Novel Neural Circuit Biomarkers of Major Depression Response to Computer-augmented CBT
Phase: NA
Conditions: Depression, Major Depressive Disorder, Depressive Disorder, Depression, Unipolar
Sponsor: University of Pennsylvania

Novel neural circuit biomarkers of major depression response to computer-augmented CBT 
 
NCT: NCT03096886  
 
Document Date: May 3, 2019 
 

Page 1 of 27
Modiﬁcation
Basic Info
Conﬁrmation Number:
cihghbcb
Protocol Number:
832295
Created By:
WONG, JOYCE X
Principal Investigator:
SHELINE, YVETTE I
Protocol Title:
Novel neural circuit biomarkers of major depression response to computer-augmented CBT (1R01MH110939 - 01A
Short Title:
CCBT fMRI R01
Protocol Description:
This is a trial of an FDA-approved treatment for MDD, computer-augmented cognitive 
behavioral therapy (CCBT), to examine novel potential neural circuit biomarkers of treatment 
response. 100 subjects total: 40 controls, 60 MDD. MDD subjects begin CCBT at the earliest 
scheduling availability. CCBT treatment lasts 8 wks. All subjects will have an fMRI at baseline 
before CCBT and a ﬁnal fMRI after the treatment phase. Those beginning CCBT later will 
complete an additional fMRI before CCBT.
Submission Type:
Biomedical Research
Application Type:
EXPEDITED Category 3 and Category 4
PennERA Protocol Status
Approved
Resubmission*
No
Are you submitting a Modiﬁcation to this protocol?*
Yes
Current Status of Study
Study Status
Currently in Progress
If study is currently in progress, please enter the following
Number of subjects enrolled at Penn since the study was initiated
4
Actual enrollment at participating centers
0
If study is closed to further enrollment, please enter the following
Number of subjects in therapy or intervention
0

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Number of subjects in long-term follow-up only
0
IRB Determination
If the change represents more than minimal risk to subjects, it must be reviewed and approved by the 
IRB at a convened meeting. For a modiﬁcation to be considered more than minimal risk, the proposed 
change would increase the risk of discomfort or decrease beneﬁt. The IRB must review and approve the 
proposed change at a convened meeting before the change can be implemented unless the change is 
necessary to eliminate an immediate hazard to the research participants. In the case of a change 
implemented to eliminate an immediate hazard to participants, the IRB will review the change to 
determine that it is consistent with ensuring the participant&prime;s continued welfare. Examples: 
Convened Board Increase in target enrollment for investigator initiated research or potential Phase I 
research Expanding inclusion or removing exclusion criteria where the new population may be at 
increased risk Revised risk information with active participants Minor risk revisions that may affect a 
subject&prime;s willingness to continue to participate Expedited Review Increase in target enrollment 
at Penn where overall enrollment target is not exceeded or potentially sponsored research Expanding 
inclusion or removing exclusion where the new population has the same expected risk as the previous, 
based on similarities of condition Revised risk information with subjects in long-term follow-up Minor 
risk revisions with no subjects enrolled to date 
Expedited Review
Modiﬁcation Summary
Please describe any required modiﬁcation to the protocol. If you are using this form to submit an 
exception or report a deviation, enter 'N/A' in the box below.
Modifying study procedures to include an additional 15 minute computer task. Informed consent forms 
have been modiﬁed to include information about this computer task.  Two key study personnel have 
been added to the study.
Risk / Beneﬁt
Does this amendment alter the Risk/Beneﬁt proﬁle of the study?
No
Change in Consent
Has there been a change in the consent documents?
Yes
If YES, please choose from the options below regarding re-consenting
Our site does not plan to obtain re-consent
Deviations
Are you reporting a deviation to this protocol?*
No
Exceptions
Are you reporting an exception to this protocol?*
No

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Protocol Details
Resubmission*
Yes
Study Personnel
Principal Investigator
Name:
SHELINE, YVETTE I
Dept / School / Div:
10579 - PS-Center for the Neuroscience of Depression & Stress
Campus Address
Mail Code
6021
Address:
3700 Hamilton Walk Richards 301
City State Zip:
Philadelphia PA 19104-6019
Phone:
215-573-0082
Fax:
215-573-0759
Pager:
Email:
sheline@mail.med.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
07/01/2019
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Study Contacts
Name:
WONG, JOYCE X
Dept / School / Div:
10579 - PS-Center for the Neuroscience of Depression & Stress
Campus Address
Mail Code
3309
Address:
OFFICE BLDG STE 100 
3535 MARKET ST 
City State Zip:
PHILADELPHIA PA 19104-3309
Phone:
215-573-4561
Fax:
-
Pager:
Email:
jowong@pennmedicine.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
03/11/2021
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA

Page 4 of 27
Name:
STOCK, JANET
Dept / School / Div:
10579 - PS-Center for the Neuroscience of Depression & Stress
Campus Address
Mail Code
6160
Address:
BIOMEDICAL RESEARCH BLDG 2
421 CURIE BLVD 
City State Zip:
PHILADELPHIA PA 19104-6160
Phone:
215-573-0085
Fax:
-
Pager:
Email:
jastock@upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
11/25/2020
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Other Investigator
Name:
THASE, MICHAEL E
Dept / School / Div:
10261 - PS-Affective Disorders Program
Campus Address
Mail Code
6021
Address:
3535 Market St-Suite 670
3535 Market St
Psychiatry
City State Zip:
Philadelphia PA 19104-3309
Phone:
215-746-6680
Fax:
215-573-0759
Pager:
Email:
thase@mail.med.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
05/09/2019
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Responsible Org (Department/School/Division):
10579 - PS-Center for the Neuroscience of Depression & Stress
Key Study Personnel
Name:
LONG, HANNAH B
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
06/04/2020
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA

Page 5 of 27
Name:
STRAVACH, GABRIELLE R
Department/School/Division:
School of Nursing
HS Training Completed:
Yes
Training Expiration Date:
10/09/2021
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
RAMAKRISHNAN, ARJUN
Department/School/Division:
NS-Neuroscience
HS Training Completed:
Yes
Training Expiration Date:
07/20/2019
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
SCULLY, MORGAN
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
09/20/2019
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
VOGELEY, GABRIELA
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
10/18/2021
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
PLATT, MICHAEL L
Department/School/Division:
Psychology
HS Training Completed:
Yes
Training Expiration Date:
09/05/2021
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
BYRD, CHRISTOPHER
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
06/25/2021
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
GREEN, GABRIELLA
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
01/25/2020
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA

Page 6 of 27
Name:
SHIMOMOTO, CHIHIRO
Department/School/Division:
School of Nursing
HS Training Completed:
Yes
Training Expiration Date:
09/07/2020
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
PROCIUK, MARIA L
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
08/13/2020
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
HEMBREE, ELIZABETH A
Department/School/Division:
PS-Psychiatry
HS Training Completed:
Yes
Training Expiration Date:
03/22/2019
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
MAKHOUL, WALID
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
09/03/2021
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
SEOK, DARSOL K
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
06/26/2020
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
LYU, MENGQUN
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
09/12/2021
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
ASELCIOGLU, IREM
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
05/02/2019
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Disclosure of Signiﬁcant Financial Interests*
Does any person who is responsible for the design, conduct, or reporting of this research protocol have 
a FINANCIAL INTEREST?
No

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Penn Intellectual Property*
To the best of the Principal Investigator's knowledge, does this protocol involve the testing, 
development or evaluation of a drug, device, product, or other type of intellectual property (IP) that is 
owned by or assigned to the University of Pennsylvania?
No
Certiﬁcation
I have reviewed the Financial Disclosure and Presumptively Prohibited Conﬂicts for Faculty 
Participating in Clinical Trials and the Financial Disclosure Policy for Research and Sponsored 
Projects  with all persons who are responsible for the design, conduct, or reporting of this research; and 
all required Disclosures have been attached to this application.
Yes
Biomedical Research
Clinical Trial*
Is this a clinical trial?
Yes
If Yes, please be aware that for each clinical trial conducted or supported by a Federal department or 
agency, one IRB-approved informed consent form used to enroll subjects must be posted by the 
awardee or the Federal department or agency component conducting the trial on a publicly available 
Federal Web site that will be established as a repository for such informed consent forms.
Investigator Initiated Trial*
Is this an investigator initiated trial?
No
Drugs or Devices*
Does this research study involve Drugs or Devices?
No
IND Exemption
For studies that fall under an IND exemption, please provide the number below
For studies including IND or IDE's, please provide the number(s) below
IDE Review*
NOTE: For research involving investigational devices, you are required to review the guidance on 
Managing Research Device Inventory. Consult the Penn Manual for Clinical Research: https://
www.med.upenn.edu/pennmanual/secure/investigational-product-management-at-sites-not-using-
investigational-drug-services-(ids).html Please check the box Yes if you have reviewed the guidance.
Yes
Research Device Management*
Please indicate how research device(s) will be managed.
Not Applicable (no investigational devices)
Drug, Herbal Product or Other Chemical Element Management *
Please indicate how drugs, herbal products or other chemical entities will be managed.
Not Applicable (no drugs, herbal products or other chemical entities)
Radiation Exposure*
Are research subjects receiving any radiation exposure (e.g. X-rays, CT, Fluoroscopy, DEXA, pQCT, 
FDG, Tc-99m, etc.) that they would not receive if they were not enrolled in this protocol?

Page 8 of 27
No
Gene Transfer*
Does this research involve gene transfer (including all vectors) to human subjects?
No
Human Source Material*
Does this research include collection or use of human source material (i.e., human blood, blood 
products, tissues or body ﬂuids)?
Yes
CACTIS and CT Studies*
Does the research involve Center for Advanced Computed Tomography Imaging Services (CACTIS) 
and CT studies that research subjects would not receive if they were not part of this protocol?
No
CAMRIS and MRI Studies*
Does the research involve Center for Advanced Magnetic Resonance Imaging and Spectroscopy 
(CAMRIS) and MRI studies that research subjects would not receive if they were not part of this 
protocol?
Yes
Investigational Agent or Device within the Operating Room*
Does the research project involve the use of an investigational agent or device within the Operating 
Room?
No
Cancer Related research not being conducted by an NCI cooperative group*
Does this protocol involve cancer-related studies in any of the following categories?
No
Processing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
No
In-House Manufacturing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
No
Medical Information Disclosure*
Does the research proposal involve the use and disclosure of research subject's medical information for 
research purposes?
Yes
If the answer is YES, indicate which items is is provided with this submission:
Modiﬁed research informed consent document that incorporates HIPAA requirements
CTRC Resources*
Does the research involve CTRC resources?
No
Pathology and Laboratory Medicine Resources*
Will samples be collected by hospital phlebotomy and/or processed or analyzed by any of the clinical 
laboratories of the University of Pennsylvania Health System?
No
Research Involves Apheresis, Cell Collection, and/or Blood Product Collection*
Does this research involve collection of blood products in the Penn Donor Center and/or the use of 
apheresis for treatment or collection of cells or other blood components?
No

Page 9 of 27
Research involving blood transfusion or drug infusions*
Will your research involve blood transfusion or infusion of study drug in 3 Ravdin Apheresis Unit for 
research purposes?
No
Trial in Radiation Oncology
Is this research a prospective trial being done in Radiation Oncology, and if so, has this protocol been 
approved by the Radiation Oncology Protocol committee?
N/A
Study in Radiation Oncology
Is this research a retrospective study being done in Radiation Oncology, and if so, has this project been 
reviewed by the Radiation Oncology Clinical Research Group?
N/A
Use of UPHS services*
Does your study require the use of University of Pennsylvania Health System (UPHS) services, tests or 
procedures*, whether considered routine care or strictly for research purposes?
No
Primary Focus*
Sociobehavioral (i.e. observational or interventional)
Protocol Interventions
x Sociobehavioral (i.e. cognitive or behavioral therapy)
Drug
Device - therapeutic
Device - diagnostic (assessing a device for sensitivity or speciﬁcity in disease diagnosis)
Surgical
Diagnostic test/procedure (research-related diagnostic test or procedure)
Obtaining human tissue for basic research or biospecimen bank
Survey instrument
None of the above
The following documents are currently attached to this item:
There are no documents attached for this item.
Sponsors
Business Administrator
Name:
MERGLIANO, EILEEN E
Dept / School / Div:
4412 - PS-Psychiatry
Phone:
215-746-6666
Fax:
215-573-0759
Pager:
Email:
emerg@upenn.edu
Department budget code
000 - 000 - 0 - 000000 - 0000 - 0000 - 0000

Page 10 of 27
Funding Sponsors
Name:
NATIONAL INSTITUTE OF MENTAL HEALTH/NIH/DHHS
Type:
UPENN Federal
Funding sponsors billing address
If you have selected a commercial or industry sponsor, please provide the appropriate address and 
contact information for the Sponsor for the purposes of billing for IRB review fees (initial review, 
continuing review and convened modiﬁcation fees apply here). If the Sponsor is not industry/
commercial, this information is not necessary to provide with your application.
Funding sponsors gift
Is this research being funded by a philanthropic gift?
No
Regulatory Sponsor
IND Sponsor
none
000 - 000 - 0 - 000000 - 0000 - 0000 - 0000
Industry Sponsor
None
Project Funding*
Is this project funded by or associated with a grant or contract?
Yes
Selected Proposals
Proposal No
Title
10058145
Novel neural circuit biomarkers of depression response to computer-augmented CBT
Sponsor Funding
Is this study funded by an industry sponsor?
No
Status of contract
The following documents are currently attached to this item:
There are no documents attached for this item.
Multi-Center Research
Penn as lead
1. Is this a multi-center study where Penn is serving as the Lead Site or the Penn PI is serving as the 
Lead Investigator?
No
Management of Information for Multi-Center Research
Penn irb of record
2. Is this a multi-center study where the Penn IRB will be asked to serve as the IRB of Record for other 
external study sites?

Page 11 of 27
No
Other Sites
No other sites
Protocol
Abstract
This is a trial of an FDA-approved treatment for Major Depressive Disorder (MDD), computer-
augmented cognitive behavioral therapy (CCBT), to examine novel potential neural circuit biomarkers 
of treatment response rather than to test efﬁcacy. We will enroll 60 subjects, 18-60 years, who are 
seeking treatment for a current episode of Major Depressive Disorder. We also will enroll 40 healthy 
controls of a similar age/sex distribution. MDD subjects will be scheduled to receive CCBT at the ﬁrst 
available appointment; all will be scheduled within 4 weeks. All subjects will have an fMRI at baseline; 
MDD subjects will have an fMRI after treatment. MDD subjects scheduled to start CCBT treatment 
after 3 weeks will complete an additional fMRI before they begin CCBT.
Objectives
Overall objectives
The overall objectives of the study are to examine novel potential neural circuit bio-markers of 
treatment response to computer-augmented cognitive behavioral therapy (CCBT) for people with MDD. 
Aim 1: Compare baseline resting state functional connectivity and task-induced activity between MDD 
and controls: Hypothesis 1a): Compared with controls, depressed participants will have disruptions in 
resting state functional connectivity in the amygdala-cognitive-executive (C-E) network and the 
amygdala-default mode network (DMN); and 1b) will have decreased emotional conﬂict task-induced 
activation in rostral/dorsal anterior cingulate cortex (ACC), dorsal lateral prefrontal cortex (DLPFC), 
and inferior frontal gyrus (IFG).  Aim 2: Assess CCBT treatment effects on resting state functional 
connectivity and task induced activity in MDD comparing post-CCBT treatment to pre-CCBT 
treatment. Hypothesis 2a) Compared with pre-CCBT neuroimaging measures, following active 
treatment there will be increase in C-E connectivity and decreased amygdala-DMN connectivity. 2b) 
These changes will be correlated with symptom reduction and 2c) increases in rostral/dorsal ACC, 
DLPFC and IFG activation during the emotional conﬂict task.  Exploratory Aim: 1a) Predict the effects 
of baseline brain measures on treatment outcomes. Hypothesis: Using clinical decision-support 
algorithms, clinical outcome trajectories and differential response to treatment will be predicted from 
baseline data (brain connectivity, task-based activity and cortical thickness). 1b) Predict the effects of 
baseline executive function on treatment outcomes. Hypothesis: Using clinical decision-support 
algorithms, clinical outcome trajectories and differential response to treatment will be predicted from 
baseline executive function data. Developing such algorithms to help determine risk trajectories is 
important for more effective treatment assignment. Secondary Aims: Data collected from actigraphy, 
saliva sample, and remote monitoring via the Beiwe cellphone application will be used as preliminary 
evidence examining the effects of sleep-wake patterns, microbiome, and total physical activity on 
treatment outcomes in individuals experiencing depression.
Primary outcome variable(s)
Aim 1: 1a) resting state functional connectivity 1b) emotional conﬂict task-induced brain activity Aim 2 
Treatment effects: 2a) amygdala-connectivity 2b) changes rostral/dorsal ACC, DLPFC and IFC 
activation during the emotional conﬂict task. Patients will serve as their own controls pre-post 
treatment. In addition, patients who wait longer for treatment (3-4 weeks) will be compared in a second 
scan with those who receive immediate treatment (1-2 weeks).
Secondary outcome variable(s)
Exploratory Aim: 1a) brain connectivity, task-based activity and cortical thickness Secondary Aims: 

Page 12 of 27
Data collected from actigraphy, saliva sample, and remote monitoring via the Beiwe cellphone 
application will be used as preliminary evidence examining the effects of sleep-wake patterns, 
microbiome, and total physical activity on treatment outcomes in individuals experiencing depression.
Background
FOR ADDITIONAL BACKGROUND INFORMATION AND SOURCE DOCUMENTATION, 
PLEASE REFER TO PROTOCOL 826910 - CCBT FMRI RESEARCH STRATEGY WITH 
REFERENCES.  Signiﬁcance of computer-augmented cognitive behavioral therapy (CCBT): The 
fundamental signiﬁcance of the proposed research is that it will examine neural circuits that have the 
potential to be novel biomarkers of depression treatment response to computer-augmented cognitive 
behavioral therapy (CCBT). Rather than testing efﬁcacy, our proposed clinical trial will, as outlined in 
NIMH NOT-14-0007, elucidate the mechanism of action of CCBT at the level of neurocircuitry. 
Speciﬁcally, we will continue previous research by Sheline and colleagues at Washington University 
and Thase and colleagues at the University of Pittsburgh, that examines CBT-induced changes in two 
key large-scale brain networks the Central-Executive Network (CEN) and Default Mode Network 
(DMN). Our current proposal will use a model of CBT that implements computer-augmented 
instructional modules to make therapy substantially more accessible and cost-effective compared to 
conventional treatment. Further, by conﬁrming that the neurocircuitry targets found for conventional 
CBT can be readily engaged by computer-assisted, self-help exercises, we will open a promising new 
avenue of research that can lead to further reﬁnements in the delivery and efﬁcacy of this form of 
therapy. CBT is the psychotherapy with the best evidence base for the treatment of depression [1, 2]. It 
has established efﬁcacy for major depressive disorder (MDD) in clinical trials in comparison both to 
attention-control conditions and antidepressant pharmacotherapy [1, 2]. Moreover, it is the one 
empirically validated form of treatment for depression that has been shown to have more durable or 
sustained effects that persist for months after therapy is stopped [3, 4]. However, although people 
seeking treatment for depression often rank CBT and related interventions as highly desirable or even 
more preferred than pharmacotherapy [5], in current practice the public health impact of CBT is 
severely restricted by the limited number of qualiﬁed therapists, their narrow geographic distribution, 
and the relatively high direct cost of a conventional 12-20 hour course of therapy. One strategy to 
address the problem of accessibility has been development of web-based CBT programs [6, 7]. The 
utility of computer-augmented models of therapy (or CCBT) such as Beating the Blues and Mood Gym 
has now been established by more than two dozen randomized controlled trials [6, 8, 9]. The Good 
Days Ahead (GDA) [10] model of CCBT that we propose to use in this study was developed primarily 
to serve as an adjunct to therapy, with the goals of complementing and streamlining the efforts of 
therapists. In both the original proof of concept study of Wright et al. [11] and our recently completed 
large scale non-inferiority study [12], outpatients with MDD obtained essentially identical beneﬁt from 
treatment with GDA and 3-4 hours of therapist contact as they did with up to 20 hours of conventional 
CBT [7, 12]. Thus, we have shown that a substantial proportion of the therapeutic action of CBT can be 
shifted from the therapists ofﬁce to the patients home or ofﬁce and, as a result, the cost of treatment can 
be reduced considerably while the convenience and accessibility of therapy is increased. Further, we 
predict that repeated practice and mastery of the guided coping exercises developed for GDA CCBT 
will signiﬁcantly enhance target engagement at the level of neurocircuitry. To conﬁrm this, the amount 
of time patients spend on the computer will be directly measured. We anticipate that this more cost 
effective form of treatment delivery will have the potential to be tailored and reﬁned to increase 
effectiveness. Understanding the mechanism of CCBT with Neural Circuits: Overview: Understanding 
the functional connectome of the human brain is a fundamental prerequisite for accurate models of both 
healthy brain function and dysfunction in MDD. Several reports have focused on structural and 
functional connectomic differences between MDD and controls [13]. Some studies have demonstrated 
metabolic differences, including prefrontal cortex hypometabolism [14] and amygdala hypermetabolism 
[15]. We ﬁrst showed task-based amygdala hyperactivity in depression [16], conﬁrmed in subsequent 
studies (reviewed in Hamilton et al., 2012 [17]), Further, resting state functional connectivity assessed 
in fMRI data is disrupted in ﬁrst-episode MDD compared with controls, with increased connectivity in 
the DMN and diminished fronto-parietal connectivity [18]. Hypoconnectivity within the frontoparietal 
network and hyperconnectivity within the DMN were also reported in a meta-analysis of MDD studies 
[19]. We and others have speculated that amygdala hyperactivity may arise from diminished top-down 
regulatory connectivity from cognitive executive networks [20]. In a recent report, we found strong 
support for this hypothesis [21].

Page 13 of 27
Study Design
Phase*
Not applicable
Design
60 subjects with MDD will be scheduled to begin CCBT early or later. Participants are randomly 
assigned to one of the two groups by a random number generated by the computer: (1) for Early CCBT 
and (2) for Later CCBT. All participant will be scheduled to start CCBT within 4 weeks after 
completing baseline assessments. Early CCBT participants will begin treatment within 2 weeks after 
the ﬁrst MRI scan and Later CCBT participants will begin treatment after 2 weeks from the ﬁrst MRI 
scan. Early CCBT participants will have two pre-treatment study visits and will be scheduled to begin 
CCBT within 0-14 days from Visit #1(screening visit) and after the completion of the ﬁrst fMRI scan. 
Late CCBT Participants will have three pre-treatment study visits (detailed above) and will be 
scheduled to start CCBT within 15-28 days from Visit #1 (screening visit) and after completing two 
fMRI scans. The two fMRI scans must be at least 14 days apart from each other. CCBT treatment is 8 
weeks.  40 healthy controls of similar age/sex will be recruited to serve as a comparison group for 
baseline MRI scanning. Members of the research team who are responsible for the assessment of 
outcomes will be blinded to MDD grouping.
Study duration
The study will enroll subjects for approximately 4 years (~2 subjects per month for 48 months). The 
length of subject participation will vary based on what group they are in. Healthy controls will 
participate for ~8 weeks; 2 study visits will occur within 1-3 weeks; remainder of study participation 
will be remote via cell phone and actigraph and one visit at end of remote monitoring.  Subjects with 
MDD will participant for up to 8-12 weeks. Variability in the study duration for each group depends on 
participant and therapist availability for visits and the availability of the MRI. The project is anticipated 
to begin subject recruitment and data collection in January 2019 and be completed by April 2021.
Resources necessary for human research protection
Describe research staff and justify that the staff are adequate in number and qualiﬁcations to conduct 
the research. Describe how you will ensure that all staff assisting with the research are adequately 
informed about the protocol and their research related duties. Please allow adequate time for the 
researchers to conduct and complete the research. Please conﬁrm that there are adequate facilities for 
the research.
The project will be managed by the investigators and dedicated coordinators. The investigators and 
staff, led by the PI, will meet monthly to review the program progress and address speciﬁc problems. 
Regular project reviews will be held twice annually. The investigators are experienced administrators 
and accomplished scientists. They have existing and effective collaborations, and this spirit will be 
carried forward in the proposed research. The PI has administrative experience as Director of the Center 
for Neuromodulation in Depression and Stress. Co-I Thase is Director of the Mood and Anxiety 
Program in the Psychiatry Department. Day-to-day management of the project will performed by two 
clinical coordinators, who will recruit patients from the Psychiatry clinics and enroll them in the study, 
and schedule the MRI scans and all behavioral assessments. Clinical research coordinators have been 
trained by the University of Pennsylvania and have experience coordinating clinical trails with these 
investigators. All investigators, key personnel, and study coordinators will meet prior to the study start 
to discuss the protocol and implementation of the protocol. All research staff will be required to review 
any signiﬁcant changes to the protocol prior to the implementation.  All staff are trained in HIPAA and 
CITI Human Subjects Research. Initial training (e.g. at start up), rater certiﬁcation standards, ongoing 
quality control (QC), and methods to ensure interrater reliability at an acceptable level will be 
performed prior to subject contact. All clinical efﬁcacy assessments will be done by the investigators or 
personnel delegated by the investigators, who are suitably trained to assess the participants. This will be 
monitored by assigning rater IDs. Interviews will be conducted by trained, experienced clinical 
coordinators and interviewers. All will receive careful and rigorous training. Interviewers will remain in 
frequent contact with the PI to maintain uniform assessment criteria and to resolve diagnostic and other 
rating issues. In addition, interviewers will meet weekly to staff any new assessments conducted. This 
careful review of diagnoses and symptoms is in place to maximize reliability. Our quality control 
procedures aim to ensure the validity of the data. This will necessitate standardization across raters 
every six months. All data will be entered directly into the database as it is accumulated. The PI will 
monitor the reliability of the data entry and insure the integrity of the database, coding, and entry 

Page 14 of 27
veriﬁcation. Both study therapists have been certiﬁed by the Academy of Cognitive Therapy and have 
successfully treated (deﬁned as scoring at least 40 on the Cognitive Therapy Scale: CTS) 10+ patients 
with CCBT. As the efﬁcacy of CBT is related to therapist skill level, therapists will be supervised by Dr. 
Thase to ensure adherence and competent delivery. The protocol adherence rating scale used in two 
earlier studies of GDA will be utilized and one quarter of the sessions will be audiotaped and scored 
using the Cognitive Therapy Scale (CTS). A CTS score of 40 is considered minimally adequate to 
conduct CBT in treatment outcome studies. The Mood & Anxiety Treatment and Research Program and 
Center for Neuromodulation in Depression and Stress are both equipped for participant visits. MRIs 
will be conducted at Stellar Chance or HUP6, with the approval of CAMRIS.
Characteristics of the Study Population
Target population
60 participants with Major Depressive Disorder, in current MD episode of at least moderate severity, as 
indicated by the SCID-5 and MADRS (greater than or equal to 20). There will be 40 healthy control 
participants of similar age/sex. Combining with subjects from protocol 826910, we will enroll 37 
additional MDD participants and 24 additional healthy controls through protocol 832295 to meet the 
overall target of 100 subjects (60 MDD, 40 Healthy controls).
Subjects enrolled by Penn Researchers
61
Subjects enrolled by Collaborating Researchers
0
Accrual
The MDD participants will be primarily recruited from the Outpatient Clinics of the University of 
Pennsylvania, including the Mood and Anxiety Disorders program, student health and the general adult 
psychiatry programs. These programs see 400+ new patients with depressive disorders each year and 
contributed 72 unmedicated MDD participants across 30 months to the recently completed 
noninferiority study of CCBT. Should the need arise, we also can recruit from the Philadelphia VA 
Medical Centers Behavioral Health Laboratory (PVAMC-BHL). As the BHL continuously screens from 
the primary care clinical population of the PVAMC, it will serve as a rich secondary recruitment 
resource for individuals for this study. As an example, from August 2013 to August 2014, 1,298 
individuals between ages 18 and 45 completed assessments within the BHL. Of the 1,194 individuals 
who completed full assessments, approximately 29.4% screened positive for MDD, providing an ample 
participant base from which to recruit. We thus anticipate no difﬁculty enrolling depressed patients into 
this study. Up to 120 participants will be consented for participation; however we anticipate that 
approximately 10% will screen fail and another 10% will either drop out during the study or have 
unusable scanner data; therefore, we aim to have 60 participants with MDD and 40 healthy control 
participants who complete the entire study with usable data.  C.10.1 Power Analysis For Aim 1, based 
on our pilot data, we assume that DLPFC in HC is positively correlated with amygdala with correlation 
of r=0.1, while in contrast it is negatively correlated in MDD with correlation r=-0.1 (standard deviation 
0.07). Similarly, our pilot data indicates that IFC in MDD is 70% less correlated with the amygdala than 
in HC (standard deviation 0.07). Given 60 MDD patients and 40 HC at baseline, we have excellent 
power (80%) to detect the differences between MDD and HC for their baseline amygdala connectivity 
in DLPFC and IFC. For subgroup analysis in subjects of each sex separately, we will also have 80% 
power to detect differences between MDD and HC. Similarly, for baseline task measures, the pilot data 
indicate up to two-fold higher activation in HC in the four targeted regions (ACC, DLPFC, IFC), 
indicating that will also have 80% power to detect such differences between MDD and HC (in males 
and females separately, as well as combining sexes) at the 95% conﬁdence level adjusting for the 
number of tests.  For Aim 2, based on our pilot data, the correlation between IFC and amygdala will 
increase by 0.09 after CCBT (standard deviation 0.05), and the correlation between precuneus and 
amygdala will decrease by 0.08 (standard deviation 0.04). We will have 80% power to identify 
treatment effects comparing the data from 30 MDD patients receiving CCBT in 1-2 weeks with 
untreated data from the subjects receiving CCBT in 3-4 weeks. We will also have 80% power to detect 
different treatment effects in males and females separately. For longitudinal changes in activation, we 

Page 15 of 27
will have 80% power to detect 20% (combined) / 26% (in each sex) or more activation in R IFC after 
CCBT, 19% / 28% or more in L IFC , 95% / 137% or more in ACC and 50% / 71% in DLPFC. The 
pilot data indicate that the activation changes will be sufﬁciently large to exceed these minimum 
detectable effects.
Key inclusion criteria
Adults 18 - 60 years old, gender inclusive 2. Willing to not take psychotropic medications for the 
duration of the study 3. Fluent in English (both verbally and written) 4. Able and willing to provide 
consent 5. Must have regular access to computer at home 6. Must own a smart phone (iPhone or 
Android) Experimental group 1) Diagnosis of MDD, experiencing current episode as determined by 
SCID-5 2) Current MDE of moderate severity, as determined by MADRS score of 20 or higher Control 
group 1) No history of MDD in lifetime 2) No indication of current, signiﬁcant depressive symptoms, 
as determined by MADRS score of 8 or lower
Key exclusion criteria
Diagnosis of severe or poorly controlled concurrent medical disorders that may cause depression or 
require medication that could cause depressive symptoms 2. Unwilling to provide informed consent 3. 
Diagnosis of concurrent DSM-5 (SCID) psychiatric disorders: any psychotic or organic mental disorder, 
bipolar disorder, active alcohol or drug dependence, primary anxiety disorder or primary eating 
disorders (primary refers to the diagnosis associated with the most functional impairment) 4. Diagnosed 
(DSM-5 criteria) by the clinical coordinator with attention deﬁcit hyperactivity disorder, learning 
disorder, borderline personality disorder, antisocial personality disorder, or paranoid personality 
disorder 5. Cannot complete questionnaires written in English 6. Have not completed at least a 10th 
grade education or a GED 7. Represent an active suicide risk 8. Have MRI contraindications (e.g., 
foreign metallic implants, pacemaker, severe claustrophobia) Experimental group 1) Score less than 20 
on the MADRS at either the initial or a second interview 2) Have previously failed to respond to a trial 
of at least 8 weeks of CBT conducted by a certiﬁed therapist) 3) Are currently demonstration a response 
to antidepressant/psychotropic medication (individuals taking a psychotropic medication may stop 
taking it for the purpose of the study ONLY if they are not receiving clinical beneﬁts from taking it and 
after meeting with one of the study doctors to discuss the risks/beneﬁts of discontinuing the medication 
and other treatment options) Control group 1) Must have no lifetime history of a major depressive 
episode 2) Must score below 8 on the MADRS
Vulnerable Populations
Children Form
Pregnant women (if the study procedures may affect the condition of the pregnant woman or 
fetus) Form
Fetuses and/or Neonates Form
Prisoners Form
Other
x None of the above populations are included in the research study
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Populations vulnerable to undue inﬂuence or coercion
Vulnerable populations are not speciﬁcally being targeted or recruited for this study. However, 
individuals who are economically disadvantaged or are employees or students of Penn may still 
participate in the study, as they would have equal potential to beneﬁt from the study as any other 
participants. Pregnant women will not be included in the study as there is the potential for unforeseen 
risks of an MRI on the fetus or pregnant women. Women of child-bearing potential will be asked to 
attest that they are not currently pregnant. Only individuals who are able to provide consent for 
themselves and have at minimum of a 10th grade education or a GED can participate.
Subject recruitment
The MDD participants will be primarily recruited from the Outpatient Clinics of the University of 
Pennsylvania, including the Mood and Anxiety Disorders program, student health, the general adult 

Page 16 of 27
psychiatry programs, and various other Penn afﬁliated clinics. Should the need arise, we also can recruit 
from the Philadelphia VA Medical Centers Behavioral Health Laboratory (PVAMC-BHL). Participants 
with MDD and healthy controls will also be recruited through the community through ﬂyers, brochures, 
and printed advertisements in newspapers and public transportation avenues (advertising materials will 
be IRB approved prior to distribution). Furthermore, we will utilize the Internet in recruitment, 
speciﬁcally Craigslist, the CNDS University-sponsored website, iConnect and the CNDS Facebook 
page (UPenn - Center for Neuromodulation in Depression and Stress); as well as Penn newsletters. All 
online postings will be IRB-approved prior to posting.  Additionally, we will be using the IRB-approved 
protocol #826348, A Feasibility Study: Department of Psychiatry Research Initiative (PI: Yvette 
Sheline, MD). Protocol #826348 is a pilot study the will continue through August 2017; the study 
collects basic contact and psychiatric intake information from Penn Behavioral Health Corporate 
Services & Departmentally. Only individuals who meet the basic criteria for this study will be 
contacted. Please see details of 826348 for further information, if necessary.  We will be incorporating 
Penn Data Store (part of DAC) as a recruitment resource. We will send the DAC a list of basic inclusion 
criteria for a report every 2 weeks. Due to the sensitive nature of the diagnosis (depression) we are 
seeking, we will ﬁrst be contacting potential participant's diagnosing provider requesting to contact his/
her patient; we will send an EPIC message to the provider, attaching the patient's chart to the message. 
We will not be viewing the patient's EMR. We will attempt to contact the provider 2 times via EPIC and 
we will seek expressed approval for permission to contact each patient (we will not contact any patients 
for which we have not received written approval from their diagnosing provider).We will attempt (up to 
2 times) to contact the patient/potential participant. If these individuals have an email on ﬁle, we will 
ﬁrst attempt to contact via email; otherwise we will use the phone number provided in EPIC. Please 
ﬁnd scripts attached for the 1st provider email, 2nd provider email, participant email, and phone script 
(participant). We would prefer to use EPIC; however, we don't know how likely providers are to 
respond to this and would like to have the secure share or email with password-protected attachment as 
an option. If using secure share or email, we ask that the provider indicate "yes" or "no" on the 
document for each of the patients we wish to contact. The provider will then send that password 
protected document to us. This protocol has been approved to use email and provide a password-
protected document which includes the patient PHI; password is sent in a separate email. Patient PHI in 
this encrypted document sent to physicians will include only ﬁrst name, last name, and MRN. This is 
the minimum necessary information we provide physicians so that they may correctly identify the 
patients we would like to reach out to about this study. The MRN will prevent errors in the situation 
where patients may have the same names.  Lastly, we will recruit through Penn's Ofﬁce of Clinical 
Research iConnect volunteer registry database. Volunteers who have consented to be contacted 
regarding studies of interest will be sorted by relevant diagnoses and invited by study team members to 
ﬁll out an online self survey to determine eligibility. Research staff will receive the volunteers contact 
information through the Ofﬁce of Clinical Research. Volunteer's contact information will be acquired 
through Penn's Ofﬁce of Clinical Research. If these individuals have an email on ﬁle, we will ﬁrst 
attempt to contact via email; otherwise we will use the phone number provided. Additionally, we will 
utilize the pre-screener tool on iConnect to decrease false positives and increase participation from 
subjects who are willing to commit to the study. Because these are general questions not containing 
protected health information and are answered with only yes or no choices, we do not feel the need to 
include a HIPAA waiver of authorization on iConnect prior to volunteers completing the pre-screener.  
In order to facilitate the enrollment of interested subjects in multiple studies, center-wide general pre-
screening forms phone screen and self-report screen will be used. The Center for Neuromodulation in 
Depression and Stress has numerous studies that all are closely related, in both purpose and eligibility 
criteria, a general pre-screening (both phone and self-report) has been created. The CNDS general 
screener has been approved for all other studies at the center, such as protocols 819654, 824132, and 
825761. Many participants will be eligible for multiple studies and will be presented the opportunity to 
participate in all studies that they are eligible for. An additional beneﬁt of a shared or general 
prescreening is that participants who do not qualify for a speciﬁc study can be informed of other studies 
they are eligible for. It will be clearly explained to all individuals that this pre-screening is for multiple 
studies and that their information will be stored in REDCap (option given to have screening done on 
paper).
Will the recruitment plan propose to use any Penn media services (communications, marketing, etc.) for 
outreach via social media avenues (examples include: Facebook, Twitter, blogging, texting, etc.) or does 
the study team plan to directly use social media to recruit for the research?
Yes

Page 17 of 27
Please identify which method(s) of social media you will utilize, the content of the text to be used, and 
the method(s) for posting this information (i.e., using Penn supported communication services). When 
proposing the text to utilize, please be aware of any social media limitations (i.e., number of characters 
allowed in a tweet) and any appropriate conﬁdentiality practices necessary to be compliant with posting 
research recruitment text.*
Facebook is currently the only social media platform we plan to use for advertising for this study. Our 
unit's Facebook page is UPenn - Center for Neuromodulation in Depression and Stress; in which we 
will only post IRB-approved study advertisements for on-going studies in our program.
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Subject compensation*
Will subjects be ﬁnancially compensated for their participation?
Yes
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If there is subject compensation, provide the schedule for compensation per study visit or session 
and total amount for entire participation, either as text or separate document
Subject compensation will vary by study group. MDD participants will receive $75.00 for the 1st MRI, 
$100.00 for the 2nd MRI, and $125.00 for the 3rd MRI, if applicable. MDD subjects have the potential 
to receive an additional $50.00 bonus for completing all of the Good Days Ahead homework for CCBT 
and 85% of the remote monitoring (e.g., Beiwe self-reports) and Good Days Ahead adherence questions 
(e.g. Ethica self-reports). Therefore, MDD participants can receive up to $225.00 to $350.00 total.  IF 
PARTICIPANTS IN THIS ARM ARE ALSO PARTICIPATING IN PROTOCOL 824132, THEY WILL 
NOT RECEIVE THE $75.00 PAYMENT FOR THE INITIAL MRI SCAN; PARTICIPANTS WILL BE 
COMPENSATED FOR THIS SCAN THROUGH PROTOCOL 824132. THEREFORE, THE 
MAXIMUM COMPENSATION FROM THIS PROTOCOL, FOR DUAL PARTICIPANTS, WILL BE 
$150 OR $$275.00.  Subject payments for the patient participants increase incrementally for MRI visits 
to encourage study completion; the bonus of $50.00 for CCBT exercise completion & remote self-
reports is to encourage treatment compliance. These participants will additionally be receiving 
diagnostic assessments and treatment for their depression at no cost.  Healthy Controls will receive 
$20.00 for completing screening assessments and $95.00 for the MRI scan. Participants will receive a 
bonus of $15 for completing 85% of the remote self-reports on Beiwe. Therefore, healthy controls can 
receives total of $130.00 if study is completed. Since healthy controls do not have the potential to 
beneﬁt from diagnostic assessments or treatment, they will receive the aforementioned compensation to 
encourage healthy individuals to participate.  IF HEALTHY CONTROL PARTICIPANTS ARE ALSO 
PARTICIPATING IN PROTOCOL 824132, THEY WILL NOT RECEIVE THE $95.00 PAYMENT 
FOR THE INITIAL MRI SCAN; PARTICIPANTS WILL BE COMPENSATED FOR THIS SCAN 
THROUGH PROTOCOL 824132. THEREFORE, THE MAXIMUM COMPENSATION FROM THIS 
PROTOCOL, FOR DUAL PARTICIPANTS, $35.  Participants will receive their human subjects 
payment at the end of their own study participation. Subjects will be compensated through University of 
Pennsylvania supported Greenphire ClinCard. This is a reloadable prepaid card (similar to a debit/credit 
card) which allows funds to be available immediately. Study staff will provide participants with a 
ClinCard Cardholder FAQ: US document (attached). Subjects who do not feel comfortable with the 
Greenphire ClinCard may be compensated by a check, in lieu of the ClinCard. We are not stating this 
option in the ICF, as we would prefer all participants to use the ClinCard for consistency; however, we 
acknowledge that not all individuals will feel comfortable with this method and therefore, if a 
participant expresses discomfort, we will then verbally offer them the option of being paid with a check. 
If participants opt to have the payment provided to them in the form of a check; it will be mailed to 
their home address. Participants will be required to complete a C-2 and a W-9, including providing their 
full social security number, in order to receive the study payment.

Page 18 of 27
Study Procedures
Suicidal Ideation and Behavior
Does this research qualify as a clinical investigation that will utilize a test article (ie- drug or biological) 
which may carry a potential for central nervous system (CNS) effect(s)?
No
Procedures
Participants will complete a phone screen or a online self-report screener to determine eligibility. If the 
participant is eligible, they will be scheduled for an in-person screening visit. Information collected 
during the pre-screening will not be used in the data analysis; pre-screening information will be 
collected and retained in REDCap. Participants will be asked to authorize the release of the medical 
records for the purposes of determining their eligibility for this study. Individuals who are patients in 
the Penn system will be asked for verbal consent during the pre-screening to release their PennChart 
electronic medical record. Data from the PennChart electronic medical record will be viewed only. The 
information will not be downloaded or stored. Individuals who are not in the Penn system will be asked 
to complete an medical record release authorization form at the screening visit after their have signed 
the informed consent. Upon receipt of their medical records, personal health information and 
identitiﬁers will be redacted to mitigate the risk of lost of conﬁdentiality and privacy. Visit 1 (Screening) 
- all participants will have the study described to them in detail, including the risks and study 
procedures as outlined in the informed consent form and will sign the ICF and HIPAA authorization, 
prior to any study procedures being completed. Participants will be screened for symptoms of 
psychological disorders and severity of major depressive symptoms by a trained research team member.  
If determined eligible, HEALTHY CONTROLS will be scheduled for return to complete a 1-hour fMRI 
scan and baseline visit, in which self-report measures, including reports of mood, behavior, and 
thoughts will be collected, as well as neuropsychological testing. Healthy controls will begin "Remote 
Monitoring" by being given an actigraph to wear 24 hours a day for 8 weeks and will have Beiwe 
installed on their cell phones. The mobile application has two elements: Passive data collection: 
Behavior data is gathered unobtrusively through a background process on the mobile device. The 
background process is launched automatically by the application once the user logs in. After the initial 
logon, the process continues to be automatically launched whenever it is not already running (on phone 
restart or other events that terminate the process). Active data collection: Surveys and other self-report 
data are gathered through user input. This is achieved in two ways: (i) the user receives a notiﬁcation 
that a survey is available and upon launch the application and they are shown all the surveys available at 
that time. Controls will return for an in-person visit following the 8 weeks of remote monitoring to 
return actigraph, have Beiwe disabled from cell phone, and receive ClinCard compensation.  If 
determined eligible at screening, MDD (EXPERIMENTAL GROUP) participants will begin CCBT 
treatment within 4 weeks after completing baseline assessments. Half of the depressed participants will 
begin 8 weeks of CCBT within 2 weeks from completing baseline assessments (Early CCBT), and the 
other half after 2 weeks from completing pre-treatment baseline assessments (Later CCBT). 
Participants are randomly assigned to either (1) Early CCBT or (2) Later CCBT based on the a number 
randomly generated by the computer. All MDD participants will receive 8 weeks of CCBT within 4 
weeks from completing baseline assessments. Participation duration may vary depending on the 
scheduling availability of the therapists, participants, and also our facilities.  All CCBT participants will 
be scheduled for return for Visit 2 to complete a 1-hour fMRI scan and baseline visit, in which self-
report measures, including reports of mood, behavior, and thoughts will be collected, as well as 
neuropsychological testing. Participants will begin "Remote Monitoring" by being given an actigraph to 
wear 24 hours a day for 8 weeks and will have Beiwe installed on their cell phones (see above for 
details of Beiwe). MDD subjects who are scheduled to begin CCBT after 2 weeks (Later CCBT) will 
complete an additional fMRI scan when they return to begin treatment. For the Later CCBT 
participants, the 2nd MRI scan is at least 2 weeks and up to 4 weeks from the 1st pre-treatment MRI 
scan.  MDD participants will also have Ethica installed on their cell phones at their and complete 1 
question/day regarding Good Days Ahead adherence on Ethica for 8 weeks when they being CCBT 
treatment. Again, this will be dependent on when subjects begin CCBT. Ethica will be used for active 
data collection, which includes surveys and other self- report data are gathered through user input. This 
is achieved in two ways: (i) the user receives a notiﬁcation that a survey is available and upon launching 
the application they are shown all the surveys available at that time. Participants will complete Good 
Days Ahead (GDA) computer training at their CCBT Week 1 visit. They will have CBT Clinical 
Contact with a licensed psychologist/psychiatrist at Weeks 1, 2, 4, 6, 8, & 9 of treatment. Additionally, 

Page 19 of 27
outcome measures will be assessed by an independent clinical evaluator (without knowledge of 
treatment assignment) at every in-person study visit. Weeks 3, 5 & 7 will be completed off-site (at 
home, preferably). Participants will have a ﬁnal 1-hour fMRI scan at end of study during CCBT Week 
9, in which self-report measures, including reports of mood, behavior, and thoughts will be collected, as 
well as neuropsychological testing.  Both MDD and healthy control participants will complete a 15-
minute computer task called "The Foraging Task" examining their responses to rewards during Visit 2. 
Foraging task Details: At the beginning of each trial, participants hold ﬁxation on a central ﬁxation 
square for 2.5 seconds. Afterwards the square turned green signaling they could make a choice. They 
needed to move the joystick to the nearby bush to earn a reward, displayed after a short period of time 
called handling time.On subsequent trials, participants could choose to go back to the same bush (stay). 
Reward however diminished for every subsequent attempt. At any point they could decide that the 
reward they are getting in that bush is not high enough and that they wanted to travel to a new non-
depleted bush. If they wanted to leave and go to the next bush, they needed to move the joystick to the 
square on the other side of the screen, and then the bushes started sliding down as if they were traveling 
to the next bush.The amount of time it took to travel to the next bush depended on the environment. In 
one block it took 5s to travel to the next bush and in another it took 20s. There were unlimited number 
of bushes in the environment but they had a ﬁnite time in each one (6 min x 2 blocks).The remuneration 
would be based on the amount of berries they have collected by the end of the session.  PLEASE SEE 
ATTACHED TABLES SHOWING SCHEDULE OF PROCEDURES FOR EACH STUDY GROUP. 
PARTICIPANTS WHO ARE ALSO PARTICIPATING IN THE 824132 PROTOCOL WILL 
PARTICIPATE IN BOTH STUDIES SIMULTANEOUSLY. VISITS 1&2 OF THE CURRENT 
PROTOCOL ARE MOSTLY ENCOMPASSED WITHIN THE FULL 824132 PROTOCOL, WITH 
THE EXCEPTION OF SOME SELF-REPORT MEASURES AND ANY CCBT PROCEDURES THAT 
WOULD OCCUR AT VISIT 2 FOR THE IMMEDIATE CCBT GROUP; THEREFORE THE 
DURATION OF THE FIRST 2 STUDY VISITS FOR DUAL PARTICIPANTS WILL BE SLIGHTLY 
LONGER THAN FOR THOSE WHO ONLY PARTICIPATE IN THIS CCBT PROTOCOL.
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Deception
Does your project use deception?
No
International Research
Are you conducting research outside of the United States?
No
Analysis Plan
C.10. Statistical Analysis: Aim 1: Aim 1a: To assess whether there is a baseline difference in amygdala 
connectivity in MDD compared to the controls, we will use a two-stage data-driven approach. The ﬁrst 
step will use multivariate distance- based matrix regression (MDMR) [85] to conduct a brain-wide test 
using the connectivity maps with the amygdala as the seed region (adjusted for in-scanner motion). This 
fully data-driven approach examines the functional connections between the amygdala and each region 
of the brain, and serves as an omnibus test of whether depression symptoms and treatment are 
associated with connectomic differences. We will then apply functional principal component regression 
(fPCR) to the amygdala-seeded correlation maps to assess patterns of baseline amygdala-connectivity 
that are associated with MDD adjusting for age and sex. fPCR extracts patterns that optimally explain 
variation in the baseline amygdala connectome across groups through eigenimages, and hence has more 
power than voxel-wise searches. These eigenimages indicate which regions contribute most to these 
patterns. The principal scores are generated by projecting each connectivity map onto the corresponding 
eigenimages, yielding a measure of the amount of signal for each subject that can be explained by a 
particular eigenimage. Guided by hypotheses generated based on the pilot observations, we will ﬁt 
fPCR separately in the target networks CEN and DMN using the 7-network solution of Yeo et al. [86] 
and test the relationship between the principal scores in MDD compared to controls using logistic 
regression adjusting for motion, age, and sex. For eigenimages with scores differing between MDD and 
HC, the spatial pattern will be characterized using a structural (Harvard-Oxford) and functional 
(Craddoc-200) atlas. We expect for fPCR to provide more sensitive and speciﬁc measurement of 
patterns of MDD-related amygdala- dysconnectivity in the CEN and DMN than regional averaging, 

Page 20 of 27
which we will also conduct for comparison. Aim 1b: To assess baseline differences between MDD and 
HC in Emotional Conﬂict task-induced activation in the dorsal ACC, DLPFC, and IFC, we will apply 
two approaches: First, perform the voxel-wise general linear model to detect group differences on the 
AHIF-AHIN contrast; Secondly, we will conduct brain-wide fPCR to explore variations that are 
associated with depression symptoms while controlling the anxiety symptoms. All analyses will be 
adjusted for age and sex, and corrected for multiple comparisons by controlling the false discovery rate. 
Aim 2: Aim 2a: To assess the effect of CCBT on the functional connectome, we will test for differences 
in amygdala-connectivity between MDD patients who receive treatment immediately (within 1-2 weeks 
of screening) and those who receive treatment later (within 3-4 weeks of screening). We will examine 
deﬁcits identiﬁed in Aim 1 to compare the MDD groups treated immediately (1-2 weeks) vs. treated 
later (3-4 weeks for changes in these regions, adjusting for motion, age and gender. We will also 
conduct a whole-brain feature search through structured functional principal component analysis 
(SFPCA) [87]. SFPCA incorporates the longitudinal design complexity and models variation in 
amygdala-connectivity induced by CCBT through dimension-reduced principal components that are 
associated with longitudinal changes. Instead of generating contrasts for each hypothesis, it utilizes all 
available data by explicitly modeling the correlation structures among the observed connectivity maps. 
Aim 2b: To assess changes of the conﬂict task-induced activity in ACC, DLPFC, and IFC, we will use 
the same techniques of SFPCA and targeted mixed-effects modeling adjusting for age and sex. We will 
also investigate the correlation between the patterns of treatment-induced connectivity and activation 
normalization. Further, we will investigate the dose-response relationship between total time engaged in 
CCBT and changes in brain connectivity and activity. Exploratory Aim: We will ﬁrst use PCR to predict 
treatment response after CCBT using the baseline amygdala-connectivity map. To avoid overﬁtting, we 
will evaluate the prediction performance using bootstrapped cross-validation by iteratively applying 
learning predictive patterns to 90% of the subjects and testing on the remaining 10%. We will assess 
treatment response using continuous score changes in depression and anxiety, and remission status 
(deﬁned by MADRS10 after CCBT). For continuous measures of response, we will assess predicted 
mean-square error (MSE) for symptomatic change in two ways: ﬁrst, we will simply estimate the 
predictive performance of the principal scores. Next, we will compare a predictive model based on 
regression with only baseline depression scores to a model with both baseline scores and principal 
scores to assess the added value of the imaging markers. For remission status, we will assess both the 
predictive performance of the principal scores and the added value of these markers above baseline 
depression scores and other demographics (age, sex, socio-economic status) using receiver- operator 
characteristic (ROC) curve analysis. Differences in the performance will be assessed by building 
conﬁdence intervals for increased area under the curve (AUC) using bootstrapped cross-validation. We 
will apply the same techniques to the contrast of parameter maps from the conﬂict task, as well as to the 
cortical thickness maps. We will build second stage meta-classiﬁers that integrate the patterns found 
using these functional and structural imaging measures using generalized linear modeling, which will 
allow us to integrate the imaging predictors with age, sex, and other demographic information. To 
assess the importance of baseline executive function measures, we will examine the improvement in 
predictive performance by including these into the meta-classiﬁers. Other machine learning algorithms 
such as support vector machines and random forests, as well as collaborative learning will also be 
explored to achieve optimal performance. We will also assess the amount of model improvement by 
incorporating joint resting-state, task-based activation, and cortical thickness patterns into the previous 
PCR model by calculating c-statistics and prediction indices (such as net reclassiﬁcation improvement 
and integrated discrimination improvement etc.) sequentially. Finally, we will investigate sparse 
patterns of association between imaging measures and depression phenotypic measures using sparse 
canonical correlation analysis. ***NOTE REGARDING DATA ANALYSIS WITH PROTOCOL 
826910*** Procedures and data elements are the same between #826910 and #832295, therefore they 
will not need to be reconciled. The data from the two study will be added together. Participant data from 
the Immediate CCBT group from #826910 and the early CCBT group from #832295 will be grouped 
together for analysis. Participant data from the Wait-list Followed by CCBT group from #826910 and 
the delayed CCBT group in #832295 will be grouped together for analysis.
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Page 21 of 27
Data conﬁdentiality
x Paper-based records will be kept in a secure location and only be accessible to personnel involved 
in the study.
x Computer-based ﬁles will only be made available to personnel involved in the study through the 
use of access privileges and passwords.
Prior to access to any study-related information, personnel will be required to sign statements 
agreeing to protect the security and conﬁdentiality of identiﬁable information.
x Wherever feasible, identiﬁers will be removed from study-related information.
A Certiﬁcate of Conﬁdentiality will be obtained, because the research could place the subject at 
risk of criminal or civil liability or cause damage to the subject's ﬁnancial standing, 
employability, or liability.
x A waiver of documentation of consent is being requested, because the only link between the 
subject and the study would be the consent document and the primary risk is a breach of 
conﬁdentiality. (This is not an option for FDA-regulated research.)
x Precautions are in place to ensure the data is secure by using passwords and encryption, because 
the research involves web-based surveys.
Audio and/or video recordings will be transcribed and then destroyed to eliminate audible 
identiﬁcation of subjects.
Subject Conﬁdentiality
All participants will be given a unique identiﬁer number (Subject ID number) that will be utilized to 
code all collected data, both electronically and on hard copies. Hard-copy data and Informed Consents: 
All data and informed consent documents that are collect on paper/hard-copies will be kept at the 
University of Pennsylvania, in the Center for Neuromodulation for Depression and Stress on the 3rd 
ﬂoor of the Richards Building. Data will be coded with the Subject ID number and will be kept 
separately from the informed consent documents. All hard-copy data and ICFs will be stored behind 
two physical locks; only study staff will have access to this secure environment. Electronic data: All 
electronic data collected from will be stored on REDCap, which is an institutionally-approved third-
party computing environment. REDCap will be used to collect some data directly (e.g., self-report 
questionnaires will be answered directly in REDCap, no paper/hard-copies will exist). Additionally, any 
data that is collected ﬁrst via hard copy/paper format (e.g., SCID) will be entered into REDCap 
following collection. Only study staff will have access to the data. Members of the study team will have 
varying access levels; dependent on their role in the study; the REDCap project administrator is the 
primary clinical research coordinator for this study, she will determine the least amount of access 
needed for each team member and give permissions to data based on the minimum necessary rule. 
There will be one key that links the subject ID number with the participants full names and contact 
information. This key will stored on a University, institutionally secured and managed network drive 
and device. Furthermore, the key will be password-protected; this password will only be shared with 
study staff. New staff will be trained on conﬁdentiality prior to handling any records.  BEIWE 
INFORMATION Data collected from Beiwe is stored securely on the mobile device temporarily. At 
regular intervals, the application checks for an available connection to the WWW. If such a connection 
is available, the data is transmitted over a secure connection to the server and deleted from the device. If 
a connection is not available or if a transmission is not successful, the data continues to be stored on the 
device until it is transmitted successfully. The data collected through the device includes data such as 
call and sms logs (including call/sms time, call duration, sms length, and phone number), location and 
device usage. Private information such as actual content of voice calls or sms messages or emails is 
never read, recorded or transmitted. Beiwe Data Storage, Encryption and Server Security The data 
described above is encrypted and transmitted to the server over a secure 128- bit SSL 3.0 connection 
using the HTTPS protocol. Extra care is taken to ensure that the request cannot be spoofed or imitated 
by an attacker through the use of unique keys that are generated dynamically for every API request 
through a unique identiﬁer and client secret that is embedded inside the application and cannot be 
accessed by any user or application. Beiwe linux-based servers are protected using a ﬁrewall and access 
control lists (ACLs), and access is restricted to Beiwe employees and contractors. Superuser activity 
and researcher activity on the server is logged for security and auditing. The servers are regularly 
updated and patched with latest security updates to ensure that there are no known threats. These 
servers host the database where the data is stored. Linux- based servers and access to the servers is 

Page 22 of 27
restricted to a few users responsible for maintaining and testing the database. For additional security, all 
the data that has personally identiﬁable information about the participant (such as e-mail) is stored in 
aseparate database from the one that has the data collected from the users and data related to the 
studies. The passively collected data from the phones as well as the actively-reported survey 
information is stored in the second database. Phone numbers and other such private information stored 
in this database are anonymized by hashing over the identiﬁers so that there is no threat to privacy 
because the data is not human readable anymore. Beiwe Data Access (through Web Dashboard) 
Researchers and study staff have access to the web dashboard through an account on the site. 
Information pertaining to a study is only available to researchers and study staff associated with that 
study. Participants or researchers not involved in the study cannot access the data through the 
dashboard. Data accessed through the dashboard is also transmitted through 128-bit SSL 3.0 connection 
using the HTTPS protocol. HTTP access is disabled. Researchers or study staff can invite participants 
through the web dashboard. They are provided an option to use the study participants name or a coded 
identiﬁer as is suitable for their study protocol. The coded identiﬁer (or name) is used to refer to the 
participant on the dashboard pages and in communication with the participants. Data available on the 
dashboard includes aggregated or processed data about the participants related to the amount of data 
being collected (number of location samples, number of phone calls), time-related information such as 
when surveys were taken, and processed data such as GBI features (from passive data) or survey scores 
(for surveys that have scoring associated with them). Researchers are also notiﬁed when passive data is 
not being collected from a participant or when participant is not answering surveys.  ETHICA 
INFORMATION (all information below was taken directly from website ethicadata.com) Data 
collected from Ethica is stored securely on the mobile device temporarily. At regular intervals, the data 
transmitted over a secure connection to the speciﬁed server in and encrypted format and deleted from 
the device once the uploaded data is validated. In the case that the phone is hacked, the upload that is 
redirected to another server would be useless without the key, which is stored separately on a secure 
server. The data collected through Ethica includes the Good Days Ahead: Questions & Prompts (IRB 
approved on 8/7/17). This study data does not contain any explicit personal identiﬁcation information 
and may contain data that can be reversed engineered to implicitly extract the participant's identity. 
Ethica will have information such as participant phone numbers for the purposes of registration. 
Enrollment into the research study in the Ethica phone app is based on invitation only. Ethica Data 
Storage, Encryption and Server Security All data on the device is encrypted using industry standard 
techniques (SSL/TLSencrypted network data transfer). In the event that the phone is lost or stolen, the 
data is protected. Data is stored in an encrypted format in a directory on the phone allocated by 
operating system for this purpose. A small cache of recent data (usually the past hour) is kept in volatile 
memory on the phone to aid in context detection for survey triggering. Because it is stored in random 
locations in the phones RAM this data is essentially unreachable to anything but the program itself. 
Data from this directory is periodically uploaded to the server speciﬁed by the Researcher in the study 
settings in its encrypted format. Even if the phone were hacked, and the upload redirected to another 
server the data would be useless to the hacker without the key, stored separately on a secure server. 
Once on the secure server, the data is decrypted, parsed, and inserted into an internal server. As soon as 
the data is successfully uploaded to the servers, uploaded data is validated, and then the data is wiped 
from the phones. Ethica Data Access (through Web Dashboard) Researchers have access to the Study 
Data database in order to monitor and analyze the data they have received for the study. None of the 
researchers will have access to the Metadata database. This ensures the Research team does not have 
access to the Participants explicit personal identiﬁcation information. Request of waiver of 
documentation of consent for PRESCREENING activity only; phone and self-report screening will be 
captured via RedCap. Participants are informed of this and given the option to verbally consent; 
however, we will not be providing them a copy of this, as some individuals will not actually participate 
in the study and therefore the only link between the subject and the study would be the consent 
document and the primary risk is a breach of conﬁdentiality. Information about study subjects will be 
kept conﬁdential and managed according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  Those regulations require a signed subject authorization 
informing the subject of the following: - What protected health information (PHI) will be collected 
from subjects in this study - Who will have access to that information and why  - Who will use or 
disclose that information - The rights of a research subject to revoke their authorization for use of their 
PHI.  In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts should be 
made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. SUBJECTS WHO CHOOSE TO PARTICIPATE IN PROTOCOL 824132 IN 

Page 23 of 27
TANDEM WITH THIS PROTOCOL WILL PROVIDE WRITTEN PERMISSION (WITHIN ICF) TO 
HAVE THEIR DATA SHARED BETWEEN STUDIES. THERE WILL BE NO ADDITIONAL 
DOCUMENTATION RETAINED FOR THIS STUDY THAT IDENTIFIES THESE SUBJECTS AS 
PARTAKING IN BOTH STUDIES
Sensitive Research Information*
Does this research involve collection of sensitive information about the subjects that should be excluded 
from the electronic medical record?
No
Subject Privacy
Privacy refers to the person's desire to control access of others to themselves. Privacy concerns people, 
whereas conﬁdentiality concerns data. Describe the strategies to protect privacy giving consideration to 
the following: The degree to which privacy can be expected in the proposed research and the safeguards 
that will be put into place to respect those boundaries. The methods used to identify and contact 
potential participants. The settings in which an individual will be interacting with an investigator. The 
privacy guidelines developed by relevant professions, professional associations and scholarly 
disciplines (e.g., psychiatry, genetic counseling, oral history, anthropology, psychology). 
Privacy refers to the person's desire to control access of others to themselves. Privacy concerns people, 
whereas conﬁdentiality concerns data. Describe the strategies to protect privacy giving consideration to 
the following: The degree to which privacy can be expected in the proposed research and the safeguards 
that will be put into place to respect those boundaries. The methods used to identify and contact 
potential participants. The settings in which an individual will be interacting with an investigator. The 
privacy guidelines developed by relevant professions, professional associations and scholarly 
disciplines (e.g., psychiatry, genetic counseling, oral history, anthropology, psychology). Several 
safeguards will be put into place for protecting the privacy of participants and the conﬁdentiality of 
research material. Staff members will be trained to understand the importance of privacy and 
conﬁdentiality. Information gathered about individual participants is maintained in secured storage 
areas at the site. All aspects of the informed consent process are done in a private consultation room. 
Study procedures will occur in a private room by personnel trained in following procedures in a manner 
in which the privacy of the participant is maintained. Only information, images, and biological samples 
necessary for the completion of this study will be collected. All computer data obtained from the 
laboratory and from research interviews will be de-identiﬁed and then only identiﬁed by a code number. 
All data will be kept in locked ﬁle cabinets behind locked doors and only made available to qualiﬁed 
research personnel.  All data will be de-identiﬁed and only code numbers will appear on any data and 
documents used for evaluation or statistical analysis for this study. Publications emanating from this 
research will not identify individual patients. HIPAA compliance will be enforced as per University of 
Pennsylvania policy. Reports from patients clinical records concerning research observations will not be 
available to outside medical facilities without the written consent of the participant.
Data Disclosure
Will the data be disclosed to anyone who is not listed under Personnel?
The following entities may have access to the data if requested: 1) Hospital or University 
representatives, to complete Hospital or University responsibilities 2) University of Pennsylvania's 
Institutional Review Board, 3) future collaborators for the advancement of scientiﬁc knowledge

Page 24 of 27
Data Protection*
x Name
x Street address, city, county, precinct, zip code, and equivalent geocodes
x All elements of dates (except year) for dates directly related to an individual and all ages over 89
x Telephone and fax number
x Electronic mail addresses
x Social security numbers
x Medical record numbers
Health plan ID numbers
Account numbers
Certiﬁcate/license numbers
Vehicle identiﬁers and serial numbers, including license plate numbers
Device identiﬁers/serial numbers
Web addresses (URLs)
Internet IP addresses
Biometric identiﬁers, incl. ﬁnger and voice prints
Full face photographic images and any comparable images
Any other unique identifying number, characteristic, or code
None
Does your research request both a waiver of HIPAA authorization for collection of patient information 
and involve providing Protected Health Information ("PHI") that is classiﬁed as a "limited data set" 
(city/town/state/zip code, dates except year, ages less than 90 or aggregate report for over 90) to a 
recipient outside of the University of Pennsylvania covered entity?
No
Tissue Specimens Obtained as Part of Research*
Are Tissue Specimens being obtained for research?
Yes
Tissue Specimens - Collected during regular care*
Will tissue specimens be collected during regulator clinical care (for treatment or diagnosis)?
No
Tissue Specimens - otherwise discarded*
Would specimens otherwise be discarded?
No
Tissue Specimens - publicly available*
Will tissue specimens be publicly available?
No
Tissue Specimens - Collected as part of research protocol*
Will tissue specimens be collected as part of the research protocol?
Yes
Tissue Specimens - Banking of blood, tissue etc. for future use*
Does research involve banking of blood, tissue, etc. for future use?
Yes
Genetic testing
If genetic testing is involved, describe the nature of the tests, including if the testing is predicative or 
exploratory in nature. If predictive, please describe plan for disclosing results to subjects and provision 

Page 25 of 27
of genetic counseling. Describe how subject conﬁdentiality will be protected Note: If no genetic testing 
is to be obtained, write: "Not applicable."
Saliva will be collected for exploratory genetic testing to explore biomarkers that may contribute to 
depression at an undetermined date; samples will be stored at the Translational Research Laboratories 
on Penn's campus. All samples will be coded with subject ID number and date of collection. No PHI 
will be kept with the samples.
Consent
1. Consent Process
Overview
Informed consent will be obtained at the initial screening visit, prior to any study procedures being 
conducted. All research team members will be trained on how to obtain informed consent. Trained staff 
will talk through the informed consent form with the participant, allowing the participant time to ask 
questions. All participant questions will be answered prior to them signing the consent form; 
participants will be given the opportunity to review the consent form with their families, friends, or 
physicians if they so choose. Participants will be encouraged to take their time to make a decision about 
participating prior to signing the consent form. The informed consent will be written at an 8th grade 
reading level. Individuals who are not capable of providing consent for themselves will not be eligible 
to participate; this include individuals who are not ﬂuent in the English language or have any disability 
that would not allow them to be able to consent for themselves (e.g., intellectual disabilities).
Children and Adolescents
Children aged 18-21 will be included in the proposed study. The investigators have had ample previous 
experience working with subjects of this age, and all study procedures are appropriate for this age 
range.
Adult Subjects Not Competent to Give Consent
Individuals who are not able to provide informed consent for themselves will not be enrolled in this 
study. All participants must not have a diagnosis of intellectual disability or any form of dementia; all 
participants must have a 10th grade education or GED.
2. Waiver of Consent
Waiver or Alteration of Informed Consent*
No Waiver Requested
Minimal Risk*
Impact on Subject Rights and Welfare*
Waiver Essential to Research*
Additional Information to Subjects
Written Statement of Research*
No
If no written statement will be provided, please provide justiﬁciation
The following documents are currently attached to this item:
There are no documents attached for this item.

Page 26 of 27
Risk / Beneﬁt
Potential Study Risks
The primary risks of Major Depressive Disorder are suffering, symptom burden, and despair including 
the risk of attempting or completing suicide, as well as persistent disability in family, social, and 
vocational roles. As in everyday practice, patients with suicidal ideation who cannot be treated on an 
outpatient basis will be excluded from this study. Whereas there are signiﬁcant risks of suffering from 
depression, there are only a few additional potential risks involved in this study. In this regard, CCBT is 
an efﬁcient form of delivery of the best-studied psychotherapy for depression, for which there is good 
evidence of efﬁcacy across numerous studies. There are no known risks of using the computer software 
employed in this study, Good Days Ahead, nor for CBT as a broader class of therapy other than 
possibility that the treatment will prove to be ineffective for a subset of patients. For the depressed 
group, there is the added potential risk of delaying the start of speciﬁed therapy as they are scheduled to 
begin CCBT either within 2 weeks or after 2 weeks from completing baseline assessments. This risk is 
offset by the remote monitoring of symptoms using the Beiwe cell phone app during wait-time to begin 
CCBT treatment. It is important to note that patients typically at least 4 or more weeks to receive 
therapy in the community, thus, this is standard care. Delayed treatment conditions have been the most 
commonly used standard of comparison for generations of studies on psychosocial treatments of 
depressed and provide the most clear-cut way to uncouple the considerable effects of spontaneous 
remission and nonspeciﬁc beneﬁts from the more speciﬁc effects of CCBT.  Although in our past 
studies it is rare (i.e., less than 1 per 200) for a patient in protocol to experience a suicidal crisis or the 
onset of psychosis, if such worsening would develop, the patient would be withdrawn from the 
protocol, hospitalized if necessary, and treated with whatever type of therapy seems most clinically 
indicated. Participants also will be asked to provide permission to be contacted if they miss visits to 
help ensure close monitoring of their conditions. The utility and safety of the form of CCBT used in this 
trial has been documented by previous studies and is, at the least, comparable to the interventions that 
people might receive in non-research settings. Likewise, the clinical assessments, including both self-
reports and observer ratings, are basically hazard-free, with the possible exceptions that participants 
may ﬁnd the assessments tiresome. There is the remote possibility that conﬁdentiality could be 
breached. There are no known risks associated with MRI scans for healthy subjects except that 
participants may experience discomfort as they will be required to lie still in a conﬁned area. 
Participants may experience claustrophobia (fear of enclosed spaces and/or anxious feelings 
accompanied by fast heart rate or shortness of breath) within the MRI scanner. In addition, the scanner 
produces a loud repetitive knocking noise during the study that some people ﬁnd bothersome.
Potential Study Beneﬁts
Participants may not receive any beneﬁts from participating in this research. However, participants may 
experience a decrease in depressive symptoms. There will be no direct beneﬁt to healthy control 
participants. Importance of the Knowledge to be Gained: Major Depressive Disorder is a recurrent, 
disabling, potentially lethal illness. Although CBT has established efﬁcacy, its utility is limited by the 
availability of experienced therapists and the cost of a full course of therapy. In clinical practice, people 
who receive treatment for depression are much more likely to receive antidepressant medications than 
CBT, and antidepressants have an intent-to-treat effectiveness of no more than 50% under optimized 
circumstances (see, for example, Trivedi et al., 2006 [7]). Moreover, the largest component of an 
antidepressant response is attributable to so called nonspeciﬁc beneﬁts, which in some analyses of 
clinical trial results can account for 75% of the clinical beneﬁt [8]. Even when antidepressant  
treatments are partially effective, residual symptoms and psychosocial impairment often persist, which 
makes it imperative to improve existing therapies or create new therapies, sequences, and/or 
combinations. The chance of relapse and recurrence is particularly high during the 6 to 9 months after 
patients discontinue acute phase antidepressant medication. Although no more effective than 
antidepressants in the shortrun, acute phase CBT alone has been shown to reduce the risk of relapse/
recurrence for some number of months after termination of therapy. As there are relatively few skilled 
and well-trained CBT therapists, any procedure that improves the efﬁciency of therapy will have great 
public health signiﬁcance by rendering treatment more available to more people. By evaluating the 
beneﬁt of CCBT, we will be able to ascertain if this model of therapy will substantially improve the 
efﬁciency of therapy. Beyond the potential beneﬁts of further establishing the merits of CCBT, there is 
the potential for improving therapy inherent in further clarifying the mechanism of action in terms of 
the impact of treatment on relevant neural circuits. If, as predicted, the speciﬁc beneﬁt of CCBT is 
derived from strengthening cognitive/executive control over dysfunctional limbic-frontal circuits, then 

Page 27 of 27
further reﬁnements in the delivery of CCBT, such as massing practice of relevant coping exercises, 
could prove to enhance treatment efﬁcacy and further strengthen the durability of gains.
Alternatives to Participation (optional)
Participants have the option to not participate. Participants will be told of alternative treatments for 
depression, including medications, somatic treatments (e.g., TMS, ETC), and talk therapy outside of the 
context of this study.
Data and Safety Monitoring
This study has been approved by Dr. Judith M. Rumsey for investigator-level monitoring on 5/17/17. 
No DSMB is required.  The principal investigator will review ongoing study procedures, discuss serious 
adverse events (SAEs) and other safety issues, and to evaluate ongoing methods for maintaining data 
integrity and conﬁdentiality. Should the investigator develop any concerns on the basis of information 
provided by the study team, she may request to examine hard or electronic copies of participants' 
research records from any of the study sites. In transferring such information, participants' identities 
will be protected by transferring only data that are de-identiﬁed (hard copies) and/or encrypted 
(electronic data). In considering the frequency of meetings, we have tried to strike a proper balance 
between maintaining participant safety and the integrity of the study, and the consequent time, 
workload, and cost to the study budget in preparing reports. Annual meetings will be sufﬁcient during 
the submission of the annual continuing review.
The following documents are currently attached to this item:
There are no documents attached for this item.
Risk / Beneﬁt Assessment
Potential Beneﬁts Versus Risks of the Research to Patients and Others. We believe that the risks 
associated with this study are small and are offset by the potential beneﬁts that patients may receive 
from participating. Any treatment for depression is associated with some chance of failure to respond or 
subsequent relapse/recurrence; in this particular trial there is the additional risk resulting from the 
delayed start of CCBT by up to 4 weeks depending on what group they are randomly assigned to. 
However, this is no different from usual standard of care treatment given that starting treatment as a 
new patient will take at least 4 weeks when scheduling with mental health service providers in the 
community outside of this study.. The protocols are designed to provide high quality clinical care to 
consenting participants, which generally exceed the standards of care for non-research settings in 
Philadelphia. Study participants are evaluated longitudinally and more rigorously in this protocol than 
they are typically in standard clinical practice. Thus, whether the adverse outcome is a slower response 
or even non-response to acute phase therapy or a subsequent relapse/recurrence, we will be able to 
provide alternate treatment or referrals immediately. There is no beneﬁt to receiving the MRI scans and, 
because the imaging is performed for research, results are not routinely shared with participants. 
However, in the event that MRI abnormalities are discovered, subjects will be informed of the ﬁnding. 
Participants experience the indirect beneﬁt of contributing to scientiﬁc knowledge.
General Attachments
The following documents are currently attached to this item:
Informed consent form (2019.04.09_ccbtgroups_icfhipaa_v2_feb2019_clean.docx)
Informed consent form (2019.04.09_ccbtgroups_icfhipaa_v2_feb2019_track.docx)
Informed consent form (2019.04.09_healthycontrol_icfhipaa_v2_feb2019_clean.docx)
Informed consent form (2019.04.09_healthycontrol_icfhipaa_v2_feb2019_track.docx)
Additional forms (2019.04.09_scheduleofassessments_ccbtgroup.docx)
Additional forms (2019.04.09_scheduleofassessments_controlgroup.docx)
Cover Letter (2019.04.10_coverletter_modiﬁcation_832295.doc)