Social Reward and Its Effect on Brain Functions in Psychotherapies for Mid- and Late-Life Depression
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Weill Medical College of Cornell University

STUDY TITLE: Social Reward and Its Effect on Brain Functions in Psychotherapies for Mid- 
and Late-Life Depression 
NCT04487730 
DOCUMENT DATE: May 21, 2024 

 
 
  
Page # i 
 
  
TITLE: Social Reward and its Effect on Brain Functions in Psychotherapies for Mid- and Late-Life 
Depression   
 
IRB Protocol #: 20-04021860 
IND/IDE #: (if applicable) 
Version Date:  5/21/2024 
Funding Source(s): NIMH 
 
Principal Investigator: 
 
Name: Nili Solomonov, PhD   
Address: 525 E 68th Street, Baker Building 
Telephone: 844 999 8746 ext. 718 
Email: Nis2051@med.cornell.edu  
 
 
Statistician: N/A 
 
Medical Monitor: N/A 
 
 
Participating Sites:  List all participating sites (include site name, PI, and contact information).  
 
Site Name: Weill Cornell Medicine 
PI: Nili Solomonov, PhD  
 
Address: 525 E 68th Street, Baker Building 
Telephone: 844 999 8746 ext. 718 
Email: Nis2051@med.cornell.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol # 20-04021860 
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Table of Contents 
CONFIDENTIALITY STATEMENT ..................................................................................... V 
LIST OF ABBREVIATIONS .............................................................................................. VII 
1. PROTOCOL SUMMARY ................................................................................................. 1 
1.1 
Schema ..................................................................................................................... 2 
1.2 
Study Objectives and End Points ......................................................................... 3 
1.2.1  Primary Objectives ........................................................................................... 3 
1.2.2  Secondary Objectives ..................................................................................... 3 
1.2.3  Exploratory Objectives .................................................................................... 3 
1.2.4 
Primary Endpoints ........................................................................................... 4 
1.2.5 
Secondary Endpoints ...................................................................................... 4 
2. BACKGROUND ................................................................................................................ 4 
2.1 
Disease ..................................................................................................................... 4 
2.2 
Investigational Agent/Device, or Surgical Treatment/Method ......................... 4 
2.3 
Rationale ................................................................................................................... 4 
2.4 
 Risk/Benefit Assessment ...................................................................................... 5 
2.4.1 
Known Potential Risks .................................................................................... 5 
2.4.2 
Known Potential Benefits ............................................................................... 5 
2.4.3 
Assessment of Potential Risks and Benefits ............................................... 5 
2.5 
Correlative Studies Background .......................................................................... 6 
3. STUDY DESIGN ............................................................................................................... 6 
3.1 
Overall Design ......................................................................................................... 6 
3.2 
Scientific Rationale for Study Design .................................................................. 6 
3.3 
Justification for Dose ............................................................................................. 7 
3.4 
End of Study Definition .......................................................................................... 7 
4. SUBJECT SELECTION ................................................................................................... 7 
4.1 
Study Population ..................................................................................................... 7 
4.2 
Inclusion Criteria ..................................................................................................... 7 
4.3 
Exclusion Criteria .................................................................................................... 8 
4.4 
Lifestyle Considerations ........................................................................................ 8 
4.5 
Screen Failures ........................................................................................................ 8 
4.6 
Strategies for Recruitment and Retention .......................................................... 8 
5. REGISTRATION PROCEDURES ................................................................................. 10 
5.1 
Subject Registration (WCM only) ....................................................................... 10 
5.2 Subject Registration (Sub-sites) ............................................................................ 10 
6. STUDY PROCEDURES ................................................................................................. 10 
6.1 
Schedule of Assessments ................................................................................... 10 

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6.1.1 
Screening Visit (-X days before start of treatment) .................................. 13 
6.1.2 
Treatment Phase ............................................................................................ 13 
6.1.2.1 
Visit 1 (baseline; Cycle 1 Day 1) ............................................................... 14 
6.1.2.2 
Visit 2 (± X day(s)) ....................................................................................... 14 
6.1.3 
Follow-up Phase ............................................................................................. 14 
7. STUDY INTERVENTION ............................................................................................... 14 
7.1 
Study Intervention/Device Description .............................................................. 14 
7.2 
Availability .............................................................................................................. 15 
7.3 
Acquisition and Accountability ........................................................................... 15 
7.4 
Formulation, Appearance, Packaging, and Labeling ...................................... 15 
7.5 
Product Storage and Stability ............................................................................. 15 
7.6 
Preparation ............................................................................................................. 15 
7.7 
Dosing and Administration .................................................................................. 16 
7.7.1 
Dosing Delays/Dose Modifications ............................................................. 16 
7.8 
General Concomitant Medication and Supportive Care Guidelines ............. 16 
7.9 
Duration of Therapy and Criteria for Removal from Study ............................. 16 
7.10  Duration of Follow Up ........................................................................................... 16 
7.11 Measures to Minimize Bias: Randomization and Blinding ............................... 16 
7.12 Study Intervention/Follow-up Compliance ......................................................... 16 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................... 17 
8.1 
Discontinuation of Study Intervention ............................................................... 17 
8.2 
Participant Discontinuation/Withdrawal from the Study ................................ 18 
8.3 
Lost to Follow Up .................................................................................................. 18 
9. CORRELATIVE/SPECIAL STUDIES ............................................................................ 18 
9.1 
Laboratory Correlative Studies ........................................................................... 18 
9.1.1 
Title – Laboratory Correlative Study #1 ...................................................... 18 
9.1.1.1 
Collection of Specimen(s) ......................................................................... 18 
9.1.1.2 
Handling of Specimen(s) ........................................................................... 18 
9.1.1.3 
Shipping of Specimen(s) (if multicenter) ................................................ 18 
9.1.1.4 
Site(s) Performing Correlative Study (if multicenter) ............................ 18 
9.2 
Special Studies ...................................................................................................... 18 
9.2.1 
Title – Special Correlative Study #1 ............................................................ 18 
9.2.1.1 
Assessment ................................................................................................. 18 
9.2.1.2 
Method of Assessment .............................................................................. 18 
9.2.1.3 
Timing of Assessment ............................................................................... 18 
10.  MEASUREMENT OF EFFECT ................................................................................... 18 
10.1 Response Criteria ................................................................................................... 19 
10.2 Duration of Response ............................................................................................ 19 
10.3 Progression-Free Survival .................................................................................... 19 

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10.4 Other Response Parameters ................................................................................. 19 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ..................................... 19 
11.1 Data Collection ........................................................................................................ 19 
11.1.1 REDCap ............................................................................................................. 19 
11.2 Regulatory Considerations ................................................................................... 19 
11.2.1 Institutional Review Board/Ethics Committee Approval ........................... 19 
11.2.2 Ethical Conduct of the Study ......................................................................... 20 
11.2.3 Informed Consent ............................................................................................ 20 
11.2.4 Compliance with Trial Registration and Results Posting Requirements 21 
11.2.5 Record Retention ............................................................................................. 21 
12. STATISTICAL CONSIDERATIONS ............................................................................ 21 
12.1 Study Design/Endpoints ........................................................................................ 22 
12.2 Sample Size/Accrual Rate ..................................................................................... 23 
12.3 Stratification Factors .............................................................................................. 23 
12.4 Analysis of Endpoints ............................................................................................ 23 
12.4.1 
Analysis of Primary Endpoints ................................................................. 23 
12.4.2 
Analysis of Secondary Endpoints ............................................................ 23 
12.5 Interim Analysis ...................................................................................................... 24 
12.6 Reporting and Exclusions ..................................................................................... 24 
12.6.1 
Evaluation of Toxicity ................................................................................ 24 
12.6.2 
Evaluation of Response ............................................................................. 24 
13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................. 24 
13.1 Adverse Event Definition ....................................................................................... 24 
13.1.1 
Investigational Agent or Device Risks (Expected Adverse Events) ... 25 
13.1.2 
Adverse Event Characteristics and Related Attributions ..................... 25 
13.1.3 
Recording of Adverse Events ................................................................... 25 
13.1.4 
Reporting of AE to WCM IRB .................................................................... 26 
13.1.5 
Reporting Events to Participants ............................................................. 26 
13.1.6 
Events of Special Interest .......................................................................... 26 
13.1.7 
Reporting of Pregnancy ............................................................................. 26 
13.2 Definition of SAE ..................................................................................................... 27 
13.2.1 
Reporting of SAE to IRB ............................................................................ 27 
13.2.2 
Reporting of SAE to FDA [For Protocols Where WCMC is the 
Sponsor-Investigator] ................................................................................................. 27 
13.2.3 
Reporting of SAE to <Insert Pharmaceutical Company Name> .......... 27 
13.3 AE/SAE Follow Up .................................................................................................. 27 
13.4 Time Period and Frequency for Event Assessment and Follow Up ............... 27 
14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS28 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO) ........................................................................................................................ 28 

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14.1.2 
Unanticipated Problem Reporting ............................................................ 29 
15. DATA AND SAFETY MONITORING PLAN (DSMP) ................................................. 29 
16. REFERENCES ............................................................................................................. 31 
APPENDIX A ...................................................................................................................... 34 
 
Statement of Compliance 
 
 
(1) [The trial will be carried out in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the Institutional Review Board (IRB) for review and approval.  
Approval of both the protocol and the consent form must be obtained before any 
participant is enrolled.  Any amendment to the protocol will require review and approval by 
the IRB before the changes are implemented to the study.  In addition, all changes to the 
consent form will be IRB-approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent, using a previously 
approved consent form.] 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM, unless disclosure on ClinicalTrials.gov is federally required. 
 
For multi-site IIT only. Remove signature lines if single site study. 
 
 
 
Weill Cornell Medicine 
_________________________________________________________________ 
Institution Name 
 
 
 
 

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______Nili Solomonov, PhD_______       ______
__________4/14/2020_______      
Principal Investigator’s Name                 Principal Investigator’s Signature     Date 
 
 
 

Protocol # 20-04021860 
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Page # vii 
 
List of Abbreviations 
 
All abbreviations used throughout the protocol must be defined. Add additional abbreviations 
specific to protocol.  
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSC 
Clinical Translational Science Center  
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
WCM 
Weill Cornell Medicine 

Protocol #  
Version Date 
 
  
Page # 1 
 
1. Protocol Summary 
 
Full Title:  
 
 
 
Social Reward Psychotherapy and its Effect on Brain Functions in 
Mid- and Late-Life Depression 
Short Title: 
 
 
 
Social Reward in Late-life Depression  
Clinical Phase: 
 
 
I, II, III, or IV 
Principal Investigator:  
Nili Solomonov, PhD  
Study Description:   
Major depression in mid- and late-life is characterized with 
abnormalities in the Positive Valence System (PVS). Exposure to 
rewarding experiences can target these abnormalities and in turn, 
reduce depression severity. Given the high prevalence of 
loneliness and social isolation in late life, socially rewarding 
interactions are especially important. Engagement in social 
interactions with significant others during reward-based 
psychotherapy reduces depression and increases behavioral 
activation. The aim of the study is to examine if exposure to 
meaningful social rewards during psychotherapy, engages PVS 
circuitry and improves mid- and late-life major depression. The 
"reward exposure" of this study will consist of meaningful social 
activities with significant others ("Engage & Connect"). The study 
will be a pilot RCT that will compare 9-week "Engage & Connect" 
vs. a Symptom Review and Psychoeducation condition (SRP) for 
adults older than 50 years with major depression. We will 
investigate changes in resting-state functional connectivity, social 
reward processing during an fMRI-based social reward task, and 
changes in behavioral outcomes over the course of treatment.  
 
Sample Size: 
 
N= 60 
Enrollment: 
 
This study will enroll 60 subjects and screen up to 90 subjects.   
Study Population: 
 
Individuals aged 50-85 with major depression  
Enrollment Period:  
The study will recruit participants over 5 years   
Study Design: 
 
This is a randomized controlled trial comparing two psychosocial 
interventions. We will assess target engagement of the PVS 
through functional connectivity at rest (rsFC), a self-report 
measure of behavioral activation (BADS), and performance on a 
novel fMRI social reward paradigm, during two psychotherapies 
for middle-aged and older adults with major depression, i.e., 
“Engage & Connect” therapy (n = 30) and a comparison condition 
of Symptom Review and Psychoeducation (SRP; n = 30). 
Participants will receive nine weekly therapy sessions. We will 
administer research assessments at baseline, Weeks 3, 5, and 9 
and MRI scans at baseline, Week 5 and 9. All participants will 
provide informed consent prior to enrolling in the study. 
Description of Sites/  
Facilities Enrolling 

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Participants: 
 
Participating sites will be the Weill Cornell Medicine Psychiatry 
Department in Manhattan and the Weill Cornell Institute of 
Geriatric Psychiatry in Westchester. 
Study Duration: 
 
July 31, 2027 
Participant Duration: 
Participation duration is estimated for approximately 9 weeks, 
which is the duration of the psychosocial intervention provided. 
Study enrollment is expected to last 5 years; we propose an 
additional 2 years for data analysis and manuscript preparation. 
The projected end date of this study is July 31, 2027. 
Study Agent/Device Name  
Intervention Description: 
Participants will be randomized to one of two psychosocial 
interventions, each consisting of 9 weekly sessions: 1) “Engage & 
Connect” – a reward-based psychotherapy aimed to increase 
engagement in rewarding social activities; 2) Symptom Review 
and Psychoeducation (SRP) aimed to track patients’ depressive 
symptoms and provide education regarding depression.  
Primary Objective: 
The principal aim of this pilot study is to examine if exposure to 
meaningful social rewards during psychotherapy engages reward 
circuitry and improves mid- and late-life major depression. We will 
test whether “Engage & Connect” leads to: 1) increase in resting 
state functional connectivity of the Positive Valence System (PVS)  
 
Secondary Objectives: 
We will test whether “Engage & Connect” leads to: 2) increase in 
behavioral activation (BADS scale); 3) reduction in depression 
severity (MADRS scale)  
 
Exploratory Objectives: Evaluate whether in “Engage & Connect” treated participants, 
change in rsFC of the PVS and behavioral activation (BADS) 
predicts subsequent reduction in depression severity (MADRS). 
Investigate changes in social reward processing over the 
course of psychotherapy using a novel Social Incentive 
Delay (SID) fMRI task  
 
Primary Endpoints: 
Change in resting state functional connectivity of the PVS over 9 
weeks;  
 
Secondary Endpoints: 
Change in BADS scores and MADRS scores over 9 weeks 
   
 
1.1 Schema 
 
The time point(s) indicated in the schematic should correspond to the time point(s) in 
Section 6.1, Schedule of Assessments, e.g., Visit 1; Visit 2; etc.    
 

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Note. 60 patients will be randomly assigned to 9-weeks of either “Engage & Connect” (N=30) or 
“SRP” (N=30); BADS = Behavioral Activation for Depression scale; MADRS = Montgomery-
Asberg Depression Rating Scale; rsFC = resting state functional connectivity; PHQ9 = Patient 
Health Questionnaire; SID Task = Social Incentive Delay Task 
 
1.2 
Study Objectives and End Points 
 
 
1.2.1  Primary Objectives  
 
Examine if exposure to meaningful social rewards during psychotherapy, engages 
reward circuitry and improves mid- and late-life major depression. The “reward 
exposure” of this study will consist of meaningful social activities with significant 
others (“Engage & Connect”). We will test whether “Engage & Connect” leads to 
change in resting state of the PVS over 9 weeks. The study will be a pilot RCT that 
will compare 9-week “Engage & Connect” vs. a Symptom Review and 
Psychoeducation condition (SRP) for adults 50-85 years old with major depression 
 
1.2.2  Secondary Objectives  
 
We will test whether “Engage & Connect” leads to: 2) increase in behavioral activation (BADS 
scale); 3) reduction in depression severity (MADRS scale).  
1.2.3  Exploratory Objectives 
 
 
 
Evaluate whether in “Engage & Connect” treated participants, change in rsFC of the 
PVS and behavioral activation (BADS) predicts subsequent reduction in depression 
severity (MADRS). 
 
Investigate changes in social reward processing over the course of psychotherapy 
using a novel Social Incentive Delay (SID) fMRI task 
 
 

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1.2.4 Primary Endpoints 
 
Change in resting state functional connectivity of the PVS over 9 weeks. 
 
1.2.5 Secondary Endpoints 
 
Change in BADS scores and MADRS scores over 9 weeks. 
 
2. Background 
 
2.1 Disease 
 
Depression in late life is common1 and associated with suffering, reduced quality of life,2 increased 
risk of cognitive dysfunction,3 dementia,4 disability, cardiac, cerebrovascular, peripheral diseases,5 
suicidality, all-cause mortality,6,7 and economic burden.8 
 
2.2 Investigational Agent/Device, or Surgical Treatment/Method 
 
 
Antidepressants have modest efficacy in late-life depression.9,10 The public health impact of 
antidepressants is attenuated by poor adherence, inadequate dosages and duration, and 
infrequent follow up of older patients, most of whom are treated in primary care practices.11,12 
Psychotherapies are efficacious in late-life major depression13–15 and well-liked by older adults.16,17 
However, too few community therapists are able to offer evidence based psychotherapies, mainly 
because of their complexity.18–21 Therefore, there is a need for streamlined efficacious 
psychotherapies that can match the skill set of community therapists.   
 
 
 
Our group developed “Engage”, a streamlined, stepped psychotherapy for mid- late-life 
depression, whose principal intervention is “reward exposure”.22 In patients with negativity bias, 
apathy, or inadequate emotional regulation interfering with “reward exposure”, “Engage” offers 
additional interventions so that “reward exposure” proceeds unimpeded. “Engage” is based on the 
view that dysfunction of Positive Valence Systems (PVS) perpetuates late-life depression.22 
“Engage” reduces late-life depression and disability.23,24 Early increase in resting state 
functional connectivity (rsFC) in PVS structures during “Engage” predicts increase in behavioral 
activation.25 Change in behavioral activation is followed by reduction of depressive symptoms.26 In 
order to further streamline “Engage” and guide its personalization, we examined whether specific 
types of “reward exposure” have higher therapeutic value. Activities involving social interactions 
with significant others (but not solitary activities) predicted subsequent increase in behavioral 
activation and reduction of depression.27 We have also documented that high perceived social 
support predicts early response to psychotherapy.28 Exposure of socially isolated older adults to 
social rewards during “Engage” led to greater reductions of depression than a ‘care as usual’ 
condition.29 The above findings underscore the therapeutic role of rewarding social interactions 
with significant others. Based on this work, we developed “Engage & Connect”, a streamlined 
version of “Engage”, whose principal intervention is exposure to meaningful, rewarding social 
activities with significant others. “Engage & Connect” aims to recondition PVS functions, increase 
behavioral activation, and lead to reduction of symptoms of depression.  
 
2.3 Rationale 
The proposed study will be the first study to test target engagement of “Engage & Connect”, 
a social reward-focused intervention for mid- and late-life depression. “Engage & Connect” 
is innovative because: 1) It is directly informed by neurobiological research and designed to 
address dysfunction of PVS, a core component of depression; 2) It is based on data 

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Page # 5 
 
demonstrating that exposure to social rewards has the highest probability to improve 
depressive symptoms; 3) It is streamlined so that it can potentially be used by community 
clinicians. The NIMH Strategies 3.1; 3.2 encourage the development of novel streamlined 
treatments informed by advances in neuroscience. 
To our knowledge, the proposed study will be the first to examine neural processing of 
social rewards in mid- and late-life depression. It is based on computational modeling, which 
identified perceived social support as the strongest predictor of early response to 
psychotherapy and examines whether PVS changes by mid-treatment predict response of 
depression to “Engage & Connect”. Along with other PVS function measures, it uses a novel 
social reward fMRI paradigm to examine PVS change and its relationship to “Engage & 
Connect” response. Behavioral tasks and clinical scales across multiple units of analysis are 
quick, cost-effective, and easy to administer, making them feasible to use in future large-
scale studies and as screening tools in clinical settings. 
  
 
2.4  Risk/Benefit Assessment  
 
 
2.4.1 Known Potential Risks 
 
Participants and family/caregivers participating in this study may be exposed to the 
following risks: 
1. The burden of responding to standardized assessments. 
2. The distress associated with discussing personal concerns with research personnel. 
3. The discomfort of an MRI scan (approximately 60 minutes per session). 
4. Worsening of patients’ depression. 
5. Skin irritation from the optional study wearable device (smartwatch). 
6. Suicide risk. 
 
2.4.2 Known Potential Benefits  
 
Enrolled participants will accrue the following benefits at no cost: 
1. A structured evaluation of psychopathology and an assessment of functional limitations 
for which interventions are needed. 
2. Nine weekly sessions of psychotherapy intervention aimed to reduce depression 
severity. 
3. Ongoing monitoring of clinical status and appropriate referral for clinical care in the event 
of deterioration. 
Additionally, some participants find research participation to be a meaningful experience. 
 
 
2.4.3 Assessment of Potential Risks and Benefits 
 
The risks for study participants are minimal. We anticipate that a portion of the 
participants will benefit from the psychotherapies delivered in our study and experience 
improvement in depression severity. Additionally, the potential knowledge to be gained 
in this study and its clinical implications are substantial. The study could provide 
evidence for a novel streamlined social reward-based psychotherapy which targets 

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network abnormalities central in mid- and late-life major depression and could potentially 
benefit patients with mid- or late-life depression in the future.  
 
 
2.5 Correlative Studies Background 
 
NA 
 
 
3. Study Design 
 
3.1 Overall Design 
The aim of the proposed study is to examine whether exposure to socially rewarding 
activities in a reward-based psychotherapy (“Engage & Connect”) leads to changes in 
Positive Valence Systems (PVS) in middle-aged and older adults with major depression. We 
will assess target engagement of the PVS through functional connectivity at rest (rsFC), a 
self-report measure of behavioral activation (BADS), and performance on a novel fMRI 
social reward paradigm, during two psychotherapies for middle-aged and older adults with 
major depression, i.e. “Engage & Connect” therapy (n = 30) and a comparison condition of 
Symptom Review and Psychoeducation (SRP; n = 30). Participants will be randomized to 
nine weekly therapy sessions. Participants may be asked to use a wearable device during 
their participation in the study. The device allows for passive sensing of movement (steps), 
heart rate,and sleep daily. Participants and therapists may be able to review their activity for 
the week to augment the sessions. We will administer research assessments at baseline, 
Weeks 3, 5, and 9 and MRI scans at baseline, Week 5 and 9. All participants will provide 
informed consent prior to enrolling in the study. All participants will be recruited at Weill 
Cornell Medicine. 
The “reward exposure” of this study will consist of meaningful social activities with significant 
others (“Engage & Connect”). The study will be a pilot RCT that will compare 9-week 
“Engage & Connect” vs. a Symptom Review and Psychoeducation condition (SRP) for 
adults older than 50 years with major depression and test the following hypotheses:  
 
During the 9 week course of “Engage & Connect” treatment there will be an:  
H1. Increase in rsFC of the PVS. 
H2. Increase in behavioral activation (BADS scale) 
H3. Reduction in depression severity (MADRS scale).  
SH. In “Engage & Connect” treated participants, change in: SH1a) rsFC of the PVS and SH1b) 
behavioral activation (BADS) will predict subsequent reduction in depression severity (MADRS). 
These relationships will not be observed in the SRP treated group. The rationale of this hypotheses 
is based on the theory that the “Engage & Connect” mechanism of action is reconditioning the PVS, 
while SRP relies on non-specific mechanisms of action. 
 
3.2 Scientific Rationale for Study Design 
The proposed study will be the first study to test target engagement of “Engage & 
Connect”, a social reward-focused intervention for mid- and late-life depression. “Engage 
& Connect” is innovative because: 1) It is directly informed by neurobiological research 
and designed to address dysfunction of PVS, a core component of depression; 2) It is 
based on data demonstrating that exposure to social rewards has the highest probability 

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Page # 7 
 
to improve depressive symptoms; 3) It is streamlined so that it can potentially be used by 
community clinicians. The NIMH Strategies 3.1; 3.2 encourage the development of novel 
streamlined treatments informed by advances in neuroscience. 
To our knowledge, the proposed study will be the first to examine neural processing of 
social rewards in mid- and late-life depression. It is based on computational modeling, 
which identified perceived social support as the strongest predictor of early response to 
psychotherapy, and examines whether PVS changes by mid-treatment predict response 
of depression to “Engage & Connect”. Along with other PVS function measures, it uses a 
novel social reward fMRI paradigm to examine PVS change and its relationship to 
“Engage & Connect” response. Behavioral tasks and clinical scales across multiple units 
of analysis, are quick, cost-effective, and easy to administer, making them feasible to 
use in future large-scale studies and as screening tools in clinical settings. 
3.3 Justification for Dose  
Selection of 9 weeks of treatment as “dosage” is based on our previous published work 
showing that this length of treatment in similar “Engage” psychotherapy studies reduces 
depressed older adults depression severity and increases their behavioral 
activation.23,26,27  
 
3.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all 
phases of the study including the last visit or the last scheduled procedure shown in the 
Schedule of Assessments (SoA), Section 6.1. The end of the study is defined as 
completion of the last visit or procedure shown in the SoA in the trial. 
 
4. Subject Selection 
 
4.1 Study Population 
 
We will recruit 60 non-demented middle-aged and older adults (aged 50-85; stratified so that 
50% are older than 65) with Major Depressive Disorder (MDD) without psychotic features, 
determined by the Structured Clinical Interview for DSM-5 (SCID). Based on previous 
studies we expect a 1.6:1 female: male ratio, reflecting higher rates of major depression 
among women. We expect an attrition rate of ~10%, comparable to previous “Engage” 
psychotherapy trials conducted at the Weill Cornell Institute of Geriatric Psychiatry. Included 
participants will not receive other psychotherapeutic or pharmacological treatments and will 
either be off antidepressants or will be on a stable dose of antidepressants for ≥ 8 weeks at 
study entry. We will exclude participants with intent or plan to attempt suicide in the near 
future, as well as those diagnosed with antisocial or borderline personality disorder (DSM-
V); dementia [Mini Mental Status Exam (MMSE) ≥ 1 SD below the mean score for patient’s 
age and education, or DSM-5 criteria]; delirium, severe or acute medical illness, i.e. 
metastatic cancer, decompensated organ failure, major surgery, recent stroke, or myocardial 
infarction. 
 
4.2 Inclusion Criteria 
 
1. Ages aged 50-85 [stratified so that 50% are older than 65] 
2. Diagnosis of unipolar major depressive disorder without psychotic features, determined 
by the SCID 
3. Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 20. 

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4. Mini Mental Status Exam (MMSE) ≤ 1 SD below the mean score for patient’s age and 
education  
5. Off antidepressants or on a stable dose of an antidepressant for 8 weeks and do not 
intend to change the dose in the next 10 weeks. 
6. Capacity to provide consent for research assessment and treatment. 
 
4.3 Exclusion Criteria  
 
 
 
1. Intent or plan to attempt suicide in the near future. 
2. History or presence of psychiatric diagnoses other than major depressive disorder 
without psychotic features, generalized anxiety disorder, persistent depressive disorder, 
or specific phobia. 
3. Use of psychotropic drugs or cholinesterase inhibitors other than use of ≤ 0.5 mg of 
lorazepam daily up to seven times per week. 
4. Neurological disorders (dementias, history of stroke, multiple sclerosis, Parkinson’s 
disease, epilepsy, etc.); cardiac, renal, or respiratory failure; severe chronic obstructive 
pulmonary disease; metastatic cancer; or debilitated states or less common medical 
illnesses that may either influence brain systems of interest or ability to participate in the 
study. A senior clinician at the institute will review any medical illnesses that does not 
appear in the list above and determine whether it interferes with the study of positive 
valence system functions in depression. 
5. Contraindications to MRI scanning including cardiac pacemaker, heart valve 
replacement, vascular stent, insulin pump, cochlear implant, any other metallic 
biomedical implant contraindicating to MRI, and claustrophobia. 
 
4.4 Lifestyle Considerations 
 
 
Not Applicable 
  
4.5 Screen Failures  
 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently randomly assigned to the study intervention or entered in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
of low depression severity or exclusion criteria related to recent change in medication may 
be rescreened. Rescreened participants should be assigned the same participant number 
as for the initial screening. 
 
4.6 Strategies for Recruitment and Retention 
 
 
Participants will be recruited from the outpatient clinic of the Weill Cornell Institute of Geriatric 
Psychiatry, community-based mental health services, community-based medical practices, and 
other community organizations. 

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Page # 9 
 
 
Additionally, participants may be recruited through the Epic MyChart subject pool, protocol 
#18120119822 ("Collecting Patient Consent to be Contacted for Research"). Patients in this subject 
pool have given consent to be contacted about research studies based on the information in their 
electronic medical record.  
We will also recruit participants through social media ads on Facebook and Instagram. We have 
used a similar approach in two active protocols #1802019007 and #1708018441. Participants who 
press on our social media ad will be presented with a brief Qualtrics survey, managed in 
collaboration with JCTO specialist, Megan Kavy, where participants can fill in their information and 
contact details if they choose to be contacted by a research assistant to discuss voluntary 
participation. Participants will also receive a link to the JCTO page of the study, as previously noted. 
Qualtrics is used via Weill Cornell’s approved resources. The PI will monitor responses to the 
survey. 
 
Eligible individuals will be invited to participate in the study after providing informed consent. 
Individuals who do not meet criteria may be offered participation for other research studies or given 
referrals for treatment in the community if desired.   
 
Recruitment of WCM clinicians:  
 
We will recruit four Masters-level therapists from those working on other psychotherapy projects at 
the Weill Cornell ALACRITY Center. Therapists will be certified to provide "Engage & Connect" or 
SRP and will be unaware of study hypotheses. Training will follow the Institute’s training procedures 
and fidelity standards. Our previous work has shown that therapists with this level of training and 
clinical experience can be trained in “Engage” and maintain high fidelity.30 Training procedures are 
described below. Therapists and research assistants administering clinical rating will remain 
unaware of study hypotheses. Therapists will be responsible for completing the Patient Health 
Questionnaire (PHQ-9) at the beginning of each session to monitor patients’ clinical states. At the 
end of each session, they will complete the “Working Alliance Inventory-12” (WAI-12) to evaluate 
the quality of the working relationship at each session. Additionally, they will complete the MULTI at 
Baseline, Week 3, 5 and 9 to evaluate their use of therapeutic techniques.   
 
All therapists are service providers on this protocol and are employed by Weill Cornell Medicine’s 
Geriatric Psychiatry Institute or participate in activities at the Geriatric Institute either full-time, part-
time, or on a contract basis. Thus, they are all paid for their time regardless of whether they 
participate in this research study or not. Therapist service providers are given the option to 
participate in this or any other research study that aligns with their interests, skills, schedule, and 
the clinical training it provides. If they are not interested, they are welcome to continue working on 
other services and research projects at the Institute. Therapists’ involvement is voluntary and in 
addition to their primary duties at the Weill Cornell ALACRITY Center. We are seeking informed 
consent from the therapists to collect basic data related to their training background (e.g., training 
history, years of experience, theoretical orientation), completion of research assessments, and use 
of study interventions. Their participation will be voluntary, and their information will be kept 
confidential. Information regarding the therapists' performance in the study will not be shared with 
employers outside of the study. Of particular importance is the need to ensure that the therapist 
understand that their decision to participate (or to withdraw participation as therapists on the study) 
will have no job ramifications.  
 
WCM clinicians working on other similar psychotherapy trials will be offered the opportunity to 

Protocol # 20-04021860 
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Page # 10 
 
participate in the study as therapists. They can choose not to participate without any negative 
consequences to their employment or benefits. Clinicians' direct supervisor will not be involved in 
the study activities and thus the main supervisory relationship will not be affected by study 
participation. Participating therapists are not the subjects of the research intervention per se, and 
we will not collect medical or psychiatric information about them. We consent the providers because 
they are administering clinical scales to monitor patients’ progress during the study period when 
they are delivering the study interventions (e.g. depression symptoms, suicide risk). 
 
 
Patients participating in this study will be compensated approximately $345 for completion of the 
study. This amount is equivalent to similar ongoing studies in our department:  
 
- 
$30 for each research assessment ($120 total) 
- 
$75 for each MRI assessment ($225 total) 
- 
 
Participants could be reimbursed for travel to and from study visits if needed. 
 
5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure 
for Subject Registration. Data will be tracked on RedCap. Clinical notes by clinicians will 
be tracked in Epic.  
 
 
 
5.2 Subject Registration (Sub-sites) 
 
For multicenter studies with a WCM as the coordinating site, please contact 
JCTOIIT@med.cornell.edu for template language for participate site registrations 
 
 
6. Study Procedures 
 
6.1 Schedule of Assessments 
 
Patient participants will be randomized to receive a 9-week course of either weekly Engage & 
Connect therapy or SRP, and research assessments will be conducted at baseline and weeks 
3, 5, and 9.  
Week 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Therapy Session 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Research 
Assessment 
x 
 
 
x 
 
x 
 
 
 
x 
MRI Scans 
x 
 
 
 
 
x 
 
 
 
x 
 
Trained research assistants unaware of study hypotheses will collect weekly clinical and self-
report ratings at each study time point. 

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Page # 11 
 
 
Instrument 
Baseline 
Week 1 
Week 
3 
Week 
5 
Week 
9 
Demographics  
 
 
 
 
 
Demographic questionnaire 
x 
 
x 
x 
x 
Brief Antidepressant Questionnaire (BAQ) 
x 
 
x 
x 
x 
Intent to Complete 
x 
 
 
 
 
Depression Severity and Anhedonia  
 
 
 
 
 
Montgomery Åsberg Depression Rating Scale 
(MADRS) 
x 
 
x 
x 
x 
Hamilton Depression Severity Scale (HAMD) 
x 
 
x 
x 
x 
The Dimensional Anhedonia Rating Scale (DARS) 
x 
 
x 
x 
x 
Behavioral Activation and Reward Measures  
 
 
 
 
 
Behavioral Activation for Depression (BADS) 
x 
 
x 
x 
x 
Anticipatory and Consummatory Interpersonal 
Pleasure Scale (ACIP) 
x 
 
x 
x 
x 
Clinical Characteristics  
x 
 
 
 
 
Mini-Mental State Examination (MMSE) 
x 
 
 
 
 
Interpersonal Problems Inventory – 32 items (IIP-32) 
x 
 
 
 
x 
Duke Social Support Index 
x 
 
x 
x 
x 
Revised UCLA Loneliness scale 
x 
 
 
 
x 
Treatment Rationale Scale  
 
x 
 
 
 
MRI tasks  
x 
 
 
x 
x 
Probabilistic Reversal Learning task 
x 
 
 
x 
x 
Social Incentive Delay task  
x 
 
 
x 
x 
Adverse Event Evaluation  
 
x------------------------------------------x 
Trained research assistants unaware of study hypotheses will collect weekly clinical and self-
report ratings at each study time point via zoom, and in person assessments will be offered if 
needed. 
 
• 
Demographics: Our demographics questionnaire includes age, gender, race, religion, 
living conditions, marital status, occupation, birth place, and education. 
• 
Medication List and History of Antidepressant Treatment: The medication list will 
also help the RA assess medical comorbidity. The Brief Antidepressant Questionnaire 
(BAQ) is used to evaluate frequency, dosage, and duration of antidepressant treatment 
for the past 3 months.  
• 
Intent to Participate: At baseline, the participants will be asked about their intent to 
complete the study. 
• 
Mini-Mental State Examination (MMSE): This brief cognitive screen will be used to 
screen for the presence of cognitive impairment. Participants will need to receive a score 
equal or above 1 SD below the mean score for patient’s age and education, or DSM-5 
criteria.  
• 
Working Alliance: The Working Alliance Inventory (WAI) is an assessment of the 

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working relationship (“alliance”) between the patient and the therapist 31. The WAI is 
administered to the patient at baseline and to both the patient and the therapist after 
each session.  
• 
The Multitheoretical List of Interventions: The MULTI is an assessment of use of 
therapeutic techniques delivered by the therapist.32 The MULTI will be filled out by the 
therapist at Baseline, Week 3, Week 5, and Week 9.  
• 
Anhedonia: The Dimensional Anhedonia Rating Scale (DARS) is a self-report scale 
assessing hedonic response over the previous few days.33 
• 
Behavioral Activation: The Behavioral Activation for Depression Scale (BADS) is 
designed to measure behaviors related to rewarding experiences that are targeted in 
therapies like Engage. 34 
• 
Depression Severity: The Montgomery-Asberg Depression Rating Scale 35, a 10-item 
severity scale, will be used to measure symptom severity. The MADRS is sensitive to 
change and is appropriate for depressed elders. It also allows us to assess suicidal 
ideation and level of risk. We will also use the Hamilton Depression Severity Scale, a 17-
item measure that is widely used and well validated.36 
• 
The Dimensional Anhedonia Rating Scale (DARS): The DARS is a 17-item measure 
which will be used to measure severity of anhedonia and changes in severity over 
time.33  
• 
Interpersonal Problems: The Interpersonal Problems Inventory – 32 items (IIP-32) 
assesses difficulties in interacting with other people 37. 
• 
Social Support: The Duke Social Support Index will be used to assessed patients’ 
subjective and instrumental support and amount of social interaction.38 
• 
Loneliness: The Revised UCLA Loneliness Scale will be used to measure patients’ 
perceived sense of loneliness.39 
• 
Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIP). A 17-item 
questionnaire aimed to evaluate patients’ anticipatory and consummatory pleasure 
associated with social and interpersonal interactions with others  
• 
Treatment Rationale Scale: A 4-item measure will be used to evaluate patients’ 
expectations of the potential benefits of treatment.40,41 
MRI Tasks  
• 
Probabilistic Reversal Learning (PRL) Task: This task is aimed to measure prediction 
error and affective salience. In this task, participants select between two simultaneously 
presented stimuli and receive positive or negative feedback following their response 
selection. They must learn, through trial and error, which stimulus dimension (color or 
category) is more likely to lead to positive feedback.42,43 This task is widely used in the 
literature and is a component of NIMH’s RDoC matrix learning criterion. 
• 
Social Incentive Delay Task (SID): We developed a novel SID task, modeled after the 
Monetary Incentive Delay task (MID), which we will use for our exploratory analyses.44,45 
The SID examines social reward anticipation and receipt (Figure 7). On incentive trials, 
the participant sees a cue stimulus, human face silhouette, indicating an anticipated 
social reward. Then, he/she responds as quickly as possible with a button press during 
target stimulus presentation (White Square). Fast response time is rewarded with 
‘thumbs up’ and happy face. Slow response is punished ‘thumbs down’ and sad face. On 
neutral trials, all performance is followed by a neutral face. The SID includes two social 
reward conditions: a) Standard: feedback from a stranger; b) Personalized: feedback 
from the patient’s therapist (i.e. an individual with likelihood of a high social reward 

Protocol # 20-04021860 
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Page # 13 
 
value). 
 
6.1.1 Screening Visit + Baseline (several days before start of treatment) 
 
Screening will include the Major Depression Module and the Screener from the SCID-V 
to ensure the participant meets the clinical criteria (see exclusion and inclusion criteria 
section)  
• Informed consent 
• Medical history and medication history  
• Demographic questionnaire 
• Brief Antidepressant Questionnaire (BAQ) 
• Intent to Complete 
• Depression Severity and Anhedonia  
• Montgomery Åsberg Depression Rating Scale (MADRS) 
• The Dimensional Anhedonia Rating Scale (DARS) 
• Behavioral Activation for Depression (BADS) 
• Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIP) 
• Mini-Mental State Examination (MMSE) 
• Interpersonal Problems Inventory – 32 items (IIP-32) 
• Duke Social Support Index 
• Revised UCLA Loneliness scale 
 
MRI tasks  
• Probabilistic Reversal Learning task 
• Social Incentive Delay task 
 
 
 
 
6.1.2 Treatment Phase 
 
 
 
 
 
Monitoring of Clinical State 
Study participants’ clinical state will be monitored by their study therapists. Therapists 
and their supervisor will discuss symptoms that may require treatment other than that 
provided by the study. The supervisor will also be available for phone calls with 
therapists between supervision sessions. If a participant requires additional care, the 
therapist and supervisor will collaborate on a referral. 
 
Therapists will administer the Patient Health Questionnaire (PHQ-9) during each 
therapy session. If a participant endorses suicidal ideation or behavior on item 9 of the 
PHQ-9 (“Thoughts that you would be better off dead, or of hurting yourself”), the 
therapist will conduct a thorough safety evaluation. If the therapist determines that the 
participant is at risk, the therapist will consult with a supervisor and/or with the director 
of the Weill Cornell Institute of Geriatric Psychiatry to determine a course of action.  
 
Additionally, research assistants will administer the MADRS during research 
assessments. If a participant endorses suicidal ideation or behavior on item 10 of the 
MADRS (“This past week, have you felt like life isn’t worth living?”), the research 
assistant will complete the Suicide Risk Assessment protocol (see attachments), which 
has been approved by NIMH for determining an increase in suicidal ideation. The 
research assistant will then report the results of the Suicide Risk Assessment to the 

Protocol # 20-04021860 
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participant’s study therapist or another clinician in the Institute of Geriatric Psychiatry, 
who will conduct a thorough safety evaluation if warranted.  
 
Depending on the level of risk, the participant may be encouraged to speak to 
his/her own clinician; the PI or therapist may call the participant’s clinician and/or 
family member; or the participant may be referred for an evaluation by a clinician 
who will conduct a thorough assessment via phone or video. . Other urgent risks 
may necessitate calling 911 or having a family member bring the participant to a 
local emergency room for evaluation. 
 
 
6.1.2.1 Visit 1 (baseline; Cycle 1 Day 1) 
 
 
Assessments will be administered based on assessment schedule above over 
the course of 9 weeks (See SoA above).  
 
 
6.1.2.2 Visit 2 (± X day(s)) 
 
 
Assessments will be administered based on assessment schedule above over 
the course of 9 weeks (See SoA above).  
 
6.1.3 Follow-up Phase 
 
 Not Applicable  
 
7. Study Intervention 
 
 
7.1 Study Intervention/Device Description   
 
We will randomize participants to 9-weeks of either weekly “Engage & Connect” therapy or 
Symptom Review and Psychoeducation (SRP) provided by licensed or license-eligible clinicians (at 
least Masters-level social workers or mental health counselors). Therapists will receive training and 
weekly supervision from the PI in collaboration with a licensed clinical psychologist and member of 
our research team, to ensure adherence to treatment protocols and address clinical issues. Trained 
research assistants, unaware of study hypotheses, will assist in administration of ratings and 
scanning procedures.. Interventions will be delivered via video or phone, in accordance with the 
institutional policy.  
 
Participants may be lent a tablet during their participation in the study to facilitate remote sessions if 
they do not have adequate technology at home. When possible, participants may be asked to use a 
wearable device that we provide during their participation in the study. The wearable device allows 
for passive sensing of movement (steps), heart rate, and sleep daily. Participants and therapists 
may be able to review their activity for the week to augment the sessions. Data will be collected 
from the device’s corresponding mobile app (e.g., device-linked app commercially used to extract 
steps, sleep, and heart rate as described above). No investigational devices or apps will be used to 
collect or extract data, and the device will be used in accordance with its approved and marketed 
use. 
 
At the end of the study, participants are required to return the mobile and/or wearable devices. This 
technology and platform are being used successfully in the other IRB-approved studies at our 

Protocol # 20-04021860 
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Page # 15 
 
ALACRITY center (19-09020810; 19-09020854). 
 
 
“Engage & Connect” 
“Engage” targets the PVS system using ‘reward exposure’ intervention – engagement in rewarding 
activities implemented in weekly ‘action plans’ developed by the depressed patient and the 
therapist.22 In patients with negativity bias, apathy, or inadequate emotional regulation, therapists 
provide targeted interventions so that reward exposure proceeds unimpeded. “Engage & Connect”, 
a modified adapted version of “Engage”, focuses on exposure to rewarding activities with significant 
others. During sessions, the therapist and patient will select a social activity (i.e. interaction with a 
significant other) and formulate a stepped plan to complete this goal. By week 3, therapists will 
assess patients’ barriers to reward exposure – negativity bias, apathy, inadequate emotion 
regulation, as well as interpersonal conflicts and social skills deficits, which may hinder social 
interactions – and address barriers through targeted strategies.  
 
Symptom Review and Psychoeducation (SRP) 
SRP is a comparison condition that resembles what a good clinician does in evaluating, reassuring, 
and educating a depressed patient. Each session begins with reviewing the depressed patient’s 
symptoms, then assessing patient’s knowledge base about depression. Identifying patient’s  
misconceptions about depression will guide the selection of educational material to be presented in 
each session. Comprehending depression-related information is contaminated by pessimism, 
denial, misconceptions, and stigma. The role of SRP therapist is to impart valuable information, 
despite these complexities. Conveying information is a process. The SRP therapist needs to be 
aware of “where the patient” is and offer information for which he/she has readiness to accept. SRP 
therapists do not engage in other interventions. Arguably, SRP is a condition with: 1) non-specific 
active therapeutic ingredients; 2)  little overlap with the therapeutic ingredients of “Engage & 
Connect”; and 3) exposure of patients to therapists equal to that of “Engage & Connect”. We used a 
similar comparison condition in a recently completed psychotherapy study of post-stroke depression 
and found that SRP leads to reduction in depression severity (R01 MH096685, PI: Alexopoulos). 
 
 
7.2 Availability 
 
Not Applicable  
 
7.3 Acquisition and Accountability  
 
 
 
Not Applicable  
 
7.4 Formulation, Appearance, Packaging, and Labeling  
 
Not Applicable  
 
7.5 Product Storage and Stability 
 
Not Applicable  
 
7.6 Preparation 
 
Not Applicable  

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7.7 Dosing and Administration 
 
All participants will receive 9- weeks of psychotherapy, either “Engage & Connect” or 
“SRP”, as indicated above.  
 
7.7.1 Dosing Delays/Dose Modifications 
 
Not Applicable  
 
7.8 General Concomitant Medication and Supportive Care Guidelines 
 
Not Applicable  
 
7.9 Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse event(s), psychosocial interventions 
will continue for a period of 9 weeks.  
 
7.10 Duration of Follow Up 
 
Participants who choose to discontinue the study will be asked and encouraged to 
complete research assessments for the remaining weeks per their agreement.  
 
7.11 Measures to Minimize Bias: Randomization and Blinding  
 
Participants will be randomly assigned to 9-weeks of either “Engage & Connect” 
psychotherapy or “SRP” psychotherapy. Therapists and research assistants administering 
clinical rating will remain unaware of study hypotheses. Trained research assistants 
unaware of study hypotheses will collect weekly clinical and self-report ratings at each study 
time point. 
 
 
7.12 Study Intervention/Follow-up Compliance 
 
Adherence to intervention will be monitored through therapist training and supervision: 
Training will include: a) Review of treatment manual (1 hour) and videotaped training session 
describing the treatment protocol and therapeutic techniques (1 hour), followed by video or in-
person Q&A session with a trainer (either the PI or a licensed clinical psychologist with expertise in 
“Engage”); b) role-play session with the trainer to practice skills; c) 3 practice sessions with an 
actor-patient to evaluate adherence to treatment using the “Engage Adherence Scales” adapted to 
Engage & Connect and “SRP Adherence Scale” adapted from previous psychotherapy trial which 
used a similar intervention (R01 MH096685, PI: Alexopoulos); d) Therapists will be required to 
achieve a ‘good’ fidelity score (≥4) on at least 3 sessions; e) Weekly supervision will focus on 
prevention of skill drift and maintenance of fidelity. 
 
Therapy sessions will be video or audio-recorded for the purposes of supervision and evaluation of 
therapist adherence to the therapy protocol (e.g., therapist interventions, therapeutic interactions, 
etc.). These recordings will not be labeled with information such as participants’ name, date of birth, 
or other identifying information. Therapists will meet with a supervisor weekly for supervision, during 

Protocol # 20-04021860 
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Page # 17 
 
which corrective feedback will be provided to therapists that show “skill drift” (i.e. fidelity scores < 4). 
Recordings samples may be processed by a transcription service in order to obtain research grade 
transcriptions while maintaining privacy and data safety regulations. The files will only be labeled by 
an alphanumeric code and remain completely separate from any identifying information 
documentation. Because these recordings may include personal identifiable information (PII) or 
protected health information (PHI), we treat all samples as confidential data. Samples may be 
transcribed by study staff, TranscribeMe, or Speech to Text Watson IBM software. If needed, files 
will be transferred using Secure File Transfer protocols managed by WMC ITS. Speech to Text 
Watson IBM follows strict data safety regulations stores data on an encrypted cloud that requires 
user authentication for access, and all data are secured by encryption both while stored in the cloud 
and in transit. 
 
 
Patient adherence to intervention (i.e. attendance) will be monitored by the PI and staff: We 
have developed procedures to minimize risk to our participants, increase retention, and create 
conditions that make study participation as comfortable as possible. To this end, we will educate 
participants regarding study procedure and commitment during the informed consent process. We 
will schedule appointments early in the day or at the participants’ convenience. Our team will call 
participants prior to each appointment to provide reminders and assist with transportation 
arrangements. Funds for transportation are included in our budget in order to increase accessibility. 
The PI or staff member will accompany participants to all MRI scans and be present during 
scanning sessions in order to maximize comfort and address any questions or concerns that may 
arise. The PI will collaborate with trained and experienced technicians at our MRI Center to reduce 
wait time and optimize efficiency of the MRI procedures. The PI will train study personnel in 
recruitment and data collection procedures with an emphasis on clear communication, sensitivity, 
and multicultural competence. These measures have led to high retention rates and participant 
satisfaction in our Institute’s randomized clinical trials. Based on data collected in previous 
psychotherapy trials at the Institute, we anticipate an attrition rate of ~10%, which has been 
incorporated into our power analyses.  
 
 
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
8.1 Discontinuation of Study Intervention 
 
Efforts will made to increase retention and reduce dropout (see above). In the event that 
a participant chooses to discontinue the study, the PI and the clinician will discuss with 
the participant, identify reasons for discontinuation and invite the participant to continue 
to attend the remaining research assessments. The PI and staff will provide the 
participant will an appropriate referral for alternative treatment if needed and/or 
requested by the participant. In the event of an emerging suicide risk, the PI will follow 
procedure for suicide risk management (See Section 13 for full description of 
procedures). The study may be discontinued and the participant may be referred for 
outpatient or inpatient treatment based on clinical indication. If a patient is at imminent 
risk for harming themselves and unwilling to agree to psychiatric hospitalization, 
involuntary admission may be needed.  
 

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8.2 Participant Discontinuation/Withdrawal from the Study 
 
• 
If any clinical adverse event (AE) or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the 
participant 
• 
Worsening of depression symptoms and/or emerging suicide risk that warrants a 
higher level of care than provided within the study (e.g. psychiatric hospitalization).  
• 
If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
• 
Participant lost to follow-up after several attempts to contact subject to schedule 
study visit. 
The reason for participant discontinuation or withdrawal from the study will be recorded 
on the Case Report Form (CRF). Subjects who give informed consent and are 
randomized but do not receive the study intervention may be replaced.  Subjects who 
give informed consent, and are randomized and receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study may be 
replaced. 
8.3 Lost to Follow Up 
 
Not Applicable  
 
9. Correlative/Special Studies  
 
Not Applicable  
 
9.1 Laboratory Correlative Studies 
Not Applicable  
 
9.1.1 Title – Laboratory Correlative Study #1 
 
9.1.1.1 Collection of Specimen(s) 
 
9.1.1.2 Handling of Specimen(s) 
 
9.1.1.3 Shipping of Specimen(s) (if multicenter) 
 
9.1.1.4 Site(s) Performing Correlative Study (if multicenter) 
 
9.2 Special Studies 
Not Applicable  
 
9.2.1 Title – Special Correlative Study #1 
 
9.2.1.1 Assessment 
 
9.2.1.2 Method of Assessment 
 
9.2.1.3 Timing of Assessment 
 
10.  Measurement of Effect 
 
Treatment effect will be measured by change in depression severity, resting state functional 
connectivity in PVS regions, and behavioral activation over the course of treatment. 
 

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10.1 Response Criteria 
 
 
Reduction in depression severity over the course of 9 weeks of treatment (slopes of change 
in MADRS scores will be calculated within mixed-effects model approach, see Statistical 
Analysis). 
 
10.2 Duration of Response  
 
Duration of response will be evaluated as reduction in depression severity (measured by 
the MADRS scale) over the course of 9 weeks of treatment.  
 
10.3 Progression-Free Survival  
 
 
Not Applicable  
 
10.4 Other Response Parameters 
 
Other endpoints and the criteria for their measurement should be entered below or 
reference should be made to the protocol section where these criteria may be found. 
 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
efficacy, and adverse event data for all enrolled subjects.  
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management 
software system that is fully supported by the Weill-Cornell Medical Center 
CTSC.  It is a tool for the creation of customized, secure data management 
systems that include Web-based data-entry forms, reporting tools, and a full 
array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data 
manipulation and export procedures.  REDCap is maintained on CTSC-owned 
servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported 
through a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 

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submitted to the appropriate Ethics Committee. Written approval of the study and all 
relevant study information must be obtained before the study center can be initiated or the 
IP is released to the Investigator. Any necessary extensions or renewals of IRB approval 
must be obtained for changes to the study, such as amendments to the protocol, the ICF, 
or other study documentation. The written approval of the IRB together with the approved 
ICF must be filed in the study files.  
The Investigator will report promptly to the IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit 
written summaries of the study status to the IRB as required. On completion of the study, 
the IRB will be notified that the study has ended.  
 
All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 
amendments will be submitted to the relevant institutional IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this 
case, the necessary action will be taken first, with the relevant protocol amendment 
following shortly thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead 
site, Weill Cornell Medicine, updated documents will be provided to participating sites, as 
applicable. Weill Cornell Medicine must approve all consent form changes prior to local 
IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities 
will be notified that the study has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the 
ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines and the 
applicable national and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable 
ethics committees and investigations will be undertaken by scientifically and medically 
qualified persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-
GCP and local regulations, as applicable, from each potential subject or each subject’s 
legally authorized representative prior to participating in the research study. Subjects who 
agree to participate will sign the approved informed consent form and will be provided a 
copy of the signed document. Due to COVID-19, informed consent will be obtained over 
the phone. In our experience, many older adults do not have access to technology that 
would allow them to consent electronically. An information sheet will be emailed to the 
participant so that it can be viewed by the participant (or mailed if email is not used). This 
will allow the participants to review the form thoroughly. Participants will be encouraged 

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to discuss any concerns or questions they may have with the member of the research 
team who is conducting the consent. Members of the research team will ensure there is 
sufficient time to pose questions and will be in contact with the Principal Investigator 
regarding any potential  concerns that need to be addressed. When possible, consent will 
be conducted over video call within a HIPAA-compliant platform (i.e. Zoom) and the 
participant could review the consent, presented over video, during the process. Zoom 
invitations will be sent to participants via email, collected at the initial phone screen phase 
as contact information and stored in a secured folder that only authorized study team 
members can access. The same procedures will be used for consent of therapists 
participating in this study.  After the consent form has been reviewed, if informed consent 
is obtained, the research will sign the “Researcher’s statement” portion of the consent 
form digitally through RedCap in order to have documentation on file.  
 
Participants may opt for an in-person informed consent meeting, which will be conducted 
in a private interview room located in the Weill Cornell Medicine Psychiatry Department. 
Participants will have the opportunity to discuss the study in detail with a member of the 
research study team, ask any questions they may have, and provide their written informed 
consent by signing the physical consent form. Only the participant and the researcher 
obtaining consent will be present for the in-person consent procedures. 
 
The initial ICF, any subsequent revised written ICF and any written information provided 
to the subject must approved by IRB prior to use. The ICF will adhere to IRB requirements, 
applicable laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to http://www.clinicaltrials.gov. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information. 
 
11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced.  After completion of the study, all 
documents and data relating to the study will be kept in an orderly manner by the 
Investigator in a secure study file.  Essential documents should be retained for 2 years 
after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the IP. In addition, all subjects’ medical records 
and other source documentation will be kept for the maximum time permitted by the 
hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
All investigator-initiated trials must include a study statistician assigned by the Division of 
Biostatistics and Epidemiology or approval to use alternate biostatistician personnel. Please 
contact Dr. Paul Christos (pac2001@med.cornell.edu) for additional information and assignment 

Protocol # 20-04021860 
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of a study statistician.  
 
Describe the statistical methods that will be used to analyze the data (chi square, t-test, 
correlation, etc.) 
 
12.1 Study Design/Endpoints 
 
The principal aim of this pilot study is to examine if exposure to meaningful social rewards 
during psychotherapy, engages reward circuitry and improves mid- and late-life major 
depression. The “reward exposure” of this study will consist of meaningful social activities with 
significant others (“Engage & Connect”). The study will be a pilot RCT that will compare 9-week 
“Engage & Connect” vs. a Symptom Review and Psychoeducation condition (SRP) for adults older 
than 50 years with major depression and test the following hypotheses:  
 
During the 9 week course of “Engage & Connect” treatment there will be an:  
H1. Increase in rsFC of the PVS. 
H2. Increase in behavioral activation (BADS scale) 
H3. Reduction in depression severity (MADRS scale).  
SH. In “Engage & Connect” treated participants, change in: SH1a) rsFC of the PVS and SH1b) 
behavioral activation (BADS) will predict subsequent reduction in depression severity (MADRS). 
These relationships will not be observed in the SRP treated group. The rationale of this hypotheses 
is based on the theory that the “Engage & Connect” mechanism of action is reconditioning the PVS, 
while SRP relies on non-specific mechanisms of action. 
 
To further investigate the PVS correlates of social reward, we developed a social reward fMRI 
paradigm, modeled after a monetary incentive delay task44 and plan to use it in analyses for 
hypothesis generation. 
 
Analysis Plan 
H1, H2, H3: During the 9-week course of “Engage & Connect” there will be an:  
H1. Increase in rsFC of the PVS 
H2. Increase in behavioral activation (BADS) 
H3. Reduction in depression severity (MADRS).  
We will implement mixed-effects models using the lme4 package in R.46 For H1, H2, and H3 we will 
include subject-specific random intercept and fixed effects for time-related parameter(s). For SH, 
We will estimate a separate mixed-effects model for each of the four a-priori PVS ROIs. Models of 
PVS ROIs will include change from baseline to Week 5, Week 5 to 9 and models of behavioral 
activation (BADS scale) and depression severity (MADRS scale) and will include change from 
baseline to Week 3 to Week 5 and Week 5 to Week 9 as independent variables. Dependent 
variables will be depression severity at Weeks 5 and Week 9 for PVS ROI models and at Weeks 3, 
5, and 9 for BADS model. We will include fixed effects for age, gender, antidepressant use, or any 
other variable that will be unbalanced between the groups. We will explore in all models the 
inclusion of higher order(s) of the time variable (e.g., quadratic, cubic, etc.) and choose the final 
model based on Bayesian Information Criterion (BIC).47 We will control the overall Type I error rate 
at 5% using Holm’s stepdown procedure to adjust for four post-hoc multiple comparisons (four PVS 
ROIs) in H1 and five comparisons (four PVS ROIs and BADS) in SH.  
SH. In “Engage & Connect” treated participants, change in: SH1a. rsFC of the PVS; and SH1b. 

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Behavioral activation (BADS) will predict subsequent reduction in depression severity (MADRS). 
These relationships will not be observed in the SRP treated group. Five mixed-effects models (as 
described above) will investigate whether change in the predictor is associated with subsequent 
change in depression severity (MADRS).  
Power Analysis 
Our primary outcome is change over 9 weeks of “Engage & Connect” in resting state functional 
connectivity (rsFC) of the Positive Valence System (PVS) (H1). Our secondary outcome measures 
are change in behavioral activation measured by the Behavioral Activation for Depression Scale 
(BADS) (H2); and depression severity, measured by the Montgomery-Asberg Depression Rating 
Scale (MADRS) (H3). Our secondary hypothesis (SH) investigates whether early change in the 
predictors (i.e. rsFC of the PVS and BADS change) predict subsequent change in depression 
severity (MADRS). We will measure rsFC at baseline, Week 5, and Week 9 and behavioral 
activation and depression severity at baseline, Week 3, Week 5, and Week 9.  
 
12.2 Sample Size/Accrual Rate 
 
The annual participant recruitment plan is as follows: 11 participants in Year 1 (5 SRP, 6 
“Engage & Connect”), 14 in Year 2 (7 per group), 17 in Year 3 (9 SRP, 8 “Engage & 
Connect”), and 18 in Year 4 (9 per group). MRI scans and clinical assessments at Weeks 5 
and 9 for 10 participants will be completed in the first four months of Year 5. Statistical 
analyses will be conducted in Year 6 and Year 7.  
 
12.3 Stratification Factors  
 
The sample will be stratified by age so that 50% of participants recruited are between ages 
65-85 and 50% are between ages 50-65. The stratification is aimed to allow investigation of 
the research questions in a balanced sample of middle-aged and older adults with major 
depression.  
 
 12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 
 
We will implement mixed-effects models using the lme4 package in R.46 For H1, H2, and 
H3 we will include subject-specific random intercept and fixed effects for time-related 
parameter(s). 
 
12.4.2 Analysis of Secondary Endpoints 
 
For SH, We will estimate a separate mixed-effects model for each of the four a-priori 
PVS ROIs. Models of PVS ROIs will include change from baseline to Week 5, Week 5 to 
9 and models of behavioral activation (BADS scale) and depression severity (MADRS 
scale) and will include change from baseline to Week 3 to Week 5 and Week 5 to Week 
9 as independent variables. Dependent variables will be depression severity at Weeks 5 
and Week 9 for PVS ROI models and at Weeks 3, 5, and 9 for BADS model. We will 
include fixed effects for age, gender, antidepressant use, or any other variable that will 
be unbalanced between the groups. We will explore in all models the inclusion of higher 
order(s) of the time variable (e.g., quadratic, cubic, etc.) and choose the final model 
based on Bayesian Information Criterion (BIC).47 We will control the overall Type I error 

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rate at 5% using Holm’s stepdown procedure to adjust for four post-hoc multiple 
comparisons (four PVS ROIs) in H1 and five comparisons (four PVS ROIs and BADS) in 
SH.  
 
12.5 Interim Analysis 
 
Interim Analysis will be conducted periodically to ensure adequate data collection and 
protocol procedures in accordance with NIMH policy and reporting requirements.  
 
 12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of Toxicity 
 
Not Applicable  
 
12.6.2 Evaluation of Response 
 
All subjects included in the study will be evaluated for treatment response at treatment 
end (See analysis plan above)  
 
 
13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by subjects or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
 
13.1 Adverse Event Definition 
 
Adverse event (AE) monitoring and reporting is a routine part of clinical research. Safety is 
monitored by evaluation of adverse events reported by subjects or observed by investigators 
or research staff, as well as by other investigations such as clinical over-read of all MRI 
scans, etc. 
 
Protocols for Addressing Adverse Events: All participants will have access to the 
telephone number of the PI and can call in an emergency. The Department of Psychiatry 
and the Weill Cornell Institute of Geriatric Psychiatry is located in within New York-
Presbyterian Hospital, which has a 24-hour emergency call system, should participants 
require urgent evaluation and care. Information how to use the hospital’s call system will be 
provided to all participants. The strategy for reporting adverse events is as follows: 
1. Clinical or study personnel will immediately notify the PI. 
2. The PI will consult with a senior clinician at the Institute to discuss potential risks and 
decide on a plan of action. 
3. The PI will notify the Weill Cornell IRB about adverse events (AEs). 
4. If the adverse event is serious (SAE), the NIMH will be informed. 

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Procedures for management of suicide risk: We will exclude participants who endorse 
intent or plan to attempt suicide in the near future at screening. During the study, 
participants’ clinical state will be monitored by their therapists. Therapists and their 
supervisor will discuss symptoms that may require treatment other than that provided by the 
study. Therapists will administer the Patient Health Questionnaire (PHQ-9) during each 
therapy session. If a participant endorses suicidal ideation or behavior on item 9, the 
therapist will conduct a thorough safety evaluation. If the participant is at risk, the therapist 
will consult with a supervisor to determine a course of action. Additionally, the research 
assistant (RA) will administer the MADRS during research assessments. If a participant 
endorses suicidal ideation or behavior on item 10, the RA will complete the Suicide Risk 
Assessment protocol, approved by NIMH for determining an increase in suicidal ideation. 
The research assistant will then report the results to the study therapist, the PI, and the 
supervisor, who will conduct a thorough safety evaluation if warranted. Depending on the 
risk, the PI or therapist may call the participant’s clinician and/or family member; or the 
participant may be referred for an evaluation by a study clinician available at the time via 
phone or video. Other urgent risks may necessitate calling 911 or having a family member 
bring the participant to a local emergency room for evaluation. 
 
Procedures for managing incidental clinically significant MRI findings: All MRI scans 
will be read by a board-certified Weill Cornell Medicine neuroradiologist. If a clinically 
significant finding is identified, an MD clinician investigator on the study protocol will notify 
the participant (in person or via phone call) and discuss the finding. With the participant’s 
permission, his/her primary care physician will be notified by the PI, and the participant will 
be informed and advised to take clinically appropriate action. The proposed MRI scan 
sequences are not optimized for diagnostic purposes and might not reveal all clinically 
significant abnormalities. Participants are informed that the MRI scan is not intended for 
diagnostic purposes, thus, undergoing the MRI scanning session is not comparable to 
receiving a clinical MRI exam. 
 
 
 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) 
 
(Include additional sections as needed for all agents of devices being utilized in the 
research study.) 
Include expected risks for agent or device.  
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
Reportable events for this study are based on relevant NIMH-defined designations: 
Adverse event: Any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with the subject’s participation in 
the research, whether or not considered related to the subject’s participation in the 
research (modified from the definition of adverse events in the 1996 International 
Conference on Harmonization E-6 Guidelines for Good Clinical Practice). 
External adverse event: From the perspective of one particular institution engaged in a 
multicenter clinical trial, external adverse events are those adverse events experienced 
by subjects enrolled by investigators at other institutions engaged in the clinical trial. 
Internal adverse event: From the perspective of one particular institution engaged in a 
multicenter clinical trial, internal adverse events are those adverse events experienced 

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by subjects enrolled by the investigator(s) at that institution. In the context of a single-
center clinical trial, all adverse events would be considered internal adverse events. 
Possibly related to the research: There is a reasonable possibility that the adverse 
event, incident, experience or outcome may have been caused by the procedures 
involved in the research (modified from the definition of associated with use of the drug 
in FDA regulations at 21 CFR 312.32(a)). 
Serious adverse event: Any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
• 
results in death; 
• 
is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in a persistent or significant disability/incapacity; 
• 
results in a congenital anomaly/birth defect; or 
• 
any other adverse event 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 (examples of such events 
include allergic bronchospasm requiring intensive treatment in the emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
13.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be 
maintained by the research staff and kept in the subject’s research chart.    
 
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
https://research.weill.cornell.edu/compliance/human-subjects-research/institutional-
review-board/human-research-compliance/immediate 
 
13.1.5 Reporting Events to Participants 
 
See above procedures for reporting incidental MRI findings to participants  
 
13.1.6 Events of Special Interest 
 
The strategy for reporting adverse events is as follows: 
1. Clinical or study personnel will immediately notify the PI. 
2. The PI will consult with a senior clinician at the Institute to discuss potential risks and 
decide on a plan of action. 
3. The PI will notify the Weill Cornell IRB about adverse events (AEs). 
4. If the adverse event is serious (SAE), the NIMH will be informed. 

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13.1.7 Reporting of Pregnancy 
 
Not Applicable  
 
13.2 Definition of SAE 
 
SAEs include death, life threatening adverse experiences, hospitalization or 
prolongation of hospitalization, disability or incapacitation, overdose, congenital 
anomalies and any other serious events that may jeopardize the subject or 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. (Modify as necessary) 
 
13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:   
 
https://research.weill.cornell.edu/compliance/human-subjects-research/institutional-
review-board/human-research-compliance/immediate 
 
13.2.2 Reporting of SAE to FDA [For Protocols Where WCMC is the Sponsor-
Investigator] 
 
Not Applicable  
 
13.2.3 Reporting of SAE to <Insert Pharmaceutical Company Name> 
 
Not Applicable  
 
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after the 
subject discontinues participation from the study.  
 
13.4 Time Period and Frequency for Event Assessment and Follow Up 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE.  

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Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
 
 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day 
of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome 
information until resolution or stabilization. 
 
14. Unanticipated Problems Involving Risks to Subjects or Others 
 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO) 
 
Reporting of UPIRTSOs will follow the guidelines of the study sponsor, the NIMH, which are 
described here: https://www.nimh.nih.gov/funding/clinical-research/nimh-reportable-events-
policy.shtml 
The reporting of UPIRTSOs applies to non-exempt human subjects research conducted or 
supported by NIMH. An incident, experience, or outcome that meets the definition of an 
UPIRTSO generally will warrant consideration of changes to the protocol or consent in order 
to protect the safety, welfare, or rights of participants or others. Examples of corrective 
actions or changes that might need to be considered in response to an UPIRTSO include: 
• 
Modification of inclusion or exclusion criteria to mitigate the newly identified risks 
• 
Implementation of additional safety monitoring procedures 
• 
Suspension of enrollment of new participants or halting of study procedures for enrolled 
participants 
• 
Modification of informed consent documents to include a description of newly recognized 
risks 
• 
Provision of additional information about newly recognized risks to previously enrolled 
participants. 
The NIMH and Office for Human Research Protections (OHRP) considers unanticipated 
problems involving risks to participants or others to 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 participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 

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14.1.2 Unanticipated Problem Reporting 
 
The PI, Dr. Solomonov, will report unanticipated problems (UPIRTSOs) to the reviewing 
Institutional Review Board (IRB) and to the Data Safety and Monitoring Board (DSMB), 
and the NIMH Program Officer. All reports will be in writing, prepared and signed by the 
PI. These reports should indicate that the monitoring entities (i.e., the PI and IRB, ISM 
and/or DSMB) and appropriate regulatory entities (e.g., OHRP, FDA) have been notified 
in accordance with the approved monitoring plan and federal regulations. 
The UPIRTSO 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 UPIRTSO;  
• 
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UPIRTSO. 
 
To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the 
following timeline:   
 
• 
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB 
and to the DCC/study sponsor within 10 business days of the investigator 
becoming aware of the event.  
• 
Any other UPIRTSO will be reported to the IRB and to the DCC/study sponsor 
within 10 business days of the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), Food and Drug Administration (FDA), and the Office for Human 
Research Protections (OHRP) within 10 business days of the IRB’s receipt of the 
report of the problem from the investigator. 
 
A timeline and flowchart for the reporting of all reportable events can be found here: 
https://www.nimh.nih.gov/funding/clinical-research/nimh-reportable-events-policy.shtml  
 
15. Data and Safety Monitoring Plan (DSMP) 
 
In consultation with NIMH program officers, we will establish a Data Safety Monitoring 
Board (DSMB) that oversees our study activities to ensure the safety of participants, the 
validity of our findings, and assesses the need for further data collection. The DSMB 
responsibilities will include: 
1. The review of protocols, informed consent procedures, and safety plans. 
2. The monitoring of study progress as reflected in the rate of participant 
recruitment, adherence to timetables, and the quality of collected data. 
3. The evaluation of the study’s risk-benefit ratio as new evidence-based treatments 
become available. 
4. The determination of whether the study should be continued, modified, or 
terminated in light of adverse events. 

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5. The analysis of interim findings and the confidentiality with which they are being 
maintained. 
6. Consultations with the investigators regarding protocol measures that impose 
undue burden on study participants or that pose possible ethical concerns or 
conflicts of interest. 
We will also provide the DSMB copies of all reports submitted to NIMH and manuscripts 
submitted for publication in professional journals. 
 
We will use the adverse event grading guidelines provided by the Office of Research 
Integrity and Assurance at Weill Cornell Medicine. We will report all adverse events to 
the IRB in the timeline indicated by Weill Cornell’s Human Research Protections 
Program Immediate Reporting Policy. As required, we will report in writing serious 
adverse events to the IRB within 5 days from the time that we become aware of their 
occurrence. We will report all other adverse events to the IRB monthly. We will submit 
individual adverse events, as well as summary tables every six months to the DSMB, but 
we will respond to the DSMB recommendation if a higher frequency of reporting is 
desirable. 
 
If there is a suicide attempt or if a participant has increased suicidal ideation while in the 
study, and after the PI takes the appropriate clinical steps for the participant’s safety,we 
will report to the IRB and DSMB according to guidelines. We will provide the DSMB 
summaries of adverse events over specified time periods and report all adverse events 
to the Weill Cornell IRB within the timeframe specified by IRB regulations. The PI will 
disclose to the NIMH reportable events in time frame consistent with NIH’s Reportable 
Events Policy. 
 
 
 
 
 
 
 

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16. References 
1.  
Leles da Costa Dias F, Teixeira AL, Cerqueira Guimarães H, et al. Prevalence of late-life 
depression and its correlates in a community-dwelling low-educated population aged 75+ 
years: The Pietà study. J Affect Disord. 2019;242:173-179. doi:10.1016/j.jad.2018.08.012 
2.  
Doraiswamy PM, Khan ZM, Donahue RMJ, Richard NE. The Spectrum of quality-of-life 
impairments in recurrent geriatric depression. Journals Gerontol Ser A Biol Sci Med Sci. 
2002;57(2):M134-M137. doi:10.1093/gerona/57.2.M134 
3.  
Mirza SS, Wolters FJ, Swanson ScD SA, et al. 10-year trajectories of depressive 
symptoms and risk of dementia: a population-based study. The Lancet Psychiatry. 
2016;3(7):628-635. doi:10.1016/S2215-0366(16)00097-3 
4.  
Cherbuin N, Kim S, Anstey KJ. Dementia risk estimates associated with measures of 
depression: a systematic review and meta-analysis. BMJ Open. 2015;5(12):e008853. 
doi:10.1136/BMJOPEN-2015-008853 
5.  
Daskalopoulou M, George J, Walters K, et al. Depression as a risk factor for the initial 
presentation of twelve cardiac, cerebrovascular, and peripheral arterial diseases: Data 
linkage Study of 1.9 million women and men. Colombo GI, ed. PLoS One. 
2016;11(4):e0153838. doi:10.1371/journal.pone.0153838 
6.  
Murphy RA, Hagaman AK, Reinders I, et al. Depressive trajectories and risk of disability 
and mortality in older adults: Longitudinal findings from the health, aging, and body 
composition study. Journals Gerontol Ser A Biol Sci Med Sci. 2016;71(2):228-235. 
doi:10.1093/gerona/glv139 
7.  
Almeida OP, Hankey GJ, Yeap BB, Golledge J, Norman PE, Flicker L. Depression, frailty, 
and all-cause mortality: A cohort study of men older than 75 years. J Am Med Dir Assoc. 
2015;16(4):296-300. doi:10.1016/J.JAMDA.2014.10.023 
8.  
Zivin K, Wharton T, Rostant O. The economic, public health, and caregiver burden of 
late-life depression. Psychiatr Clin North Am. 2013;36(4):631-649. 
doi:10.1016/j.psc.2013.08.008 
9.  
Nelson JC, Delucchi K, Schneider LS. Efficacy of second generation antidepressants in 
late-life depression: A meta-analysis of the evidence. Am J Geriatr Psychiatry. 
2008;16(7):558-567. doi:10.1097/01.JGP.0000308883.64832.ED 
10.  
Roose SP, Sackeim HA, Ranga Rama Krishnan K, et al. Antidepressant 
pharmacotherapy in the treatment of depression in the very old: A Randomized, placebo-
controlled trial. Am J Psychiatry. 2004;161:2050-2059. doi:10.1176/appi.ajp.161.11.2050 
11.  
Cristancho P, Lenze EJ, Dixon D, et al. Executive function predicts antidepressant 
treatment noncompletion in late-life depression. J Clin Psychiatry. 2018;79(3):1555-2101. 
doi:10.4088/JCP.16m11371 
12.  
Sirey JA, Banerjee S, Marino P, et al. Adherence to depression treatment in primary care. 
JAMA Psychiatry. 2017;74(11):1129-1135. doi:10.1001/jamapsychiatry.2017.3047 
13.  
Alexopoulos GS, Raue PJ, Kanellopoulos D, Mackin S, Arean PA. Problem solving 
therapy for the depression-executive dysfunction syndrome of late life. Int J Geriatr 
Psychiatry. 2008;23:782-788. doi:10.1002/gps.1988 
14.  
Morimoto SS, Kanellopoulos D, Manning KJ, Alexopoulos GS. Diagnosis and treatment 
of depression and cognitive impairment in late life. Ann N Y Acad Sci. 2015;1345(1):36-
46. doi:10.1111/nyas.12669 
15.  
Areán PA, Raue P, Mackin RS, Kanellopoulos D, McCulloch C, Alexopoulos GS. 
Problem-Solving Therapy and Supportive Therapy in older adults with major depression 
and executive dysfunction. Am J Psychiatry. 2010;167(11):1391-1398. 
doi:10.1176/appi.ajp.2010.09091327 
16.  
Renn BN, Areán PA. Psychosocial treatment options for major depressive disorder in 
older adults. Curr Treat options psychiatry. 2017;4(1):1-12. doi:10.1007/s40501-017-

Protocol # 20-04021860 
5.21.2024 
 
Page # 32 
 
0100-6 
17.  
McHugh Power JE, Steptoe A, Kee F, Lawlor BA. Loneliness and social engagement in 
older adults: A bivariate dual change score analysis. Psychol Aging. 2018;34(1):152-162. 
doi:10.1037/pag0000287 
18.  
Chambers DA. Advancing the Science of Implementation: A Workshop Summary. Adm 
Policy Ment Heal Ment Heal Serv Res. 2008;35(1-2):3-10. doi:10.1007/s10488-007-0146-
7 
19.  
Stahmer AC, Aarons G. Attitudes toward adoption of evidence-based practices: A 
comparison of autism early intervention providers and children’s mental health providers. 
Psychol Serv. 2009;6(3):223-234. doi:10.1037/a0010738 
20.  
Thornicroft G. Evidence-based mental health care and implementation science in low- 
and middle-income countries. Epidemiol Psychiatr Sci. 2012;21(3):241-244. 
doi:10.1017/S2045796012000261 
21.  
Arean PA, Raue PJ, Sirey JA, Snowden M. Implementing evidence-based 
psychotherapies in settings serving older adults: Challenges and solutions. Psychiatr 
Serv. 2012;63(6):605-607. doi:10.1176/appi.ps.201100078 
22.  
Alexopoulos GS, Areán PA. A model for streamlining psychotherapy in the RDoC era: the 
example of “Engage”. Mol Psychiatry. 2014;19(1):14-19. doi:10.1038/mp.2013.150 
23.  
Alexopoulos GS, Raue PJ, Gunning F, et al. “Engage” therapy: Behavioral activation and 
improvement of late-life major depression. Am J Geriatr Psychiatry. 2016;24(4):320-326. 
doi:10.1016/J.JAGP.2015.11.006 
24.  
Alexopoulos GS, Raue PJ, Kiosses DN, Seirup JK, Banerjee S, Arean PA. Comparing 
engage with PST in late-life major depression: A preliminary report. Am J Geriatr 
Psychiatry. 2015;23(5):506-513. doi:10.1016/j.jagp.2014.06.008 
25.  
Solomonov N, Victoria LW, Dunlop K, et al. Resting State Functional Connectivity and 
Outcomes of Psychotherapies for Late-Life Depression. Am J Geriatr Psychiatry. April 
2020. doi:10.1016/j.jagp.2020.04.008 
26.  
Alexopoulos GS, O’Neil R, Banerjee S, et al. “Engage” therapy: Prediction of change of 
late-life major depression. J Affect Disord. 2017;221:192-197. 
doi:10.1016/j.jad.2017.06.037 
27.  
Solomonov N, Bress JN, Anne Sirey JA, et al. Engagement in socially and interpersonally 
rewarding activities as a predictor of outcome in ‘Engage’ behavioral activation therapy 
for late-life depression. Am J Geriatr Psychiatry. 2019;27(6):571-578. 
doi:https://doi.org/10.1016/j.jagp.2018.12.033 
28.  
Solomonov N, Lee J, Banerjee S, et al. Predictors of early risk for treatment nonresponse 
in psychotherapies for late-life depression: A machine learning approach. Mol Psychiatry. 
2020. 
29.  
Van Orden KA, Arean PA, Silva C, Reynolds C, Conwell Y. Socially Engage: A Pilot 
Randomized Trial of “Engage” Psychotherapy to Target Low Social Engagement and 
Suicide Risk in Later Life.; 2019. 
30.  
Sirey JA, Raue PJ, Solomonov N, et al. Community delivery of brief therapy for 
depressed older adults impacted by Hurricane Sandy. Transl Behav Med. 2020. 
31.  
Tracey TJ, Kokotovic AM. Factor Structure of the Working Alliance Inventory. Vol 1.; 
1989. 
https://s3.amazonaws.com/academia.edu.documents/45314040/Factor_Structure_of_the
_Working_Alliance20160503-23234-
pnwuzi.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1548616964&Sign
ature=UCZXH8YsKTLPT3UxkWO6iON3bxI%3D&response-content-
disposition=inline%3B filename%3DFactor_structure_of_the_Working_Alliance.pdf. 
Accessed January 27, 2019. 

Protocol # 20-04021860 
5.21.2024 
 
Page # 33 
 
32.  
Solomonov N, McCarthy KS, Gorman BS, Barber JP. The Multitheoretical List of 
Therapeutic Interventions – 30 items (MULTI-30). Psychother Res. 2018. 
doi:10.1080/10503307.2017.1422216 
33.  
Rizvi SJ, Quilty LC, Sproule BA, Cyriac A, Michael Bagby R, Kennedy SH. Development 
and validation of the Dimensional Anhedonia Rating Scale (DARS) in a community 
sample and individuals with major depression. Psychiatry Res. 2015;229(1-2):109-119. 
doi:10.1016/j.psychres.2015.07.062 
34.  
Kanter JW, Mulick PS, Busch AM, Berlin KS, Martell CR. The Behavioral Activation for 
Depression Scale (BADS): Psychometric Properties and Factor Structure. J Psychopathol 
Behav Assess. 2007;29(3):191-202. doi:10.1007/s10862-006-9038-5 
35.  
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry. 1979;134(4):382-389. doi:10.1192/bjp.134.4.382 
36.  
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-
62. 
37.  
Barkham M, Hardy GE, Startup M. The IIP-32: A short version of the Inventory of 
Interpersonal Problems. Br J Clin Psychol. 1996. doi:10.1111/j.2044-
8260.1996.tb01159.x 
38.  
Koenig HG, Westlund RE, Linda George MK, Hughes DC, Blazer DG, Hybels C. 
Abbreviating the Duke Social Support Index for use in chronically ill elderly individuals. 
Psychosomatics. 1993;34:61-69. doi:10.1016/S0033-3182(93)71928-3 
39.  
Russell DW. UCLA Loneliness Scale (Version 3): Reliability, Validity, and Factor 
Structure. J Pers Assess. 1996;66(1):20-40. doi:10.1207/s15327752jpa6601_2 
40.  
Borkovec TD, Nau SD. Credibility of analogue therapy rationales. J Behav Ther Exp 
Psychiatry. 1972;3(4):257-260. doi:10.1016/0005-7916(72)90045-6 
41.  
Borkovec TD, Abel JL, Newman H. Effects of psychotherapy on comorbid conditions in 
generalized anxiety disorder. J Consult Clin Psychol. 1995;63(3):479-483. 
doi:10.1037/0022-006X.63.3.479 
42.  
Cools R, Clark L, Owen AM, Robbins TW. Defining the Neural Mechanisms of 
Probabilistic Reversal Learning Using Event-Related Functional Magnetic Resonance 
Imaging. J Neurosci. 2002;22(11):4563-4567. doi:10.1523/jneurosci.22-11-04563.2002 
43.  
Dombrovski AY, Clark L, Siegle GJ, et al. Reward/Punishment reversal learning in older 
suicide attempters. Am J Psychiatry. 2010;167(6):699-707. 
doi:10.1176/appi.ajp.2009.09030407 
44.  
Knutson B, Westdorp A, Kaiser E, Hommer D. FMRI visualization of brain activity during 
a Monetary Incentive Delay Task. Neuroimage. 2000;12(1):20-27. 
doi:10.1006/NIMG.2000.0593 
45.  
Knutson B, Bhanji JP, Cooney RE, Atlas LY, Gotlib IH. Neural Responses to Monetary 
Incentives in Major Depression. Biol Psychiatry. 2008;63(7):686-692. 
doi:10.1016/J.BIOPSYCH.2007.07.023 
46.  
Bates D, Mächler M, Zurich E, Bolker BM, Walker SC. Fitting Linear Mixed-Effects 
Models Using Lme4. https://arxiv.org/pdf/1406.5823.pdf. Accessed November 14, 2018. 
47.  
Schwarz G. Estimating the dimension of a model. Ann Stat. 1978;6(2):461-464. 
 

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Appendix A