Novel Neural Circuit Biomarkers of Major Depression Response to CCBT

This study is a randomized study. 60 subjects with MDD will be randomly assigned (1:1) to
immediately receive 8 weeks of CCBT or delayed treatment, consisting of up to 4 weeks of
waitlist, followed by 8 weeks of CCBT. 40 healthy controls of similar age/sex will be
recruited to serve as a comparison group for baseline magnetic resonance imaging (MRI)
scanning.

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 the participants
are randomized to. Healthy controls will participate for approximately 8 weeks. Subjects with
MDD who were randomized to Early CCBT will participate for approximately 8 weeks; subjects
with MDD who were randomized to Late CCBT will participate for approximately 12 weeks.
Variability in the study duration for each group depends on each subjects' personal
availability for visits and the availability of the magnetic resonance scanner.

Potential participants will complete a phone screen to determine eligibility. If the
individual is eligible, the individual will be scheduled for an in-person screening visit.
Information collected during the phone screening will not be used in the data analysis; phone
screening information will be collected and retained in REDCap.

Screening Visit - 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
informed consent form (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 an 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. The HIPAA-compliant
phone app Beiwe and actigraph setup will take place during the baseline visit. Participants
will complete mood monitoring questions on the phone app and also have their activity levels
monitored by the phone app and the actigraph for the duration of the study.

If determined eligible at screening, MDD (EXPERIMENTAL GROUP) participants will be randomized
(1:1) as follows: One half of the depressed participants will be randomized to receive 8
weeks of CCBT immediately after completing pretreatment assessments and the remainder will be
randomized to a waitlist of up to 4 weeks followed by 8 weeks of CCBT.

MDD, EARLY CCBT GROUP Early CCBT participants will be scheduled for return to complete an
fMRI scan at the baseline visit, in which self-report measures, including reports of mood,
behavior, and thoughts will be collected, as well as neuropsychological testing. The phone
apps Beiwe and Ethica and actigraph setup will take place during the baseline visit.
Participants will complete mood monitoring questions on the phone apps and also have their
activity levels monitored by the phone app and the actigraph for the duration of the study.
Participants will complete Good Days Ahead (GDA) computer training throughout the 8 weeks of
CCBT, and having 6 encounters with a licensed psychologist/psychiatrist. Additionally,
outcome measures will be assessed by an independent clinical evaluator (without knowledge of
treatment assignment) every other week. As soon as can be arranged after Week 9 of CCBT
treatment (last CCBT Clinical Contact), participants will return to complete an fMRI scan and
end of study visit, in which self-report measures, including reports of mood, behavior, and
thoughts will be collected, as well as neuropsychological testing.

MDD, LATE CCBT GROUP Late CCBT participants will be scheduled for return to complete an 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. The phone apps Beiwe
and Ethica and actigraph setup will take place during the baseline visit. During the 2-4 week
waitlist phase, participants will complete mood monitoring questions on the phone apps and
also have their activity levels monitored by the phone app and the actigraph.

At the conclusion of the waitlist of up to 4 weeks, participants will complete a second fMRI
scan and complete self-report measures, including reports of mood, behavior, and thoughts
will be collected, as well as neuropsychological testing.

Participants will then enter the CCBT phase and will complete Good Days Ahead (GDA) computer
training throughout the 8 weeks of CCBT. They will have 6 encounters with a licensed
psychologist/psychiatrist at multiple time points during this period. Additionally, outcome
measures will be assessed by an independent clinical evaluator (without knowledge of
treatment assignment) every other week during this study phase. At Week 9 of CCBT treatment
(last CCBT Clinical Contact), participants will complete a 1-hour fMRI scan and self-report
measures, including reports of mood, behavior, and thoughts will be collected, as well as
neuropsychological testing.

This clinical trial has two IRB protocol numbers: 826910 and 832295. The data collected
through both protocol numbers will be analyzed together to accomplish the target of 100
subjects for this clinical trial.

Inclusion Criteria:

1. 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. Has reliable access to a private computer or electronic tablet

6. Owns a smart phone (iPhone or Android) with ability to download apps

Experimental group 1) Diagnosis of MDD, experiencing current episode as determined by
SCID-5 2) Current major depressive episode 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

Exclusion Criteria:

1. 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 general education degree (GED)

7. Represent an active suicide risk

8. Centrally acting antiadrenergic agents

9. Have MRI contraindications (e.g., foreign metallic implants, pacemaker, severe
claustrophobia)

10. Currently demonstrating a response to antidepressant/psychotropic medication

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