Role Of Non-Specific Effects in The Treatment of Depression With Esketamine
Phase: NA
Conditions: Depressive Episode
Sponsor: Yale University

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STUDY PROTOCOL
Social Behavioral Template
Role Of Non-Specific Effects in The 
Treatment of depression with Esketamine 
(ROSETTE)
 Protocol Number
2000034829
Protocol Version
Version Date: 3/6/24
 Version # 2
Clinical Trials Registration Number (if applicable)
Confidentiality Statement:
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NCT05910775

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Synopsis
Purpose
We aim to examine the magnitude of non-specific effects in the treatment of depressive 
episodes with esketamine, by providing patients in the “intervention” group with a pre-
treatment presentation and post-treatment “follow up” session, to assess whether non-
specific effects can be used effectively to improve the effectiveness of treatment with 
esketamine.
Objectives
Primary Objective:
To determine whether a positive presentation before first treatment improves expectation 
of improvement from treatment in patients receiving esketamine for a depressive episode 
within 24 hours after the first treatment. 
Secondary Objectives:
To determine whether a post-treatment follow up session to provide encouragement and 
reassurance improves expectation of improvement from treatment in patients receiving 
esketamine for a depressive episode within 24 hours after the first treatment. 
To determine whether a positive presentation results in an improved response from 
treatment in patients receiving esketamine for a depressive episode as measured by 
MADRS score within 24 hours after the first treatment.
To determine whether a positive presentation before first treatment, combined with a post-
treatment follow up session after first treatment, result in an improved response from 
treatment in patients receiving esketamine for a depressive episode as measured by 
MADRS score by the end of the acute course of esketamine treatment.,  
Study Population
Adult patients with major depressive disorder for whom it has been determined by their 
primary mental health provider that esketamine is an appropriate treatment and have 
already been deemed appropriate and scheduled for clinical esketamine treatment at Yale 
Interventional Psychiatry Service.
Number of Participants
We aim to enroll a total of 34 patients (17 per arm) for this study. 
Study Design
Patients who are deemed clinically appropriate for esketamine will be approached for 
participation in the study. The eligible and consented participants will be randomized at a 
1:1 ratio into “intervention” and TAU groups, with the intervention group being presented 
with the presentation prior to the first treatment, and to receive a “follow up” session within 
24 hours after the first treatment. Both groups will otherwise receive treatment as usual 
during the course.  Assessments including treatment expectations and depression 
severity will be done at baseline, within 24 hours after treatments 1, 2 and 8.

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Study Duration
2 years
Outcome Variables
Primary outcome: Group difference in change in question 6 of the CEQ-6 from baseline to 
after the presentation
Secondary Outcome: Group difference in change in MADRS score from baseline to 24 
hours after first treatment
Exploratory outcomes:
Group difference in change in CEQ-6 from baseline to 24 hours after first treatment and 
after follow-up session
Group difference in change in MADRS score by the end of the acute series of treatments
Group difference in the side effect profile
Locations/Facilities
Yale Psychiatry hospital (YPH) Interventional Psychiatry Services (IPS) unit
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Abbreviations
Abbreviation 
Explanation
AE
Adverse Events
CMP
Clinical monitoring plan
CEQ-6
Credibility and Expectancy Scale
CRF
Case report form
DCC
Data coordination center
DHHS
Department of Health and Human Services
DSMB
Data Safety Monitoring Board
DRE
Department of Health and Human Services
EC
Ethics Committee
eCRF
Electronic Case Report Forms
GCP
Good clinical practice
HIPAA
Health Insurance Portability and 
Accountability Act
MADRS
Montgomery-Asberg Depression Rating 
Scale
NCT
National Clinical Trial
NIH
National Institutes of Health
PI
Principal Investigator
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QA
Quality Assurance
QC
Quality Control
QIDS-SR
Quick Inventory of Depressive 
Symptomatology
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
TAU
Treatment as usual
UP
Unanticipated Problem
YCCI
Yale center for clinical investigation
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Glossary of Terms
Glossary
Explanation
Adverse Event
Any event associated with esketamine 
treatment or the virtual presentation and 
follow-up sessions whether or not 
considered therapy related.
Dysgeusia
Altered taste
Serious adverse event
Serious adverse events (SAEs) are defined 
as AEs that result in death, are life-
threatening, require hospitalization, or result 
in prolongation of existing hospitalization, 
permanent or significant disability a 
persistent or significant incapacity or 
substantial disruption of the ability to 
conduct normal life functions, or a 
congenital anomaly/birth defect.  
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Table of Contents
Synopsis ..................................................................................................................................2
Purpose................................................................................................................................2
Objectives.............................................................................................................................2
Study Population ..................................................................................................................2
Number of Participants.........................................................................................................2
Study Design........................................................................................................................2
Study Duration......................................................................................................................3
Outcome Variables...............................................................................................................3
Locations/Facilities...............................................................................................................3
Abbreviations ...........................................................................................................................4
Glossary of Terms....................................................................................................................6
Protocol Revision History.......................................................................................................10
1 ..........................................................................................................................................Background
...............................................................................................................................................11
1.1
Background .............................................................................................................11
1.2
Prior Experience .....................................................................................................11
2 ........................................................................................................................Rationale/Significance
...............................................................................................................................................12
2.1
Rationale and Study Significance............................................................................12
2.2
Risks........................................................................................................................12
2.3
Anticipated Benefits.................................................................................................13
3 ..........................................................................................................Study Purpose and Objectives
...............................................................................................................................................13
3.1
Purpose ...................................................................................................................13
3.2
Hypothesis...............................................................................................................13
3.3
Objectives................................................................................................................14
4........................................................................................................................................Study Design
...............................................................................................................................................14
4.1
Study Duration.........................................................................................................17
4.2
Outcome Variables/Endpoints.................................................................................17
4.2.1
Primary Outcome Variables/Endpoints ............................................................17
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4.2.2
Secondary and Exploratory Outcome Variables/Endpoints .............................17
5................................................................................................................................Study Participants
...............................................................................................................................................17
5.1
Study Population .....................................................................................................17
5.2
Number of Participants............................................................................................17
5.3
Eligibility Criteria......................................................................................................17
5.4
Recruitment Procedures..........................................................................................18
5.5
Consent/Assent Procedures/HIPAA Authorization..................................................18
6................................................................................................................Study Methods/Procedures
...............................................................................................................................................19
6.1
Study Procedures....................................................................................................19
6.1.1
Data Collection.................................................................................................22
6.2
Method of Assignment/Randomization....................................................................22
6.3
Adverse Events Definition and Reporting................................................................23
6.4
Reaction Management ............................................................................................23
6.5
Withdrawal Procedures ...........................................................................................24
6.6
Locations/Facilities ..................................................................................................25
7 .................................................................................................................................Statistical Design
...............................................................................................................................................26
7.1
Sample Size Considerations ...................................................................................26
7.2
Planned Analyses....................................................................................................26
7.2.1
Secondary Objective Analyses ........................................................................26
7.2.2
Analysis of Subject Characteristics .................................................................26
7.2.3
Interim Analysis ...............................................................................................27
7.3
Data Relevance.......................................................................................................27
7.4
Data Coding.............................................................................................................27
7.5
Data Analysis Tools.................................................................................................27
7.6
Data Monitoring .......................................................................................................28
7.7
Handling of Missing Data.........................................................................................28
8...............................................................................Data/Specimen Handling and Record Keeping
...............................................................................................................................................28
8.1
Subject Data Confidentiality ....................................................................................28
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8.2
Data Quality Assurance...........................................................................................29
8.3
Data or Specimen Storage/Security ........................................................................29
8.4
Study Records.........................................................................................................29
8.5
Access to Source.....................................................................................................30
8.6
Retention of Records...............................................................................................30
8.7
Data and Safety Monitoring Plan.............................................................................31
9..........................................................................................................................Study Considerations
...............................................................................................................................................31
9.1
Institutional Review Board (IRB) Review.................................................................31
9.2
Research Personnel Training..................................................................................31
9.3
Study Monitoring......................................................................................................32
9.4
Unanticipated Problems and Protocol Deviations ...................................................32
9.5
Study Discontinuation..............................................................................................33
9.6
Study Completion ....................................................................................................33
9.7
Conflict of Interest Management Plan .....................................................................33
9.8
Funding Source .......................................................................................................34
9.9
Publication Plan.......................................................................................................34
10.........................................................................................................................................Appendices
...............................................................................................................................................35
11......................................................................................................................................List of Tables
...............................................................................................................................................38
12 .........................................................................................................................................References
...............................................................................................................................................38
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Protocol Revision History
Version 
Date
Summary of Substantial Changes
Include the IRB approved protocol version number and date for each revision of the protocol. All 
version history should remain in the table and never be deleted. The oldest IRB approved version of 
the protocol should be listed on the top row. The most recent IRB approved version should be listed 
on the bottom row.
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1 Background
1.1
Background
Non-specific treatment effects and more specifically placebo effects have been recognized 
as major factors contributing to the effectiveness of various therapies for more than two 
centuries1 As early as 1955 Beecher noted that placebo effects can be quite beneficial and 
should be studied further2.  However, more recently placebo effects have largely been 
viewed as a nuisance in the conduct of clinical trials and most efforts have been directed at 
minimizing the effect to better isolate the true specific-treatment effect3. Understanding the 
factors that contribute to the non-specific effects of a treatment, including the placebo and 
nocebo effects (negative effects experienced in concordance with the expected side effect) 
could improve our ability to provide effective treatment to patients with little added costs to 
the health care system4. 
Significant advances have been made in our understanding of the basic factors contributing 
to the placebo and nocebo effects over last few decades5. It is theorized that the culmination 
of verbal, social and conditioned “cues” create an expectancy for a specific therapeutic 
response driving the powerful placebo effect5. Recent work has begun to elucidate the 
neurobiological mechanisms underlying this effect. While moderate to large placebo 
response rates have been observed in a broad range of medical diseases ranging from 
neurological disorders6 and depression7,8 to cardiovascular disorders9, much of the 
mechanistic research in this area has been focused on the study of pain management as it 
is most amenable to studies examining the rapid onset of the effect. The narrow scope of the 
mechanistic research leaves questions about generalizability and applicability of the findings 
to other disorders in question. The discovery of rapidly acting antidepressant medications 
such as ketamine now allows for the efficient investigation of placebo and nocebo effects in 
patients suffering from depression.  
Yale has been a leader in the development of rapidly acting antidepressant treatments and 
the Interventional Psychiatry Service (IPS) at Yale Psychiatric Hospital (YPH) currently 
provides over 70 ketamine/esketamine treatments for major depressive disorder (MDD) per 
week.  Throughout the conduct of nearly 20 years of clinical trials and 8 years of clinical care 
with these treatments, clinicians and investigators working in the program have been 
increasingly intrigued by the non-specific contributions of the treatments to the clinical 
response. The data from the existing phase 2 and 3 trials of esketamine10 have 
demonstrated much higher than expected rates of response in the placebo treated groups 
which also suggests a notable non-specific component to the treatment. 
1.2
Prior Experience 
NA.
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2 Rationale/Significance
2.1
Rationale and Study Significance 
Based on the available evidence, non-specific effects are thought to be responsible for a 
notable portion of treatments’ effects and side effects. Considering the prevalence of 
depressive disorders and their significant burden on the society11, any potential 
improvements in effectiveness can have far reaching benefits for our patients and the 
society. This project aims to methodologically examine the magnitude of non-specific effects 
in the treatment of depressive episodes with esketamine, to explore the moderators and 
mediators of the effect, and to assess whether the non-specific effects can be used 
effectively to improve the effectiveness of this treatment.
The data collected in this initial study will be used to provide support for future study 
proposals designed to more thoroughly evaluate the moderators and mediators of the effect 
employing the wide range assessment tools and imaging modalities available here at Yale. 
Furthermore, the laboratory model created through this initial study can be further optimized 
and modified for use with novel treatments currently under investigation for mental health 
and other disorders, namely psychedelic treatments.
2.2
Risks
Intervention-specific Risks
The main risk to participants in the current study consists of a change in the level of 
effectiveness and side effects from treatment as a result of the study intervention. 
Specifically, the “intervention” group may experience a different rate of response, or notice 
side effects to a different degree than the “treatment as usual” group. 
Although non-specific effects in general are believed to be responsible for a significant 
portion of the treatment’s effects, as the current study only targets a small subcategory of 
non-specific factors, the magnitude of increased risk will be limited. Furthermore, the study is 
designed to create a difference between groups mainly by potentially improving the 
outcomes of the “intervention” group. 
The “intervention” group may also experience more dysgeusia which is one of the mild and 
temporary side effects of esketamine, as a result of intentionally highlighting it in the 
presentation. 
Additionally, the “intervention” group may experience some distress during the “post-
treatment” session, particularly if they need to review and discuss distressing or 
uncomfortable experiences from the treatment. 
Psychiatric Assessment and Symptom Rating
Discussing symptoms or past experiences can sometimes be stressful. All included 
evaluations are non-invasive and have been used without difficulty or adverse events in 
previous studies and clinical practice. 
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In order to minimize risks associated with the psychiatric ratings and ensure the accuracy of 
reporting, these measures will be administered by trained research staff. Participants will be 
informed that they do not need to answer any question on the rating scales or questionnaires 
that make them feel uncomfortable. Participants will also be informed they can take a break if 
they become tired from any of the questions or ratings.
Confidentiality
Loss of confidentiality is another potential hazard of any research protocol. The investigators 
follow a system of specific precautions to ensure the confidentiality of data in this protocol.
Private identifiable information will be collected (name, date of birth, age, telephone number, 
address, medical and psychiatric history, diagnoses, laboratory tests, and psychiatric rating 
scores) but will be kept confidential and will not be divulged in any publication emanating from 
this work. Please see section 8.1, for the protections in place to mitigate confidentiality risks. 
2.3
Anticipated Benefits
Participants may or may not benefit from the study through improvement in their clinical 
outcomes. Both groups will have extensive contact with the research team in addition to the 
usual clinical care team, which may provide some additional benefit to patients. Participants 
will be paid for their participation in the study. They will be paid $50 for completing each non-
presentation visit (Screening visit, 24 hours post 1-st treatment, 72 hours post 8th treatment), 
which makes it up to 150 dollars in total if they complete the study. They will not be paid for 
the presentation visit. They will receive a debit card upon consenting and completing the 
screening visit and the reimbursement will be loaded to the card after completing each of the 
mentioned visits. 
The results of this initial study would benefit the field by providing a better understanding of 
the role of non-specific effects, and whether and to what extent these effects can be 
optimized. 
3 Study Purpose and Objectives
3.1
Purpose
We aim to examine the magnitude of non-specific effects in the treatment of depressive 
episodes with esketamine, by providing patients in the “intervention” group with a pre-
treatment presentation and post-treatment “follow up” session, to assess whether non-
specific effects can be used effectively to improve the effectiveness of treatment with 
esketamine.
3.2
Hypothesis
Hypothesis 1: A positive presentation highlighting the rapid onset effects and positive 
therapeutic outcomes observed in prior clinical trials and clinical care will increase the 
expectation of improvement from esketamine treatment compared to the treatment-as usual 
(TAU) group.
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Hypothesis 2: A post-treatment “debriefing” session after first the treatment to provide 
encouragement and reassurance, will further consolidate the expectation of improvement 
from esketamine treatment.
Hypothesis 3: A positive presentation highlighting the rapid onset effects and positive 
therapeutic outcomes observed in prior clinical trials and clinical care combined with a post-
treatment “debriefing” session after first the treatment to provide encouragement and 
reassurance will enhance treatment response compared to the TAU group.
Hypothesis 4: Highlighting a specific side effect during the presentation will result in a 
difference on the side effect profile of the treatment.
3.3
Objectives
Primary Objective:
To determine whether a positive presentation before first treatment improves expectation of 
improvement from treatment in patients receiving esketamine for a depressive episode 
within 24 hours after the first treatment. 
Secondary Objective:
To determine whether a post-treatment debriefing session to provide encouragement and 
reassurance improves expectation of improvement from treatment in patients receiving 
esketamine for a depressive episode within 24 hours after the first treatment. 
To determine whether a positive presentation result in an improved response from treatment 
in patients receiving esketamine for a depressive episode as measured by MADRS score 
within 24 hours after the first treatment.
To determine whether a positive presentation before first treatment, combined with a post-
treatment debriefing session after first treatment, result in an improved response from 
treatment in patients receiving esketamine for a depressive episode as measured by 
MADRS score by the end of the acute course of esketamine treatment.
4 Study Design
Approach and consent:
Patients who are deemed clinically appropriate for esketamine will be approached for 
participation in the study. They will be provided with information regarding the study, 
including that they will be randomized into two groups with the “intervention” group receiving 
an informative presentation prior to the first treatment. They will be informed that the goal is 
to assess the effect of this presentation with regard to its ability to provide sufficient and 
appropriate information surrounding the treatment. Participants will not be informed at the 
time of recruitment that we hypothesize the content to potentially affect the tolerability and 
effectiveness of the treatment course. They will be informed about the full nature of the study 
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at a end of treatment debriefing session at the end of their participation (further details 
below). 
Randomization
Participants will be randomized at a 1:1 ratio into “intervention” and TAU groups, with the 
intervention group being presented with the presentation prior to the first treatment, and to 
receive a “debriefing” session within 24 hours after the first treatment. Both groups will 
otherwise receive treatment as usual during the course. 
Intervention
The intervention consists of a short presentation provided to the participants within 72 hours 
prior to the first treatment of the acute course (see study course below). Both groups will 
receive the information considered necessary for informed consent for esketamine treatment 
as part of usual clinical care. The presentation will be in addition to this process. The 
presentation will be factual, however it will emphasize the effectiveness of the treatment, and 
provide notable encouragement and reassurance. The actual treatments will be provided as 
usual with no change or alteration in dosing, course or other aspects of the treatment.
The intervention group will additionally receive a follow up session within 24 hours after the 
first treatment to provide encouragement and reassurance. There are two different versions 
for the follow up session, with each participant receiving one of the versions depending on 
whether they have noticed any improvements since the first treatment. The contents of these 
sessions will remain factual, but with differing emphasis on encouragement and reassurance 
depending on participants’ experience with the first treatment.
Study course
Participants in the intervention group will receive the presentation within 48 hours before the 
first treatment of the acute course of esketamine. They will also receive the follow up session 
within 24 hours after the first treatment, immediately after assessments are completed.
Assessments will be done at baseline, within 24 hours after treatments 1, 2 and 8, as 
detailed in Table 1. Assessments will be identical for both groups, with the exceptions 
described below.
Assessments
Intervention group specific assessments:
Participants will provide feedback regarding the presentation using a custom form (Appendix 
1) before treatment 1 and at the end of treatment visit.
Assessments received by both groups:
Participants’ expectations will be assessed by Treatment Credibility and Expectancy Scale 
(CEQ-6). 
Symptom severity will be assessed by a blinded assessor using a Clinician Rated Outcome 
questionnaire (MADRS) and a Patient Rated Outcome questionnaire (QIDS-SR16). 
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Side effects will be assessed by a custom questionnaire (Appendix 2) based on the side 
effects reported on the prescription label for esketamine. 
End of treatment debriefing session:
A debriefing session will be held at the end of the study at the 1-month follow up visit, 
immediately after the last set of assessments are completed. During this session participants 
will be informed about the nature of the study in detail, including the hypothesized effects of 
non-specific factors on overall treatment efficacy, and [for participants in intervention group] 
the intentional emphasis of a minor side effect (dysgeusia) during the presentation 
compared to usual care. Participants will be given a chance to ask any questions regarding 
the study. 
Study Flow Diagram 
Total N: 34
Pre-screen potential participants by inclusion and exclusion criteria; schedule screening 
visit.
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Prescreen
Screening visit
<, Day -14 to 
Day -16>
Visit 2
<Day -3 to 0>
Visit 3
<Day 0> 
Visit 4
<Within 24 hr
After Visit 3>
Visit 5
<Immediately
before 2nd 
treatment>
Visit 6
<within 72hrs after
8th treatment>
Conduct informed consent process. Perform baseline assessments.
<Demographics, MADRS score, QIDS, CADSS, Expectations>
Post Treatment 1 Assessments
+Debriefing session after assessments
(Intervention group only)
Final Assessments
“TAU” arm
“intervention” arm
N = 28 
Pre-treatment Presentation
Randomize
Start esketamine treatment
Pre-Treatment 2 assessments
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4.1
Study Duration
The study is anticipated to be completed in two years
4.2
Outcome Variables/Endpoints
4.2.1
Primary Outcome Variables/Endpoints
Primary outcome: Group difference in change in question 6 of the CEQ-6 from baseline to 
after the presentation
4.2.2
Secondary and Exploratory Outcome Variables/Endpoints
Secondary Outcome: Group difference in change in MADRS score from baseline to 24 hours 
after first treatment
Exploratory outcomes:
Group difference in change in CEQ-6 from baseline to 24 hours after first treatment and after 
follow-up session
Group difference in change in MADRS score by the end of the acute series of treatments
Group difference in the side effect profile
5 Study Participants
5.1
Study Population
Adult patients with a depressive episode for whom it has been determined by their primary 
mental health provider that esketamine is an appropriate treatment and have already been 
deemed appropriate and scheduled for clinical esketamine treatment at Yale Interventional 
Psychiatry Service according to existing FDA REMS that includes diagnoses of treatment 
resistant depression, or depression with suicidal ideation, will be eligible for participation in 
the study. 
5.2
Number of Participants
We aim to enroll a total of 34 patients (17 per arm) for this study. 
5.3
Eligibility Criteria
Inclusion criteria: 
To take part in this study, the following eligibility criteria must be met:

Participants must be either male or female and at least 18 years old

Deemed clinically appropriate to receive esketamine by a Yale Interventional 
Psychiatry physician.
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
Written consent for the study procedures

Ability and willingness, in the investigator's judgement, to comply with the study 
schedule, treatment plan, and other trial requirements for the duration of the study.
Exclusion criteria: 
Any individual who meets any of the following criteria will be excluded from participation in 
this study: 

Hearing or visual impairment to the degree that would interfere with ability to view the 
presentation 

Difficulty in understanding spoken or written English 

Unable to provide informed consent 

Dementia or other cognitive disorder or intellectual disability that would impair the 
subject’s ability to understand the presentation (per investigator judgment) 

Any other medical or psychiatric comorbidity that the investigator judges would put 
the participant at additional undue risk due to study participation or would impair 
subject’s ability to participate in the study. 

Previous Esketamine or ketamine treatment 

Unable to give informed consent 

Was previously enrolled/randomized into the trial
Note: Since only patients who have already been deemed clinically appropriate and are 
planned to receive esketamine are approached, and participation in the study does not 
influence patients receiving or not receiving esketamine, exclusions for this medication are 
not included in the study exclusion criteria.
5.4
Recruitment Procedures 
Potential subjects will be referred to the study team by the interventional psychiatry 
physician who has seen the patient in clinical evaluation for esketamine, after ascertaining 
their agreement to be approached for the study. At this time, the patient will be reached out 
by a study team member and informed about the study. 
5.5
Consent/Assent Procedures/HIPAA Authorization

Consent forms describing in detail the study intervention, study procedures, and risks 
are given to the participant and written documentation of informed consent is 
required prior to starting procedures/administering study intervention. 

Consent forms will be Institutional Review Board (IRB)-approved and the participant 
will be asked to read and review the document. The study team member consenting 
the participant will explain the research study to the participant and answer any 
questions that may arise. This conversation will take place in a private room.
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
Participants will have the opportunity to carefully review the written consent form and 
ask questions prior to signing. The participants should have the opportunity to 
discuss the study with their family or surrogates or think about it prior to agreeing to 
participate.

Participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed 
consent document will be given to the participants for their records.

Note: Given the nature of the study, the consent form will not provide details about 
the main objectives of the study, but will provide a general outline, explaining that the 
goal is to assess various ways of presenting relevant information to patients, and 
various ways of follow up after the first treatment. The true objectives of the study will 
be explained in detail during the debriefing session after the conclusion of all study 
procedures for each participant.
6 Study Methods/Procedures
6.1
Study Procedures
Potential subjects will be referred to the study team by the interventional psychiatry 
physician who has seen the patient in clinical evaluation for esketamine, after ascertaining 
their agreement to be approached for the study. At this time, the patient will be reached out 
by a study team member and informed about the study. 
Screening / Intake Visit 
It is estimated the screening intake will take approximately 2 hours. It will consist of the 
following procedures and assessments and can be completed in up to 5 days: 
a.
Informed Consent: A delegated study team member will discuss risks and benefits of 
participation and review the study overview with the patient as explained above. The 
patient will sign the informed consent form prior to any study procedures being 
performed. 
b.
Clinical and Demographic Intake (including medical and psychiatric history, 
medication history, and current medications) 
c.
Montgomery-Asberg Depression Rating Scale (MADRS) and Quick Inventory of 
Depressive Symptomatology (QIDS-SR16)
d.
CEQ-6 questionnaire regarding upcoming treatment course with esketamine 
e.
Review of Inclusion/Exclusion Criteria by investigator
Presentation Visit (Intervention group only)
The intervention consists of a short virtual (via Zoom or similar technology) presentation 
provided to the participants, within 72 hours before the first treatment with esketamine. The 
presentation includes predetermined slides and content (the presenter will cover the same 
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slides and topics but will avoid a strict script to retain the personalized feeling of the 
presentation, an aspect believed to be crucial to the non-specific effects. Further, patients 
are allowed to engage, ask questions etc.) The presentation will remain factual and provide 
information from peer-reviewed literature. However, it is designed to convey a strong positive 
message, highlighting the effectiveness of the treatment. Additionally, a mild and temporary 
known side effect of the treatment (dysgeusia) will be intentionally highlighted to assess the 
4th hypothesis.
Treatment visits:
Both groups will receive the usual treatment and care. Immediately before first and second 
treatments both groups will complete the CEQ-6 questionnaire. Additionally, the intervention 
group will complete the presentation feedback form prior to the first treatment. The rest of 
the treatments (i.e. treatments 3 to 8) will be done without any assessments. 
Follow-up visit:
Twenty-four hours after the first treatment, CEQ-6, MADRS, QIDS, side effects, and adverse 
effects will be collected. Additionally, patients in the intervention group will receive a follow-
up session after their first esketamine treatment. The follow up session will utilize one of two 
versions: “early-responder” content will be presented to patients with a noticeable 
improvement after first treatment, providing encouragement. “Early non-responder” content 
will be presented to patients with no noticeable improvement after first treatment, providing 
reassurance.
End of study visit:
During the end of study visit, MADRS, QIDS and side effects information will be collected. 
Additionally, a debriefing session will be held, immediately after the last set of assessments 
are completed. During this session participants will be informed about the nature of the study 
in detail, including the hypothesized effects of non-specific factors on overall treatment 
efficacy, and [for participants in intervention group] the intentional emphasis of a minor side 
effect (dysgeusia) during the presentation compared to usual care. Participants will be given 
a chance to ask any questions regarding the study.
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Table 1: Visit Schedule Table 
Timeline based on 
ketamine/esketamine 
treatments
Screening 
session
Within 72h 
before 
treatment 1
(intervention 
group only)
Immediately 
before 
Treatment 1
24hr post 
dose 1
Immediately 
before Treatment 
2
Within 72 hours 
after 8th 
treatment
Day (subject to 
clinical treatment 
schedule)
-16±14
-3
0
1
5±3
30±3
Interventions
Presentation
X
Follow up session
X
End of Treatment 
Debriefing
X
Assessments
Demographics 
X
MADRS
X
X
X
QIDS
X
X
X
Presentation quality 
feedback*
X
Side effects*
X
X
Expectations**
X
X
X
X
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6.1.1
Data Collection
Data collection for the study will be conducted in several stages. Firstly, the eligible 
participants will be approached and consented to participate in the study. A delegated study 
team member will discuss risks and benefits of participation and review the study overview 
with the patient as explained above. The patient will sign the informed consent form prior to 
any study procedures being performed. After that a trained research study team member will 
collect clinical and demographic information (including medical and psychiatric history, 
medication history, and current medications) using a custom questionnaire. After that 
symptom severity will be assessed by a trained and blinded assessor using a Clinician 
Rated Outcome questionnaire (MADRS) and a Patient Rated Outcome questionnaire (QIDS-
SR16). Then participant expectations regarding upcoming treatment course with esketamine 
will be accessed using the Treatment Credibility and Expectancy Scale (CEQ-6) 
questionnaire. After this visit the investigator will review the Inclusion and Exclusion Criteria. 
If the participant is eligible, randomization will take place.  
After randomization and within 72 hours before first treatment, participants in the intervention 
group will receive a virtual presentation on the benefits and potential side effects of 
esketamine. The presentation will be factual, however it will emphasize the effectiveness of 
the treatment, and provide notable encouragement and reassurance. The actual treatments 
will be provided as usual with no change or alteration in dosing, course or other aspects of 
the treatment. 
Participants in intervention group will provide feedback regarding the presentation using a 
custom form before treatment 1. (See appendix 1)
Twenty-four hours after the first treatment, participants’ expectations will be assessed by 
Treatment Credibility and Expectancy Scale (CEQ-6). 
Symptom severity will be assessed by a trained and blinded assessor using a Clinician 
Rated Outcome questionnaire (MADRS) and a Patient Rated Outcome questionnaire (QIDS-
SR16). 
Side effects will be assessed by a custom questionnaire based on the side effects reported 
on the prescription label for esketamine. (See appendix 2)
All data collected will be stored and managed securely and will be regularly monitored to 
ensure its quality and accuracy.
6.2
Method of Assignment/Randomization 
The randomization process in the study will occur after the screening visit and once the 
eligibility criteria have been checked and it has been determined by the PI that the subject 
qualifies. The eligible patients will be randomly assigned to either the intervention group or 
the TAU group with a 1:1 ratio.  Randomization will be conducted using the sequentially 
numbered, opaque sealed envelopes (SNOSE)12.  
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6.3
Adverse Events Definition and Reporting
Study investigators will be able to remove patients from the trial based on their clinical 
discretion and specific patient outcomes. Any adverse events, including grading of severity 
and attribution to research will be reported. 
In this study, AEs will be defined as any event associated with virtual presentation and 
follow-up sessions whether or not considered intervention related. This includes any 
physical, psychological or emotional harm, or any other unintended effects experienced by 
the participant. Adverse events will be considered from the time of consent and will be 
monitored and recorded throughout the study. AEs evaluation will be done 24 hours after the 
first treatment and within 72 hours after 8th treatment. Participants will be asked to report 
any AEs they experience, either spontaneously or during the study visits. AEs will be 
recorded on the appropriate CRF. Patients will be closely monitored for adverse events. 
The following adverse events will be collected from the time of randomization for the study: 

Adverse events that are not listed in the current labeling for esketamine. This 
includes events that are similar to those on the labeling but differ from the event 
because of greater severity or specificity. 

Study Treatment Discontinuation Adverse Events 

Events that lead to the discontinuation of esketamine will be collected for the study. 
These events will be recorded on either an AE or an SAE form. 
The study team will document the AEs, its severity, relationship to the intervention, and the 
actions taken to address it.
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect.
Note: In addition to AEs as described above, a separate side effect form will be collected 
during the trial which will solely focus on known side effects of esketamine as per the current 
labeling (See appendix 2). 
6.4
Reaction Management
Reaction management refers to the actions taken to manage any adverse events (AEs) that 
occur during the study. In the event that a participant experiences an AE, the study team will 
take appropriate measures to manage the reaction, minimize harm, and ensure the safety 
and well-being of the participant.
The first step in reaction management is to identify and document the AE. Participants will 
be asked to report any AEs they experience, either spontaneously or during the study visits. 
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The study team will document the AE, its severity, relationship to the intervention, and the 
actions taken to address it.
Based on the severity of the AE, the study team may take various actions to manage the 
reaction. For minor AEs, such as mild nausea or headache, the study team may provide 
advice or over-the-counter medications to alleviate the symptoms. For more serious AEs, 
such as hospitalization, the study team will take immediate action to ensure the safety and 
well-being of the participant.
If necessary, the study team may discontinue the intervention for a participant experiencing 
a serious adverse event. Participants who experience a serious adverse event will be 
referred to their treating physician or a specialist for further evaluation and management.
6.5
Withdrawal Procedures
The withdrawal procedure refers to the process for removing a participant from the study if 
they decide to discontinue their participation or they may be withdrawn at the discretion of 
the investigator at any time. 
Participants may withdraw or be withdrawn from the study for various reasons, including 
adverse events, dissatisfaction with the study, personal circumstances, or inability of the 
subject to comply with the protocol-required schedule of study visits. In the event of a 
participant wishing to withdraw from the study, they will inform the study team. 
The study team will inquire about the reason for withdrawal and document the reason and 
any relevant information related to the participant's decision. The investigator should also 
request the subject to return for an end-of-study visit to assess AEs/SAEs, safety 
endpoints, outcome events, and vital status. The investigator should also follow‐up with 
the subject regarding any unresolved adverse events. Any unresolved events at the end 
of study or withdrawal should be followed for 2 weeks, until resolution, or until an 
adequate treatment plan is in place. 
If the subject withdraws from the study and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data 
should be collected. Adequate documentation of this request should be obtained and 
retained in the subject’s source file. True withdrawal of consent should be initiated by the 
subject and in writing. Data collected before the withdrawal of consent may be retained and 
used for analysis. 
Patients who Withdraw from Treatment but not study
Participants may also decide to withdraw from the intervention but not the study for any 
reason.  Or an investigator may withdraw a participant from the intervention for the 
following reasons:

Significant study intervention non-compliance
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
If any clinical adverse event (AE),  or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the 
participant

Medical condition which requires discontinuation of the study intervention

If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation

Study termination
Subjects who sign the informed consent form and are randomized but do not receive the 
study intervention may be replaced. Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are 
withdrawn or discontinued from the study, will not be replaced. 
For participants who withdraw from treatment prior to 8th esketamine treatment and are not 
replaced, we will try to continue to collect the MADRS, the QIDS, and adverse events as 
indicated by study protocol. 
If a participant withdraws from the study, they will no longer receive the intervention and he 
study team will ensure that the participant's privacy and confidentiality are maintained and 
that all personal information is handled in accordance with relevant regulations.
The study team will also ensure that any data collected from the participant up to the point of 
withdrawal is analyzed and reported in accordance with the study protocol. 
6.6
Locations/Facilities
This is a single-site trial that will take place at Yale University (New Haven, CT). Treatments 
will take place at Yale Psychiatric Hospital (YPH, part of Yale New Haven Hospital; YNHH), 
Interventional psychiatry services (IPS). Clinical assessments will take place at YPH or 
virtually via HIPAA compliant technology (e.g. Yale Zoom), as applicable.
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7 Statistical Design
7.1
Sample Size Considerations
While to our knowledge there are no analogous studies in the literature to use as a basis for 
sample size calculation, we used the data from the two active groups of a relatively similar 
study of open-label vs placebo-controlled citalopram7 to calculate sample size for the current 
study. Based on this data, sample size per arm was calculated as follows13:
To account for dropouts, we have chosen a sample size of 34 participants (17 per arm) 
during the two years of the study. 
7.2
Planned Analyses
Data will be examined prior to analysis using descriptive statistics, presented as means ± SD 
or median (interquartile range) for continuous characteristics, and as frequencies (%) for 
categorical characteristics.
Where appropriate, randomized groups will be compared on baseline continuous 
characteristics (e.g. age) using two-sample Welch’s t-test or Wilcoxon rank sum test, and on 
categorical characteristics using the chi-square test or Fisher’s exact test as appropriate. 
Continuous outcome measures will be assessed for normality using histograms and Q-Q 
plots, and transformations will be applied as necessary. Between groups primary and 
secondary outcomes (CEQ-6, MADRS and QIDS) will be considered significant using a two-
tailed alpha threshold of 0.05. 
The primary and secondary outcomes (CEQ-6, MADRS, QIDS) will be compared between 
groups using a linear mixed model with group (intervention, TAU) included as a between-
subjects factor and time (see study timepoints) included as a within-subjects factor. The 
group by time interaction will be modeled. The correlation between multiple measurements 
in different timepoints within each subject will be modeled with random effects with the best-
fitting model determined using information criteria. 
7.2.1
Secondary Objective Analyses 
Please see above for the analysis of secondary efficacy outcomes (MADRS and QIDS). To 
examine the safety and tolerability of the intervention for the duration of the study, we will 
use descriptive statistics to characterize the rates of these events in the intervention group. 
7.2.2
Analysis of Subject Characteristics 
Baseline characteristics will be examined using descriptive statistics, presented as means ± 
SD or median (interquartile range) for continuous characteristics, and as frequencies (%) for 
categorical characteristics. Baseline characteristics include age, sex, ethnicity, 
socioeconomic status, treatment expectation (CEQ-6) and psychiatric symptoms (MADRS, 
QIDS).
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7.2.3
Interim Analysis 
NA
7.3
Data Relevance
In the study, the primary research question is whether a positive presentation highlighting 
the rapid onset effects and positive therapeutic outcomes of esketamine treatment, before 
first treatment improves expectation of improvement from treatment in patients receiving 
esketamine compared to the treatment-as-usual (TAU) group. 
The secondary research question is whether a positive presentation results in an improved 
response from treatment in patients receiving esketamine for a depressive episode as 
measured by MADRS score within 24 hours after the first treatment.
To answer these questions, the data collected will include expectations of improvement 
assessed by the Treatment Credibility and Expectancy Scale (CEQ-6), symptom severity 
assessed by Clinician Rated Outcome questionnaire (MADRS) and Patient Rated Outcome 
questionnaire (QID-SR16), and side effects assessed by a custom questionnaire. These 
data points will be analyzed and compared between the intervention and TAU groups to 
determine if there is a difference in treatment response and whether the non-specific effects 
of the positive presentation and follow-up session have an impact.
7.4
Data Coding
In this study, data coding will be necessary for several aspects of the data collection, 
including participant characteristics, treatment groups, and outcome measures.
For participant characteristics, such as age, gender, and baseline symptom severity, 
appropriate codes can be assigned to easily categorize and analyze the data. For example, 
age can be coded as continuous or categorical (e.g., 18-25, 26-35, 36-45, etc.), and gender 
can be coded as binary (male/female).
For treatment groups, a binary code can be assigned to each participant, with 0 representing 
the treatment-as-usual group and 1 representing the intervention group. This will allow for 
comparison between the two groups.
For outcome measures, such as symptom severity and side effects, appropriate scoring 
systems or coding will need to be established. The symptom severity can be measured 
using the Clinician-Rated Outcome questionnaire (MADRS) and Patient-Rated Outcome 
questionnaire (QID-SR16), and these scores can be transformed into categorical or 
continuous variables for analysis. For the side effects, a custom questionnaire based on the 
side effects reported on the prescription label for esketamine will be used and side effects 
can be coded as present or absent.
7.5
Data Analysis Tools
R version 3.3 will be used.
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7.6
Data Monitoring
Given the minimal-risk nature of the study, and as patients are simultaneously receiving 
treatment as part of usual clinical care, no external monitoring will be done. 
7.7
Handling of Missing Data
Our primary analyses will be intent-to-treat using all available data. We will undertake 
sensitivity analyses to assess the impact of the missing response data on our conclusions. 
We will perform single-step (e.g., missing values on the response variable replaced by 
predicted values from linear or generalized linear models of the longitudinal data over time) 
or multiple imputation and compare the performance of the imputed data results compared 
to complete case analyses. It is important to note that the linear mixed model method we 
propose to use is valid under the assumption that missing data is missing at random (MAR). 
Since it is not possible to test the MAR assumption and since for every MNAR model there is 
an equally well-fitting MAR model, we believe that the only suitable approach is to perform 
sensitivity analyses according to different plausible scenarios for missing data and make 
sure the conclusions are consistent. If the results are not consistent depending on the 
assumptions for missing data we will report the conclusions based on each set of 
assumptions.
8 Data/Specimen Handling and Record 
Keeping
8.1
Subject Data Confidentiality
Participant confidentiality and privacy is strictly held in confidence by the participating 
investigators, their staff, and the sponsor(s)/funding agency. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. 
All research activities will be conducted in as private a setting as possible.
Representatives of the Institutional Review Board (IRB), regulatory agencies or study 
sponsor/funding agency may inspect all documents and records required to be maintained 
by the investigator for the participants in this study. The study site will permit access to such 
records.
The study participant's contact information will be securely stored at study site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, 
regulatory, or sponsor/funding agency requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the office of the PI. This will not include the 
participant's contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data entry 
and study management systems used will be secured and password protected. At the end of 
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the study, all study databases will be de-identified and archived on the server used by the 
PI’s lab.
8.2
Data Quality Assurance
Data quality assurance is a crucial aspect of this study to ensure the validity and reliability of 
the results. A number of steps will be taken to maintain data quality, including the use of 
standardized and validated assessment tools (CEQ-6, MADRS, QID-SR16, and custom 
questionnaire), training of the blinded assessor to ensure consistent administration of the 
assessment tools, regular monitoring of data collection to identify and address any 
discrepancies, and proper storage and management of the collected data. 
We will perform internal quality management of study conduct, data collection, 
documentation and completion. 
8.3
Data or Specimen Storage/Security
The study participant's contact information will be securely stored at study site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, 
regulatory, or sponsor/funding agency requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the office of the PI. This will not include the 
participant's contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data entry 
and study management systems used will be secured and password protected. At the end of 
the study, all study databases will be de-identified and archived on the server used by the 
PI’s lab.
Data collection is the responsibility of the clinical trial staff under the supervision of the 
primary investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. All source documents will be 
completed in a neat, legible manner to ensure accurate interpretation of data.
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study. Data recorded in the 
electronic case report form (eCRF) derived from source documents should be consistent 
with the data recorded on the source documents.
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) will be entered into an online database approved for high-risk data 
as per Yale’s data classification). Clinical data will be entered directly from the source 
documents.
8.4
Study Records
The following documents will be considered study records:

Consent forms

Case report forms

Subjects’ medical records
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
Protocol

Regulatory documents
Study records will be securely stored in the PI’s office for internal use during the study. The 
PI is responsible for maintaining the study documentation. All study research members will 
have access to study records. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, 
regulatory, or sponsor/funding agency requirements.
The study records will not include the participant's contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used will be 
secured and password protected. At the end of the study, all study databases will be de-
identified and archived on the server used by the PI’s lab.
8.5
Access to Source
Source data include all information and original records of clinical findings, observations, or 
other activities necessary for the reconstruction and evaluation of the trial. 
Source documentation include:

Study records

Electronic medical records

Laboratory reports

Memoranda

Subject diaries

Subject questionnaires 

Recorded data from automated instruments. 
Source documents should be neat and legible. When making changes or corrections, the 
original entry should be crossed out with a single line, initialed and dated.
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study. Data recorded in the 
electronic case report form (eCRF) derived from source documents should be consistent 
with the data recorded on the source documents. 
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) will be entered into an online database as described above. 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities.
8.6
Retention of Records
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Study documents will be retained for a minimum of 2 years after the completion of the study. 
These records will be securely stored and accessible to authorized individuals, such as 
study personnel and regulatory agencies, when needed. 
8.7
Data and Safety Monitoring Plan 
We do not anticipate any adverse events. The principal investigator (PI) will monitor the 
data, assure protocol compliance, and conduct the safety reviews at least annually.  The PI 
evaluates whether the study should continue unchanged, require modifications, or close to 
enrollment.  Any Reportable Events (which are events that are serious or life-threatening and 
unanticipated (or anticipated but occurring with a greater frequency than expected) and 
possibly, probably, or definitely related) Unanticipated Problems Involving Risks to Subjects 
or Others (UPIRSO) will be reported to the IRB and any appropriate funding and regulatory 
agencies. Unanticipated Problems Involving Risks to Subjects or Others that may require a 
temporary or permanent interruption of study activities (if possible) will be reported, followed 
by a written report within 5 calendar days of my becoming aware of the event to the IRB and 
any appropriate funding and regulatory agencies.  The PI will apprise fellow investigators 
and study personnel of all UPIRSOs and adverse events that occur during the conduct of 
this research project.  The PI will report all UPIRSOs and adverse events that occur during 
the conduct of this research project to other applicable oversight bodies as required within 
applicable reporting timeframes.
9 Study Considerations
9.1
Institutional Review Board (IRB) Review
The protocol will be submitted to the IRB for review and approval. Approval of the protocol 
must be obtained before initiating any research activity. Any change to the protocol will 
require an approved IRB amendment before implementation.  The IRB will have final 
determination whether informed consent and HIPAA authorization are required.  
Study closure will be submitted to the IRB after all research activities have been completed.    
Other study events (e.g. data breaches, protocol deviations) will be submitted per Yale 
policies.
9.2
Research Personnel Training
The training will cover all aspects of the study design, protocol, and procedures, including 
ethical considerations, informed consent and data collection. The training will be 
documented and kept on file for future reference and potential audits.
The training process will cover the following key areas:

Study objectives and hypotheses - The research assistants will have a clear 
understanding of the overall aim and specific hypotheses of the study.
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
Study protocol and procedures - The research assistants will be familiar with the 
study protocol and procedures, including patient enrolment, data collection, and 
adverse event reporting.

Data collection instruments - The research assistants will be trained on the use of the 
study’s data collection instruments, including the clinician-rated and patient-rated 
outcome questionnaires and the custom side effect questionnaire.

Patient interaction - The research assistants will be trained on how to interact with 
patients during the study, including how to approach patients for participation, explain 
the study’s aims and procedures, and handle any questions or concerns that may 
arise.

Confidentiality and ethics - The research assistants will be trained on the importance 
of maintaining patient confidentiality and adhering to ethical standards in research.

Data management and analysis - The research assistants will be familiar with the 
data management including data coding, data entry, data monitoring, and handling of 
missing data.
The training process will also include a hands-on component, such as role-playing or mock 
data collection, and then doing real data collection with supervision for the first two times to 
help the research assistants gain practical experience and ensure they are confident in their 
role. 
9.3
Study Monitoring 
Study monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, that the 
facilities and staffing are adequate for continued study conduct, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with International 
Council for Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s) including federal, state and local regulations and institutional policies and 
procedures. In addition to all applicable regulatory bodies, the Yale Center for Clinical 
Investigation (YCCI), as the sponsor of the study, will oversee the study. 
9.4
Unanticipated Problems and Protocol Deviations
A protocol deviation is any noncompliance with the protocol. The noncompliance may be 
either on the part of the participant, the investigator, or the study staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly.
It is the responsibility of the investigator to identify and report deviations within five working 
days of identification of the protocol deviation. All deviations must be addressed in study 
source documents, reported to the study sponsor, and the reviewing Institutional Review 
Board (IRB) per their policies.
Unanticipated problems involving risks to participants or others include, in general, any 
incident, experience, or outcome that meets all of the following criteria:
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
Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
Institutional Review Board (IRB)-approved research protocol and informed consent 
document; and (b) the characteristics of the participant population being studied;

Related or possibly related to participation in the research ("possibly related" means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and

Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.
If the study team becomes aware of an unanticipated problem (e.g. data breach, protocol 
deviation), the event will be reported to the IRB by email.
The UP report will include the following information:
Protocol identifying information: protocol title and number, PI's name, and the IRB project 
number;

A detailed description of the event, incident, experience, or outcome;

An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;

A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP.
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:

UPs will be reported to the IRB within five of the investigator becoming aware of the 
event.
9.5
Study Discontinuation
The study might be discontinued in several circumstances, including if there are any adverse 
events or safety concerns that put the participants at risk, if the enrollment rate is 
significantly lower than expected and impacts the validity of the results,  or if there are 
changes in regulations or ethical guidelines that make it necessary to discontinue the study. 
Additionally, the principal investigator may choose to discontinue the study if it is found to be 
ineffective or if funding for the study is withdrawn. In any of these circumstances, the 
participants will be informed and appropriate measures will be taken to ensure their safety 
and wellbeing.
9.6
Study Completion
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This study is expected to continue for two years. The expected completion date is 5/2025.  
IRB and the sponsored will be notified if the completion date of the study is expected to 
changed, as applicable. 
9.7
Conflict of Interest Management Plan 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership in conjunction with the appropriate conflict of interest review 
committee has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.
 All investigators will follow the applicable conflict of interest policies.
9.8
Funding Source
The study is funded by YCCI by a UL1 Clinical Junior Faculty Pilot Award.
9.9
Publication Plan
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: National Institutes of Health (NIH) Public Access Policy, which 
ensures that the public has access to the published results of NIH funded research. It 
requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication.
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.
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10 Appendices
Appendix #
Title
Section
Topic
Appendix 1 
Feedback form
4
Study design
Appendix 2
Adverse events 
form
4
Study design
Appendix 1 – Presentation Feedback Form
With regards to the presentation you just received, please answer the following questions:
- The overall information provided was informative
Fully disagree
 
Fully agree
0
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9
10
- The slides were helpful
Fully disagree
 
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9
10
- The presenter was able to relay the information effectively
Fully disagree
 
Fully agree
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8
9
10
- My questions were satisfactorily addressed either during the presentation or afterwards by 
the presenter
Fully disagree
 
Fully agree
0
1
2
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9
10
- I wish I could receive a similar presentation for any treatments I receive in the future 
(psychiatric or non-psychiatric)
Fully disagree
 
Fully agree
0
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Appendix 2- Side Effects Questionnaire
Please ask each of the items below from the participant. Provide explanation for items as 
appropriate (e.g., for tachycardia you can mention “heart racing” or “rapid heartbeat”)
Tachycardia 
☐None 
☐Mild
☐Moderate
☐Severe
Vertigo 
☐None 
☐Mild
☐Moderate
☐Severe
Nausea
☐None 
☐Mild
☐Moderate
☐Severe
Vomiting
☐None 
☐Mild
☐Moderate
☐Severe
Diarrhea
☐None 
☐Mild
☐Moderate
☐Severe
Dry Mouth
☐None 
☐Mild
☐Moderate
☐Severe
Constipation
☐None 
☐Mild
☐Moderate
☐Severe
Feeling drunk
☐None 
☐Mild
☐Moderate
☐Severe
Feeling abnormal
☐None 
☐Mild
☐Moderate
☐Severe
Increased blood pressure
☐None 
☐Mild
☐Moderate
☐Severe
Dizziness
☐None 
☐Mild
☐Moderate
☐Severe
Sedation
☐None 
☐Mild
☐Moderate
☐Severe
Headache 
☐None 
☐Mild
☐Moderate
☐Severe
Dysgeusia
☐None 
☐Mild
☐Moderate
☐Severe
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Hypoesthesia
☐None 
☐Mild
☐Moderate
☐Severe
Lethargy
☐None 
☐Mild
☐Moderate
☐Severe
Dysarthria
☐None 
☐Mild
☐Moderate
☐Severe
Tremor
☐None 
☐Mild
☐Moderate
☐Severe
Mental impairment
☐None 
☐Mild
☐Moderate
☐Severe
Dissociation
☐None 
☐Mild
☐Moderate
☐Severe
Anxiety
☐None 
☐Mild
☐Moderate
☐Severe
Insomnia
☐None 
☐Mild
☐Moderate
☐Severe
Euphoric mood
☐None 
☐Mild
☐Moderate
☐Severe
Pollakiuria
☐None 
☐Mild
☐Moderate
☐Severe
Nasal discomfort
☐None 
☐Mild
☐Moderate
☐Severe
Throat irritation
☐None 
☐Mild
☐Moderate
☐Severe
Oropharyngeal pain
☐None 
☐Mild
☐Moderate
☐Severe
Hyperhidrosis
☐None 
☐Mild
☐Moderate
☐Severe
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11 List of Tables
1
Table 1: Visit Schedule Table
12 References
1.
Colagiuri B, Schenk LA, Kessler MD, Dorsey SG, Colloca L. The placebo effect: 
From concepts to genes. Neuroscience. Oct 29 2015;307:171-90. 
doi:10.1016/j.neuroscience.2015.08.017
2.
Beecher HK. The powerful placebo. J Am Med Assoc. Dec 24 1955;159(17):1602-6. 
doi:10.1001/jama.1955.02960340022006
3.
Evans K, Colloca L, Pecina M, Katz N. What can be done to control the placebo 
response in clinical trials? A narrative review. Contemp Clin Trials. Aug 2021;107:106503. 
doi:10.1016/j.cct.2021.106503
4.
Kaptchuk TJ, Miller FG. Placebo Effects in Medicine. N Engl J Med. Jul 2 
2015;373(1):8-9. doi:10.1056/NEJMp1504023
5.
Colloca L, Barsky AJ. Placebo and Nocebo Effects. N Engl J Med. Feb 6 
2020;382(6):554-561. doi:10.1056/NEJMra1907805
6.
Choi JH, Shin C, Kim HJ, Jeon B. Placebo response in degenerative cerebellar 
ataxias: a descriptive review of randomized, placebo-controlled trials. J Neurol. Jan 
2022;269(1):62-71. doi:10.1007/s00415-020-10306-7
7.
Rutherford BR, Wall MM, Brown PJ, et al. Patient Expectancy as a Mediator of 
Placebo Effects in Antidepressant Clinical Trials. Am J Psychiatry. Feb 1 2017;174(2):135-
142. doi:10.1176/appi.ajp.2016.16020225
8.
Kirsch I. Antidepressants and the Placebo Effect. Z Psychol. 2014;222(3):128-134. 
doi:10.1027/2151-2604/a000176
9.
Olshansky B. Placebo and nocebo in cardiovascular health: implications for 
healthcare, research, and the doctor-patient relationship. J Am Coll Cardiol. Jan 30 
2007;49(4):415-21. doi:10.1016/j.jacc.2006.09.036
10.
Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and Safety of Esketamine Nasal 
Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-
TRANSFORM-3. Am J Geriatr Psychiatry. Feb 2020;28(2):121-141. 
doi:10.1016/j.jagp.2019.10.008
11.
WHO Depression Fact Sheet. https://www.who.int/en/news-room/fact-
sheets/detail/depression
12.
Doig GS, Simpson F. Randomization and allocation concealment: a practical guide 
for researchers. J Crit Care. Jun 2005;20(2):187-91; discussion 191-3. 
doi:10.1016/j.jcrc.2005.04.005
13.
Zhong B. How to calculate sample size in randomized controlled trial? J Thorac Dis. 
Dec 2009;1(1):51-4. 
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