mann). The resulting effects on vital signs for the eleven patients 
scanned under protocol #5786 are presented as a function of time in Table 1 below for the duration of the 
ketamine injection. These modest increases all peaked and largely resolved by 75 minutes, with vitals 
returning to near baseline.
 
Table 1. Effects of ketamine on systolic and diastolic blood pressure in a group of patients
(n=11). The dose of ketamine was 0.5 mg/kg given over 40 minutes.
 Tim
e
(min
) 
 Systolic BP during 
Ketamine (mm Hg)
 Diastolic BP during 
Ketamine (mm Hg)
Pulse during 
Ketamine 
 0
 111
 70
 69
5 
113 
72 
63 
 10
116 
73 
69 
 15
116 
73 
72 


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 20
121 
75 
68 
 25
121 
78 
73 
 30
120 
77 
72 
 35
124 
78 
73 
 40
122 
78 
79 
 45
122 
78 
74 
 50
116 
75
73 
 55
121 
76 
74 
 60
123 
76 
75 
 65
124 
79 
75 
 70
121 
81 
76 
 75
114 
75 
76 
 
2. MRI and fMRI Scan
The MRI scanner uses a large magnet (3 Tesla) 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. Subjects will be asked to notify us if this is the case. The long-term effects of being
placed in a magnet of 3T are unknown. 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. 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 the body. Occasionally,
some people experience nervousness or claustrophobic feelings due to the scanner's small
space. Despite these experiences, in our experience, no one has had sensations from the
scanning that did not stop as soon as the scanning stopped. The MRI scan is not painful, but
having to lie still in the enclosed space of the scanning table is uncomfortable for some people.
 
c. Pregnancy
Although there are no known risks associated with pregnancy, we will not scan
someone who is known to be pregnant. 
 
Describe procedures for minimizing risks
Describe procedures for minimizing risks
ii) Specific measures and precautions
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 history of
cardiovascular illness. A physician, Dr. Michael Grunebaum (ACLS certified 05/22/2012; copy of
certification attached), will be present during the procedure. If physician coverage for Dr.
Grunebaum is needed (such as vacation), then another ACLS-certified MIND physician (Drs.
Matthew Milak or Martin Lan), who has been trained in the infusion procedure, will be present.


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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. For
these reasons, the medical risks involved in participation in this study will be minimized.
 
iii) Psychiatric or Behavioral Risks. 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 (10). 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 N=27 depressed bipolar patients without any serious adverse events (1, 2). Subjects will be 
informed that immediate effects of the infusion may be unpleasant and they may feel worse.
 
iv) Specific measures and precautions
The experiment will be carried out in the presence of at least one psychiatrist. Severe
agitation, hyperarousal, or psychosis 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. Immediate post-infusion ratings will include safety questions 
about suicidal ideation.
 
2.A.3. Side Effects of Other Medications
Diphenhydramine, hydroxyzine: The potential side effects are dizziness, drowsiness, a drugged
feeling, and dry mouth.
 
2.B. Other medication related risks:
Benzodiazepine/Stimulant taper:  As described under Study Procedures, During the 72 hours before 
baseline MRI scans, PRN diphenhydramine, hydroxyzine, or quetiapine will be permitted for insomnia or 
anxiety. No zolpidem, benzodiazepine, or stimulant will be permitted during this time. Subjects who at 
enrollment are taking a benzodiazepine or stimulant will be tapered during the weeks between enrollment 
and the scan/infusion phase. We will monitor patients for signs of withdrawal, such as severe anxiety, 
diaphoresis, tachycardia (HR greater than 100), or hypertension (BP greater than 140/90) and if such signs 
are present, or subjects cannot tolerate the taper, or feel a need for an adjustment, then the taper will be 
extended or the subject can be withdrawn from the protocol. 
Fixed Dose:  Current mood stabilizers, antipsychotic and antidepressant medications will be maintained at a 
stable dose during the 2 weeks prior to scanning/infusion. Minor dose adjustments may be made pre-
infusion, such as to reduce side effects. If a subject feels they need an adjustment, they can be withdrawn 
from the protocol.


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Delay to Treatment: We will schedule the scans and infusion as soon as possible. Patients on 
psychotropic medications may continue them as described in Procedures. Patients may experience 
worsening of their depressive symptoms during this period and this will be discussed with all subjects as 
part of the consent process.
Non-response: There is a chance that the medications and/or dosages used in this study will not
be helpful or that a participant may feel worse during participation in the study. Participants will be
encouraged to tell their doctor if they feel worse during the study.
 
Other Risks Associated with Antidepressant Use:
The Food and Drug Administration (FDA) has issued a public health advisory concerning a
possible link between worsening depression, and, in rare cases, suicidal thoughts or behavior in
adults younger than 25 years of age treated with certain antidepressant medications (including
those in this study). This FDA advisory will be discussed with all subjects as part of the consent
process.
 
2.C. Risks from Intravenous Catheters. 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.
 
2.D. Blood Drawing: The risks associated with drawing blood are slight discomfort and
occasional bruising. There is no risk of anemia in a physically healthy person with the amounts of
blood drawn in this study.
 
2.E. Interviews: Psychiatric interviews and neuropsychological testing can sometimes be
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.
 
2.F. Saliva sampling: This procedure has no significant risks other than minor inconvenience.
 
2.G. Pregnancy: Pregnancy is one of the study’s exclusion criteria and will be ascertained at
screening with a pregnancy test. 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. A pregnancy test will be repeated within 24 hours pre-infusion. If a patient becomes pregnant
during the study, they will be withdrawn from research and treated clinically.
 
2. H. Electrocardiogram
An electrocardiogram has no serious risks. On rare occasions a rash may develop where the
electrodes are placed which usually resolves without treatment.
 
3. Data and Safety Monitoring Plan: The Principal Investigator will be responsible for monitoring
the safety and sound clinical care of all study participants through a weekly team meeting and as
needed.


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3.a. Adverse events. Serious adverse events will be reported per regulatory requirements. Other
adverse events will be monitored using the SAFTEE-GI (17) and a weekly meeting of the research
team.
3.b. Data and Safety Monitoring Board
i) Membership: The Data Safety Monitoring Board (DSMB) that is already in place for our ongoing 
ketamine/midazolam study in unipolar depression (IRB 6598) will also monitor the add-on study described 
in this protocol. The three DSMB members are experienced researchers from other institutions.
ii) Responsibilities: Throughout the study, notification of any Serious Adverse Events (SAEs) as
well as any investigator-initiated changes in the protocol will be submitted to the DSMB when they
are submitted to the IRB. Based on its review of the protocol, the DSMB will identify the data
parameters and format of the information to be regularly reported. The DSMB may at any time
request additional information from the Principal Investigator. The DSMB may monitor study charts
or delegate this task to the personnel of the New York State Psychiatric Institute IRB.
Other than SAEs, adverse events will be tabulated and submitted to the IRB and DSMB annually.
SAEs are also reviewed by the Incident Review Committee of the New York State Psychiatric
Institute. The DSMB will initially be given data blinded to treatment status but may request
unblinding if there is a safety concern.
Based on review of safety data, the DSMB will make recommendations concerning the conduct of
the study. These may include amending safety monitoring procedures, modifying the protocol or
consent, terminating the study or continuing the study as designed.
iii) DSMB Meetings will be on a semi-annual basis but can be more frequent as indicated.
Meetings:
iv) Reports: The discussions and decisions of the DSMB will be summarized in written reports
and provided to the NIMH Program Officer in annual reports.
v) HIPAA Procedures: This grant will go through Columbia University and will be conducted at
the New York State Psychiatric Institute and Columbia University Medical Center. All HIPAA
requirements will be followed including forms for patients to sign and receive a copy to keep as
part of the informed consent process.
 
4. Discomfort during MRI scanning
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. Our research staff will be
present at all times, and a staff psychologist or psychiatrist will be available at all times. If subjects 
experience significant anxiety or claustrophobia, we will offer them the option of administering a short-
acting benzodiazepine, and performing only structural and DTI scans. If subjects do not complete fMRI 
tasks due to anxiety/claustrophobia, they may perform these tasks on a computer outside of the scanner.
 
Pregnancy: 
Women of child-bearing age will be required to have a pregnancy test administered after enrolling in the 
study as well as on the day of each MRI scan prior to scanning, and within 24 hours of the ketamine 
infusion. In addition, nursing mothers will also be excluded from the study. 


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Methods to Protect Confidentiality
Describe methods to protect confidentiality
Records will be kept in locked storage and access will be allowed only to members of the research team or
institutional personnel as part of a routine audit. Research records, like other medical and clinical records,
will be kept confidential to the extent permitted by law. Once a patient enrolls in the project they are given a
code number for all subsequent computer data and/or lab forms. The code list and patient names as well
as all data are kept in locked offices with access limited to those directly responsible for
maintenance of these files by the research team. The data capture system we will use in this study,
StudyTRAX, has been used as a data repository for NIH sponsored projects at NYSPI and is HIPAA
compliant. Data sets are de-identified as defined in HIPAA 45 C.F.R. §164.514 (b)(2).
Will the study be conducted under a certificate of confidentiality?
No
Direct Benefits to Subjects  
Direct Benefits to Subjects
Subjects will receive a complete medical, neurological and psychiatric evaluation, results of which will be
communicated to them. Subjects are not expected to benefit directly from participation in this study,
however, patients will be offered a total of six months of medication based treatment for depression. 
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.
We will give patients a modest inconvenience payment of $20 cash for each outpatient visit at which
research data are collected, which we believe will not be coercive but will help recruitment and decrease
attrition. Patients will not receive payment for research assessments, MRI scans or procedures during the 
inpatient stay. Healthy controls will be compensated with $75 for completing the first MRI scan and $125 
for completing the second MRI scan. Compensation for the second scan is higher to incentivize completion 
of both scans, which is necessary for the data to be of use.
References
References
(1) DiazGranados N, Ibrahim L, Brutsche NE et al. A randomized add-on trial of an N-methyl-D-aspartate 
antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010;67(8):793-802.


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(2) Zarate CA, Jr., Brutsche NE, Ibrahim L et al. Replication of ketamine's antidepressant efficacy in bipolar 
depression: a randomized controlled add-on trial. Biol Psychiatry 2012;71:939-46. 
(3) Grunebaum MF, Ellis SP, Duan N, Burke AK, Oquendo MA, Mann JJ. Pilot randomized
clinical trial of an SSRI vs bupropion: effects on suicidal behavior, ideation, and mood in major
depression. Neuropsychopharmacology 2012 February;37(3):697-706. 
(4) Beck AT, Kovacs M, Weissman A. Assessment of suicidal intention: The scale for suicide
ideation. J Consult Clin Psychol 1979;47(2):343-52.
(5) Berman RM, Cappiello A, Anand A et al. Antidepressant effects of ketamine in depressed patients. Biol 
Psychiatry 2000 February 15;47(4):351-4.
(6) Zarate CA, Jr., Singh JB, Carlson PJ et al. A Randomized Trial of an N-methyl-D-aspartate Antagonist 
in Treatment-Resistant Major Depression. Arch Gen Psychiatry 2006 August 1;63(8):856-64.
(7) Kudoh A, Takahira Y, Katagai H, Takazawa T. Small-dose ketamine improves the postoperative state of 
depressed patients. Anesth Analg 2002;95:114-8.
(8) Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit 
measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009;66(5):522-6.
(9) DiazGranados N, Ibrahim LA, Brutsche NE et al. Rapid resolution of suicidal ideation after a single 
infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive 
disorder. J Clin Psychiatry 2010;71(12):1605-11.
(10) Krystal JH, Karper LP, Seibyl JP et al. Subanesthetic effects of the noncompetitive NMDA
antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine
responses. Arch Gen Psychiatry 1994;51(3):199-214.
(11) Brunton LL, Lazo JS, Parker KL. Goodman & Gilman's The Pharmacological Basis of
Therapeutics. 11th ed. New York: McGraw-Hill; 2006.
(12) Evers AS, Maze M, Kharasch ED. Anesthetic Pharmacology: basic principles and clinical
practice. Cambridge: Cambridge University Press; 2011.
(13) Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: Pharmacology and Uses.
Anesthesiology 1985;62:310-24.
(14) Davey HM, Barratt AL, Butow PN, Deeks JJ. A one-item question with a Likert or Visual
Analog Scale adequately measured current anxiety. J Clin Epidemiol 2007 April;60(4):356-60. 
(15) Christe C, Janssens JP, Armenian B, Herrmann F, Vogt N. Midazolam sedation for upper
gastrointestinal endoscopy in older persons: a randomized, double-blind, placebo-controlled study.
J Am Geriatr Soc 2000;48(11):1398-403.
(16) Weinbroum AA, Szold O, Ogorek D, Flaishon R. The midazolam-induced paradox
phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the
literature. Eur J Anaesthesiol 2001;18(12):789-97.
(17) Levine J, Schooler NR. SAFTEE: a technique for the systematic assessment of side effects
in clinical trials. Psychopharmacol Bull 1986;22:343-81.


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Form #PP2: HIPAA Authorization for Research 4.14.14 
New York State Psychiatric Institute (NYSPI) 
Authorization to Use or Disclose Health Information during a Research Study 
Protocol Number: 
Principal Investigator: 
Name of Study: 
Before researchers can use or share any identifiable health information (“Health Information”) about you as part of the 
above study (the “Research”), the New York State Psychiatric Institute (NYSPI) is required to obtain your authorization. You agree 
to allow the following individuals and entities to use and disclose Health Information about you as described below: 
•
New York State Psychiatric Institute (NYSPI), your doctors and other health care providers, if any, and
•
The Principal Investigator and his/her staff (together “Researchers”).   Researchers may include staff of NYSPI, the New York
State Office of Mental Health (OMH), Research Foundation for Mental Hygiene, Inc. (RFMH), and Columbia University (CU),
provided such staff is a part of the study, and
•
Providers of services for the Research at CU, NYSPI and/or RFMH, such as MRI or PET, or  Central Reference Laboratories 
(NKI), if indicated in the consent form.
1.
The Health Information that may be used and/or disclosed for this Research includes:
All information collected during the Research as told to you in the Informed Consent Form.   
Health Information in your clinical research record which includes the results of physical exams, medical and 
psychiatric history, laboratory or diagnostic tests, or Health Information relating to a particular condition that is related  to 
the Research. 
Additional information may include: 
2.
The Health Information listed above may be disclosed to:
Researchers and their staff at the following organizations involved with this Research: 
The Sponsor of the Research, 
and its agents and contractors (together, “Sponsor”); and  
Representatives of regulatory and government agencies, institutional review boards, representatives of the Researchers 
and their institutions to the level needed to carry out their responsibilities related to the conduct of the research.   
Private laboratories and other persons and organizations that analyze your health information in connection with 
this study 
Other (family members or significant others, study buddies, outside agencies etc.) Specify: 
3.
By giving permission to release your Health Information as described above, you understand that your Health
Information may be disclosed to individuals or entities which are not required to comply with the federal and state privacy laws
which govern the use and disclosure of personal Health Information by NYSPI.   This means that once your Health

Columbia University Medical Center


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Ketamine in bipolar depression
Michael F. Grunebaum, MD
6785


Form #PP2: HIPAA Authorization for Research 4.1.14 
Information has been disclosed to a third party which does not have to follow these laws (e.g., a drug company or the Sponsor 
of the Research), it may no longer be protected under the HIPAA or NYS Mental Hygiene Law requirements but is subject to the 
terms of the consent form and may be subject to other state or federal privacy laws or regulations.  
4.
Please note that:
•
You do not have to sign this Authorization form, but if you do not, you may not be able to participate in the study or
receive study related care.  You may change your mind at any time and for any reason. If you do so, you may no
longer be allowed to participate in the study.  If you withdraw this Authorization the research staff and the Sponsor, if this
is sponsored research, may still use or disclose Health Information containing identifying information they already have
collected about you as needed to maintain the reliability of the research.  Any request to withdraw this Authorization
must be made in writing to (enter name and contact information below):
•
While the Research is going on, you may not be allowed to review the Health Information in your clinical research
record that has been created or collected by NYSPI.   When this research has been completed you may be allowed to see
this information.  If it is needed for your care, your Health Information will be given to you or your Doctor.
5.
This Authorization does not have an end date.
6.
You will be given a copy of this form after you have signed it.
I agree to the use and disclosure of Health Information about me as described above: 
__________________________________________                _____________________ 
Signature of Participant/ Legal Representative    
Date 
______________________________________ 
Printed Name of Participant 
______________________________________ 
Relationship of Legal Representative to Participant (if applicable) 
We also ask you or your legal representative to initial the statements below: 
I have received a copy of the NYSPI/OMH Notice of Privacy Practices. 
Michael Grunebaum, MD, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, 
New York, NY 10032

SAP_001.pdf: 
 
 
Study Title:  Ketamine for Suicidality in Bipolar Depression 
 
NCT number:  NCT01944293 
 
Date:  5/14/2019 
 


Statistical methods 
 
The intent-to-treat analysis included all randomized participants. We used R software (r-project.org) and 
SPSS version 23 (IBM, Armonk, NY, USA). Univariate tests compared groups on baseline characteristics. 
Histograms were inspected for normality. The primary hypothesis was tested using a linear regression 
model of day 1 SSI (SSIday1) with baseline SSI (SSIBL) and treatment as the predictors: SSIday1 ~ SSIBL + 
treatment. Secondary analyses tested treatment effect on response and remission. Effect size 
calculations used Cohen’s d and number needed to treat (NNT). We used regression models analogous 
to that for SSI to test effects on depression, mania, and anxiety. The POMS was analyzed with a 
generalized least squares (GLS) model over its three assessment time-points. Since at randomization  
only one subject was not taking psychiatric medications and only one subject had baseline SSI <8, we did 
not adjust for the randomization strata. We tested a repeated measures analysis of covariance 
(ANCOVA) model of SSI, including 230 minute and day 1 assessments, analyzed response to the open- 
label ketamine infusion, and tested the correlation between change in depressive symptoms and change 
in SSI. We plotted mean SSI during the 6-week follow-up in those randomized to ketamine and 
performed paired t tests of the score each week compared to baseline. We investigated infusion effects 
on neurocognition and explored relationships of clinical variables with CAR, serum BDNF, and post- 
infusion plasma ketamine, norketamine and dehydronorketamine.31 Safety analyses investigated 
dissociative, psychotomimetic and cardio-respiratory effects.