Clinical trial NCT02708849
Conditions: Mental Disorders
Sponsor: Yale University
Start date: 2015-06-01; Completion date: 2020-03-01
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to characterize the effects of a single, sub-anesthetic dose of ketamine in rs-fMRI in healthy subjects. Post-ketamine rs-fMRI data will demonstrate a pattern of increased global brain connectivity (GBC) in fronto-temporal cortex.

Detailed description:
In this study, healthy participants will be randomized into one of two parallel groups: (a) open-label ketamine and active lamotrigine, or (b) open-label ketamine with a matched-placebo control (i.e., sugar pill). All participants will complete a baseline rs-fMRI approximately 1-week prior to the ketamine infusion and a follow-up rs-fMRI 24-hours post-infusion. The subanesthetic dose of ketamine (0.23mg/kg bolus followed by 0.58mg/kg infusion over approximately 60 minutes) will be administered via intravenous infusion to occur during the MRS scan. Participants will be administered lamotrigine (300 mg oral dose) or the matched-placebo control about 2-hours prior to the start of the infusion.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Ketamine intervention 2: Lamotrigine intervention 3: Placebo
Intervention descriptions: intervention 1: The subanesthetic dose of ketamine (0.23mg/kg bolus followed by 0.58mg/kg infusion over approximately 60 minutes) will be administered via intravenous infusion intervention 2: lamotrigine (300 mg oral dose) or the matched-placebo control about 2-hours prior to the start of the infusion of ketamine intervention 3: oral dose placebo

Protocol documents:
Prot_SAP_000.pdf: 
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YALE UNIVERSITY
                                  HUMAN INVESTIGATION COMMITTEE
                                     Application to Involve Human Subjects in Biomedical Research
100 FR1 (2013-1) 
DATE STAMPED-RECEIVED
PROTOCOL NUMBER
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: The Sustained Effects of Ketamine
Principal Investigator: Chadi G. Abdallah, 
M.D.
Yale Academic Appointment: Assistant Professor
Department: Psychiatry
Campus Address: Yale Depression Research Program (YDRP), 100 York Street, Suite 2J, New Haven, 
CT 06511
Campus Phone: (347) 987- 0717
Fax: (203) 974-7662
Pager: 
E-mail: 
chadi.abdallah@yale.edu
Protocol Correspondent Name & Address (if different than PI):
 Prerana Purohit
Campus Phone: 203-932-5711 
x5667
Fax: 
E-mail: prerana.purohit@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
Campus Phone: 
Fax: 
E-mail: 
Business Manager:
Campus Phone :
Fax :
E-mail
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)           
 NA
Yale Academic Appointment:
Please refer to the HIC website for application 
instructions and information required to complete 
this application.  The Instructions are available at 
http://www.yale.edu/hrpp/forms-
templates/biomedical.html 
Submit the original application and one (1) copy 
of all materials including relevant sections of the 
grant which funds this project (if applicable) to 
the HIC.  
HIC OFFICE USE ONLY
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Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research. 
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
Yes
No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
Yes
No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as con-investigators on a protocol with a 
Yale University Principal Investigator must also have a current financial disclosure form on file 
with the University’s Conflict of Interest Office. If this has not been done, the individual(s) 
should 
follow 
this 
link 
to 
the 
COI 
Office 
Website 
to 
complete 
the 
form:  
http://www.yale.edu/coi/  
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
 
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail: 
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a. Internal Location[s] of the Study:
 Magnetic Resonance Research Center 
 Yale University PET Center
     (MR-TAC)   
 YCCI/Church Street Research Unit (CSRU)
 Yale Cancer Center/Clinical Trials Office (CTO)       
 YCCI/Hospital Research Unit (HRU)
 Yale Cancer Center/Smilow
 YCCI/Keck Laboratories
 Yale-New Haven Hospital
 Yale-New Haven Hospital—Saint Raphael 
Campus
 Cancer Data Repository/Tumor Registry
 Specify Other Yale Location: Yale Depression Research Program (YDRP)
b. External Location[s]:
 APT Foundation, Inc.
 Haskins Laboratories
 Connecticut Mental Health Center
 John B. Pierce Laboratory, Inc.
 Clinical Neuroscience Research Unit (CNRU)    
Veterans Affairs Hospital, West Haven
 Other Locations, Specify:  
 International Research Site 
(Specify location(s)):
c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date: 
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found at 
 http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. It is expected this project will last for 5 years. 
3. Research Type/Phase: (Check all that apply)
a. Study Type
   
 Single Center Study
   
 Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes 
No 
  
 Coordinating Center/Data Management
  
 Other: 
b. Study Phase
 N/A
    
 Pilot
 Phase I
 Phase II
 Phase III
 Phase IV
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 Other (Specify) 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found in the instructions section 4c:
 Clinical Research: Patient-Oriented
  
 Clinical Research: Outcomes and 
 Clinical Research: Epidemiologic and Behavioral 
                Health Services
 Translational Research #1 (“Bench-to-Bedside”)    
 Interdisciplinary Research
 Translational Research #2 (“Bedside-to-Community”) 
 Community-Based Research
5.   Is this study a clinical trial? Yes 
No 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or 
 contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes 
 No
7. Will this study have a billable service? A Billable Service is defined as a service or procedure 
that will be ordered, performed or result in charging in EPIC for individuals who are enrolled in 
a clinical research study, regardless if the charge is intended to be paid by the subject/their 
insurance or the research study.
 Yes 
 No
If you answered "yes", this study will need to be set up in OnCore Support
http://medicine.yale.edu/ymg/systems/ppm/index.aspx 
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8. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No ___  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? 
Yes.
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
 
No.
c. Will a novel approach using existing equipment be applied?
 
No.
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
SECTION IV:
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the
      research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’
      rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the
      study or any change and I will obtain continuing approval of this study prior to the expiration date     
      of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to
      participants.

I am in compliance with the requirements set by the University and qualify to serve as the
      principal investigator of this project or have acquired the appropriate approval from the 
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at
      Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a
smooth transfer of investigator responsibilities.
_____
 
PI Name (PRINT) and Signature
Date
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Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
 Yes (provide a description of that interest in a separate letter addressed to the HIC.)
 No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC)
No
I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
conduct this trial appropriately.
   ____________________________
   Chair Name (PRINT) and Signature  
    
 Date
   _________________________________
As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the 
      necessary resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of
      human subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions
      Prior to initiating the study or revision and will obtain continuing approval prior to the expiration
      of any approval period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated 
      problems involving risk to participants. 

I am in compliance with the requirements set forth by the University and qualify to serve as
      the faculty advisor of this project.
___________
______
_____
    Advisor Name (PRINT) and Signature
Date
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   Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
  ______________________________________
    YNHH HSPA Name (PRINT) and Signature       
Date
SECTION V: RESEARCH PLAN
1.
Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses 
to be tested. 
Ketamine is an anesthetic agent, recently found to exert a rapid and potent 
antidepressant effect in severely depressed patients. Mounting evidence indicates 
that a ketamine-induced surge in glutamate neurotransmission, particularly in the 
frontal cortex, plays a crucial role in the antidepressant and psychotomimetic effects 
of the drug. Our preliminary data also suggests ketamine has a normalizing effect on 
long-range neural dysconnectivity in Major Depressive Disorder (MDD), and that 
these changes in functional connectivity, as measured by resting state functional 
MRI (rs-fMRI), are related to the antidepressant effect of the drug. 
A better understanding of the mechanism of neuropsychiatric effects of ketamine are 
critically important, as pharmacological modulation of these effects can assist in the 
development of new medications for the treatment of multiple psychiatric disorders 
including depression and schizophrenia. The aims of the current proposal are to 
provide insight into (a) the impact of ketamine on functional connectivity as 
measured by rs-fMRI; (b) the relationship between rs-fMRI alterations and 
ketamine-induced neurochemical changes in glutamate; and (c) to investigate the 
influence of a glutamate release inhibitor (i.e., lamotrigine) on these ketamine-
induced neural alterations in healthy volunteers using safe, minimally invasive, 
state-of-the-art multi-modal neuroimaging and behavioral assessment. Further 
examination of the effects of ketamine-induced changes in neural connectivity as 
well as the impact of a pre-treatment dose of lamotrigine can provide key insight into 
the role of glutamate and the mechanism of ketamine’s rapid antidepressant and 
perceptual effects and its influence on neural connectivity.
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
Aim 1: To characterize the effects of a single, sub-anesthetic dose of ketamine in 
rs-fMRI in healthy subjects. 
Design: Twenty-four healthy participants will be randomized into one of two 
parallel groups—ketamine+lamotrigine or ketamine+placebo—and will complete 
pre- and post-ketamine rs-fMRI. 
Hypothesis 1: Post-ketamine rs-fMRI data will demonstrate a pattern of 
increased global brain connectivity (GBC) in fronto-temporal cortex.

Aim 2: To examine the relationship between ketamine-induced glutamate 
alterations and changes in rs-fMRI of healthy subjects. 
Design: Using MRS we will measure alterations in glutamate levels during 
ketamine infusion and correlate this data to rs-fMRI changes. 
Hypothesis 2: Ketamine-induced glutamate alterations will positively correlate 
with changes in GBC. 

Aim 3: To examine the effect of administering a glutamate release inhibitor, 
lamotrigine, prior to ketamine infusion on neural network configuration and 
connectivity.       
Design: Participants will be randomized to receive 300 mg oral lamotrigine or a 
matched-placebo medication 2-hours prior to ketamine infusion. 
Hypothesis 3: Lamotrigine will attenuate the effect of ketamine-induced GBC 
enhancement in the neural network. 
2. Background: Describe the background information that led to the plan for this 
project. Provide references to support the expectation of obtaining useful scientific 
data.
Ketamine
Major Depressive Disorder (MDD) is a leading cause of disability worldwide 1, with a 
21-fold increase of suicide attempts during major depressive episodes 2. In the 
United States, the estimated lifetime prevalence is approximately seventeen percent 
3. While more than 20 antidepressant medications are currently available, the 
efficacy of these medications is limited 4-7. Moreover, traditional antidepressants, all 
of which target the monoaminergic system, take weeks to months to reach their full 
clinical effects 8. Hence, there is an urgent need for a novel class of antidepressants 
that can offer (1) rapid acting effects and (2) efficacy in patients not achieving 
adequate benefit from existing medications. Over the last decade, accumulating 
evidence has shown that low dose of ketamine, a N-methyl-D-aspartate (NMDA) 
receptor antagonist, may possess both of these properties 9. 
NMDA receptor dysfunction has been implicated in the pathophysiologic processes 
of depression, schizophrenia, and other psychiatric illnesses 10,11.  Ketamine is now 
the prototype for a new generation of antidepressants that rapidly alleviates 
depression and demonstrates efficacy even in patients with symptoms that are 
refractory to currently available treatments. The association between glutamate 
alterations and psychotomimetic effects of ketamine in human has been suggested 
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by studies showing that glutamate release inhibitors, such as lamotrigine (an 
anticonvulsant drug) or group II metabotropic agonists, attenuate these behavioral 
symptoms 12-15. 
To date, more than 15 studies have investigated the efficacy of 0.5 mg/kg ketamine 
infusion in more than 300 depressed patients 16-31. These studies consistently 
showed a rapid antidepressant action within 4-hours of ketamine’s administration, 
with a short-term response rate ranging from 43% to 90% 25,32. This antidepressant 
effect was sustained for 7-28 days after a single ketamine infusion 19,29, and for an 
average of 19-days after repeated dosing 32. These rapid and potent antidepressant 
effects were also demonstrated in patient groups known to respond poorly to current 
antidepressants, such as patients diagnosed with bipolar disorder and patients with 
depressive symptoms that did not respond to electroconvulsive therapy (ECT) 17,22.
Animal Studies: The antidepressant effects of ketamine appear unique in the sense 
that the time of peak response, 4 to 72 hours post administration, is extremely rapid 
but is generally believed to be well after the drug has been metabolized and cleared 
from the body (t1/2 4 minutes; terminal plasma t1/2 2.5 hours).  Although the exact 
neurobiological mechanisms associated with ketamine’s rapid and sustained 
antidepressant effect remain largely unknown, recent animal studies have begun to 
elucidate downstream effects of ketamine that may underlie the beneficial effects in 
depressed patients.  In brief, convergent evidence suggests that at subanesthetic 
doses, ketamine’s antagonism of the glutamatergic NMDA receptor is the first step in 
a cascade of events that includes rapid increases in presynaptic glutamate release, 
enhanced regional activity in excitatory networks and ultimately marked changes in 
synaptic plasticity and connectivity.  Recent animal studies have begun to elucidate 
downstream effects of ketamine that may underlie its beneficial effects in depressed 
patients.  In brief, convergent evidence suggests that, at subanesthetic doses, 
ketamine’s antagonism of NMDA receptors rapidly triggers 3 consecutive events: 1st 
a presynaptic disinhibition of glutamatergic neurons leading to a synaptic glutamate 
surge, 2nd an increased activation of AMPA receptors, and 3rd a post-synaptic 
activation of neuroplasticity-related signaling pathways resulting in overall 
synaptogenesis and synaptic potentiation (for a recent review see Ref. 33). These 
acute effects of ketamine treatment rapidly oppose the stress induced prefrontal 
neuronal atrophy and synaptic dysconnectivity 34. 
In rodents, microdialysis and electrophysiological studies consistently indicate that 
low doses of ketamine and other NMDA receptor antagonists induce a “glutamate 
surge” in the prefrontal cortex 35-43. This glutamate surge has been confirmed by 
carbon-13 (13C) Magnetic Resonance Spectroscopy (MRS) studies suggesting an 
increase in glutamate/glutamine cycling, as reflected by the 13C incorporation into 
glutamate (enrichment) following injection of subanesthetic dose of ketamine 44. At 
higher doses of ketamine, there are no changes or even a decrease in extracellular 
glutamate and in glutamate cycling 37,44. Of interest, synaptogenesis and the 
antidepressant effects of ketamine are also limited to subanesthetic doses 45. Hence, 
there is a dose-response parallel between the glutamate surge, synaptogenesis, and 
the antidepressant effects of ketamine. Further evidence supporting the crucial role 
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of glutamate neurotransmission in ketamine’s effect comes from a well-replicated 
finding in rodents demonstrating that AMPA receptor activation is required for the 
antidepressant effect of ketamine 45-48. Consistent with this hypothesis, Dr. Duman’s 
group (at Yale University) recently showed that blocking group II metabotropic 
receptors – receptors known to inhibit glutamate release – exerts a mTOR-
dependent rapid antidepressant-like effect and synaptogenesis in a fashion similar to 
ketamine 49. In addition to the antidepressant effect, the psychotomimetic effect of 
ketamine appears to be affected by glutamate neurotransmission. In that regard, 
glutamate release inhibitors has been repeatedly shown to block many of the 
physiological and behavioral effects of ketamine and other NMDA receptor 
antagonists in animal models of psychosis 38,41,50-55.
Human Studies: As noted, the association between glutamate alterations and 
psychotomimetic effects of ketamine in humans has been suggested by studies 
showing that glutamate release inhibitors, such as lamotrigine or group II 
metabotropic agonists, attenuate these behavioral symptoms 12-15. Yet, a major 
challenge to the glutamate surge hypothesis is to quantitatively demonstrate the 
glutamate neurotransmission changes in vivo in human. Glutamate and glutamine 
are two abundant brain metabolites that can be detected using conventional 1H-
MRS. However, 1H-MRS measures total (intra & extracellular) glutamate level in a 
brain region of interest, which may reflect many processes other than glutamatergic 
neurotransmission. In addition, at low- and mid-field strengths (1.5 – 4.7 Tesla) the 
1H spectroscopy signal from glutamate is difficult to distinguish from glutamine 56, 
which affects the reliability of these measures. An early 4T 1H-MRS study in healthy 
subjects reported a transient increase in glutamine levels, but not glutamate, in the 
anterior cingulate following ketamine administration 57. A recent 3T 1H -MRS study 
– using comparable doses, timing, and region of interest – reported increased 
glutamate levels, but not Glx (glutamate + glutamine), during ketamine infusion 58. 
Other 1H-MRS studies reported no changes in Glx or glutamate levels during or 
following infusion of ketamine 18,59. Thus, overall 1H-MRS studies show alterations in 
the glutamatergic system induced by ketamine but fail to provide consistent results. 
Our studies using 
13C-MRS to measure ketamine’s effect on glutamatergic 
neurotransmission are currently underway (HIC#1305011972).
Plasticity and Connectivity: The term “synaptic plasticity” applies to the mechanisms 
through which neural circuits regulate their excitability and connectivity, particularly 
in the context of adaptation, i.e., phenomena including development, learning, 
coping with stress, and aging 60. These phenomena are accomplished by regulating 
synaptic strength (e.g. changing the number of α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptors) and synaptic number (e.g. altering 
dendritic spine density and shape). Of note, synaptic and extrasynaptic NMDA 
receptors have opposing effects on synaptic plasticity, promoting or reducing 
synaptic strength respectively 61. Synaptic plasticity could be “local” such as long-
term potentiation (LTP) or “global” such as homeostatic plasticity. The latter is of 
particular relevance to clinical depression, which is associated with reduced 
prefrontal synaptic connectivity (see below). A major form of homeostatic plasticity 
is “synaptic scaling”, that regulates the overall strength of neuronal synaptic 
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connectivity. For example, a prolonged increase in neuronal activities produces a 
downscaling in overall synaptic strength 62. Synaptic scaling is regulated by 
inflammatory cytokines (e.g. Tumor Necrosis Factor) 63 and by neurotrophins (e.g. 
brain-derived neurotrophic factor (BDNF)) 64, alteration in both factors have been 
associated with depression 60,65.
Over the past two decades, convergent evidence highlighted the role of synaptic 
homeostasis in the pathophysiology and treatment of depression 66,67. In particular, 
prolonged stress and depression have been associated with neuronal atrophy and 
overall synaptic depression in the prefrontal cortex (PFC) and the hippocampus 68-70, 
while other brain regions such as the amygdala and nucleus accumbens showed 
changes consistent with neuronal hypertrophy and synaptic potentiation 71,72. These 
synaptic changes are believed to be the result of stress-induced altered glutamate 
release and astroglial loss leading to sustained increase in extracellular glutamate 
which precipitates excitotoxicity, altered synaptic strength, reduced dendritic spine 
density, dendritic retraction, and reduced dendritic branching in the PFC 67,73. It has 
been proposed that down-regulation of the PFC activity leads to gain of function in 
other brain regions negatively controlled by the PFC such as the amygdala, a brain 
region associated with increased anxiety and hypothalamic-pituitary-adrenal (HPA) 
axis reactivity 74.
In this model, prefrontal synaptic deficits and the subsequent neuronal 
dysconnectivity are critical to the progress and treatment of depression. Molecular 
studies have started to identify signaling pathways implicated in the observed stress-
related synaptic dysfunction. It has been found that synaptic deficits are precipitated 
by reduction in neurotrophins such as BDNF 60, and by inhibition of the mammalian 
target of rapamycin (mTOR) signaling pathway 75. Inhibition of mTOR signaling or 
reduction of BDNF leads to depressive-like behavior and blocks the effect of 
antidepressants in animal models of depression 60,75. Enhancing mTOR signaling or 
increasing BDNF produces antidepressant effects in preclinical studies 60,75. In 
humans, reduced central and peripheral BDNF levels were found in depressed 
patients 60,76 and a functional variant of BDNF polymorphism (Val66Met) has been 
related to depression, especially in males 77. Together these data posit that enhancing 
DBNF 
and 
mTOR 
signaling 
leading 
to 
prefrontal 
synaptic 
formation 
(synaptogenesis), and reversal of stress/depression-induced neuronal atrophy and 
synaptic dysconnectivity is a required step for efficacious antidepressant treatment. 
Traditional antidepressants, targeting the monoaminergic system, were found to 
increase BDNF and synaptogenesis 60,67. However, these effects were only evident 
following chronic treatment, which is in line with the delayed antidepressant 
response to these drugs in humans. Therefore, it is proposed that rapid acting 
antidepressants would need to directly target the induction of mTOR signaling, the 
increase 
of 
BDNF 
levels, 
and 
the 
ultimate 
enhancement 
of 
prefrontal 
synaptogenesis. 
Lamotrigine
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As noted above, lamotrigine is an anticonvulsant drug.  It is also used in the 
treatment of bipolar disorder, specifically in the treatment and prevention of bipolar 
depressive episodes 
78. It is a use-dependent sodium channel blocker and 
phenyltriazine derivative, which has been demonstrated to possess multiple 
mechanisms of action 79,80. Briefly, these include the selective blockade of the N- and 
P-type calcium channels in focal brain regions, and the voltage-dependent blockade 
of sodium channels via its action on the slow inactivation state that occurs when 
sodium channels are over-activated. This drug has also been shown to inhibit the 
release of excitatory amino acids such as glutamate and aspartate, and may have 
some agonistic effects on γ-aminobutyric acid (GABA). It selectively suppresses 
neuronal over-activities without affecting the basal neurophysiological state, which 
has clear implications in neuronal stabilization, and may also be a plausible 
explanation of its action in bipolar disorder, even though the pathophysiology of this 
condition is less clear 79. Lamotrigine is also believed to act on serotonin reuptake, 
which may contribute to its antidepressant effects 79,81. There is evidence of 
peripheral glutamate dysregulation in bipolar disorder 82, and the glutamatergic 
activity of lamotrigine may also be implicated in its therapeutic and neuroprotective 
effects. Lamotrigine levels have been shown to peak at 1 to 4 hours after oral 
administration, with a mean of 2 hours.
Several studies have found that lamotrigine reduced the neuropsychiatric effects of 
ketamine in healthy subjects 12 as well as preventing some BOLD signal changes in a 
neuroimaging study 13. In a pioneering Yale study exploring the impact of 
lamotrigine on ketamine’s influence on glutamate, healthy subjects were given 300 
mg of lamotrigine approximately two hours prior to a ketamine infusion (0.25 mg/kg 
by intravenous bolus and 0.65 mg/kg per hour by intravenous infusion). Those 
subjects who received lamotrigine demonstrated significantly decreased ketamine-
induced perceptual disturbances as assessed by the Clinician Administered 
Dissociative States Scale, as well as reduced positive and negative psychotomimetic 
symptoms as assessed by the Brief Psychotic Symptoms Scale, and reductions in 
learning and memory impairment. Of note, those participants who received 
lamotrigine showed increases in the rapid mood enhancing effects of ketamine 12. In 
another study hoping to identify the mechanisms of action of ketamine in inducing 
symptoms and to determine the role of increased glutamate release in these 
alterations, participants were pretreated with lamotrigine, prior to a ketamine 
infusion to examine which effects of ketamine appear to be mediated by increased 
glutamate release 13. They found that ketamine administration induced a rapid and 
focal decrease in the ventromedial frontal cortex, including the orbitofrontal cortex 
and subgenual cingulate, which strongly predicted its dissociative effects. They also 
noted increased activity in the mid-posterior cingulate, thalamus, and temporal 
cortical regions. They found that lamotrigine pre-treatment prevented many of the 
BOLD signal changes 13. In the current proposal, we want to explore further the 
impact of lamotrigine on ketamine-induced changes in rs-fMRI and the relationship 
between alterations in glutamate levels and rs-fMRI changes. 
Resting State fMRI
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Resting state fMRI studies in MDD have revealed increased functional connectivity 
in multiple brain regions 83-89, perhaps most notably the dorsal nexus, in the DMPFC 
region, with considerable overlapping connections across networks 89. Studies 
characterizing the effects of ketamine on connectivity in MDD are lacking. Ketamine 
has been shown to induce greatest antidepressant response 24-hours after 
administration; therefore, we believe it is imperative to examine connectivity at this 
time point in order to determine whether there are changes in functional 
connectivity. These data are of utmost importance to guide development of novel 
medications that would induce a similar response in the human brain. Examination 
of functional connectivity at rest, as examined by rs-fMRI can provide fundamental 
insights regarding the underlying functional neural architecture 
90. Chronic 
treatment with SSRIs appears to reduce this abnormally heightened connectivity 
91,92. Interestingly, ketamine was found to rapidly reduce (i.e., normalize) functional 
connectivity in the dorsal nexus region of healthy controls 24-hours post-infusion 88. 
Our pilot data collected from three healthy subjects who were administered 
intravenous ketamine (0.23 mg/kg over 1 minute followed by 0.58 mg/kg/h over 75) 
suggests a pattern of increased Global Brain Connectivity (GBC, as measured by Cole 
and colleagues 93) in the fronto-temporal cortex, but reduced GBC in the occipito-
parietal regions. The GBC value of each voxel is the average of its time series 
correlation with all other voxels, providing a measure of nodal strength in a graph-
based network. We used voxel-wise paired t-tests pre-/post-ketamine and a p value 
of 0.05 uncorrected and cluster threshold at 100 voxels. 
Similarly, in collaboration with James Murrough at Mount Sinai, we have recently 
identified an abnormal pattern of GBC in MDD, where we found an anteroposterior 
dissociation of reduced prefrontal cortex (PFC) GBC but increased parietal-occipital-
cerebellar GBC. A set of complementary analyses has shown that these brain network 
alterations were largely driven by increased connectivity within the PFC, but reduced 
long-range connectivity between the PFC and other brain regions. Following 
ketamine treatment, we found clusters of increased GBC in the dorsomedial PFC 
(DMPFC), dorsolateral PFC (DLPFC), the insula, and the caudate (corrected p < 
0.05). In contrast, there was a reduction in GBC in the posterior cingulate, 
precuneus, medial and lateral occipital, fusiform, and cerebellum (corrected p < 
0.05). Reduction in depression scores correlated with the increase in GBC in the 
caudate and PFC (uncorrected p < 0.01). Overall, the complementary analyses 
showed reduction in connectivity within the PFC, but increased connectivity between 
the PFC and other brain regions following ketamine treatment.
Summary
While these preliminary data strongly support the efficacy of ketamine, there are 
several 
limitations 
that 
hinder 
its 
widespread 
use 
including 
its 
acute 
psychotomimetic and dissociative effects 94. Convergent evidence indicates that a 
ketamine-induced glutamate neurotransmission surge in frontal brain regions plays 
a crucial role in the antidepressant and psychotomimetic effect of the drug. However, 
this glutamate surge has been difficult to demonstrate in humans. In the current 
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proposal, we will implement state-of-the-art multi-modal neuroimaging methods to 
examine the role of ketamine-induced glutamate alterations on connectivity in rs-
fMRI, the relationship between the alterations in connectivity and glutamate 
changes, and the impact of lamotrigine, a glutamate inhibitor. This will provide 
critical information concerning the impact of ketamine on neural connectivity and 
use of lamotrigine will allow us to confirm target engagement and the impact of 
blocking the glutamate system, furthering our understanding of the mechanisms of 
action and the role of glutamate in ketamine’s effects. Moreover, given the well-
characterized similarity between ketamine’s acute psychotomimetic effects and 
psychosis 10, our ongoing studies are highly significant since the specific data 
generated with ketamine can equally contribute to the understanding and drug 
development of mood disorder and schizophrenia, devastating mental illnesses 
affecting millions of patients around the world 1.
3. Research Plan: Summarize the study design and research procedures using non-
technical language that can be readily understood by someone outside the discipline. 
Be sure to distinguish between standard of care vs. research procedures when 
applicable, and include any flowcharts of visits specifying their individual times and 
lengths. Describe the setting in which the research will take place.
A.   Overview:   In this study, 32 healthy participants will be randomized into one of 
two parallel groups: (a) open-label ketamine and active lamotrigine, or (b) open-
label ketamine with a matched-placebo control (i.e., sugar pill). All participants will 
complete a baseline rs-fMRI approximately 1-week prior to the ketamine infusion 
and a follow-up rs-fMRI 24-hours post-infusion. The subanesthetic dose of ketamine 
(0.23mg/kg bolus followed by 0.58mg/kg infusion over approximately 60 minutes) 
will be administered via intravenous infusion to occur during the MRS scan. 
Participants will be administered lamotrigine (300 mg oral dose) or the matched-
placebo control about 2-hours prior to the start of the infusion. 
B.   Experimental Subjects:  Twenty-four healthy subjects between the ages of 21-65 
years will be recruited for this study through advertising and referral from clinics in 
the community.  Subjects will complete an informed consent process and will be 
thoroughly screened for inclusion and exclusion criteria as described below.
B.1.
Restrictions
Subjects will be advised not to drive or operate heavy machinery for at least 24-hours 
after completing the infusion.
Subjects will be asked to refrain from alcohol use for one-week prior to each MRS 
session. 
Subjects must agree to use a barrier method (e.g., condom) as contraception for a 2-
week period following the study drug. 
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Subjects will be advised to refrain from undergoing any elective surgeries, including 
dental work, for a 2-week period following the study drug.  
B.2.
Discontinuation of subjects
Criteria for discontinuation
Subjects may be discontinued from study treatment and assessments at any time.  
Specific reasons for discontinuing a subject from this study are:

Voluntary discontinuation by the subject, who is at any time free to 
discontinue his/her participation in the study without prejudice to further 
treatment.

Adverse reaction to ketamine or lamotrigine. 

Inability to complete MR studies due to claustrophobia or other. 

Stopping birth control or positive pregnancy test.

Safety reasons as judged by the investigator.

Severe non-compliance to protocol as judged by the investigator.

Incorrect enrollment (i.e., the subject does not meet the required 
inclusion/exclusion criteria for the study).
Subject lost to follow-up.
A subject that discontinues will always be asked about the reason(s) for 
discontinuation and the presence of any adverse events.  If possible, they will be 
seen and assessed by the investigator.  Adverse events will be followed up as 
medically necessary.
C.   Pre-Study Screening Procedure and Initial Assessments: After an initial 
phone screen to determine obvious exclusions from the study protocol, potential 
subjects will be invited for a clinic pre-screen and personally interviewed. All 
subjects will have an initial screening assessment that includes a complete 
medical history, physical examination, laboratory testing, HIV and Hep B & C 
testing, psychiatric history, and standardized psychiatric and cognitive 
assessments.
C.1.   Historical and Demographic Information: Each subject will complete a 
demographic form containing commonly information that is routinely assessed in 
biomedical research protocols. Specifically, this document will elicit information 
about the subjects’ demographics, including education level, socioeconomic 
status, race and ethnicity. In addition, it will also request information on the 
subject’s family history of mental illness.
C.2.   Screening Physical Exam and Laboratories: All subjects will have a standard 
physical examination at the time of the initial screening.  Routine laboratory 
studies including a complete blood count (CBC) w/ differential, a comprehensive 
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metabolic panel (e.g., BUN/creatinine, glucose, sodium, potassium, chloride, 
carbon dioxide, calcium, AST, ALT, fT4, TSH, bilirubin, total protein, VDRL, 
vitamin B12, folate, etc.), a complete lipid panel, electrolytes, HIV, hepatitis B 
and C. A urine sample will be taken and used for a urinalysis drug panel and 
pregnancy testing. All subjects will also complete an ECG. Care will be taken to 
exclude pregnant women.  All female subjects will have a pregnancy test prior to 
participating in each MR study. 
C.3.   Screening Psychiatric Assessments: All subjects will have a psychiatric 
interview. In addition to the standard psychiatric and mental status examination, 
subjects will receive a structured diagnostic interview—the Structured Clinical 
Interview for DSM-IV Disorders (SCID). Baseline and follow-up ratings will also 
be obtained via assessment measures of depression, anxiety, and adverse effects 
(see Table 1). 
D.   Ongoing Clinical Assessments:  
D.1.   
Medical Assessments:  
Physical examination (including vital sign 
determination) and clinical laboratories (discussed in greater detail previously) 
will be completed at the first visit.  Urine toxicology screen and breathalyzer will 
be performed on the morning of each testing day, and the results will be 
determined before proceeding with the infusion.  At the discretion of the study 
physician, the subject will be disqualified if urine toxicology results are positive 
for any substances of abuse or if his/her breathalyzer reveals recent alcohol 
intake.  A pregnancy test will also be administered to all reproductive age females 
enrolled in the study prior to participation. Pregnant subjects will be excluded.  
In addition, subjects who test positive for HIV or viral hepatitis (hepatitis B 
and/or C) will be excluded as a means to protect the subjects and research staff 
from the increased potential risks blood borne pathogen transmission and 
ketamine infusion.
Table 1. Baseline measures utilized in this study
Baseline Assessments
Medical Assessments
Rating Scales
Demographic Data
Vital signs
BPRS
Psychiatric History
Physical examination
CADSS
Medical History
Mental status exam
PANSS
SCID
MMSE
Laboratory Assessment
ECG
PSQI
PSWQ
VAS
Cogstate Cognitive Tasks
Abbreviations: Structured Clinical Interview for DSM IV (SCID), Mini Mental Status Exam 
(MMSE), Electrocardiogram (ECG), Brief Psychiatric Rating Scale (BPRS), Clinician-Administered 
Dissociative States Scale (CADSS), Positive and Negative Syndrome Scale (PANSS), Pittsburgh 
Sleep Quality Index (PSQI), Penn State Worry Questionnaire (PSWQ), VAS (Visual Analog Scale 
of Mood States). 
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D.2.   
Psychiatric Assessments:  Ratings are performed by trained research 
personnel, whose performance is evaluated routinely.  The primary investigator 
supervises the administration of clinical measures.  Each of the psychiatric 
assessment instruments is briefly described below.
1.
Alcohol and Consumption Habits: This is a brief measure that documents 
alcohol, caffeine, and nicotine habits. 
2. Behavioral Inhibition & Activation Scales (BIS/BAS): The BIS/BAS is a self-
report scale designed to assess dispositional sensitivity to the behavioral 
inhibition system (BIS) and the behavioral activation or behavioral approach 
system (BAS). 
3. Big Five Inventory (BFI): The BFI measures an individual on the Big Five 
Factors (dimensions) of personality (Goldberg, 1993). Each of the factors is then 
further divided into personality facets. 
4. Brief Psychotic Rating Scale (BPRS): The BPRS is a standardized instrument 
that contains scales assessing psychotic symptoms including positive and 
negative symptoms, activation and emotional distress.
5. Clinician-Administered Dissociative States Scale (CADSS): The CADSS has self 
and interviewer-administered items including 5 subscales, generated a priori, 
evaluating dissociation including altered environmental perception, time 
perception, spatial/body perception, derealization and memory impairment.
6. Clinical Global Impressions Scale (CGI) and the Patient Global Impressions 
Scale (PGI): The CGI and PGI are widely used instruments, which assess overall 
severity of illness on a 1 to 7 point scale with 1 indicating “normal, not at all ill” 
and 7 indicating “among the most extremely ill patients.” These instruments also 
assess global improvement on a 1-to-7 point scale with 1 indicating “very much 
improved,” 4 indicating “no change” and 7 indicating “very much worse.” 
7. Clinician Administered Dissociative States Scale (CADSS): The CADSS has self 
and interviewer-administered items including 5 subscales, generated a priori, 
evaluating dissociation including altered environmental perception, time 
perception, spatial/body perception, derealization and memory impairment. 
8. Cognitive tasks: This will include Cogstate, a well-validated short computerized 
cognitive tasks. These short computerized tasks along with a brief 
neuropsychological battery will assess cognitive functions. 
9. Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a brief 
clinician administered and standardized measure that uniquely assesses essential 
information about suicide behavior, ideation, lethality and severity, and 
distinguishes between suicidal occurrences and non-suicidal self-injury. 
10. Early Trauma Inventory (ETI-SR): The ETI-SR is a self-report instrument to 
assess childhood trauma and includes physical, emotional and sexual abuse as 
well as general traumas. 
11. Global Perceived Early Life Stress (GPELS): The GPELS is a self-report of 
perceived stress during childhood. 
12. Hamilton Anxiety Rating Scale (HAM-A): The HAM-A is a standardized 
clinician-rated instrument to evaluate the severity of anxiety symptoms. 
13. Klein Loss Scale (KLS): The KLS is a self-report of parental loss or separation 
during childhood. 
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14. Life Events Checklist (LEC): The LEC is a self-report instrument that measures 
reports of traumatic life events. 
15. Massachusetts 
General 
Hospital 
Antidepressant 
Treatment 
History 
Questionnaire (MGH-ATRQ)-This is a self-rated questionnaire used to determine 
treatment resistance in major depressive disorder. 
16. Mini Mental Status Exam (MMSE): is a brief, clinician-administered instrument 
used to measure cognitive status and mental orientation.  It will be given only at 
baseline.
17. Modified Military Acute Concussion Evaluation (MACE) - The MACE is a 
concussion screening tool for the acute assessment of service members involved 
in a potentially concussive event. 
18. Montgomery-Asberg Depression Rating Scale (MADRS): The MADRS is a 
standardized instrument to ascertain depressed mood and neurovegetative signs 
and symptoms of depression. 
19. Penn State Worry Questionnaire (PSWQ): The PSWQ is a self-report 
questionnaire to assess for ‘worry’ symptoms that are typical of generalized 
anxiety. 
20.Pittsburgh Sleep Quality Index (PSQI): The PSQI is a self-report questionnaire to 
assess sleep quality and sleep disturbance. 
21. Positive and Negative Symptom Scale (PANSS): The PANSS is commonly used 
to measure the severity of symptoms in psychotic disorders. It is a clinician- 
administered scale and includes three categories of symptoms: (1) positive 
symptoms, such as hallucination and delusion; (2) negative symptoms, such as 
flat affect and difficulty in abstract thinking; (3) general psychopathology, such as 
mannerisms and posturing. 
22.PTSD Checklist (PCL): The PCL is used to measure PTSD symptoms and is a self-
report questionnaire that has high reliability. 
23.Quick Inventory of Depressive Symptoms – Self-Report (QIDS-SR): The QIDS-
SR is a patient-rated depression instrument. 
24.Sheehan Disability Scale (SDS): The SDS is a brief self-rated measure of 
disability and impairment. 
25.Beck Suicide Ideation Scale (BSI): The BSI is a 21-item self-report questionnaire 
that may be used to identify the presence and severity of suicidal ideation. Items 
on this measure also assess the respondent's suicidal plans, deterrents to 
suicide, and the level of openness to revealing suicidal thoughts.
26.Systematic Assessment for Treatment Emergent Events (SAFTEE): The SAFTEE 
is a commonly used instrument originally developed by NIMH and adapted into a 
self-report instrument. It examines, in systematic fashion, possible treatment-
emergent side effects and probes for specific adverse symptoms, including 
suicidal thoughts and behaviors, and self-injurious behavior. 
27. Structured Clinical Interview for DSM Disorders (SCID) will be used to provide 
current 
and 
past 
diagnoses 
of 
psychiatric 
disorders, 
notably 
the 
inclusion/exclusion criteria of a current major depressive episode.  
28.Socio-demographic/General Information: At intake, demographic data and 
medical history will be assessed with interviews and self-report forms that 
provide data on age, race, socioeconomic status, marital status, educational and 
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occupational levels, and significant medical history.  These are adapted from 
previous diagnostic and clinical studies at this center. 
D.3.   Biochemical Analyses:  10 mL of blood are drawn for the analysis of 
ketamine levels.  
Plasma ketamine levels are ascertained via a gas 
chromatography-mass spectroscopy assay developed by Edward Domino M.D. 95. 
E.   Lamotrigine Administration: Subjects randomized to the active lamotrigine 
group will receive a 300 mg oral dose of the drug 2-hours prior to the start of the 
ketamine-infusion. Lamotrigine levels will be measured using commercially 
available radioimmunoassay kits.
A physician who is trained and has experience with lamotrigine and possible 
allergic and other adverse events will remain in attendance at all sessions that 
involve drug administration. 
F. Ketamine Administration:  Subjects will complete one test day.  Following an 
overnight fast, IV lines will be inserted into the antecubital vein. They will receive 
ketamine (0.23mg/kg bolus followed by 0.58mg/kg infusion over approximately 
60 minutes). 
A physician who is trained and has significant experience with both ketamine and 
infusion studies will remain in attendance at all sessions that involve ketamine 
infusion. The subjects will also be attended by a nurse who will accompany them 
through the study sessions, from the insertion of bilateral cannulae for drug 
infusion and blood sampling, through to recovery following ketamine infusion.
Baseline Test Session (Test Session 1 Day-0-)

T -15 min:
Urine toxicology; Urine pregnancy test (women only); 
Breathalyzer; MRI Safety Data Sheet; Metal Detector     

T -0 min:
rs-fMRI (and other imaging protocols on the 3T scanner)

Post fMRI
Brief neuropsychological battery 
Test session 1 (Day #1)

T -120 min:
Vital signs *; Urine toxicology; Urine pregnancy test (women 
only); Breathalyzer; PSWQ, PSQI, MRI Safety Data Sheet; 
Metal Detector; Lamotrigine or matched-placebo control 
administration 

T-90 min: 
Intravenous lines started

T -45 min:
MRS setup and baseline scan

T-0 min:
Ketamine infusion begins (0.23mg/kg bolus followed by 
0.58mg/kg infused over 60 minutes)
T 5-75:
MRS acquisition continues
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Blood samples for ketamine, norketamine and lamotrigine 
levels will be repeated at 15, 30, 60, and 75 minutes **

T 90:
Vital signs, eat a meal, VAS, BPRS, CADSS, PANSS 

T 300:
Participants may be discharged home after being cleared by a 
study physician.
*Blood pressure, heart rate, and oxygen saturation will be recorded every 10-20 
minutes during infusion (T0-75 minutes).
Follow-up After Test Infusion (Day #2)

T -15 min:
Urine toxicology; Urine pregnancy test (women only); 
Breathalyzer; MRI Safety Data Sheet; Metal Detector     
           

T -0 min:
rs-fMRI (and other imaging protocols on the 3T scanner)

Post fMRI
Brief neuropsychological battery
Follow-up (1-week, 4-weeks, 8-weeks): 
All participants will be contacted by telephone 1-week, 4-weeks, and 8-weeks post-
infusion and lamotrigine administration to assess for residual effects of ketamine or 
lamotrigine and other adverse events (AEs). 
Table 2. Schedule of Study Events
Visit
1- Baseline 
2-fMRI 
3-MRS / Infusion
4-24-hr 
fMRI
Alcohol & Consumption
x
BFI
x
Blood draw/labs
x
BIS/BAS
x
BSI
x
x
x
Breathalyzer
x
x
x
x
CADSS
x
CGI-S/I and PGI-S/I 
x
Collect AEs and SAEs
x
x
x
Cognitive Tasks
Practice
x
x
x
Concomitant Meds
x
x
x
x
C-SSRS
x
Demographics
x
ECG
x
ETI-SR
x
GPELS
x
HAM-A
x
x
x
x
*Informed Consent
x
Ketamine Infusion
x
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KLS
x
LEC 
x
MADRS
x
x
x
x
M-MACE
x
MGH-ATRQ
x
Medical Evaluation
x
PANSS
x
PCL
x
x
x
x
PSQI
x
x
x
x
PSWQ
x
x
x
x
QIDS-SR
x
x
x
x
Lamotrigine/Placebo 
Dose
x
SAFTEE
x
SCID-IV
x
SDS
x
Serum Pregnancy
x
Urinalysis
x
x
Urine Pregnancy
x
x
x
Vital Signs
x
x
*Informed consent will be obtained prior to any study procedure.
Abbreviations: Big Five Inventory (BFI), Behavioral Inhibition & Activation Scales 
(BIS/BAS), Clinician Administered Dissociative States Scale (CADSS), Clinical Global 
Impression 
Severity/Improvement 
(CGI-S/I), 
Patient 
Global 
Impression-
Severity/Improvement (PGI-S/I), Cogstate and brief neuropsychological battery 
comprises the cognitive testing portion, Columbia-Suicide Severity Rating Scale (C-
SSRS), electrocardiogram (ECG), Early Trauma Inventory – Self Report (ETI-SR), 
Global Perceived Early-Life Stress (GPELS), Hamilton Anxiety Rating Scale (HAM-A), 
Klein Loss Scale (KLS), Life Events Checklist (LEC), Montgomery-Asberg Depression 
Rating Scale (MADRS), Modified Military Acute Concussion Evaluation (M-MACE), 
MGH Antidepressant Treatment Response Questionnaire (MGH-ATRP), Positive and 
Negative Symptom Scale (PANSS), Pittsburgh Sleep Quality Index (PSQI), Penn State 
Worry Questionnaire (PSWQ), Quick Inventory of Depressive Symptomatology – Self 
Report (QIDS-SR), Systematic Assessment for Treatment Emergent Events (SAFTEE), 
Structured Clinical Interview for DSM IV (SCID), Sheehan Disability Scale (SDS). 
1H-MRS Methods: 1H-MRS will be used to measure glutamate concentrations in 
the frontal cortex using tissue segmentation processing to control for difference in tissue 
composition between subjects. Participants may be asked to return for one repeat 
session due to inadequate image acquisition or time constraints. This repeat session 
would be scheduled a minimum of 4-weeks after the original session to minimize carry-
over effects and to minimize any potential risk from repeat dosing of ketamine or 
lamotrigine.  No more than one repeat session would be conducted. A brief description 
of the methods is provided below.
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An 8-channel RF array (7.0 T magnet) will be used for RF transmission and 
signal reception. In the frontal cortex, the volume of primarily gray matter will be 
selected as a rectangular box placed across the anterior cingulate.  The frontal white 
matter voxel will have identical dimensions offset from the midline. The sequence will 
be applied in pairs 96 to yield sub-spectra that contain either macromolecules alone or 
macromolecules combined with the metabolites of interest.  Briefly, one sub-spectrum is 
acquired with a hyperbolic secant inversion pulse applied across the spectral bandwidth, 
followed by an inversion-recovery delay to null the metabolites, and one sub-spectrum is 
acquired without the inversion pulse.  The macromolecules will be measured directly 
from the metabolite-nulled sub-spectrum.  The macromolecule sub-spectrum will be 
subtracted from the other sub-spectrum to obtain a spectrum of metabolites alone.  The 
data will be acquired in interleaved fashion, toggling between individual inverted and 
uninverted acquisitions, in short blocks.  Each block will be stored, and the sequence 
will run for about 20-minutes to yield pairs of sub-spectra.  Experience has shown that 
over 90% of subjects are able to lie still and tolerate this duration of scan.  A spectrum of 
the water in the voxel will be obtained using the same pulse sequence and TE with the 
water suppression disabled.  
Spectral fitting will be performed to quantify the 
metabolites, and all metabolite measurements will be reported not only based on 
comparisons to creatine but as ratios to the tissue water peak. 
Magnetic Resonance Imaging: Scans will be collected on a Siemens TIM Trio 3.0 Tesla 
MRI scanner located at the Yale Magnetic Resonance Research Center (MRRC), using 
standard MRRC sequences. The scan protocol consists of a 3-plane localizer collected 
from three cardinal planes. These images serve as a localizer series for the other 
acquisitions. The remaining multi-modal magnetic resonance pulse sequences may 
include: two high resolution T1-weighted imaging (MPRAGE or FLASH); high 
resolution T2-weighted imaging (SPACE); three-dimensional chemical shift imaging 
(CSI) provides high signal to noise 1H spectra; BOLD gradient echo planar imaging at 
rest and/or during FMRI tasks (e.g. trauma-related cues); high angular diffusion 
weighted imaging, arterial spin labeling (ASL), susceptibility weighted imaging, and 
ultra-high resolution T1 anatomical imaging (400 micron x 400 micron x 800 micron). 
FMRI tasks will be back-projected onto a screen by a high contrast projector connected 
to a laptop computer. Behavioral responses will be recorded during FMRI tasks with an 
optical response system. During the MRI scan, participants will be asked to perform 
certain tasks. They will be given detailed instructions by the experimenter explaining the 
task instructions. During some of the cognitive tasks they may see various distracting 
images some of which will be photographs. These photographs that they will see may 
cover a broad range of contents, including slides of flowers, children, families, people’s 
faces, insects, animals, sports, and graphic slides similar to those that might be seen in a 
newscast or documentary of war footage (including mutilated individuals and dead 
bodies). Many people experience some degree of distress when viewing the most graphic 
pictures. If they will be shown these graphic images they will have an opportunity to 
view some sample pictures to make certain that they understand the types of slides they 
will see during the study and the level of intensity that the pictures may contain. They 
will be able to choose if they are comfortable with each level of intensity. If they agree to 
look at the pictures and become upset during the scanning they may indicate their 
distress and the pictures will be stopped. We will remind them that they may ask to stop 
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viewing the pictures at any time during the testing and still continue in the study. 
Participants may be asked to return for a repeat session due to inadequate image 
acquisition or time constraints. No more than three repeat sessions will be attempted.
4. Genetic Testing   
N/A 
A. Describe
i.
the types of future research to be conducted using the materials, specifying 
if immortalization of cell lines, whole exome or genome sequencing, 
genome wide association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which 
material will be received
iii. the types of information about the donor/individual contributors that will 
be entered into a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or 
distributing for future research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the 
identifiers that connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no 
longer identified: that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials 
5. Subject Population: Provide a detailed description of the types of human subjects 
who will be recruited into this study.
Twenty-four healthy subjects, between the ages of 21-65 will be recruited.  Subjects 
will be accepted into the protocol after an opportunity to review and provide 
voluntary written informed consent (see attached) and completion of an extensive 
medical and psychiatric history, physical examination, mental status examination 
and routine laboratory assessments.  Participants will be enrolled if they meet the 
inclusion criteria mentioned below (see section 7).  
Additional demographic, 
diagnostic and other clinical data, including family psychiatric and substance misuse 
history and treatment history will be obtained during the face-to-face clinical 
assessment.  All such data will be recorded in written and/or electronic format(s). 
6. Check off all classifications of subjects that will be specifically recruited for 
enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the 
population of subjects requiring special safeguards and provide a justification for 
their involvement.
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 Children
 Healthy 
Fetal material, placenta, or dead fetus
 Non-English Speaking
 Prisoners
 Economically disadvantaged persons
 Decisionally Impaired
 Employees
 Pregnant women and/or 
fetuses
 Yale Students 
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state 
as potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements).
For the current study, healthy subjects are needed to investigate the effect of ketamine 
on functional connectivity and the impact of lamotrigine. An extensive medical and 
psychiatric assessment, as described above, will be conducted to exclude subjects who 
are at increased risk. Yale students are eligible for this study if they meet the inclusion 
and exclusion criteria. Yale students who are supervised/mentored by members of the 
research team will not be enrolled.
Females of childbearing potential will likely be enrolled, and, as mentioned above, 
safeguards will be instituted, e.g. serum pregnancy test and reproductive counseling, to 
prevent pregnant patients from enrolling or subjects conceiving, respectively, during 
this investigation.
7. What are the criteria used to determine subject inclusion or    exclusion?
Inclusion Criteria:

Male or female between the ages of 21-65 years. Females will be included if they 
are not pregnant and agreed to utilize a barrier method contraceptive (e.g., 
condom or diaphragm with spermicide) tubal ligation, abstinence, or partner 
with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.

Able to provide written informed consent according to Yale HIC guidelines.

Agree to refrain from elective surgeries (including dental) for a 2-week period 
following study drug.  

Able to read and write English as a primary language.
Exclusion Criteria:

Personal history of mood, anxiety, or psychotic axis I DSM-IV disorders 
confirmed after comprehensive psychiatric evaluation.

Any history of serious medical or neurological illness.

Any signs of major medical or neurological illness on examination or as a result 
of ECG screening or laboratory studies.

A first-degree family member with history of schizophrenia.

Lifetime history of psychoactive substance or alcohol dependence or substance or 
alcohol abuse (other than nicotine or caffeine abuse), or drinking more that 5 
drinks/week during the last year.
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
Abnormality on physical examination.  A subject with a clinical abnormality may 
be included only if the study physician considers the abnormality will not 
introduce additional risk factors and will not interfere with the study procedure 
(e.g. uncontrolled hypertension, hyperthyroidism, or hypothyroidism will be 
excluded).

A positive pre-study (screening) urine drug screen or, at the study physician’s 
discretion on any drug screens given before the scans.

Pregnant or lactating women or a positive urine pregnancy test for women of 
child-bearing potential at screening or prior to any imaging day.

Positive HIV or Hepatitis B/C tests. This test will take place at the screening visit. 
Subjects will be invited back either for their next study visit or for a HIV/Hep 
debriefing session. A study clinician will inform them in person of the results. 
They will be given access to counselling and advised of the appropriate next steps.

Has received either prescribed or over-the-counter (OTC) centrally active 
medicine or herbal supplements within the week prior to the MRI scan.  Subjects 
who have taken OTC medication or herbal supplements may still be entered into 
the study, if, in the opinion of the principal/co-investigator, the medication 
received will not interfere with the study procedures or compromise safety.

Any history indicating learning disability, mental retardation, or attention deficit 
disorder.

Known sensitivity to ketamine.

Known sensitivity to lamotrigine. 

Body weight of 250 pounds or greater.

History of claustrophobia.

Presence of cardiac pacemaker or other electronic device or ferromagnetic metal 
foreign bodies in vulnerable positions as assessed by a standard pre-MRI 
screening questionnaire.

Donation of blood in excess of 500 mL within 56 days prior to dosing.

History of sensitivity to heparin or heparin-induced thrombocytopenia.

Resting blood pressure lower than 90/60 or higher than 150/90, or resting heart 
rate lower than 45/min or higher than 100/min.
8. How will eligibility be determined, and by whom? 
Subject eligibility will first be assessed via telephone screening.  If the subject seems to 
be a likely candidate for inclusion in this protocol, he or she will be evaluated for study 
eligibility in person.  Telephone screens will occur by experienced research personnel 
adept with this process. Suitability for enrollment and randomization will be assessed by 
experienced study clinicians, via face-to-face evaluations and discussion with research 
teams.
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
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The risks involved with this study include (a) ketamine administration; (b) lamotrigine 
administration; (c) phlebotomy; (d) MR studies; and (e) clinical assessments.
A.
Ketamine administration
Ketamine is a dissociative anesthetic that has been used clinically since the late 
1960s 95.  Despite extensive experience, there is no clear and compelling evidence of 
long-term toxicity associated with ketamine administration in medically supervised 
settings 97,98.  However, there are acute medical and neuropsychiatric sequelae that 
deserve special consideration.  The ketamine doses employed in the healthy group have 
been specifically selected to produce mild to moderate behavioral effects without 
significant sedation.  At these doses, ketamine produces a transient alteration of 
consciousness including altered sensory processing, and thought processes.  Initially, 
subjects frequently feel “drunk” and giddiness is common.  As blood levels increase, 
blood pressure and heart rate increase moderately.  This increase is transient and not 
considered clinically significant.  Subjects report differences in complex problem solving 
evident on frontal lobe and delayed memory tasks, some subjects may report a 
narrowing of their concentration, feeling distant from surroundings, and enhanced 
perception of some sensory stimuli.  Subjects sometimes report blurred vision and 
nystagmus.  Alterations in the perception of time, body boundaries, and illusions occur.  
Subjects may experience visual distortions, altered perception of orientation in space, 
and inability to control thought processes.  Subjects may report feeling quite distanced 
from their surroundings, describe altered awareness of their bodies, and they may close 
their eyes.  During this period, they are still oriented to time and place.  They can 
complete ratings scales testing memory without impairment, their rate of finger tapping 
is unchanged and the latency of their response on continuous performance tasks of 
attention is not increased.  However, some individuals feel that they cannot control the 
experience and find it frightening.  Vivid dreams and poor sleep quality after infusion of 
ketamine has also been reported, although dream content was not necessarily unusual 
and alterations in sleep were not reported on subsequent nights.
The doses used in this protocol produce blood levels that are 1/6 to 1/3 of those 
produced clinically when ketamine is used as an anesthetic. Short-term safety data 
showed that adverse events in response to ketamine infusion have been mild and 
transient, with no evidence of any clinically significant or persistent adverse effects 109.  
Adverse events included nausea and vomiting, sedation, anxiety, hypotension, insomnia 
and nightmares and transient pain in the infusion arm.
B. Lamotrigine 
Lamotrigine is an anticonvulsant or anti-epileptic medication. It is also used to 
delay mood episodes in adults with bipolar disorder. Long-term administration of 
lamotrigine has been associated with a rash 99. This rash can be quite serious and 
require hospitalization and discontinuation of treatment. However, single doses of the 
drug have not been associated with this side effect and in studies that have used this in 
conjunction with ketamine, no participants developed rash 12. There are currently no 
known factors identified to predict the risk of occurrence or the severity of the rash 
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caused by lamotrigine. Nearly all cases of the rash have occurred within 2- to 8-weeks of 
treatment initiation. Possible allergic reactions to lamotrigine include: hives fever, 
swollen glands, painful sores in or around the eyes and mouth, difficulty breathing, 
swelling of the face, lips, tongue, or throat. Possible side effects include worsening mood 
or behavior changes, depression, anxiety, agitation, irritability, thoughts of suicide and 
self-harm, restlessness, hyperactivity, dizziness, drowsiness, blurred vision, loss of 
coordination, fatigue. 
C.
Phlebotomy
In addition to the IV lines, we may need to draw additional blood for the routine 
laboratory testing. Inserting a needle into a vein is safe when done by professionals 
under clean conditions. Sometimes a bruise will occur at the puncture site and on rare 
occasions a blood clot or an infection may form in the vein.  During the intravenous line 
placement for the infusion, a bruise may occur at the puncture site, and very rarely, an 
infection may develop. If this occurs, appropriate treatment will be instituted 
immediately.
Risks associated with blood loss are minimal. Less than 200 cc will be drawn, and this 
represents 40% of a 500 cc blood donation. 
D.
MR Studies
Magnetic resonance imaging (MRI) and spectroscopy (MRS) will be performed at the 
same time at Yale Medical School, Magnetic Resonance Research Center in both a 3T 
(fMRI) and 7T (MRS) system. The methods used to obtain the MRI are employed for 1H-
spectroscopy with the addition of water signal suppression. MRI may be considered 1H-
MRS of water. 
Magnetic resonance (MR) is a technique that uses magnetism and radio waves, not x-
rays, to take pictures and measure chemicals of various parts of the body.  The United 
States Food and Drug Administration (FDA) has set guidelines for magnet strength and 
exposure to radio waves, and we carefully observe those guidelines.
Subjects will be watched closely throughout the MR study.  Some people may feel 
uncomfortable or anxious.  If this happens to a subject, they may ask to stop the study at 
any time and we will take them out of the MR scanner.  On rare occasions, some people 
might feel dizzy, get an upset stomach, have a metallic taste or feel tingling sensations or 
muscle twitches.  These sensations usually go away quickly but subjects are instructed to 
tell the research staff if they have them. fMRI Task: During the MRI scan, participants 
will be asked to perform certain tasks. They will be given detailed instructions by the 
experimenter explaining the task instructions. During some of the cognitive tasks they 
may see various distracting images some of which will be photographs. As in the 
behavioral assessment portion, the photographs that they will see may cover a broad 
range of contents, including slides of flowers, children, families, people’s faces, insects, 
animals, sports, and graphic slides similar to those that might be seen in a newscast or 
documentary of war footage (including mutilated individuals and dead bodies). Many 
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people experience some degree of distress when viewing the most graphic pictures. If 
they will be shown these graphic images they will have an opportunity to view some 
sample pictures to make certain that they understand the types of slides they will see 
during the study and the level of intensity that the pictures may contain. They will be 
able to choose if they are comfortable with each level of intensity. If they agree to look at 
the pictures and become upset during the scanning they may indicate their distress and 
the pictures will be stopped. We will remind them that they may ask to stop viewing the 
pictures at any time during the testing and still continue in the study. 
There are some risks with an MR study for certain people.  Applicants may be excluded 
if they have a pacemaker or some metal objects inside their body because the strong 
magnets in the MR scanner might harm them.  Another risk is a metallic object flying 
through the air toward the magnet and hitting the subject.  To reduce this risk we 
require that all people involved with the study remove all metal from their clothing and 
all metal objects from their pockets.  Subjects will walk through a metal detector prior to 
entering the magnet room. Nothing metal can be brought into the magnet room at any 
time.  Also, once the subject is in the magnet, the door to the room will be closed so that 
no one from outside accidentally goes near the magnet.
Subjects are instructed to read and answer very carefully the questions on the MR Safety 
Questionnaire related to their personal safety.  They are instructed during the consent 
process to take a moment to be sure that they have read the MR Safety Questionnaire 
and to be sure to tell the staff any information they think might be important. This MR 
study is for research purposes only and is not in any way a clinical examination.  The 
scans performed in this study are not designed to find abnormalities.  The primary 
investigator, the lab, and the Magnetic Resonance Research Center are not qualified to 
interpret the MR scans and are not responsible for providing a diagnostic evaluation of 
the images.  If a worrisome finding is seen on a subject’s scan, a radiologist or another 
physician will be asked to review the relevant images.  
Based on his or her 
recommendation (if any), the primary investigator or consulting physician will contact 
the subject, inform them of the finding, and recommend that they seek medical advice 
as a precautionary measure.  The decision for additional examination or treatment 
would lie solely with the subject and their physician.  The investigators, the consulting 
physician, the Magnetic Resonance Research Center, and Yale University are not 
responsible for any examination or treatment that the subject receives based on these 
findings.  The images collected in this study are not a clinical MR exam and for that 
reason, they will not be made available for diagnostic purposes.
E.
Psychiatric Evaluation, Clinical Assessments: 
These are all non-invasive, should add no risk, and have been used without difficulty or 
adverse events in our previous studies with a similar population.  
The major 
disadvantage is the time taken to complete them. The psychiatric evaluation and clinical 
assessments included in the baseline-screening visit are expected to take approximately 
60-90 minutes to complete (this includes all clinician-administered interviews and 
ratings and all self-report measures). The ratings on visit day 2 are expected to require 
approximately 30 minutes. The measures given on the day of the infusion are expected 
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to require approximately 45-60 minutes to complete (again including all clinician-
administered and self-report ratings. Our past experience with these measures indicates 
that they are acceptable to patients.  Only subjects' code numbers will be recorded on 
the forms themselves to protect confidentiality.
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will 
be minimized.
A.
Recruitment and Informed Consent
Subjects will be recruited from the Yale-New Haven area by advertisements on 
the Internet and radio, in local newspapers, posters in the area, and referrals from 
community clinicians. Prior to enrollment, subjects will have face-to-face interviews 
with one of the investigators where the nature of the project, the risks, the benefits, and 
the alternatives to participation in the project will be discussed with the subject and, if 
necessary, the subject's family. A focused history will be taken and a checklist of hazards 
will be reviewed with the subject. If, following these discussions, the subject continues to 
be interested in the project, informed written consent will be obtained on the consent 
form approved by the Yale University Human Investigation Committee (HIC). 
Thereafter, the project investigators assume clinical responsibility for the care of the 
subject. 
B.
Protection Against Risk
General risk-minimizing strategies: 1. Effective screening to exclude subjects who 
would be placed at a greater risk. This includes a comprehensive psychiatric and medical 
evaluation, physical examination, and the screening studies performed before starting 
studies (see above). Trained staff, under the supervision of the PI, will conduct all 
screening procedures. 2. The investigator or a designated person will explain the 
benefits and risks of participation in the study to each subject. Subjects will be asked to 
verbalize their understanding of all aspects of the consent, including risks, benefit and 
alternatives. The voluntary nature of research studies is always emphasized. 3. All 
subject information will be kept confidential and only members of the investigative team 
with appropriate IRB/HIC and HIPAA training will have access to the study data. Data 
will be maintained and secured in locked file cabinets or password protected electronic 
media. A numbering code will be used to assign a unique identifier to each subject. 4. A 
Data and Safety Monitoring Plan is described below.
A primary concern is impact by magnetic objects accidentally brought into the magnet 
room, anxiousness, irritation due to the IV blood sampling, and perceptual disturbances 
during ketamine infusion. The precautions taken to minimize the risks in these studies 
are described below:
C.
Metal Object
To minimize the chance of a magnetic object entering the magnet room the 
following precautions are taken:
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1.
All personnel involved in the study must go through training provided by the 
MRRC. 
2. The subject is screened in the MRRC for metal objects prior to being allowed into 
the magnet room
3. Once the subject is in the room only the research team members who have 
successfully completed the MRRC safety requirements will be allowed into the 
room. 
If an accident occurs, 911/EMS will be activated. All personnel are trained in an 
established procedure for removing the subject from the magnet. Due to the close 
proximity to the hospital the time required for the ambulance team to arrive will be 
under 5 minutes. All personnel involved in the study are trained in this procedure. There 
will be an M.D. present at all times who will be able to perform immediate resuscitation 
in the unlikely event it is needed.
D.
Subject Monitoring and Emergency Procedures
An experienced clinical research team will closely monitor the subjects. All of the 
information obtained from subjects participating in this study will be coded by numbers 
and kept in locked files in the research unit to ensure confidentiality. One member of the 
two to three person team will watch the subjects while in the magnet room. Visual and 
verbal contact will be maintained throughout the imaging and spectroscopy. Subjects 
who become claustrophobic in the magnet will be removed immediately from the 
magnet room. Subjects who experience distress in the magnetic room for any reason 
including seizures, loss of consciousness, pain will be removed from the magnet room in 
accordance with well-established procedures developed for the MRRC. All team 
members will be thoroughly familiar with the established emergency plan. A 
nonmagnetic stretcher will be on standby next to the entrance to the magnet. 
Nonmagnetic oral airways, Ambubag, and stethoscope are stored with the emergency 
stretcher in the magnet room. Should an emergency arise, one member of the 
spectroscopy team will telephone the 911/EMS operator and have an ambulance with 
personnel trained in resuscitation sent to the MRRC. The other members will remove 
the patient via stretcher from the magnet room taking the patient to the part of the 
MRRC designated for cardiopulmonary resuscitation.  If immediate resuscitation is 
needed the physician present during the study will perform this procedure. 
C.
Anxiousness
If a subject is anxious and expresses a desire to leave the magnet then the study 
will be immediately terminated.
E.
IV Irritation
If there is irritation due to IV blood sampling, the physician present during the 
study will examine the subject, and the study will be terminated if the subject is in pain. 
G.
Effects of ketamine
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Our group here at Yale pioneered ketamine studies in healthy subjects and in 
depression, and has been performing these studies since early 1990s. Before 
participating, healthy subjects undergo careful psychiatric and medical evaluation.  A 
research nurse and study physician are available at all times during test sessions to 
provide support and consistent “reality testing” for individuals experiencing confusion 
or transient psychosis.  If a subject reports that symptoms cannot be tolerated, the 
ketamine infusion will be stopped.
Subjects will be observed for at least an hour after the termination of testing, and if 
intolerable physical or behavioral symptoms persist, subjects will be admitted to the 
Clinical Neuroscience Research Unit at the Connecticut Mental Health Center for 
further observation and overnight if necessary.  Participants will be informed that they 
may not drive or operate machinery for 24 hours after end of test day procedures, and 
study staff will ensure that they are picked up by a responsible adult or safely reach their 
home on alternate transportation.  Subjects will be provided a number to call to reach an 
on-call research psychiatrist (24-hours/day) should unpleasant effects occur after 
subjects have left the testing facility.  
Medication effects will be reviewed and 
“debriefed” with subjects following each test day by a study clinician.  If necessary, 
subjects will be administered oral diazepam to reduce residual symptoms and their 
participation in the study will be terminated if necessary.  Such subjects will be 
monitored as found appropriate by the study physicians.
We are also taking a number of precautions to help reduce the chance of having an 
unpleasant response to ketamine or to reduce the severity of any lingering medication 
effects.  These precautions include:
1) A physician who is trained and has significant experience with ketamine 
infusion studies will remain in attendance at all sessions ketamine infusion 
and will be responsible for the infusions. The subjects will also be attended by 
a research nurse who will accompany them through the study sessions, from 
the insertion of bilateral cannulae for drug infusion and blood sampling, 
through to recovery following ketamine infusion.
2) Medications are available (Valium) to relieve distress related to the behavioral 
effects of ketamine.
3) We will ask the subject to remain at the Yale MRRC recovery room for several 
hours after the behavioral effects of ketamine should have worn off.
4) We will review the test day with the subjects to deal with their feelings and 
reactions to each test day before they leave.
5) We will ask the subject to contact us at any time if any unpleasant effects 
occur.
6) We will ask the subject not to engage in demanding work in the day following 
the test sessions and we will work with the subject to schedule the test days 
accordingly.
7) If the subject has any lingering medication effects, such as sedation, we will 
terminate the remaining test days and work with him/her until these side 
effects have resolved.
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8) If the subject develops psychiatric symptoms, we may admit him/her to the 
hospital.  This may be involuntary if he/she is in danger of harming yourself 
or others.
9) We will also contact the subject at 1-week, 4-weeks, and 8-weeks after the 
ketamine infusion and possible lamotrigine administration to assess for any 
concerns, side effects, or other AEs. 
H. Effects of lamotrigine: Although a single dose of lamotrigine is expected to 
produce minimal to no side effects12,13, participants will be informed of potential side 
effects and will be asked to report any emerging symptoms. Adverse events will be 
recorded on the test day and during follow-ups.
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety 
Monitoring Plan (DSMP) based on the investigator’s risk assessment stated below. 
(Note: the HIC will make the final determination of the risk to subjects.) For more 
information, see the Instructions, page 24.
a. What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
The investigator’s assessment of the overall risk for subjects participating in this study is 
moderate.
b. If children are involved, what is the investigator’s assessment of the overall 
risk level for the children participating in this study? 
Not applicable. 
c.
Copy, paste, and then tailor an appropriate Data and Safety Monitoring 
Plan 
from  http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal/moderate risk
iii. High risk
d. For multi-site studies for which the Yale PI serves as the lead investigator:
i. How will adverse events and unanticipated problems involving risks to 
subjects or others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
Moderate Risk DSMP
1. Personnel responsible for the safety review and its frequency:
The principal investigator, Chadi Abdallah, M.D., will be responsible for monitoring the 
data, assuring protocol compliance, and conducting the safety reviews at the specified 
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frequency which must be conducted at a minimum of every 6 months (including when 
reapproval of the protocol is sought). During the review process, the principal 
investigator (monitor) will evaluate whether the study should continue unchanged, 
require modification/amendment, continue or close to enrollment. Either the principal 
investigator or the HIC have the authority to stop or suspend the study or require 
modifications.
2. The risks associated with the current study are deemed moderate for the 
following reasons: 
1. We do not view the risks associated with ketamine as minimal. 
2. We do not view the risks associated with the combined use of ketamine and 1H-MRS 
imaging as minimal
3. Given the now established safety and validity of the current research of ketamine in 
our prior work, we do not view the proposed study as high risk.
Although we have assessed the proposed study as one of moderate risk, the potential 
exists for anticipated and/or unanticipated adverse events, serious or otherwise, to 
occur since it is not possible to predict with certainty the absolute risk in any given 
individual or in advance of first-hand experience with the proposed study methods. 
Therefore, we provide a plan for monitoring the data and safety of the proposed study as 
follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures / design by the principal investigator, Chadi 
Abdallah, M.D., according to the following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s).
e.) 
Unrelated: 
Adverse 
event 
is 
clearly 
not 
related 
to 
investigational 
procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
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The following scale will be used in grading the severity of adverse events noted during 
the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe
5. Plan for Determining Seriousness of Adverse Events: 
Serious Adverse Events:
In addition to grading the adverse event, Dr. Abdallah will determine whether the 
adverse event meets the criteria for a Serious Adverse Event (SAE). An adverse event is 
considered serious if it:
1. is life-threatening
2. results in in-patient hospitalization or prolongation of existing hospitalization
3. results in persistent or significant disability or incapacity
4. results in a congenital anomaly or birth defect OR
5. results in death
6. based upon appropriate medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one of the other outcomes listed 
in this definition, or
7. adversely affects the risk/benefit ratio of the study
An adverse event may be graded as severe but still not meet the criteria for a Serious 
Adverse Event. Similarly, an adverse event may be graded as moderate but still meet the 
criteria for an SAE. It is important for the PI to consider the grade of the event as well as 
its “seriousness” when determining whether reporting to the HIC or HSC is necessary.
6. Plan for reporting serious AND unanticipated AND related adverse 
events anticipated adverse events occurring at a greater frequency than 
expected, and other unanticipated problems involving risks to subjects or 
others to the HIC 
The investigator will report the following types of adverse events to the HIC: 
a) serious AND unanticipated AND possibly, probably or definitely related events;
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b) anticipated adverse events occurring with a greater frequency than expected; and c) 
other unanticipated problems involving risks to subjects or others.
These adverse events or unanticipated problems involving risks to subjects or others will 
be reported to the HIC or HSC within 48 hours of it becoming known to the investigator, 
using the appropriate forms found on the website.
7. Plan for reporting adverse events to co-investigators on the study, 
funding and regulatory agencies
For the current study, the following individuals, funding, and/or regulatory agencies will 
be notified:
□ All Co-Investigators listed on the protocol.
The principal investigator, Chadi Abdallah, M.D., will conduct a review of all adverse 
events upon completion of every study subject. The principal investigator will evaluate 
the frequency and severity of the adverse events and determine if modifications to the 
protocol or consent form are required.
12. Statistical Considerations: Describe the statistical analyses that support the 
study design. 
The sample size (n=32) was selected based on previous reports13. fMRI processing and 
GBC analyses will be conducted as previously reported100. A paired t-test will be 
conducted to examine the effects of ketamine on GBC (Aim 1). A linear mixed model will 
examine the effects of ketamine and ketamine-by-lamotrigine interaction on cortical 
glutamate levels. Delta glutamate (during infusion minus baseline) will be correlated 
with delta GBC (post infusion minus baseline) (Aim 2). A t-test will compare delta GBC 
between the lamotrigine and placebo groups (Aim 3). Similar analyses will be conducted 
to examine the effects of ketamine and lamotrigine on the secondary outcomes, i.e. gln 
level, gaba level, cortical thickness, subcortical ROIs volumes, fractional anisotropy and 
mean diffusion, and amygdala activation.
 
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS 
AND DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest 
of the section.
A.  DRUGS, BIOLOGICS and RADIOTRACERS
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1.
Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the 
drug(s) 
biologic(s)  or radiotracer(s) being used? Identify whether FDA approval has been granted 
and for what indication(s). 
I.
Ketamine has U.S. Food and Drug Administration (USFDA) approval as the only 
anesthetic for diagnostic and surgical procedures that do not require skeletal muscle 
relaxation.  
Ketamine is also indicated for anesthesia induction prior to the 
administration of other general anesthetic agents or to augment low potency anesthetics 
such as nitrous oxide.
II. Lamotrigine has U.S. Food and Drug Administration (USFDA) approval as an 
anticonvulsant. It is also indicated for use in bipolar disorder. 
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, 
the FDA, or a radiotracer regulated by the RDRC, must provide the following information:  
a. What is the Investigational New Drug (IND) number assigned by the FDA?
Not applicable. 
 
b. Who holds the IND? 
Not applicable. 
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA 
must provide the IND number: _______________
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: 
(check if appropriate)_____________
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, 
complete the application and attach a copy to this submission.     
Alternatively, an exemption from IND filing requirements may be sought for a 
clinical
 investigation of a drug product that is lawfully marketed in the United States. If there is no 
IND and
 an exemption is being sought, review the following categories and complete the category that 
applies
 (and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can 
be
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exempt from IND regulations if all of the following are yes:
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in 
support
     of a new indication for use or to be used to support any other significant change in the 
labeling for
     the drug.  
 Yes  
 No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug 
product, and
      the intention of the investigation is NOT to support a significant change in the advertising 
for the
      product. 
 Yes  
 No
iii.  The investigation does NOT involve a route of administration or dosage level or use in 
populations
      or other factor that significantly increases the risks (or decreases the acceptability of the 
risks)   
      associated with the use of the drug product. 
 Yes  
 No
iv. The investigation will be conducted in compliance with the requirements for institutional 
(HIC)   
      review and with the requirements for informed consent of the FDA regulations (21 CFR 
Part 50  and 21 CFR Part 56). 
 Yes  
 No
v.   The investigation will be conducted in compliance with the requirements regarding 
promotion and charging for investigational drugs. 
 Yes  
 No
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
 i. The clinical investigation is for an in vitro diagnostic biological product that involves 
one or
more of the following (check all that apply):
 Blood grouping serum
 Reagent red blood cells 
 Anti-human globulin
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms 
the
diagnosis made by another, medically established, diagnostic product or procedure; and
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
 The drug is intended solely for tests in vitro or in laboratory research animals if 
shipped in accordance with 21 CFR 312.60
Exempt Category 4
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 A clinical investigation involving use of a placebo if the investigation does not 
otherwise require submission of an IND.
2. Background Information: Provide a description of previous human use, known risks, 
and data addressing dosage(s), interval(s), route(s) of administration, and any other 
factors that might influence risks. If this is the first time this drug is being administered to 
humans, include relevant data on animal models. 
I. Ketamine has been administered to over 10,000 patients and reported in greater than 
100 individual research investigations, including many (as previously cited) from our 
department.  Ketamine has a wide margin of safety and is typically provided in doses of 
1-4.5 mg/kg IV over 1 minute as a sole anesthetic agent.  In the majority of psychiatric 
investigations in depressed subjects to date, ketamine has been administered at 
subanesthetic doses (typically 0.5mg/kg infused over 40 minutes). In healthy subjects, 
the typical subanesthetic doses used are about 0.23 mg/kg bolus of over 1 minute 
followed by 0.58 mg/kg/hour infusion (e.g. Refs 12,101-105; Also, ongoing investigations 
include: HIC 1111009365, HIC 0908005593, HIC 1009007439).  Extensive experience 
suggests that ketamine administration is not associated with long-term toxicity.  The 
doses of ketamine administered produce blood levels 1/3 - 1/6 those associated with 
blood levels achieved when ketamine is used as a primary surgical anesthetic. Since 
1989, studies at our department administered ketamine on over 800 occasions to over 
300 subjects. Our group has extensive experience using ketamine in psychiatric 
research.
In healthy subjects: In addition to the recently found rapid-acting antidepressant effect, 
ketamine has been extensively used in human research as a model of psychosis owing to 
its acute psychotomimetic and cognitive adverse effects 106. In healthy volunteers, 
subanesthetic doses of ketamine induce transient perceptual disturbances, dissociative 
experiences, cognitive dysfunction, affective changes, thought disorder, and mild 
physical symptoms 107. These studies showed dose-dependent effects with increased 
symptoms at higher doses 10,108,109. However, the symptoms were transient, starting 
within minutes of ketamine infusion and lasting up to 2-hours 10. Recently, Perry and 
colleagues at Yale reviewed a dataset of 450 healthy subjects who collectively received a 
total of 833 ketamine infusions in a medically supervised setting as part of laboratory 
studies 97. This report noticed no evidence of serious adverse events, residual sequelae, 
or sensitization. Only 2% of subjects experienced non-serious adverse reactions. These 
emerging side effects resolved by the end of the test day in all subjects, except for one 
participant who experienced symptoms for 4-days 97.
II. Lamotrigine: 
As noted above, lamotrigine is an anticonvulsant drug.  It is also used in the 
treatment of bipolar disorder, specifically in the treatment and prevention of bipolar 
depressive episodes 78. Lamotrigine is also believed to act on serotonin reuptake, 
which may contribute to its antidepressant effects 79,81. There is evidence of 
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peripheral glutamate dysregulation in bipolar disorder 82, and the glutamatergic 
activity of lamotrigine may also be implicated in its therapeutic and neuroprotective 
effects. Lamotrigine levels have been shown to peak at 1 to 4 hours after oral 
administration, with a mean of 2 hours.
Several studies have found that lamotrigine reduced the neuropsychiatric effects of 
ketamine in healthy subjects 12 as well as preventing some BOLD signal changes in a 
neuroimaging study 13. In a pioneering Yale study exploring the impact of 
lamotrigine on ketamine’s influence on glutamate, healthy subjects were given 300 
mg of lamotrigine approximately two hours prior to a ketamine infusion (0.25 mg/kg 
by intravenous bolus and 0.65 mg/kg per hour by intravenous infusion). Those 
subjects who received lamotrigine demonstrated significantly decreased ketamine-
induced perceptual disturbances as assessed by the Clinician Administered 
Dissociative States Scale, as well as reduced positive and negative psychotomimetic 
symptoms as assessed by the Brief Psychotic Symptoms Scale, and reductions in 
learning and memory impairment. Of note, those participants who received 
lamotrigine showed increases in the rapid mood enhancing effects of ketamine 12. In 
another study hoping to identify the mechanisms of action of ketamine in inducing 
symptoms and to determine the role of increased glutamate release in these 
alterations, participants were pretreated with lamotrigine, prior to a ketamine 
infusion to examine which effects of ketamine appear to be mediated by increased 
glutamate release 13. They found that ketamine administration induced a rapid and 
focal decrease in the ventromedial frontal cortex, including the orbitofrontal cortex 
and subgenual cingulate, which strongly predicted its dissociative effects. They also 
noted increased activity in the mid-posterior cingulate, thalamus, and temporal 
cortical regions. They found that lamotrigine pre-treatment prevented many of the 
BOLD signal changes 13. In the current proposal, we want to explore further the 
impact of lamotrigine on ketamine-induced changes in rs-fMRI and the relationship 
between alterations in glutamate levels and rs-fMRI changes. 
3. Source: 
a) Identify the source of the drug or biologic to be used. 
I.
Ketamine will be obtained from the Yale New Haven Hospital Investigational 
Drug Service.  
II. 
Lamotrigine will be obtained from the Yale New Haven Hospital Investigational 
Drug Service.
b) Is the drug provided free of charge to subjects? 
 Yes  
 No
    If yes, by whom? 
No drug will be administered except during the MRS scans, where a physician and a 
nurse from the research team will administer the drug as described in the methods.
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4. Storage, Preparation and Use: Describe the method of storage, preparation, stability 
information, and for parenteral products, method of sterilization and method of testing 
sterility and pyrogenicity. 
Check applicable Investigational Drug Service utilized:
     
   YNHH IDS                                                                      
   Yale Cancer Center 
     
   CMHC Pharmacy                                                          
  West Haven VA
     
   PET Center                                                     
    None      
     
    Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, 
explain in detail how the PI will oversee these aspects of drug accountability, storage, 
and preparation.  
  
5. Use of Placebo: 
 Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
In this study neither ketamine, lamotrigine, or the matched-placebo are used for 
therapeutic purposes. They will be used in healthy volunteers to determine underlying 
neurobiological mechanisms and not for treatment purposes.
a.
Describe the safety and efficacy of other available therapies. If there are no other
available therapies, state this.
b.   State the maximum total length of time a participant may receive placebo while on the 
study. 
c.   Address the greatest potential harm that may come to a participant as a result of  
receiving    
  
   placebo. 
d.   Describe the procedures that are in place to safeguard participants receiving placebo. 
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
 Yes  
 No See HIC Application Instructions to view controlled substance listings. 
If yes, is the use of the controlled substance considered:
 Therapeutic: The use of the controlled substance, within the context of the research, 
has the potential to benefit the research participant.
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic 
research study involving human subjects may require that the investigator obtain a 
Laboratory Research License. Examples include controlled substances used for basic 
imaging, observation or biochemical studies or other non-therapeutic purposes. See 
Instructions for further information.
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this 
project
Are subjects provided the opportunity to continue to receive the study drug(s) after the 
study has ended?
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 Yes   If yes, describe the conditions under which continued access to study drug(s) 
may apply as well as conditions for termination of such access. 
 
 No    If no, explain why this is acceptable.
 B.  DEVICES
1. Are there any investigational devices used or investigational procedures performed at 
YNHH, e.g., YNHH Operating Room or YNHH Heart and Vascular Center?  Yes 
  No 
If Yes, please be aware of the following requirements:
a. A YNHH New Product/Trial Request Form must be completed;  
b. Your request must be reviewed and approved by a Hospital Committee 
before patients may be scheduled; and  
c. The notice of approval from YNHH must be submitted to the HIC for the 
protocol file. 
Please contact Gina D’Agostino, gina.d’agostino@ynhh.org or 203-688-5052, to initiate 
the process. 
2. What is the name of the device to be studied in this protocol?
Has this device been FDA approved? 
 Yes  
 No
If yes, state for what indication.
3. Background Information: Provide a description of previous human use, known risks, 
and any other factors that might influence risks. If this is the first time this device is being 
used in humans, include relevant data on animal models. 
4. Source: 
a) Identify the source of the device to be used. 
b) Is the device provided free of charge to subjects? 
 Yes  
 No
5. What is the PI’s assessment of risk level (significant or non-significant) associated with 
the use of the device? 
 Significant Risk (SR) Device Study: A study of a device that presents a potential 
for serious risk to the health, safety, or welfare of a participant and 1) is intended as an 
implant; 2) is used in supporting or sustaining human life; or otherwise prevents 
impairment of human health; 3) is of substantial importance in diagnosing, curing, 
mitigating or treating disease, or otherwise prevents impairment of human health; or 4) 
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otherwise presents a potential for serious risk to the health, safety, or welfare of a 
participant.   
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the 
FDA.
What is the IDE number assigned by the FDA? 
Did the FDA approve this IDE as Category A (experimental/investigational) or as 
Category B (non-experimental/investigational)?
Who holds the IDE?
 Non-Significant Risk (NSR) Device Study: A study of a device that does not meet 
the   definition for a significant risk device and does not present a potential for serious 
risk to the health, safety, or welfare of participants.  Note that if the HIC concurs with this 
determination, an IDE is not required.
6.  Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE 
and there also are exemptions to the requirement for an IDE.  See the criteria in the HIC 
Application Instructions, Section VI.B.4 at 
http://www.yale.edu/hrpp/resources/docs/100FR1aHICProtocol_Application_Instructio
ns5-25-11.pdf to determine if these pertain to this study.
  
 Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application 
Instructions are met, copy and paste the completed relevant section from the 
Instructions into this application.
7.   Investigational device accountability:
a. State how the PI, or named designee, ensures that an investigational 
device is used only in accordance with the research protocol approved by 
the HIC, and maintains control of the investigational device as follows:
Maintains appropriate records, including receipt of shipment, inventory 
at the site, dispensation or use by each participant, and final disposition and/or 
the return of the investigational device (or other disposal if applicable):
Documents pertinent information assigned to the investigational device (e.g., date, 
quantity, batch or serial number, expiration date if applicable, and unique code number):
Stores the investigational device according to the manufacturer's recommendations with 
respect to temperature, humidity, lighting, and other environmental considerations:
Ensures that the device is stored in a secure area with limited access in accordance with 
applicable regulatory requirements:
Distributes the investigational device to subjects enrolled in the IRB-approved protocol:
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SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1.
Targeted Enrollment: Give the number of subjects:
a.   targeted for enrollment at Yale for this protocol:__32___
b.    If this is a multi-site study, give the total number of subjects targeted across all 
sites___ 
2.
Indicate recruitment methods below.  Attach copies of any recruitment 
materials that will be used.
 Flyers
 Internet/Web Postings
 Radio
 Posters
 Mass E-mail Solicitation
 
Telephone
 Letter
 
 Departmental/Center Website
 Television
 Medical Record Review
 Departmental/Center Research Boards
 Newspaper
 Departmental/Center Newsletters
 Web-Based Clinical Trial Registries
  YCCI Recruitment database
 Clinicaltrials.gov Registry (do not send materials to 
HIC)
 Other (describe): Wallet-sized recruitment cards. 
3.
 Recruitment Procedures: 
a. Describe how potential subjects will be identified.
Subjects will be identified via their response to advertisements and/or internal 
recruiting through the research clinics.
b. Describe how potential subjects are contacted. 
Subjects will be contacted via the most convenient means and personal preference, e.g. 
telephone and e-mail.
c.Who is recruiting potential subjects? 
All available research staff is responsible for recruiting potential subjects.
4.
Screening Procedures
a. be used to screen potential subjects for eligibility prior to the potential subject 
coming to the research office? 
 Yes  
 No
b.  If yes, identify below all health information to be collected as part of screening 
and check off any of the following HIPAA identifiers to be collected and 
retained by the research team during this screening process. 
HEALTH INFORMATION TO BE COLLECTED:
HIPAA identifiers: 
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 Names 
 All geographic subdivisions smaller than a State, including: street address, city, county, 
precinct, zip codes and their equivalent geocodes, except for the initial three digits of a zip 
code if, according to the current publicly-available data from the Bureau of the Census: (1) 
the geographic unit formed by combining all zip codes with the same three initial digits 
contains more than 20,000 people, and (2) the initial three digits of a zip code for all such 
geographic units containing 20,000 or fewer people is changed to 000. 
  Telephone numbers
 Fax numbers 
 E-mail addresses
 Social Security numbers 
 Medical record numbers
 Health plan beneficiary numbers 
 Account numbers 
  All elements of dates (except year) for dates related to an individual, including: birth date, 
admission date, discharge date, date of death, all ages over 89 and all elements of dates 
(including year) indicative of such age, except that such ages and elements may be aggregated 
into a single category of age 90 or older 
 Certificate/license numbers 
 Vehicle identifiers and serial numbers, including license plate numbers 
 Device identifiers and serial numbers 
 Web Universal Resource Locators (URLs) 
 Internet Protocol (IP) address numbers 
 Biometric identifiers, including finger and voice prints 
 Full face photographic images and any comparable images 
 Any other unique identifying numbers, characteristics, or codes 
5.
Assessment of Current Health Provider Relationship for HIPAA 
Consideration:
Does the Investigator or any member of the research team have a direct existing 
clinical relationship with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
 No
If yes, describe the nature of this relationship.
Some of the subjects recruited into this study will have had prior contact with research 
clinics and/or may have participated in a prior approved experimental protocol.
6.
 (When requesting a waiver of HIPAA Authorization for either the entire study, or for 
recruitment purposes only.  Note: if you are collecting PHI as part of a phone or email screen, 
you must request a HIPAA waiver for recruitment purposes.)
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A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 2/ 8/ 2 0 1 8 V A LI D T H R O U G H 2/ 1 1/ 2 0 1 9
Pa ge 4 5  of 5 8
Versi o n: 0 8/ 1 9/ 2 0 1 5
C h o o s e o n e:  F or e ntir e st u d y: _ _ _ _ _ _ F or r e cr uit m e nt p ur p os es o nl y:   
✔
i.
D es cri b e w h y it w o ul d b e i m pr a cti c a bl e t o o bt ai n t h e s u bj e ct’s a ut h oriz ati o n 
f or us e / dis cl os ur e of t his d at a;
ii.
If r e q u esti n g a w ai v er of si g n e d  a ut h oriz ati o n, d es cri b e w h y it w o ul d b e 
i m pr a cti c a bl e t o o bt ai n t h e s u bj e ct’s si g n e d a ut h oriz ati o n f or us e / dis cl os ur e 
of t his d at a;
I n or d er t o d et er mi n e if a s u bj e ct is eli gi bl e t o c o m e i n t o t h e cli ni c f or a 
s cr e e ni n g visit, w e c o n d u ct p h o n e s cr e e ns. 
W e as k t h eir p er missi o n t o r e c or d 
d at a, a n d t ell t h e m t h at e v er yt hi n g w e writ e d o w n is c o nfi d e nti al a n d will b e 
k e pt i n a l o c k e d c a bi n et. T h er ef or e, d u e t o pr es cr e e ni n g o n t h e p h o n e, w e 
c a n n ot g et t h eir si g n e d a ut h oriz ati o n.  
W e c a n o nl y g et t h eir v er b al 
a ut h oriz ati o n.
B y si g ni n g  t hi s p r ot o c ol a p pli c ati o n, t h e i n v e sti g at o r a s s u r e s t h at t h e 
p r ot e ct e d h e alt h i nf o r m ati o n f o r w hi c h a 
W ai v e r of A ut h o ri z ati o n h a s 
b e e n r e q u e st e d will n ot b e r e u s e d o r di s cl o s e d t o a n y p e r s o n o r e ntit y 
ot h e r t h a n t h o s e li st e d i n t hi s a p pli c ati o n, e x c e pt a s r e q ui r e d b y l a w, 
f o r a ut h o ri z e d o v e r si g ht of t hi s r e s e a r c h st u d y, o r a s s p e cifi c all y 
a p p r o v e d f o r u s e i n a n ot h e r st u d y b y a n I R B.
R es e a r c h e rs a r e  r e mi n d e d t h at u n a ut h o riz e d dis cl os u r es of P HI t o i n di vi d u als o utsi d e 
of t h e Y al e HI P A A- C o v e r e d e ntit y m ust b e a c c o u nt e d f o r i n t h e “ a c c o u nti n g f o r 
dis cl os u r es l o g”, b y s u bj e ct n a m e, p u r p os e, d at e, r e ci pi e nts, a n d a d es c ri pti o n of 
i nf o r m ati o n p r o vi d e d.  L o gs a r e t o b e f o r w a r d e d t o t h e D e p ut y HI P A A P ri v a c y Offi c e r.
7.
R e q ui r e d HI P A A  A ut h o ri z ati o n: If t h e r es e ar c h i n v ol v es t h e cr e ati o n, us e or 
dis cl os ur e of pr ot e ct e d h e alt h i nf or m ati o n ( P HI), s e p ar at e s u bj e ct a ut h oriz ati o n is 
r e q uir e d u n d er t h e HI P A A Pri v a c y R ul e. I n di c at e w hi c h of t h e f oll o wi n g f or ms ar e 
b ei n g pr o vi d e d:
 C o m p o u n d  C o ns e nt a n d A ut h oriz ati o n f or m
 HI P A A R es e ar c h A ut h oriz ati o n F or m
C o n s e nt P e r s o n n el:  
8.
P r o c e s s of  C o n s e nt / A s s e nt: D es cri b e t h e s etti n g a n d c o n diti o ns u n d er w hi c h 
c o ns e nt / ass e nt will b e o bt ai n e d, i n cl u di n g p ar e nt al p er missi o n or s urr o g at e p er missi o n 
a n d t h e st e ps t a k e n t o e ns ur e s u bj e cts’ i n d e p e n d e nt d e cisi o n- m a ki n g. 
If a n i n di vi d u al a p p e ars t o m e et e nr oll m e nt crit eri a a n d is i nt er est e d i n p arti ci p ati n g, a 
f a c e-t o-f a c e i nt er vi e w is c o n d u ct e d, b y o n e of t h e pr oj e ct i n v esti g at ors. A r el e as e of 
i nf or m ati o n is o bt ai n e d f or r e vi e w of a n y a v ail a bl e hist ori c al a n d cli ni c al d at a. A writt e n 
a ut h oriz ati o n f or m ( S e e Att a c h e d) is als o o bt ai n e d fr o m e a c h s u bj e ct, p er mitti n g t h e 
r es e ar c h t e a m t o us e, cr e at e, or dis cl os e t h e s u bj e ct's P HI f or r es e ar c h p ur p os es. T h e 
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 2/ 8/ 2 0 1 8 V A LI D T H R O U G H 2/ 1 1/ 2 0 1 9


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nature of the project, procedures, relative risks and benefits, and alternatives to 
participation in the project are discussed with the individual. Following this discussion, 
the individual is given a copy of the consent form to review at their leisure, and any 
questions are answered.
If the individual remains interested in the project, written informed consent (see 
Attached) is obtained, and medical and psychiatric screening procedures are undertaken 
to confirm eligibility. A copy of the consent form is provided to all participants.
If the individual decides not to participate in this study, the decision not to participate 
does not affect eligibility to participate in future studies, to receive treatment at the 
Connecticut Mental Health Center, or to receive treatment on a private basis from a 
referring clinician.
9. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: 
Indicate how the personnel obtaining consent will assess the potential subject’s ability 
and capacity to consent to the research being proposed. 
As mentioned above, after trained and knowledgeable research personnel explain all 
aspects of the research protocol with a consent form at hand, the potential subject will 
be asked to communicate a reciprocal understanding of the protocol.  This “say back” 
method has demonstrated reliability among educators in ascertaining degree of 
comprehension.
10. Documentation of Consent/Assent: Specify the documents that will be used during 
the consent/assent process. Copies of all documents should be appended to the protocol, 
in the same format that they will be given to subjects. 
Research personnel capable of determining consent will conduct this process with the 
most up-to-date copies of the Yale informed consent documentations at hand. Yale 
consent forms has been appended to this document.
11. Non-English Speaking Subjects: Explain provisions in place to ensure 
comprehension for research involving non-English speaking subjects. Translated copies of 
all consent materials must be submitted for approval prior to use. 
Not applicable. 
12.Consent Waiver: In certain circumstances, the HIC may grant a waiver of 
signed consent, or a full waiver of consent, depending on the study. If you will 
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request either a waiver of consent, or a waiver of signed consent for this study, complete 
the appropriate section below.  
 
 Not requesting a consent waiver 
 
 Requesting a waiver of signed consent
       
 Requesting a full waiver of consent
   
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
 Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the 
research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research activity pose greater than minimal risk? 
 Yes If you answered yes, stop. A waiver cannot be granted.  Please 
note: Recruitment/screening is generally a minimal risk research activity  
 No 
AND
d. Does the research include any activities that would require signed consent in a 
non-research context? 
 Yes  
 No
 Requesting a waiver of signed consent for the Entire Study (Note that an 
information sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the 
research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research pose greater than minimal risk? 
 Yes If you answered 
yes, stop. A waiver cannot be granted.    
 No 
AND
d. Does the research include any activities that would require signed consent in a 
non-research context? 
 Yes  
 No
B. Full waiver of consent: (No consent from subjects will be obtained for the activity.) 
 Requesting a waiver of consent for Recruitment/Screening only 
a. Does the research activity pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted. Please 
note: Recruitment/screening is generally a minimal risk research activity 
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 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared 
with subjects at a later date? 
 Requesting a full waiver of consent for the Entire Study (Note: If 
PHI is collected, information here must match Section VII, question 
6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted.  
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared 
with subjects at a later date? 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
a.    What protected health information (medical information along with the HIPAA 
identifiers) about subjects will be collected and used for the research?   
       
b.    How will the research data be collected, recorded and stored? 
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable 
Hard   
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other
d.    What methods and procedures will be used to safeguard the confidentiality and 
security of    
the identifiable study data and the storage media indicated above during and after 
the subject’s participation in the study?
Do all portable devices contain encryption software? 
 Yes   
 No
         If no, see http://hipaa.yale.edu/guidance/policy.html
 
e. What will be done with the data when the research is completed? Are there plans to 
destroy     the identifiable data? If yes, describe how, by whom and when identifiers 
will be destroyed. If no, describe how the data and/or identifiers will be secured.
After subject participation in the study has ceased, written confidential PHI will be 
transported from the YDRP to be stored in patient records (CMHC basement).  All 
electronic PHI (ePHI) will continue to be encrypted and password-protected after 
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subject participation.  Both written and ePHI will be destroyed after the protocol is 
completed at a time designated by the primary investigator.
f.   Who will have access to the protected health information (such as the research 
sponsor, the  investigator, the research staff, all research monitors, FDA, Yale Cancer 
Center Data and Safety Monitoring Committee (DSMC), SSC, etc.)? (please distinguish 
between PHI and de-identified data). 
All pre-identified research personnel, Yale HIC and NIMH will have access to written 
and ePHI throughout and after the completion of the study until the data is destroyed at 
the discretion of the primary investigators.
g.   If appropriate, has a Certificate of Confidentiality been obtained?
Yes: Because this study contains sensitive information and drug testing and is funded by 
the NIH, per the Notice of Changes to NIH Policy for Issuing Certificates of 
Confidentiality (NOT-OD-17-109), effective October 1, 2017, this study is assumed to 
now have a Certificate of Confidentiality, subjects are anticipated to be protected.
h.   Are any of the study procedures likely to yield information subject to mandatory 
reporting   requirements? (e.g. HIV testing – reporting of communicable diseases; 
parent interview -incidents of child abuse, elderly abuse, etc.). Please verify to whom 
such instances will need to be reported. 
HIV, Hepatitis B and C testing, as part of the screening assessment, may yield 
information that we are legally required to disclose to the State of Connecticut and/or 
CDC as reportable infections. Any identifiable information obtained in connection with 
this protocol remains confidential. Information is disclosed only with the subject's prior 
authorization or as required by U.S. and State law. Information that we are legally 
required to disclose includes abuse of a child or elderly person, or certain reportable 
infectious disease.
SECTION IX: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result 
from the research, either to the subject(s) or to society at large. (Payment of subjects is 
not considered a benefit in this context of the risk benefit assessment.) 
There is no direct clinical benefit for participating in this study. The present studies may 
benefit others by providing insight into depression and schizophrenia. It may provide 
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specific information about the effect of subanesthetic dose of ketamine on the human 
brain and may provide guidance in further exploring potential mechanisms for the rapid 
antidepressant effect of ketamine as well as provide potentially important information 
related to the pathophysiology of psychosis. This information may in turn provide novel 
diagnostic tests, and may help target new drug development.
The relative risks and inconveniences associated with participation in this study, 
including ketamine administration, MRS and venipuncture procedures are balanced by 
the potential benefits to society.
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.     Alternatives: What other alternatives are available to the study subjects outside of the 
research?
The current study is not for treatment purposes and the subjects do not need to 
participate. 
2. 
Payments for Participation (Economic Considerations): Describe any 
payments that will be made to subjects, the amount and schedule of payments, and the 
conditions for receiving this compensation. 
All participants will be compensated for their participation. Subjects will be paid $40 for
screening, $60 for each MRI study (2 studies total), $40 for each cognitive testing 
session (2 sessions total), and $300 for ketamine infusion test day. Failed imaging 
studies will be repeated and subjects will be paid additionally for the repeated scan. If 
participation in the scans has already begun and must be cancelled before completion, 
then compensation will be based on involvement in the study at a rate of $20 per hour. 
Reasonable transportation costs up to $100 on the infusion day will be reimbursed. 
Receipts must be submitted. 
Therefore, we anticipate the subject’s total earning – if he/she participates in all 
sessions – is $540. At the principal investigator's discretion, further subject payment 
may be made for travel, parking, lodging, food or transportation.
The debit cards will be offered through the YCCI OnCore ePayments system and will be our  
preferred payment option. Subjects will be informed that they will receive payment via a Bank   
of America pre-paid debit card.  We will provide their name, address, and telephone number to 
the Bank of America for processing and their card will be related to their name and number.  
Their SSN or other information will not be provided. All compensation information will be 
discussed in the informed consent process.  
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3.
Costs for Participation (Economic Considerations): Clearly describe the 
subject’s costs associated with participation in the research, and the interventions or 
procedures of the study that will be provided at no cost to subjects.   
The only costs associated with the study are transportation to and from appointments. 
All services and evaluations are provided free of charge.
4.
In Case of Injury: This section is required for any research involving more than 
minimal risk.
a.     Will medical treatment be available if research-related injury occurs? 
b.     Where and from whom may treatment be obtained? 
c.     Are there any limits to the treatment being provided? 
d.     Who will pay for this treatment? 
e.     How will the medical treatment be accessed by subjects? 
Medical treatment will be offered to the subjects for any physical injuries that 
they receive as a result of participating in this research. However, the subject or his/her 
insurance company is responsible for the cost. As required by Federal regulations, all 
subjects will be told that if they are physically injured, no additional financial 
compensation is available.
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