Reducing Suicide Risk in Adolescents and Young Adults Via a Psychobehavioral Intervention to Regularize Daily Rhythms and Improve Brain Circuitry Functioning
Phase: NA
Conditions: Bipolar Disorder, Major Depressive Disorder, Mood Disorders, Suicide, Suicidal Ideation
Sponsor: Yale University

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol  2000032361
Reducing Suicide Risk in Adolescents and Young Adults via a Psychobehavioral Intervention to 
Regularize Daily Rhythms and Improve Brain Circuitry Functioning
Protocol Version
8/27/24
 Version:9
Clinical Trials Registration Number (if applicable): NCT05317481
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
2
Synopsis
Purpose
The purpose of this study is to advance a non-pharmacologic suicide preventive intervention with wide 
dissemination potential as an innovative high-yield solution to reduce suicide rates. We aim to achieve 
this with this study of Brain Emotion Circuitry Self-Monitoring and Regulation Therapy for Daily 
Rhythms (BE-SMART-DR), a modification of Social Rhythm Therapy (SRT) that provides self-directed 
strategies to regularize sleep and other DRs to reduce short-term suicide risk that can be used lifelong 
to potentially also reduce long-term suicide risk. 
Please note: the methods of this study are largely the same as in our currently approved HIC protocol 
0407026910. This new protocol is for an expanded study with new funding from the American 
Foundation for the Prevention of Suicide. The main difference is we may exclude more lower risk 
subjects who have never had any suicidality, and that there is a psychoeducational control condition 
subjects can be randomized to, but we will be including similar subjects, methods are largely similar, 
and as in 0407026910 the intervention will be administration in addition to current treatment in the 
community and no subject will be asked to stop any treatment in the community.
Objectives
1) Show pre-post BE-SMART-DR suicidal ideation and propensity (SI/P) decreases associated with DR 
regularity and quality increases
2) Show pre-post BE-SMART-DR improvements in the functioning of a brain system that subserves 
emotional and other behavioral control (i.e., a hypothalamus-amygdala-ventral prefrontal cortex 
(vPFC), (HAV), system)
Study Population
We plan to study adolescents and young adults with diagnostic and statistical manual of mental 
disorders 5 (DSM5) diagnoses of bipolar disorder (BD) I, II or Otherwise Specified (OS) or major 
depressive disorder (MDD), as they have been shown to have HAV system dysfunction and high suicide 
rates, and there is preliminary evidence that BE-SMART-DR has beneficial effects on the brain and in 
reducing suicide risk in this population.
Number of Participants
We plan to enroll 128 (estimating 25% attrition to 96 completers) participants based on statistical 
power analysis.
Study Design
This is a randomized control trial (RCT) with blind subjects randomized 2:1 (using block randomization) 
to BE-SMART-DR or a psychoeducational control comparator condition (CC). Participation will include 
research clinical/behavioral interviews and symptom self-ratings, magnetic resonance imaging (MRI) 
scanning, actigraphy wearables, and use of MetricWire app on smartphones for ecological momentary 
assessment (EMA).  Subjects randomized to BE-SMART-DR will participate in 12 weekly sessions with a 
research therapist with the first, middle and last sessions in person, remaining sessions offered by 
secure video or audio telecommunication and 6-month in person follow-up. Subjects randomized to 
the CC will participate in 12 weekly sessions consisting of watching pre-taped videos facilitated by a 
research coordinator with the first and middle in-person visits, and with the last session done in 
person with their study coordinator. Subjects will participate in a total of three MRI scans on their in-
person visits excluding the 6-month follow-up.
Study Duration
For each subject: about 9 months (12 weekly session and re-assessments 6-months after 12 weekly 
session completion).
Overall research project: anticipated to be at least 3 years.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
3
 Abbreviations
Abbreviation 
Explanation
AE 
Adverse Event 
ASRM
Altman Self-Rating Mania Scale
BD
Bipolar Disorder
BE-SMART-DR
Brain Emotion Circuitry Targeted Self-Monitoring and Regulation Therapy for 
Daily Rhythms
BHI
Beck Hopelessness Scale
BIS
Barratt Impulsiveness Scale
BSRS
Brief Social Rhythm Scale
CASA
Child and Adolescent Services Assessment
CC
Control Comparator Condition
CHRT-SR
Concise Health Risk Tracking Scale – Self Report
CSHF
Columbia Suicide History Form
CSQ
Client Satisfaction Questionnaire
C-SSRS
Columbia Suicide Severity Rating 
CTQ
Childhood Trauma Questionnaire
DERS
Difficulties in Emotion Regulation Scale
DISP
Diagnostic Interview for Sleep Patterns and Disorders
DR
Daily Rhythm
DSM5
Diagnostic and Statistical Manual 5
DSMP
 Data Safety Monitoring Plan
EHI
Edinburgh Handedness Inventory
EMA
Ecological Momentary Assessment
ERS
Emotion Reactivity Scale
FHE
Family History - Epidemiology
fMRI
Functional Magnetic Resonance Imaging
HAV
Hypothalamus-Amygdala-Ventral Prefrontal
HDRS
Hamilton Depression Rating Scale
HSPT
Human Subject Protection Training 
KSADS-PL 
Kiddie Schedule for Affective Disorders and Schizophrenia -Present and 
Lifetime
LAR
Legally Authorized Representative
MCQ
Munich Chronotype Questionnaire
MLS
Medical Lethality Scale
MDD
Major Depressive Disorder
MDRP
Mood Disorders Research Program
Outcome Variables
The primary outcome variables include for SI/P the Beck Scale for Suicidal Ideation (SSI) and Concise 
Health Risk Tracking (CHRT) scale, for DR regularity and quality the social rhythm metric (SRM), brief 
social rhythm scale (BSRS) and Pittsburgh Sleep Quality Inventory (PSQI) and for brain functioning 
functional MRI (fMRI) measures of the HAV. 
Locations/Facilities
Mood Disorders Research Program, 60 Temple St. Suite 6B and
Magnetic Resonance Research Center at the Anlyan Center, 300 Cedar Street
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
4
mMARCH
Motor Activity Research Consortium for Health
MRI
Magnetic Resonance Imaging
NIH  
National Institutes of Health 
OS 
Otherwise Specified
PDS
Pubertal Development Scale
PFC
Prefrontal Cortex
PHI
Protected Health Information
PI
Principal Investigator 
PMAS
Promis Medication Adherence Scale
PSQI
Pittsburgh Sleep Quality Index 
QIDS-SR 
Quick Inventory of Depression Symptomology-Self Report
RCT
Randomized Clinical Trial
SA
Suicide Attempt
SAE 
Serious Adverse Event
SAFE-T
Suicide Assessment Five-Step Evaluation and Triage 
SCID-5 PD
Structured Clinical Interview for DSM-5 Personality Disorder
SCID-5 RV 
Structured Clinical Interview for DSM-5-Research Version 
SES 
Socioeconomic Status 
SI
Suicidal Ideation
SI/P
Suicidal Ideation/Propensity
SRM 
Social Rhythm Metric 
SRT
Social Rhythm Therapy 
SSI
Scale for Suicide Ideation
STBs
Suicidal Thoughts and Behaviors 
UP
Unanticipated Problem 
UPIRSO
Unanticipated Problems Involving Risks to Subjects or Others
vPFC
Ventral Prefrontal Cortex
WASI
The Wechsler Abbreviated Scale of Intelligence
YMRS
Young Mania Rating Scale 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
5
Protocol Revision History
Version Date
Summary of Substantial Changes
12/13/22
Adding MetricWire App and their research portal for our EMA
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
6
Table of Contents
Preface....................................................................................................................................................1
Synopsis..................................................................................................................................................2
Purpose...................................................................................................................................................2
Objectives...............................................................................................................................................2
Study Population ....................................................................................................................................2
Number of Participants ..........................................................................................................................2
Study Design...........................................................................................................................................2
Study Duration........................................................................................................................................2
Outcome Variables .................................................................................................................................3
Locations/Facilities .................................................................................................................................3
Abbreviations ......................................................................................................................................3-4
Protocol Revision History .......................................................................................................................5
1
Background.....................................................................................................................................6
1.1
Background.............................................................................................................................6
1.2
Prior Experience (if applicable) ..............................................................................................8
2
Rationale/Significance ....................................................................................................................8
2.1
Rationale and Study Significance............................................................................................8
2.2
Risks........................................................................................................................................8
2.3
Anticipated Benefits .............................................................................................................10
3
Study Purpose and Objectives......................................................................................................10
3.1
Purpose.................................................................................................................................10
3.2
Hypothesis ............................................................................................................................10
3.3
Objectives .............................................................................................................................10
4
Study Design.................................................................................................................................11
4.1
Study Duration......................................................................................................................12
4.2
Outcome Variables/Endpoints..............................................................................................12
4.2.1
Primary Outcome Variables/Endpoints ........................................................................12
4.2.2
Secondary and Exploratory Outcome Variables/Endpoints (if applicable)...................13
5
Study Participants.........................................................................................................................13
5.1
Study Population ..................................................................................................................13
5.2
Number of Participants.........................................................................................................13
5.3
Eligibility Criteria...................................................................................................................13
5.4
Recruitment Procedures ......................................................................................................13
5.5
Consent/Assent Procedures/HIPAA Authorization...............................................................14
6
Study Methods/Procedures..........................................................................................................14
6.1
Study Procedures..................................................................................................................14
6.1.1
Data Collection..............................................................................................................18
6.2
Method of Assignment/Randomization (if applicable).........................................................19
6.3
Adverse Events Definition and Reporting.............................................................................19
6.4
Reaction Management .........................................................................................................19
6.5
Withdrawal Procedures........................................................................................................19
6.6
Locations/Facilities ...............................................................................................................20
7
Statistical Design...........................................................................................................................20
7.1
Sample Size Considerations..................................................................................................20
7.2
Planned Analyses..................................................................................................................20
7.2.1
Secondary Objective Analyses (if applicable) ...............................................................21
7.2.2
Analysis of Subject Characteristics (if applicable).........................................................21
7.2.3
Interim Analysis (if applicable)......................................................................................21
7.3
Data Relevance.....................................................................................................................21
7.4
Data Coding ..........................................................................................................................21
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
7
7.5
Data Analysis Tools...............................................................................................................21
7.6
Data Monitoring ...................................................................................................................21
7.7
Handling of Missing Data......................................................................................................21
8
Data/Specimen Handling and Record Keeping.............................................................................22
8.1
Subject Data Confidentiality .................................................................................................22
8.2
Data Quality Assurance.........................................................................................................22
8.3
Data or Specimen Storage/Security......................................................................................22
8.4
Study Records.......................................................................................................................22
8.5
Access to Source...................................................................................................................23
8.6
Retention of Records............................................................................................................23
8.7
Data and Safety Monitoring Plan..........................................................................................23
9
Study Considerations....................................................................................................................24
9.1
Institutional Review Board (IRB) Review ..............................................................................24
9.2
Research Personnel Training ................................................................................................24
9.3
Study Monitoring..................................................................................................................25
9.4
Unanticipated Problems and Protocol Deviations................................................................25
9.5
Study Discontinuation...........................................................................................................26
9.6
Study Completion .................................................................................................................26
9.7
Conflict of Interest Management Plan..................................................................................27
9.8
Funding Source .....................................................................................................................27
9.9
Publication Plan ....................................................................................................................27
10
Appendices ...............................................................................................................................28
          
1.
Background
1.1 Background:
Sleep and other daily rhythm (DR) irregularities are robust risk factors for suicide thoughts and 
behaviors (STBs). Targeting them may have direct effects in reducing STBs, and indirect effects via 
multiple paths, as regularizing DRs has beneficial effects on psychiatric and other medical conditions 
that also increase suicide risk. Self-strategies to improve DR regularity in adolescence/young 
adulthood, when brain systems that DRs affect are maturing, lifelong habits are established, and STBs 
often first emerge, could reduce short-term, and potentially lifelong, suicide risk. While studies show 
negative effects of DR disruptions, research is scarce on interventions to improve DR regularity and 
thereby STBs and their underlying brain mechanisms. Multi-modal clinically relevant 
symptom/behavioral and functional magnetic resonance imaging (fMRI) measures can elucidate 
underlying biological and psychological mechanisms. 
The Principal Investigator (PI) and Co-Investigators have long performed and have established STB research, 
safety methods and other infrastructure. BE-SMART-DR has shown high acceptability and feasibility, 
especially as most sessions are provided via secure videoteleconferencing. This suggests its potential 
for widespread national dissemination, broad clinical implementation, and substantial impact on the 
goal to reduce national suicide rates. Elucidation of brain circuitry changes could increase 
understanding of mechanisms underlying development and prevention of STBs, improving early risk 
detection and generation of additional targeted preventive strategies. Therefore, we will study BE-
SMART-DR to target a hypothalamus-amygdala-ventral prefrontal cortex (vPFC) (HAV) brain system, 
that subserves brain functions important in STBs, e.g., emotional and other behavioral control, and is 
sensitive to DR changes, and anticipate that it will lead to reductions in mood symptoms and suicide 
propensity.
References: (please see references 1-22 in Appendices Section 10)
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
8
1.2 Prior Experience: 
For the proposed study, we draw on our review of 2 decades of STB imaging studies, findings from our 
many years of study of adolescents/young adults with BD and MDD and in association with STBs, and 
methods from our international “HOPES” consortium to study brain markers of STBs, for which we 
are a lead site. This study was designed based on our prior NIMH-funded work with BE-SMART and our 
preliminary data.
2.
Rationale/Significance
2.1 Rationale and Study Significance: 
The purpose of this study is to advance a non-pharmacologic suicide preventive intervention with wide 
dissemination potential as an innovative high-yield solution to reduce suicide rates. We plan to study 
adolescents and young adults as they have high and rising rates of suicide, and adolescents/young 
adults with BD and MDD, as these disorders are present in the majority who die by suicide. There is no 
standard of care for this population to reduce suicide risk. We plan to study BE-SMART-DR, a 
modification of Social Rhythm Therapy (SRT) that provides self-directed strategies to regularize sleep 
and other DRs to reduce short-term suicide risk and that has shown preliminary evidence for reducing 
mood symptoms and suicide propensity (Sankar et al. Telehealth social rhythm therapy to reduce 
mood symptoms and suicide propensity in adolescents and young adults with bipolar disorder. 
American Journal of Psychotherapy, 2021 Jul 23. doi: 10.1176/appi.psychotherapy.20210011.)
2.2 Risks:
Diagnostic Assessment and Symptom Ratings: Discussing symptoms or past experiences can 
sometimes be stressful. These procedures will be described to the subject, and if applicable, to the 
legal authorized representative (LAR). Interviews will be conducted by trained staff of the Yale Mood 
Disorders Research Program (MDRP). Interviewers will be specifically trained to collect only information 
necessary for the purposes of this study. Interviews will be conducted in a professional and skillful 
manner. If a subject asks that information from the diagnostic interview be communicated to their 
community clinician and provides consent, an investigator from the study will provide the requested 
information to their clinician. Procedures for symptom worsening are as below.
Conditions:  BE-SMART is designed to help individuals to develop healthier ways to regulate emotions, 
and the CC is designed to provide education about health. The therapy and CC are therefore not 
anticipated to worsen symptoms. They are adjunctive to outside treatments such as pharmacotherapy 
(i.e., no subject will be asked to modify their treatment in the community). It is possible the subject 
could feel worse during the course of the study. By the nature of mood disorders, symptoms of the 
disorders can fluctuate.  If there is worsening of symptoms of concern to the subject or observed by 
the PI, other study personnel or their LAR if applicable,  the subject can stop at any time and their 
study coordinator or therapist can help the subject inform their outside clinician. 
Magnetic Resonance Imaging (MRI): MRI is a technique that uses magnetic 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. The subject will be watched closely throughout the study.  
Some people may feel uncomfortable or anxious.  If this happens, subjects 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 the subject is asked to tell the research staff if they have any 
of these symptoms. There are some risks with an MR study for certain people.  If the subject has a 
pacemaker or some metal objects inside of their body, they may not be in this study because the 
strong magnets in the MR scanner might harm them. Another risk is the possibility of metal objects 
being pulled into the magnet and hitting the subject. To reduce this risk, subjects are carefully 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
9
screened by trained personnel verbally and are required to sign an MRI safety sheet confirming what, 
if any, metal is in or on their body. We require that all people involved with the study remove all metal 
from their clothing and all metal objects from their pockets.  We also ask all people involved with the 
study when at the MRRC to walk through a detector designed to detect metal objects. It is important 
to know that no 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 removed from the scanner immediately if they are anxious or want to stop 
and then are evaluated by a study clinician. Pregnant women are excluded. The neuroradiologist will 
review incidental findings with the PI who will provide clinical recommendations if indicated.  Subjects 
will participate in a total of three MRI scans on their in-person visits excluding the 6-month follow-up.
EMA and Actigraphy Devices:  
We will provide an actigraphy device to subjects during their participation.  These devices do not have 
internet capability and do not hold protected health information (PHI).  If a device is lost or stolen, there 
is no way to link the stored data to its user. The actigraphy device may be uncomfortable on the wrist 
of the wearer.  If this happens the subject can discontinue wearing the device and return it to the study 
staff.
EMA questions will be similar to those used in our HIC protocol 0407026910 from the NIMH Electronic 
Diary Codebook (uploaded to IRES IRB Documents).  The MetricWire app will prompt subjects to 
answer EMA questions on their smartphones. MetricWire app (developed and owned by MetricWire 
Inc), has previously been utilized in clinical and academic research, and is HIPPA compliant.  The app 
encrypts data on participants’ phones and while data is wirelessly transferred.  The app randomly 
generates an identification code that contains numbers and letters and remains consistent for each 
subject throughout the smartphone assessment period. We will assist subjects in installing the app on 
their smartphone once they start their participation in the study and assist them in  removing the app 
at participation completion. If a subject does not own a smartphone, one will be supplied for their use 
during their participation in this study.
Included in the EMA daily events to be rated, subjects will be asked at each assessment to what extent 
they are having positive and negative thoughts since last questionnaire, and to rate the impact the 
event had on them on a 7-point Likert scale ranging from extremely positive (1) to extremely negative 
(7).  This impact variable will be recoded into 3 categories that indicate positive events (score 1-3), 
neutral events (score 4), or negative events (score 5-7).  
If ‘YES’ is endorsed for thoughts of harming yourself or of suicide, we plan to use methods adopted 
by the Motor Activity Research Consortium for Health (mMarch) international mood network 
research consortium, led by NIMH intramural investigator Dr. Merikangas, as in their NIMH Electronic 
Diary Codebook Questions adapted for Adolescent Depression, as well as in our work in HIC protocol 
0407026910.  Subjects will receive the following alert on their device that will provide specific 
instructions and phone numbers to contact (as agreed in the permission/consent/ assent process). 
“IMPORTANT: 
The information you are providing now is not immediately transmitted to our study team.  If you think 
that you are at the slightest risk of hurting yourself, please call your outside clinician and to get help 
right away, go to the nearest hospital or call 211 or 911.  You can also call the suicide and crisis lifeline 
to speak with a trained counselor at: 9-8-8
 
Suicidal Ideation and Behavior: Only subjects who are undergoing current mental health care in the 
community will be enrolled in the study and outside clinicians will be communicated with for any 
concerns. In the event a subject is judged to be at increased risk for suicide at any time during the study, 
we will implement the Suicide Assessment Five-step Evaluation and Triage (SAFE-T) plan, a commonly 
used/validated protocol for suicide assessment. The five-step plan involves identifying risk factors and 
protective factors, conducting a suicide inquiry, determining risk level and interventions, and documenting a 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
10
treatment plan. For imminent risk, EMS system/Police (911) will be activated. Until EMS/police arrive, study 
personnel will attempt to stay with the subject if being seen in person or will attempt to stay on 
videotelecommunication or telephone with the subject during remote procedures that may include 
prescreening, the consenting process, weekly sessions, or interviews. Every subject is asked to confirm 
their secure and private location with study personnel at the start of any remote activities. Subjects 
will be removed from the study if the judgment of PI is concern of subject having active suicidal or 
homicidal ideation or plan.
Risk of Injury:  Subjects do not give up their legal rights by participating in this study.  We will not 
provide financial compensation for injury or lost wages for the treatment of research-related injury. 
The subjects (or if minors their LARs) or their insurance company will be responsible for the charges for the 
treatment of any physical injuries sustained as consequence of their participation in this research.  Per federal 
regulations we will inform subjects that no financial compensation will be provided in the event of a 
physical injury that they sustain.  
2.3 Anticipated Benefits:
There are general benefits of this research with regard to understanding the pathophysiology 
involved in BD and MDD and in suicide risk. Subjects assigned to the BE-SMART-DR condition 
may benefit by participating in the treatment by having a reduction in current symptoms and 
suicide risk and potentially learning beneficial lifelong behavioral strategies. Subjects assigned to the 
CC group may benefit from the psychoeducation provided.
3.
Study Purpose and Objectives
3.1 Purpose:
The purpose of this protocol is to advance a non-pharmacologic suicide preventive intervention with 
wide dissemination potential as an innovative high-yield solution to reduce suicide rates and provide 
self-directed strategies to regularize sleep and other DRs to reduce short-term suicide risk that can be 
used lifelong to potentially also reduce long-term suicide risk. 
3.2 Hypotheses:
Hypothesis 1: BE-SMART-DR, vs. CC, will show greater
Hyp1a: decreases in SI/P (SSI23, CHRT24) and
Hyp1b: increases in DR regularity and quality (SRM25-29, BSRS29,30, PSQI31), and
Hyp1c: DR increases will be negatively associated with SI/P.       
             
Hypothesis 2: BE- SMART-DR, vs. CC, will show greater
Hyp2a: hypothalamus and PFC increases, and amygdala reductions, in responses, and HAV connectivity 
improvements. 
Hyp2b: Brain changes will be associated with DR and SI/P changes.
3.3 Objectives:
Primary Objective 1: Show pre-post BE-SMART-DR SI/P decreases associated with DR regularity and 
quality increases
Primary Objective 2: Show pre-post BE-SMART-DR improvements in HAV system function 
Exploratory Objective: Explore, at lower and higher time intervals, indicators of BE-SMART-DR related 
SI/P early and sustained changes. This will include exploring if at midpoint, improved HAV function 
shows evidence of mediating associations between DR and SI/P changes, whether actigraphy and EMA 
may be earlier indicators of SI/P decreases, and if DR and SI/P improvements will be sustained at 6-
months.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
11
4.
Study Design
BE-SMART-DR is a manualized 12 week intervention with weekly one-to-one sessions and between-
session assignments. It is adjunctive to treatment in the community. It is a modification of the SRT 
part of IPSRT (Interpersonal and Social Rhythm Therapy) which is a widely used, evidenced based 
treatment for mood disorders (IPSRT.org). The modifications include sessions delivered by telehealth 
(3 sessions in person and the remainder offered by videotelecommunictation) and taking into 
account developmental considerations (e.g., include school in addition to work, ask questions about 
social media). These were performed with our ongoing collaborator at the University of Pittsburgh, 
Dr. Holly Swartz, who is one of the founders and leading researchers of IPSRT. Our program has 
more than 4 years of experience in administering BE-SMART-DR. This has been in our HIC approved 
protocol #26910 with funding by a multi-year NIMH grant and two foundations. This protocol is 
similar to protocol #26910 but the funders required a separate protocol for the work of this grant. 
A central feature of BE-SMART-DR sessions is training participants in strategies to enhance healthy 
behaviors of self-monitoring and regularization of DRs. In brief, Session 1: Therapist builds rapport, 
discusses illness and suicide thoughts and behavior) STB history and safety planning, introduces SRT 
principles to connect changes in DRs to illness episode and STB onsets and the SRM (social rhythm 
metric questionnaire). S2: Focuses on psychoeducation about mood disorders, STBs and routines. S3-
5: Devoted to understanding determinants of a stable body clock. Goals are created to achieve more 
regular DRs, including developing strategies that are conducive to good sleep, regular daily activities, 
and understanding the impact of changes in routine on mood and STBs. S6: Focuses on identification 
of short- and long-term DR-related goals. S7: This midpoint session reviews concepts from prior 
sessions, progress to date, and identifies DR-related goals for remaining sessions. S8: Devoted to 
understanding social media and online activity and impact on DRs. S9: Ways to anticipate/manage DR 
disruptions and help subjects to understand the implications of having a mood disorder, STBs and 
impact on their self-concept and long-term life goals. S10: Discuss impact of relationships on DRs and 
plans for termination. S11/12, discuss termination and have focus on warning signs, relapse 
presentation and safety planning around STB. S12: Final session also reviews treatment gains and clear 
follow-up plans. In all sessions, STBs are screened before starting and STB discussion is woven in and 
safety prioritized. This includes the SAFE-T plan, a commonly used and validated protocol for suicide 
risk assessment, based on APA guidelines. 
Participants will be randomized 2:1 (provided by statistician) to BE-SMART-DR or the control condition 
(CC); participants will be blind to their assigned condition. The CC is modeled on previous adjunctive 
psychoeducational CCs widely used in randomized clinical trials of psychotherapy for mood and 
related disorders in adults and youths and that yield high ratings of credibility and expectancy. CC will 
consist of structured sessions of psychoeducational videos, monitored by a research coordinator and 
matched for BE-SMART-DR session number and time. CC is presented to individuals as providing a 
broad range of information and from which individuals can extract the most relevant portions. As with 
BE-SMART-DR, CC will be adjunctive to treatment as usual and include SAFE-T and other safety 
procedures. CC will emphasize strategies to manage the stress of a mental disorder and stigma, and 
health and wellness. It will offer tips on well-established self-help strategies e.g. a healthy diet, regular 
moderate exercise and seeking social support when distressed. As typical in similar CCs, subjects will 
not be provided with specific information on particular therapeutic strategies for mood disorders or 
STBs.
Both conditions consist of four in person visits that will take place on weeks 1, 7 and 12 and 
again 6 months after the subject participated in the 12th session of their assigned condition. 
In person visits will consist of a 90 minute MRI scanning session (3 total scans during participation) 
on the 3T Prisma system at the Anlyan Center and the option for the interview to be done in person 
or remotely. Subjects will also complete weekly self-ratings of symptoms, participate in wearing an 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
12
actigraphy device on their wrist and complete EMA when prompted using the MetricWire app on their 
smartphone for two week periods at the beginning, middle and end of the study. 
At 6 months, after their last session, subjects will again be asked to wear actigraphy devices and 
complete EMA for 2 weeks prior to the 6-month follow-up interview (devices will be mailed to the 
subjects as needed).  
In Summary:
Pre, mid, post: session, interview, self-assessments, MRI scan, 2 weeks actigraphy and smartphone EMA
Weekly over 12 weeks: sessions and self-ratings
6 months after the last session: interview, self-assessments, 2 weeks actigraphy and smartphone EMA
4.1 Study Duration:
The expected duration of subject participation is 9 months.
The estimated duration for the entire study is a minimum of 3 years. 
4.2 Outcome Variables/Endpoints:
4.2.1
Primary Outcome Variables:
SI/P:
SSI: is an interviewer-administered scale that is one of the most widely used measures to assess 
suicidal ideation. It has 19 items scored 0–2; scoring ≥3 showed increased suicide risk. Its use as a 
primary STB measure is consistent with randomized clinical trial recommendations.
CHRT: The CHRT is a brief self-report measure that has excellent internal consistency and face validity 
and is used in risk assessment and to guide treatment interventions. Scores have significantly 
predicted suicidality-related SAEs within 6 months, controlling for mood and comorbidity, and are 
sensitive to changes. We will use the CHRT Propensity score (9 items) that covers domains of 
pessimism, helplessness, despair and perceived lack of social support. The four domains are strongly 
inter-correlated (p <.001), and each of the four domains is also strongly-correlated with the Propensity 
and CHRT total scores (p <.001).  The CHRT predicts suicide attempts and events with at least 80% 
sensitivity in adolescents at high-risk for suicide, with a one point increase in the Propensity score  
associated with a 7.2% increase in the likelihood of any suicidal event and a 12.8% increase in the 
likelihood of a SA.
DRs:
SRM: The 5-item self-report SRM-5, with daily logs reviewed weekly, has long been used as a therapy 
tool. It is considered gold standard for measuring rhythm regularity with good validity and test-retest 
reliability.
BSRS: The BSRS is a self-rated and is a validated scale to measure DR regularity for 10 activities that 
include social contexts. Higher scores indicate higher irregularity. Cronbach's alpha/test-retest 
reliability is 82/r=.70).
PSQI: The PSQI is a clinician administered instrument used to measure the quality and patterns of 
sleep. Higher scores indicate worse sleep quality; its measure “daytime dysfunctions” predicts wish to 
die. Sensitivity/specificity are 89.6%/86.5% for disordered sleep. Validity is supported by concurrent 
sleep polysomnographs.
FMRI: We will use state-of-the-art fMRI measures of hypothalamus and PFC responses, and HAV 
connectivity.
4.2.2
Secondary and Exploratory Outcome Variables/Endpoints (if applicable):
Data based on actigraphy and EMA measures will be explored. Actigraphy measures to be explored 
may include inter-daily stability, intra-daily variability and relative amplitude, day-time activity (M10 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
13
activity) and sleep quality (L5 activity). For EMA, we plan to explore responses to questions that 
include ones related to STBs, sleep and other DRs and mood.
5.
Study Participants
5.1 Study Population:
We plan to enroll individuals ages 16-29 years, of all genders, sexual orientations, races, and ethnicities, 
in proportions representative of the population in the greater New Haven area with DSM5 diagnoses 
of BD I, II or OS or MDD.  
5.2 Number of Participants:
We plan to enroll 128 subjects and estimate 25% attrition with 96 who complete the study. 
5.3 Eligibility Criteria:
Eligibility:  
Eligibility will be determined by the staff consenting subjects, who are supervised by the PI. All study 
personnel working with this adolescent/adult population will have completed Good Clinical Practice 
trainings and be IRB approved personnel.  
Inclusion Criteria:
All Subjects:
1. ages 16 to 29 years
2. with DSM5 BD I, II or OS or MDD
3. will have a history of 1 or more SAs and/or a score of at least 3 on the SSI.  
Exclusion criteria: 
1) Significant medical or neurologic illness (especially if related to cerebral tissue),
2) MRI contraindication,
3) pregnancy (urine test)
4) current moderate or severe alcohol/other substance use disorders except caffeine/nicotine
5) positive urine screen for benzodiazepines, cocaine, amphetamines, phencyclidine, opiates, 
oxycodone; not cannabis as its use is common in this population and it can remain positive for a month
6) current evidence-based individual psychotherapy (e.g. cognitive behavioral therapy, dialectical 
behavioral therapy,) or treatment directly targeting brain regions of interest e.g. transcranial magnetic 
stimulation or electro-convulsive therapy, 
7) current psychosis
8) inability to provide informed consent, including IQ<70, YMRS32 >25, or too symptomatic
by PI’s judgment
9) active suicidal plan or intent or Columbia Suicide Severity Rating Scale (C-SSRS) 33,34  stage “4” risk 
(some intent to carry out the plan; as indicated by multisite study assessing suicide risk in RCTs or if 
revealed on any rating scale or in judgment of any study clinician.
10) homicidal ideation
5.4 Recruitment Procedures: 
Through a variety of efforts, subjects will be informed about our study. Study inclusion and exclusion 
criteria and procedures will be discussed with Yale-affiliated clinicians, psychiatric facilities in CT 
including YNHPH and Silver Hill, as well as clinicians in the surrounding community. We will provide 
verbal and written information about the study to inform them so they may provide the verbal/written 
materials to interested individuals. HIC-approved advertisements for this study will be distributed widely. 
This includes websites (e.g. YCCI website, and the Yale University Department of Psychiatry website) 
and flyers distributed throughout the community (e.g., within school systems given prior authorized 
permission to do so) and placed at varied locations throughout New Haven and surrounding towns. 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
14
We will also be sending out information packets to area clinicians in private practice, group practices, 
community agencies, and public-school systems (e.g., school counselors with prior permission). In 
addition, the study will be discussed and contact information for the program will be provided at 
educational presentations.  We will get HIC prior approval for flyers and ads we wish to place in media 
such as newspaper and magazines. 
5.5 Consent/Assent Procedures/HIPAA Authorization:
Consenting will be performed in person in a private room or if remote, the subject will notify staff of 
their secure and private location and secure telecommunication will be used via Yale Zoom account.  
The HIC approved consenting study staff will read aloud and review with the subject (and LAR if the 
subject is a minor) the consent/assent/permission, in terms suited to the subject’s comprehension, 
including the purposes, procedures, and potential risks associated with their participation in the study 
and of their rights as research subjects. Study staff will encourage questions and ensure understanding 
by asking open ended question about the consent information throughout the consenting process. 
Consenting study staff include: Hilary Blumberg MD, , program manager Susan Quatrano, study 
coordinators and therapists Erin Carrubba LPC and Bernadette Lecza LPC.
Both written LAR permission and adolescent assent will be obtained for all minors under the age of 18 
years invited to participate. This enhances independent decision-making by never assuming the 
subject automatically wants to participate after reading the consent form. We will provide more time 
for the processing of the information when going over the assent form with the minor. We will have 
subjects who turn 18 years of age, during their participation in the study, sign an adult consent form 
at the start of their next study visit. 
Signed documentation of informed consent or adolescent assent/LAR permission is required prior to 
starting any study procedures. The signed original forms are kept in locked cabinets in the MDRP’s 
office suite at 60 Temple Street.  Subjects signing remotely will be asked to send the signed form or a 
photo of the signed form to study staff via mail, email, or fax.
Subjects/LARs have the option to decline participation, or if they have initially agreed to participate 
to withdraw their/ the minor’s participation at any time during the study. They can talk with the 
minor’s outside clinician about other treatment options or find an alternate study to participate in. 
They will be informed that withdrawing from the study will involve no penalty or loss of benefits to 
which they are otherwise entitled and will not harm their relationship with their own doctors or with 
Yale-New Haven Hospital. Subjects will be reimbursed for any parts of the study they have 
participated in and travel expenses as indicated in the HIC-approved consent/permission/assent 
forms.
Compound Authorization and Consent/Assent/Permission Forms (attached in IRES):
1.
For Subjects with a Mood Disorder: Psychotherapy Study for Ages 18 Years and Older 
2.
For Subjects with a Mood Disorder: Psychotherapy Study for Ages 13-17 Years
3.
For Legally Authorized Representative of an Adolescent with a Mood Disorder: Psychotherapy 
Study for Ages 13-17 years
Consent to Video/Audio Recordings are attached to each of the 3 forms above 
6.
Study Methods/Procedures
6.1 Study Procedures:
Pre-screening will be performed by study staff by phone, video telecommunication or in-person. 
Collected information will be limited to the necessary PHI for re-contact and to determine eligibility. 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
15
The privacy of the potential participant and the confidentiality of information collected about them 
will be protected by utilizing the same procedures as done in the screening visit. 
At the screening visit, a member of the research team will discuss all aspects of the study: its purpose, 
the procedures that will be performed and potential risks of the procedures. If the potential subject is 
considered eligible for the study and agrees (and the LAR if the subject is a minor) to enroll, the 
potential adult subject or minor/LAR will be asked to sign the consent or assent/permission form(s). Once 
consented, the subject will participate in research interviewing, self-assessments, MRI scanning, a session, 
receive the actigraphy device, will be assisted in downloading the EMA MetricWire app on their smartphone 
or provided a smartphone with MetricWire app for use for the following two weeks. This visit will last 
approximately 7-8 hours. 
The subject/LAR will sign a Release of Information form that will allow us to contact the subject’s 
outside clinician and provide them with the information on their patient’s participation and to provide 
contact information for study staff in the event concerns arise.  The release may also be helpful in 
clarifying information such as diagnosis and, if necessary, requesting psychiatric medical records for review 
for diagnostic and treatment history information.
Study personnel will administer an interview to the subject and, if minor, the LAR will additionally be 
interviewed about the subject in private  and separately from the subject to ensure privacy.  The 
interview may be performed in person in a private office or remotely in a private secure 
telecommunication room (Yale Zoom account). Remote subjects will notify staff of their secure and 
private location before the interview starts.
Prior to scanning, subjects will be asked to practice computerized versions of the tasks that will be 
administered in the scanner to familiarize them with the functional MRI.  We will also collect urine to 
test for toxicology and, if the subject is female, test for pregnancy. Results of the testing will be 
discussed only with the subject, including if the subject is a minor. A member of the research team will 
accompany the subject to the Anlyan Center and remain for the duration of the scanning that takes 
approximately 90 minutes. The scanning will be performed on a 3-Tesla Prisma MR scanner.
 
The conditions consist of either 12 weeks of a weekly manualized one-to-one therapy session lasting 
under 1 hour and between-session assignments or 12 weeks of a weekly viewing session of pre-taped 
videos lasting under 1 hour and overseen by a study coordinator. First, mid and last sessions (weeks 1, 
7, 12) will be  in-person at the MDRP; remaining sessions will be offered remote by secure video or 
audio telecommunication, as subjects reported this enhanced convenience, adherence and this yielded 
high ratings of credibility and expectancy. The CC will consist of structured sessions, matched for BE-
SMART-DR session number and time. The week 12 session for CC participants will be conducted in-
person as a 1:1 session with the study coordinator. As with BE-SMART-DR, CC will be adjunctive to 
treatment as usual and include SAFE-T and other safety procedures. CC will offer tips on well-established self-
help strategies to manage health and wellness e.g., a healthy diet, regular moderate exercise and seeking social 
support when distressed. As typical in similar CCs, strategies will not be provided for the regularization of DRs 
that are considered the active ingredients of BE-SMART-DR.
Visit Schedule (with economic compensation consideration):
Weeks 1, 7, 12: In person visits  will include: Session (remote option available), interviewer ratings 
(remote option available) ($30), self-ratings ($10), MRI ($50), EMA ($15), actigraphy ($15). 
Additionally, week 1 cognitive testing ($30) will be included. Total week 1: $150; weeks 7 and 12: $120. 
Weeks 2-6, 8-11: Remote session and self-ratings ($10): Total for 9 remote visits: $90.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
16
6-month follow-up: Interview and self-ratings ($30), EMA ($15), actigraphy ($15): 
Total: $60 
Overall total for the visits: $540.00
Subjects will be compensated/reimbursed cash at the end of each in person study visit (this will include 
compensation for remote sessions and self-ratings since last in person visit).  For subjects completing 
between-visit components and unable to attend their visit in-person, they will be compensated with 
a digital gift card emailed to them by their study coordinator.
Subjects will be reimbursed for reasonable travel expenses and if parking at Temple Street or Temple 
Medical garage the subject will be reimbursed $22.  Any other reasonable expenses will be made per 
PI discretion.
The research procedures and use of devices are free of charge, but we do ask that any devices 
provided for use during the study are returned back to staff after each use. 
Self-Ratings Completed by Subjects  
Completed Daily:
-* SRM (BE-SMART-DR subjects complete daily for duration of participation).
Completed Weekly and at 6-Month Follow-Up:
-Altman Self Rating Mania Scale (ASRM)35,36: a scale designed to assess the presence and/or severity 
of manic symptoms (5 items)
-Quick Inventory of Depressive Symptomatology Self Report (QIDS-SR)37-39: a scale to screen for 
depression and measure changes in severity of symptoms (16-items)
*The following information will be provided in Qualtrics prior to filling out the first question of this 
inventory as one question refers to suicidal ideation. The information provides specific instructions and 
phone numbers to contact (as agreed in the permission/consent/ assent process). 
“IMPORTANT: 
The information you are providing now is not immediately transmitted to our study team.  If you think 
that you are at the slightest risk of hurting yourself, please call your outside clinician and to get help 
right away, go to the nearest hospital or call 988, 211, or 911.  You can also call a suicide hotline to 
speak with a trained counselor at: 
1-800-273-TALK (1-800-273-8255) 
or 
1-800-SUICIDE (1-800-784-2433). 
Completed at Week 1 only:
-Edinburgh Handedness Inventory (EHI)40,41: a questionnaire that assesses right- and left-hand 
preference with good test re-test reliability (10 items) 
-Childhood Trauma Questionnaire (CTQ)42,43: a scale that measures 5 types of maltreatment that are 
associated with increased risk for suicide (28 items)
-Pubertal Development Scale (PDS)44: a questionnaire that rates pubertal development ranging from 
immature to fully developed
-Gender Identity and Sexual Orientation45: a self-rated questionnaire on gender identity and sexual 
orientation (3 items)
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
17
-COVID-19 Exposure Rating: We’ve chosen relevant COVID-19 exposure questions for a self-rating 
that were taken from longitudinal surveys that allow for data sets to be comparable. The questions in 
the COVID-19 Rating were selected from the following sources:

Welcome longitudinal population studies (LPS) (website pending)

COVID-Mental Health tracker (COVID-MH) (http://www.suicideresearch.info/tracking-the-
impact-of-the- covid-19-pandemic-on-mental-wellbeing-study-covid-mh)

UCL COVID-19 Social Study (UCLSS) (https://www.covidsocialstudy.org/)

The Coronavirus Health Impact Survey (CRISIS) (http://www.crisissurvey.org/)
Completed Weeks 1, 7, 12 (and 6-Month Follow-Up excluding SRM):
-SRM, BSRS, PSQI and CHRT 
-Actigraphy wearable over a 2 week period.
-EMA via MetricWire app on smartphone 4x/day over a 2 week period 
-Barratt Impulsiveness Scale-11 (BIS-11)47: a scale that measures trait impulsiveness which is 
associated with risk for suicide behavior (30 items) 
-Beck Hopelessness Scale (BHI)48: a scale designed to assess the extent of positive and negative beliefs 
about the future. Hopelessness will be assessed as it is a leading risk factor for suicide (20 true/false 
items)
-Difficulties in Emotion Regulation Scale (DERS)50,51: a measure used to assess the emotion regulation 
problems among adolescents and adults (36 items) -Emotion Reactivity Scale (ERS)52: a measure of 
emotion sensitivity, intensity, and persistence (21 items)
-Munich Chronotype Questionnaire (MCQT)53: a scale to assess individual phase of entrainment on 
work and work-free days (19 items)
-NIH PROMIS Medication Adherence Scale (PMAS)54:  a scale used to assess self-reported medication 
adherence behaviors (12 items)
  
Completed Week 12 only:
-Client Satisfaction Questionnaire (CSQ)55,56: will assess satisfaction with treatment (8 items)
Assessments Administered by Study Staff
 
Collected at Visit 1 only:
-Socioeconomic Status (SES) 57: a widely used assessment of socioeconomic status
-The Wechsler Abbreviated Scale of Intelligence (WASI)58: a widely used brief interviewer administered 
IQ test designed to assess specific and overall cognitive capabilities
-Family History – Epidemiology (FHE)59: an assessment used to collect pedigree psychiatric information 
(after week 1, if any indication there could be a change, will repeat) 
-Pittsburgh Structured Clinical Interview for Sleep Disorders (SCID-SLP) 67: an instrument provided by 
our collaborator used to identify history of sleep issues (after week 1, if any indication there could be 
a change, will repeat) (after week 1, if any indication of sleep issues, will repeat)
-Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD)66: a semi structured 
diagnostic interview to assess the 10 DSM-5 Personality Disorders as well as Other Specified 
Personality 
Collected at Weeks 1, 7, 12 and 6-Month Follow-Up:
-Child and Adolescent Services Assessment (CASA)49: a reliable self- and parent-report instrument, used to 
track mental health services
-Columbia Suicide History Form (CSHF)33,34: considered a gold-standard scale to gather history of 
lifetime suicide behavior (after week 1 only interim changes will be assessed)
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
18
-Columbia Suicide Severity Rating Scale (C-SSRS) 33,34: is a questionnaire widely used in clinical and 
research settings to assess the severity of recent suicidal ideation and behavior (after week 1 only 
interim changes will be assessed)
-Hamilton Depression Rating Scale (HDRS)62,63 : a widely used rating scale used to assess symptoms of 
depression; the 29 item version probes “atypical” depressive symptoms often present in mood 
disorders in adolescents and young adults (29 items)
- Medical Lethality Suicide Scale (MLS)64: an interviewer-administered scale that measures the medical 
severity of suicide attempts 
-Scale for Suicide Ideation (SSI)23: a widely used rating scale that assesses current intensity of attitudes, 
plans, and behaviors to commit suicide (19 item)
-Schedule for Affective Disorders and Schizophrenia for School Aged Children - Present and Lifetime 
Version (K-SADS-PL)65 (for minors only): a semi-structured diagnostic interview that provides 
assessment of present episode and lifetime history of psychiatric illness in children according to DSM-
IV criteria. It has good test-retest and inter-rater reliability. The K-SADS-PL is completed by 
interviewing the child and his/her LAR separately. Final diagnoses are made by incorporating all 
sources of data and using best estimate procedures. It will be used to confirm psychiatric diagnosis 
and items may be explored in analyses (after week 1, interview for changes)
-Structured Clinical Interview for DSM SCID-5 for Adults Aged 18 and Over – Present and Lifetime 
Research Version (SCID-5) 66: a structured diagnostic interview that provides assessment of present 
episode and lifetime history of psychiatric illness in adults according to DSM-5 criteria.  It is completed 
by interviewing the subject. It will be used to confirm psychiatric diagnosis and items may be explored 
in analyses (after week 1, interview for changes)
-Young Mania Rating Scale (YMRS) 32: a clinician administered tool used to rate the severity of 
symptoms of mania (11 items)
Collected weeks 1, 7, 12:
-MRI Metal Screening Form (filled out by participant/LAR and reviewed with staff)
-MRI Data Form (includes height and weight from which will calculate BMI, current medications, 
menstrual phase)
-Urine for toxicology and for females pregnancy 
6.1.1
Data Collection:
The data are collected, recorded and stored by trained research personnel. The subject may be 
asked to utilize a computer or phone for sessions via videotelecommunication, wear an actigraphy 
device, use a smartphone to respond to EMA prompts and fill out self-reports through Qualtrics. 
Subjects will complete self ratings through the Yale approved online software survey, Qualtrics. 
Clinical ratings and assessments (paper/pencil) administered by study staff will contain no PHI and be 
stored in locked file cabinets in a locked office suite. Data will be recorded onto master excel 
spreadsheets that will be saved on a Yale secure server. Scanning data is collected by trained 
technologists and will be stored on password-protected and encrypted computers in compliance 
with HIPAA regulations. 
There is no identifiable data on the actigraphy device we supply and they do not have GPS or any 
other location recording capability. Deidentified raw actigraphy activity data is downloaded to a 
desktop app and converted to files that only the researchers on this project can match to subjects.  
EMA responses submitted using MetricWire app are immediately synced to HIPAA-Compliant 
servers in the United States and removed from the subject’s smartphone.  The data are encrypted 
end-to-end during transmission and MetricWire servers use an Encryption Token to verify that the 
data is coming from the correct source (authenticity) and that the data have not been modified in-
transit (integrity).
Video and audio recordings through ZOOM will be hosted by Yale staff with Yale Zoom accounts, 
which are HIPAA compliant.  
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
19
Letter and number codes with the link to subjects’ identifiers will be stored in a separate computer 
file on the Yale University fileserver and access will be limited to authorized personnel.  This file will 
be backed-up in encrypted form using Yale University encryption software and will be stored in 
encrypted form on office desktop computers located in the locked office suite at MDRP. Only de-
identified subject data will also be stored on unencrypted electronic databases.  Laptops and 
computers will be password protected. 
6.2 Method of Assignment/Randomization (if applicable): 
Subjects will be blind and randomized 2:1 using block randomization to BE-SMART-DR or CC. Subjects will 
be blinded to assignment.  The therapist will not be blinded, but the staff member administering the 
structured interviews at weeks 1, 7, 12 and 6 months will be blinded to subjects’ condition. 
6.3 Adverse Events Definition and Reporting:
Adverse event (AE) means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related. 
An 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 AE, 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. 
6.4 Reaction Management:
Study personnel will be trained in safety, risk and protection methods.
All subjects participating in this study will have an outside clinician and this clinician will be 
communicated with by study staff should any concerns arise.  If a study clinician believes it will be 
beneficial to the subject or the subject/LAR requests, we will speak with their clinician. 
The SAFE-T plan will be discussed with the subject at initial visit and referred to and implemented throughout 
the study as needed.
For imminent risk, EMS system/Police (911) will be activated. Study personnel will attempt to stay on 
videotelecommunication or with participants until EMS/Police arrive. Subjects will be removed from 
the study if the judgment of the PI is concern of the subject having active suicidal or homicidal ideation 
or plan.
Subjects will be prompted to complete daily EMA questions and depending on how they respond may 
receive the following information:
If you think that you are at the slightest risk of hurting yourself, please call your outside clinician and 
to get help right away, go to the nearest hospital or call 211 or 911.  You can also call a suicide hotline 
to speak with a trained counselor at:
1-800-273-TALK (1-800-273-8255)
or
1-800-SUICIDE (1-800-784-2433).
6.5 Withdrawal Procedures:
Subjects are free to stop and withdraw from this study at any time during its course. Information on 
withdrawal procedures is provided in the informed consent forms and will be discussed with the 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
20
subject during the consenting process. Subjects may also ask that their data be anonymized and can 
take away permission to use and disclose of their health information at any time. Subjects may 
withdraw their permission by telling the study staff or by writing to the PI, Dr. Hilary Blumberg, at 
MDRP 60 Temple ST Suite 6B, New Haven, CT 06510.  This will cancel any future appointments. 
Withdrawing from the study will involve no penalty or loss of benefits to the subjects and will not 
harm their relationship with their doctors or with Yale-New Haven Hospital. When a subject withdraws 
from the study, no new identifying health information will be gathered after that date. Information 
that has already been gathered may still be used and given to others as necessary to ensure the 
integrity of the study and/or study oversight.
The researchers may withdraw subjects in the research if necessary. This may occur, for example, if 
the researchers believe the subject may need more services than there are provided in this protocol 
or if new exclusion criteria emerge.
6.6 Locations/Facilities:
Mood Disorders Research Program, 60 Temple St. Suite 6B and Magnetic Resonance Research Center at 
the Anlyan Center, 300 Cedar Street
7.
Statistical Design
7.1 Sample Size Considerations:
Hyp 1a,b Power: Estimating 25% attrition, power is based on 64 BE-SMART-DR and 32 CC completers 
and assume an alpha=.05 threshold for primary analyses. We estimate that we will have 80% power 
to detect small/medium within-subject difference for both BE-SMART-DR (d’=0.36) and CC (d’=0.51) 
groups. For between-group comparisons, we can detect a medium effect of d≥0.61. 
Hyp 1c Power: We estimate that our proposed sample will provide 80% power to detect 
small/medium associations both across (r=.28) and within (BE-SMART-DR r=.34, CC r=.47) groups.
Hyp2a/b/c Power: We estimate that our proposed sample will provide 80% power to detect 
small/medium associations both across (r=.28) and within (BE-SMART-DR r=.34, CC r=.47) groups.
These estimates compare favorably with anticipated effects and estimates in our pilot data. 
7.2 Planned Analyses:
Statistical consultation will be available with Dr. Blumberg’s longstanding collaborators Ralitza 
Gueorguieva and Brian Pittman, experts in analyses of clinical and neuroimaging data. Prior to 
hypothesis testing, descriptive statistics and graphs will be used to summarize the data. Distributions 
of summary scores will be examined for outliers. Data will be checked for adherence to normal 
distribution using normal probability plots and Kolmogorov-Smirnov test. If necessary, 
transformations will be used to meet assumptions for analyses. If this cannot be achieved, appropriate 
nonparametric methods will be used. 
Hyp1a/b Testing: Linear mixed models will evaluate rating scales (Hyp1a: SSI, CHRT; Hyp1b: SRM, 
BSRS, PSQI) as dependent variables with time (pre-, post-session) as a within-subjects factor and group 
(BE-SMART-DR, CC) as a between-subjects factor. All interactions will be modeled. Least square means 
and standard errors will be estimated and plotted to assess significant effects. Exploratory analyses 
will assess sensitivity of results after adjustment for community-based mental health treatment, and 
medication classes, doses, adherence, duration by including the variables as additional predictors in 
the models. Additional covariates e.g. demographic, symptom, behavior, course and other illness 
features, as above will be considered in the models, one at a time.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
21
Hyp1c Testing: Pre-post change scores for DRs (SRM, BSRS, PSQI) and SI/P (SSI, CHRT) will be 
calculated. An ANCOVA model will include SI/P changes as dependent variables, and group and DR 
changes as between-subjects factors. Overall and group slopes will be estimated from the model.
Hyp2a/b/c Testing: HAV system changes (Hyp2a) will be analyzed using a similar mixed model as 
described for Aim1a above, with region (hypothalamus, amygdala, vPFC) included as the within-
subjects factor. Associations between brain changes and symptom/behavioral (DR, SI/P) changes 
(Hyp2b) will be analyzed as for Hyp1c.
7.2.1 Secondary Objective Analyses: 
To test whether early changes in the HAV system mediate BE-SMART-DR effects on SI/P, early (pre-
mid) DR changes (SRM, BSRS, PSQI) will serve as predictor, and early brain changes as mediators, while 
pre-post changes in SSI, CHRT will represent the dependent variables. A series of regression models 
testing for between-group differences in the mediator and the outcome, and testing for associations 
between the mediator and outcome, will be employed. A last regression model will test the joint 
effects of both group and the mediator. We will examine model coefficients to determine any partial 
or full mediating effects of brain function on BE-SMART-DR-induced reductions on SI/P. The estimated 
indirect effect will be tested for significance using bootstrapping procedures. Changes in Actigraphy/EMA 
measures will be analyzed using a similar model as described for Hyp1a/b. Secondary analyses will 
examine more refined changes over time using all available time points, including binned EMA/actigraphy 
summary measures (see below). We will fit time as categorical since we do not a priori know whether 
the change over time will be best described with a linear or curvilinear function. In post hoc analyses, 
we will test for linear and quadratic effects of time or will consider transformations of time (e.g. log) 
to assess which shape best describes the patterns of change in repeated measures over time. 
Sustained SI/P and DR changes will be modeled similarly to Hyp1a/b. 
7.3 Data Relevance:
The data will be collected to accomplish the study aims and test the study hypotheses.
7.4 Data Coding:
Data will receive an alpha numeric code that does not have identifiers. The link between the code and 
identifiers will be stored on Yale’s secure server and access will be only by the PI and selected program 
personnel, such as program manager Susan Quatrano.
7.5 Data Analysis Tools:
Imaging software to be used will include widely used and locally developed programs such as BioImage 
Suite (www.bioimagesuite.org) software. Analyses will also be performed using widely used software, 
such as SAS (Cary, NC).
7.6 Data Monitoring:
See Study Monitoring Section 9.3
7.7 Handling of Missing Data:
All analyses will be intent-to-treat and will be based on mixed models for regions of interest. The mixed 
effects approach is advantageous as it is unaffected by randomly missing data and allows greater 
flexibility in modeling the correlation structure of repeated measures data. Sensitivity analyses under 
informative dropout will be performed as necessary.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
22
8.
Data/Specimen Handling and Record Keeping
8.1 Subject Data Confidentiality:
Subject confidentiality and privacy is strictly held by the participating investigators, their staff, and the 
sponsor(s)/funding agency. All staff members that come into contact with the data are fully trained to 
the current HIPAA regulations and are informed as to the proper use of all data. 
Representatives of the Institutional Review Board (IRB), regulatory agencies or funding agency may inspect all 
documents and records required to be maintained by the investigator for the subjects in this study. 
The study site will permit access to such records. 
The collection of sensitive PHI will be limited to only what is necessary to achieve the aims of the 
research; only trained study personnel will collect this data. All research activities will be conducted 
in as private a setting as possible. The subject will be asked to do sessions in a location where the 
subject can speak confidentially. There is no identifiable data on the actigraphy or EMA devices that 
we supply, and they don’t have GPS or any other location recording capability. If a device is lost, there 
is no way to track it back to the user as it doesn’t hold personally identifying information.  Deidentified 
raw actigraphy and EMA data is downloaded to a desktop app and converted to files that only the 
researchers on this project can match to subjects.  Hard copy documents with PHI will be kept in a 
locked cabinet within a locked office suite and other data without PHI will be kept separate from PHI. 
Subject research data will be identified by a unique alphanumeric code that does not have any 
identifying information and will be stored separately from the subject’s contact or identifying 
information. 
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.
8.2 Data Quality Assurance:
Quality control and assurance of data will be a continuous practice and will happen in real-time, close 
enough to the data collection to ensure the integrity and validity of the data. Errors will be corrected 
as soon as possible following identification. Unexpected errors requiring new corrective procedures 
will be addressed with PI as soon as possible.
The subjects themselves directly enter their self-reported data into Qualtrics as they respond to 
survey items. Staff complete a review of the data entered for each subject following the completion 
of each visit. Data entered into a master spreadsheet will be cross checked for errors by another 
member of our staff. Scanning data will be analyzed quarterly with quality control analyses to confirm 
scanner functionality and that the task is functioning correctly.  
8.3 Data or Specimen Storage/Security:
See 6.1.1 Data Collection
8.4 Study Records:
The PI will ensure that staff with delegated responsibilities for generating, recording, reviewing, and 
maintaining clinical data and records follow the most stringent requirements and comply with 
IRB/HIC and institutional requirements, policies and procedures. This may include (but are not 
limited to) regulatory documents, protocols, consent forms, medical records, laboratory reports, 
subject diaries, subject questionnaires and recorded data.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
23
8.5 Access to Source:
The PI will ensure study staff maintains adequate and accurate source documents and records that 
include all pertinent observations on each subject. Source data will be attributable, legible, 
contemporaneous, original, accurate, and complete. When making changes or corrections, the 
original entry will be crossed out with a single line, initialed and dated, will be traceable, will not 
obscure the original entry, and will be explained if necessary. All study staff will protect confidentiality 
of records that could identify subjects in accordance with all applicable regulatory requirements.
Upon request of the monitor, auditor, IRB/HIC, or regulatory authority, the investigator will make all 
requested clinical related records available for direct access in order to examine, analyze, verify, and 
reproduce any records and reports that are important to the evaluation of the study. Any party with 
direct access should take all reasonable precautions within the constraints of the applicable regulatory 
requirement(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary 
information.
8.6 Retention of Records:
Once all data for this project has been collected and results of these studies published, study data 
will remain securely stored at MDRP indefinitely after being stripped of all subject identifiers by 
zeroing and will be available to other qualified researchers. Any such request for study data which 
meets reasonable standards of scientific integrity will be considered. 
When the study is over, the MetricWire Research Team will delete EMA data collected for this study 
from their servers and they will not retain any additional copies of the data on their servers or in the 
MetricWire application.
8.7 Data and Safety Monitoring Plan: 
This protocol presents greater than minimal risks to the subjects and AE are not anticipated, but the 
potential exists for anticipated and/or unanticipated AEs, 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. In the unlikely event that AEs occur, serious 
unanticipated AEs will be reported within 48 hours to the HIC (using HIC form 6A) and within 10 
business days to the National Institutes of Health. The investigator will specify whether the serious 
unanticipated AE is considered related to the study.  
We will summarize all adverse and unexpected events in our annual request for re-approval 
application to the HIC. The PI will evaluate the adverse and unexpected events and study data at one-
year intervals and determine whether the adverse and unexpected events affects the Risk/Benefit 
ratio of the study and whether modifications to the protocol (at Risks to subjects) or consent form (at 
Risks and Inconveniences) are required. The PI will be responsible for overall data and safety 
monitoring of this protocol. 
The risks associated with the current study are deemed for the following reasons: 
1.
We do not view the risks associated with BES-MART-DR as minimal risks.
2.
Given the now established safety and validity of the current BE-SMART-DR in our prior work, we 
do not view the proposed studies as high risk.
Although we have assessed the proposed study as one of greater than minimal risk, the potential 
exists for anticipated and/or unanticipated AEs, 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:
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
24
Attribution of Adverse Events:
AEs will be monitored for each subject participating in the study and attributed to the study 
procedures / design by the PI (Hilary Blumberg, MD) according with the following categories:
a.) Definite: AE is clearly related to investigational procedures(s)/agent(s).
b.) Probable: AE is likely related to investigational procedures(s)/agent(s).
c.) Possible: AE may be related to investigational procedures(s)/agent(s).
d.) Unlikely: AE is likely not to be related to the investigational procedures(s)/agent(s).
e.) Unrelated: AE is clearly not related to investigational procedures(s)/agent(s).
Plan for Grading Adverse Events:
The following scale will be used in grading the severity of AEs noted during the study:
1.
Mild AE
2.
Moderate AE
3.
Severe 
Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:
In addition to grading the AE, the PI will determine whether the AE meets the criteria for a Serious 
Adverse Event (SAE).  An adverse event is considered serious if:
1.
Death;
2.
A life-threatening experience in-patient hospitalization or prolongation of existing hospitalization; 
3.
A persistent or significant disability or incapacity; 
4.
A congenital anomaly or birth defect; OR
5.
Any other AE that, 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. 
An AE may be graded as severe but still not meet the criteria for a SAE.  Similarly, an AE may be graded 
as moderate but still meet the criteria for an SAE. The PI will consider the grade of the event as well 
as its “seriousness” when determining whether reporting to the IRB is necessary.
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:
All study personnel working with this child/adolescent/adult population will have completed Good 
Clinical Practice trainings and Human Subject Protection Training (HSPT).  
Study personnel include experts in clinical care, and research assessments and studies of adults and 
children with mood disorders and with suicide thoughts and behaviors. Research staff members have 
been specifically trained in the administration of the assessments of the proposed study and have 
established high reliability. Study staff not providing subject therapy or sessions will be blinded to 
condition and will administer diagnostic, symptom and behavioral/cognitive testing to BE-SMART-DR 
and CC subjects on weeks 1, 7, 12 and at 6- month follow-up.
The 2 therapists (also performing research coordinator functions at MDRP) are trained in 
assessments related to emotion processing and regulation, mood and suicide in children and adults 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
25
and each have >20yrs experience administering research therapies and by study start >4 years in BE-
SMART-DR. They will be randomly assigned to cases across conditions with emphasis placed on 
ensuring they understand the important distinctions of each and there is no “bleeding” between 
BE-SMART-DR and CC, in order to preserve data integrity/fidelity. Drs. Blumberg, Silverman will 
closely supervise each therapist weekly. To be eligible to rate, raters will score within one point of 
each other on each scale item. All sessions will be recorded and 25% of sessions, randomly selected, 
will be rated for fidelity. Of these, 10% will be rated by both raters to ensure inter-rater reliability.
9.3 Study Monitoring: 
The PI will provide ongoing supervision and evaluation of the activities of the study, including the 
frequency and severity of adverse events and whether new risks have been identified and whether 
appropriate progress is being made. Personnel responsible for the safety review and its frequency:  
The PI will be responsible for monitoring the data, assuring protocol compliance, and conducting the safety 
reviews at the specified 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 PI (monitor) will 
evaluate whether the study should continue unchanged, require modification/amendment, or close to 
enrollment.  The PI, the Institutional Review Board (IRB) or the HIC or the study sponsor have the 
authority to stop or suspend the study or require modifications.
We will have an Independent Safety Monitor (ISM) who will be an independent physician and 
appropriate expert with relevant expertise whose primary responsibility will be to provide 
independent study monitoring.
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 subject, the investigator, or the study site staff. As a result of deviations, corrective 
actions have been developed by the site and will be implemented promptly.
The PI is responsible to identify and report Unanticipated Problems Involving Risks to Subjects or 
Others (UPIRSOs) including adverse events that meet the reporting criteria and therefore should be 
considered as UPIRSOs.  UPIRSOs may be medical or non-medical in nature and include – but are not 
limited to – serious, unexpected, and related adverse events and unanticipated adverse device effects.  
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the 
appropriate forms found on the website. All related events involving risk but not meeting the prompt 
reporting requirements described in IRB Policy 710 will be reported to the IRB in summary form at the 
time of continuing review. If appropriate, such summary may be a simple brief statement that events 
have occurred at the expected frequency and level of severity as previously documented.  All 
deviations will be addressed in study source documents.
The PI will report the following types of adverse events to all Co-Investigators on the protocol, study 
sponsor, and the reviewing Institutional Review Board (IRB) per their policies.
 Any incident, experience or outcome that meets ALL 3 of the following criteria:
Unanticipated problems involving risks to subjects or others include, in general, any incident, 
experience, or outcome that meets all of the following criteria:

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 
subject population being studied;
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
26

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 subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.
Timeframe for Reporting:
1. Events that may require a temporary or permanent interruption of study activities by the PI or 
sponsor to avoid potential harm to subjects will be reported to the IRB immediately (if possible), 
followed by a written report to the IRB using the UPIRSO Reporting Form (710 FR 4) no more than 5 
calendar days after the Yale PI becomes aware of the event. 
2. Internal Events will be reported to the IRB using the UPIRSO Reporting Form (710 FR 4) within 5 
calendar days of the PI becoming aware of the event. 
3. External Events should be reported to the IRB using the UPIRSO Reporting Form  (710 FR 4) within 
5 calendar days of the Yale University PI becoming aware of the event ONLY IF either of the following 
are true:
(a) The Yale PI has concluded that an immediate change to the protocol is necessary to address the 
risks raised by the event, OR 
(b) A monitoring entity (e.g., an external IRB at the site where the problem or event occurred, the 
sponsor, or the Data Safety Monitoring Board) has required modifications/amendments to the 
research protocol or consent documents as a result of the event.
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.
9.5 Study Discontinuation:
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB.
9.6 Study Completion:
The expected date of study completion will be at least 3 years after the official start date.  A study 
closure form will be submitted for IRB to review and verify the study is eligible for closure. If longer 
time is needed to complete the study, extensions will be requested to the HIC.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
27
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
American Foundation for Suicide Prevention
9.9 Publication Plan
The PI has primary responsibility for publishing the study results and the sponsor does not have 
requirements for their involvement in publication.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
28
10. Appendices
Appendix #
Title
Section
Topic
REFERENCES 
1. Van Harmelen AL, Schmaal L, Blumberg HP. (2019): Journal of Affective Disorders Special Issue on 
Suicide-Related Research: Hopeful progress but much research urgently needed. J Affect 
Disord 251: 39-41.
2. Goldstein TR, Bridge JA, Brent DA. (2008): Sleep disturbance preceding completed suicide in 
adolescents. J Consult Clin Psychol 76: 84.
3. Bernert RA, Kim JS, Iwata NG, Perlis ML. (2015): Sleep disturbances as an evidence-based suicide 
risk factor. Curr Psychiatry Rep 17: 554.
4. Pigeon WR, Pinquart M, Conner K. (2012): Meta-analysis of sleep disturbance and suicidal thoughts 
and behaviors. The Journal of clinical psychiatry.
5. Sarchiapone M, Mandelli L, Carli V, Iosue M, Wasserman C, Hadlaczky G, et al. (2014): Hours of sleep 
in adolescents and its association with anxiety, emotional concerns, and suicidal ideation. 
Sleep Medicine 15: 248-254.
6. McClung CA. (2013): How might circadian rhythms control mood? Let me count the ways. Biological 
psychiatry 74: 242-249.
7. Benard V, Etain B, Vaiva G, Boudebesse C, Yeim S, Benizri C, et al. (2019): Sleep and circadian 
rhythms as possible trait markers of suicide attempt in bipolar disorders: An actigraphy study. 
Journal of affective disorders 244: 1-8.
8. Fergusson DM, Woodward LJ, Horwood LJ. (2000): Risk factors and life processes associated with 
the onset of suicidal behaviour during adolescence and early adulthood. Psychological 
medicine 30: 23-39.,
9. Brent DA, Perper JA, Goldstein CE, Kolko DJ, Allan MJ, Allman CJ, et al. (1988): Risk factors for 
adolescent suicide: a comparison of adolescent suicide victims with suicidal inpatients. 
Archives of general psychiatry 45: 581-588.
10. Nock MK, Green JG, Hwang I, McLaughlin KA, Sampson NA, Zaslavsky AM, et al. (2013): Prevalence, 
correlates, and treatment of lifetime suicidal behavior among adolescents: results from the 
National Comorbidity Survey Replication Adolescent Supplement. JAMA psychiatry 70: 300-
310.
11. Grandin LD, Alloy LB, Abramson LY. (2006): The social zeitgeber theory, circadian rhythms, and 
mood disorders: review and evaluation. Clinical psychology review 26: 679-694.
12. Alloy LB, Ng TH, Titone MK, Boland EM. (2017): Circadian rhythm dysregulation in bipolar spectrum 
disorders. Current psychiatry reports 19: 21.
13. Jones SH. (2001): Circadian rhythms, multilevel models of emotion and bipolar disorder—an initial 
step towards integration? Clinical psychology review 21: 1193-1209.
14. Fan S, Lippard ETC, Sankar A, Wallace A, Johnston JAY, Wang F, et al. (2019): Gray and white matter 
differences in adolescents and young adults with prior suicide attempts across bipolar and 
major depressive disorders. J Affect Disord 245: 1089-1097.
15. Johnston JA, Wang F, Liu J, Blond BN, Wallace A, Liu J, et al. (2017): Multimodal Neuroimaging of 
Frontolimbic Structure and Function Associated With Suicide Attempts in Adolescents and 
Young Adults With Bipolar Disorder. Am J Psychiatry: appiajp201615050652.
16. Lippard ETC, Johnston JAY, Spencer L, Quatrano S, Fan S, Sankar A, et al. (2019): Preliminary 
examination of gray and white matter structure and longitudinal structural changes in frontal 
systems associated with future suicide attempts in adolescents and young adults with mood 
disorders. J Affect Disord 245: 1139-1148.
17. Cox Lippard ET, Johnston JA, Blumberg HP. (2014): Neurobiological risk factors for suicide: insights 
from brain imaging. Am J Prev Med 47: S152-162.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
29
18. Lebowitz ER, Blumberg HP, Silverman WK. (2019): Negative peer social interactions and oxytocin 
levels linked to suicidal ideation in anxious youth. J Affect Disord 245: 806-811.
19. Depp CA, Thompson WK, Frank E, Swartz HA. (2017): Prediction of near-term increases in suicidal 
ideation in recently depressed patients with bipolar II disorder using intensive longitudinal 
data. J Affect Disord 208: 363-368.
20. Novick DM, Swartz HA, Frank E. (2010): Suicide attempts in bipolar I and bipolar II disorder: a 
review and meta-analysis of the evidence. Bipolar Disord 12: 1-9.
21. Rucci P, Frank E, Kostelnik B, Fagiolini A, Mallinger AG, Swartz HA, et al. (2002): Suicide attempts 
in patients with bipolar I disorder during acute and maintenance phases of intensive 
treatment with pharmacotherapy and adjunctive psychotherapy. Am J Psychiatry 159: 1160-
1164.
22. Silverman WK, Pettit JW. (2018): Developmental Window of Opportunity: Implications of Parent-
Child Psychotherapy for Early Childhood Depression Treatment. Am J Psychiatry 175: 1051-
1053.
23. Beck AT, Kovacs M, Weissman A. (1979): Assessment of suicidal intention: the scale for suicide 
ideation. J Consult Clin Psychol 47: 343-352.
24. Ostacher MJ, Nierenberg AA, Rabideau D, Reilly-Harrington NA, Sylvia LG, Gold AK, et al. (2015): 
A clinical measure of suicidal ideation, suicidal behavior, and associated symptoms in bipolar 
disorder: Psychometric properties of the Concise Health Risk Tracking Self-Report (CHRT-SR). 
J Psychiatr Res 71: 126-133.
25. Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, et al. (2005): Two-year 
outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. 
Arch Gen Psychiatry 62: 996-1004.
26. Hlastala SA, Frank E. (2006): Adapting interpersonal and social rhythm therapy to the 
developmental needs of adolescents with bipolar disorder. Dev Psychopathol 18: 1267-1288.
27. Monk TH, Frank E, Potts JM, Kupfer DJ. (2002): A simple way to measure daily lifestyle regularity. 
J Sleep Res 11: 183-190.
28. Monk TH, Petrie SR, Hayes AJ, Kupfer DJ. (1994): Regularity of daily life in relation to personality, 
age, gender, sleep quality and circadian rhythms. J Sleep Res 3: 196-205.
29. Monk TH, Flaherty JF, Frank E, Hoskinson K, Kupfer DJ. (1990): The Social Rhythm Metric. An 
instrument to quantify the daily rhythms of life. J Nerv Ment Dis 178: 120-126.
30. Margraf J, Lavallee K, Zhang X, Schneider S. (2016): Social rhythm and mental health: a cross-
cultural comparison. PloS one 11: e0150312.
31. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. (1989): The Pittsburgh Sleep 
Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 28: 193-
213.
32. Young RC, Biggs JT, Ziegler VE, Meyer DA. (1978): A rating scale for mania: reliability, validity and 
sensitivity. Br J Psychiatry 133: 429-435.
33. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. (2011): The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite 
studies with adolescents and adults. Am J Psychiatry 168: 1266-1277.
34. Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, et al. (2008): Columbia-suicide severity 
rating scale (C-SSRS). New York, NY: Columbia University Medical Center.
35. Altman E, Hedeker D, Peterson JL, Davis JM. (2001): A comparative evaluation of three self-rating 
scales for acute mania. Biol Psychiatry 50: 468-471.
36. Altman EG, Hedeker D, Peterson JL, Davis JM. (1997): The Altman Self-Rating Mania Scale. Biol 
Psychiatry 42: 948-955.
37. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. (2003): The 16-Item Quick 
Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-
SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry 54: 573-
583.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
30
38. Bernstein IH, Rush AJ, Suppes T, Trivedi MH, Woo A, Kyutoku Y, et al. (2009): A psychometric 
evaluation of the clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C16) in 
patients with bipolar disorder. Int J Methods Psychiatr Res 18: 138-146.
39. Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, et al. (2004): The Inventory of 
Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick 
Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in 
public sector patients with mood disorders: a psychometric evaluation. Psychol Med 34: 73-82.
40. Oldfield RC. (1971): The assessment and analysis of handedness: the Edinburgh inventory. 
Neuropsychologia 9: 97-113.
41. Ransil BJ, Schachter SC. (1994): Test-retest reliability of the Edinburgh Handedness Inventory and 
Global Handedness preference measurements, and their correlation. Percept Mot Skills 79: 
1355-1372.
42. Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, et al. (2003): Development and 
validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl 
27: 169-190.
43. Scher CD, Stein MB, Asmundson GJ, McCreary DR, Forde DR. (2001): The childhood trauma 
questionnaire in a community sample: psychometric properties and normative data. J Trauma 
Stress 14: 843-857.
44. Petersen A, Crockett L, Richards M, Boxer A. (1988): A self-report measure of pubertal status: 
Reliability, validity, and initial norms. J of Youth and Adolescence 17: 117-133.
45. Haas A, Eliason M, Mays V, Mathy R, Cochran S. (2011): D” Augelli AR, Clayton PJ. Suicide and suicide 
risk in lesbian, gay, bisexual, and transgender populations: Review and recommendations. 
Journal of Homosexuality 58: 10-51.
47. Patton JH, Stanford MS, Barratt ES. (1995): Factor structure of the Barratt impulsiveness scale. J Clin 
Psychol 51: 768-774.
48. Beck AT, Steer R, Beck Hopelessness Scale, San Antonio, TX, The Psychological Corporation, 1988.
49. Schwartz KTG, Bowling AA, Dickerson JF, Lynch FL, Brent DA, Porta G, et al. (2018): The Child and 
Adolescent Services Assessment: Interrater Reliability and Predictors of Rater Disagreement. 
Adm Policy Ment Health 45: 944-957.
50. Gratz K, Roemer L. (2003): Multidimensional assessment of emotion regulation and dysregulation: 
development, factor structure, and initial validation of the difficulties in emotion regulation 
scale. J Psychopatholoy Behav Assessment 26: 41-54.
51. Neumann A, van Lier PA, Gratz KL, Koot HM. (2010): Multidimensional assessment of emotion 
regulation difficulties in adolescents using the Difficulties in Emotion Regulation Scale. 
Assessment 17: 138-149.
52. Nock MK, Wedig MM, Holmberg EB, Hooley JM. (2008): The emotion reactivity scale: development, 
evaluation, and relation to self-injurious thoughts and behaviors. Behav Ther 39: 107-116.
53. Shahid A, Wilkinson K, Marcu S, Shapiro CM (2011): Munich Chronotype Questionnaire (MCTQ).  
STOP, THAT and One Hundred Other Sleep Scales: Springer, pp 245-247.
54. Peipert JD, Badawy SM, Baik SH, Oswald LB, Efficace F, Garcia SF, et al. (2020): Development of the 
NIH Patient-Reported Outcomes Measurement Information System (PROMIS) Medication 
Adherence Scale (PMAS). Patient Preference and Adherence 14: 971-983
55. Attkisson CC, Zwick R. (1982): The Client Satisfaction Questionnaire: Psychometric properties and 
correlations with service utilization and psychotherapy outcome. Evaluation and program 
planning 5: 233-237.
56. Shapiro JP, Welker CJ, Jacobson BJ. (1997): The Youth Client Satisfaction Questionnaire: development, 
construct validation, and factor structure. J Clin Child Psychol 26: 87-98.
57. Hollingshead AB, Four factor index of social status. New Haven: Yale University, 1975.
58. Psychological-Corporation, Wechsler Abbreviated Scale of Intelligence Manual, San Antonio, TX, 
Harcourt Brace & Company, 1999.
59. Lish JD, Weissman MM, Adams PB, Hoven CW, Bird H. (1995): Family psychiatric screening 
instruments for epidemiologic studies: pilot testing and validation. Psychiatry Res 57: 169-180.
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024

APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024
Protocol Number 2000032361
8/7/24 Version 9
31
60. First MB, Spitzer RL, Gibbon M, Williams JBW, Structured Clinical Interview for DSM-5 Axis I & 
Personality Disorders New York, New York State Psychiatric Institute, 2015.
61. First MB, Standardized evaluation in clinical practice, 1st ed, Washington, DC, American Psychiatric 
Pub., 2003.
62. Williams JBW, Link MJ, Rosenthal NE, Terman M, Structured interview guide for the Hamilton 
depression rating scale: seasonal affective disorder version (SIGH-SAD), New York, NY, New York 
State Psychiatric Institute, 1994.
63. Hamilton M. (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56-62.
64. Beck AT, Beck R, Kovacs M. (1975): Classification of suicidal behaviors: I. Quantifying intent and 
medical lethality. Am J Psychiatry 132: 285-287.
65. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al. (1997): Schedule for Affective 
Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS-PL): 
Initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36: 980-988.
66. First MB, Spitzer RL, Gibbon M, Williams JBW, Structured Clinical Interview for DSM-5 Axis I & 
Personality Disorders New York, New York State Psychiatric Institute, 2015.
67. Merikangas KR, Zhang J, Emsellem H, Swanson SA, Vgontzas A, Belouad F, et al. (2014): The structured 
diagnostic interview for sleep patterns and disorders: rationale and initial evaluation. Sleep Med 
15: 530-535.
. 
APPROVED BY THE YALE UNIVERSITY IRB 9/24/2024