Anhedonia, Development, and Emotions: Phenotyping and Therapeutics (ADEPT) Study
Phase: PHASE4
Conditions: Depression, Anhedonia
Sponsor: Erika Forbes

 
 
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Study Protocol 
 
 
 
 
 
Official Title: 
 
Anhedonia, Development, and Emotions: Phenotyping and Therapeutics (ADEPT) 
 
ClinicalTrials.gov ID (NCT number): 
NCT05487885 
 
Protocol Date: 
2/19/2025 
 
Scientific Background 
 
Anhedonia—difficulties with reward-focused motivation, anticipation, and effort—
predicts poor treatment response and pernicious clinical course in people with 
depression. A core symptom that also anchors a subtype of depression, anhedonia 
often precedes the emergence of serious psychopathology, increases risk for 
suicidality, and reduces the likelihood of responding to pharmacologic or 
psychosocial treatment (McMakin et al., 2012; Rizvi et al., 2016). 
 
Adolescence to young adulthood is the optimal developmental point for 
investigating anhedonia in order to improve treatment outcomes. Adolescence is a 
period of vulnerability for anhedonia, possibly through convergence of changes in 
frontostriatal reward, dopamine (DA), and reward-related behavioral systems. 
Anhedonia and depression both begin during adolescence, perhaps not 
coincidentally during the development of anhedonia’s putative neural substrate, the 
frontostriatal reward system. This neurobehavioral shift, in combination with an 
early stage in the clinical course of depression, creates an opportunity during 
adolescence and early adulthood to understand and potentially change the influence 

 
 
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of anhedonia. 
 
The development of anhedonia could reflect diminished DA availability, 
undermining frontostriatal reward integration and resulting in the persistence of 
depression or related changes in mood and behavior. 
DA can be measured non-invasively by MRI proxy. Brain tissue iron is critical for 
DA synthesis (Ortega et al., 2007; Zucca et al., 2017), is predominant in the basal 
ganglia (Haacke et al., 2005), increases through early adulthood (Larsen & Luna, 
2018; Peterson et al., 2019), is associated with PET indices of DA availability 
(Larsen et al, 2020), mediates developmental specialization of frontostriatal 
functional connectivity through adolescence (Parr et al, 2021), and can be 
measured non-invasively with MRI. Three indirect indices of DA availability 
depend on brain tissue iron: R2’ is linearly related to striatal tissue iron (Sedlacik et 
al., 2014), which co-localizes with DA vesicles (Larsen et al., 2020); T2* is a 
relative measure of tissue iron that can be obtained from fMRI; Neuromelanin 
(NM) is the pigment that indicates density of nigrostriatal DA neurons (Sulzer et 
al., 2018; Cassidy et al., 2019). 
 
Inflammation is associated with anhedonia and depression, perhaps particularly in 
adolescence, and is postulated to exert its influence through changes in striatal 
dopamine and function in frontostriatal reward circuitry. The relation of 
inflammation to depression, including in adolescents, is widely documented 
(Mitchell & Goldstein, 2014), with anhedonia postulated as a specific 
neuroinflammation-related symptom (Miller & Raison, 2016). Low striatal DA 
availability and signaling are considered a key mechanism of the inflammation-
depression association (Felger & Treadway, 2017). The immune system undergoes 
considerable development during adolescence (Osugi et al., 1995), with putative 
consequences for anhedonia (Brenhouse & Schwarz, 2016). 
 
Assessing positive affect, social experiences, sleep, and symptoms in real life and 
real time provides rich, powerful information on how anhedonia operates in 
relation to functioning. Beyond the traditional, retrospective, lab-based measures of 
anhedonia, techniques to measure real-life experiences and behavior using 
smartphone apps provide greater temporal, featural, and contextual precision that 
will advance understanding of anhedonia. Social experiences reveal the 
consequences of anhedonia for functioning, and sleep is critical to affect 
regulation. 
 
TBS to dmPFC holds promise for reducing anhedonia and improving clinical 
course in young people with depression. In contrast to the long-duration, 

 
 
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dorsolateral prefrontal cortex-focused TMS approach to depression, we have used 
TBS—a briefer and more easily tolerated form of TMS—to dmPFC, a target in 
frontostriatal reward circuitry. Based on our findings and the literature (e.g., Forbes 
& Dahl, 2012), our guiding hypothesis is that youth with depression exhibit 
excessive dmPFC response, which serves to dampen VS responding. Thus, our 
goal is to reduce dmPFC activity through continuous TBS. 
 
PA Training is a psychosocial add-on intervention that could enhance the effects of 
TBS. PA Therapy (Craske et al., 2016) is an innovative cognitive and experiential 
technique developed to address anhedonia specifically and, ideally, change altered 
patterns of frontostriatal function. Standing in contrast to Cognitive Behavioral 
Therapy, PA training has efficacy for enhancing positive affect and reducing 
negative affect (Craske et al., 2018). This treatment can be easily applied, and we 
propose that it will enhance neural circuit-level changes elicited by TBS. 
 
Examining the development of anhedonia can provide critical knowledge about its 
role in the course and severity of depression, its influence on healthy functioning, 
and the functional consequences of disrupting its influence with therapeutic 
approaches involving neuromodulatory, cognitive-behavioral, and pharmacologic 
techniques. This developmental focus will provide a foundation for optimal 
treatment assignment, development of more effective treatments, and the 
opportunity to put young people on a path toward resilience and thriving. 
 
The innovation of the study lies in its strategy for capturing anhedonia, 
manipulating its mechanisms, and trying to improve the clinical profile of young 
people who experience it. The features that make it innovative and high-impact 
include its longitudinal examination of early anhedonia; use of a frontostriatal 
rather than a dorsolateral PFC target, compressed schedule, and theta burst for 
TMS; addition of PA Therapy-based cognitive-behavioral exercises to TBS; non-
invasive measurement of DA availability; and multi-modal investigation of 
anhedonia (across neuroimaging, neuromodulation, cutting-edge pharmacotherapy, 
immunology, ambulatory experience sampling and sensor technology, and 
sophisticated computational techniques). 
 
 
Study Objectives 
 
Goal 1. Uncover the complex nature of anhedonia using high dimensional, multi-
modal data that captures neural, behavioral, and experiential mechanisms in 
adolescents and young adults with depression. We will focus on function in neural 

 
 
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reward circuitry using resting and task fMRI; dopamine (DA) availability using 
MRI; inflammatory markers; ecological momentary assessment (EMA) of mood, 
social experiences, and symptoms; and sensor technology to assess motor activity, 
location (e.g., proportion of time spent at home), sleep/wake patterns, and social 
context (e.g., isolation). Machine learning techniques will compute digital 
phenotyping, cross-method computational phenotyping, and clustering profiles. 
The hypothesis is that anhedonic depression is characterized by disrupted 
frontostriatal function, low dopamine availability, altered inflammatory markers, 
low activity level, and social isolation. In addition, phenotypes based on this 
combination of methods will be detectable. 
 
Goal 2. Manipulate the neural mechanisms of anhedonia using 3 treatments found 
to improve anhedonia, putatively through influence on frontostriatal function. 
These are (1) continuous theta burst stimulation (cTBS), a form of transcranial 
magnetic stimulation, to dorsomedial prefrontal cortex (dmPFC); (2) positive affect 
(PA) exercises drawn from a psychosocial treatment shown to improve PA and 
treat depression. All participants will receive a 20-session (2/day), 2-week course 
of cTBS targeting frontostriatal reward circuitry. With a brain target related to 
anhedonia, more dense schedule, and briefer administration than standard 
transcranial magnetic stimulation (TMS) for depression, we will attempt to 
improve anhedonia and depression by reducing (1) high dmPFC function, which 
we have found is associated with adolescent anhedonia (Healey et al., 2014) and 
(2) dmPFC dampening of ventral striatal (VS) response. Participants who receive 
TBS will receive PA exercises drawn from PA Therapy (Craske et al.). Outcomes 
will include anhedonia phenotypes computed in Goal 1, as well as traditional 
clinical variables and brain function. 
 
Goal 3. Conduct sophisticated analytics to examine the association of 
computational phenotypes of anhedonia with device/pharmacologic response, 
clinical course, and functioning over 1 year. To connect the descriptive analytics of 
Goal 1 with treatment response (Goal 2), development, and clinical course, we will 
use machine learning techniques with our high-dimensional, integrative, multi-
modal data to examine predictors of response to TBS and the relation of biological, 
digital, and clinical factors in the persistence of anhedonia and its phenotypes. We 
will also be able to test other questions, including within-person pathways to 
healthy functioning; prescriptive analytics to consider how to assign to TMS; 
change point analyses for fluctuation in anhedonia after treatment; and 
contributions to worsening or improvement of anhedonia over 1 year. 
 
 

 
 
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Study Design & Methods 
 
The study has a longitudinal design in which participants complete 2 sets of 
activities: 
 
Phase 1: Phenotyping. This includes assessment with diagnostic interview, 
questionnaires, behavioral tasks, MRI, app-based digital assessment, and blood 
draw for inflammatory markers. These activities will occur at 4 time points over 
the course of 1 year/participant (study entry, approximately 4 months, 
approximately 5 months, and approximately 1 year), and all participants will 
complete them. 
 
Phase 2: Therapeutic activities: 20 theta burst stimulation (TBS) sessions for all 
participants and 10 sessions of either positive affect (PA) training or control 
training. 
 
This design allows the phenotyping and description of anhedonic depression; the 
prediction of response to treatment; the computation of prescriptive treatment 
assignment retrospectively; and the detection of changes in phenotype and 
component characteristics (e.g., functional connectivity of reward circuitry) in 
relation to treatment, development, and time. Ultimately, the knowledge gained 
will inform the prevention and treatment of anhedonic depression by taking a 
clinical neuroscience approach to understanding this condition, its mechanisms, 
and its improvement with treatment. 
 
The primary endpoints are anhedonia severity and depressive disorder. The 
secondary endpoints include frontostriatal circuit function, DA availability, 
peripheral inflammation, reward behavior, subjective positive affect, locomotion 
and motor activity, sleep characteristics, and phenotype severity/group. 
 
The ADEPT Study will be divided into 2 Phases, with phenotyping in Phase 1 and 
therapeutics in Phase 2. Phase 1 includes MRI, blood draw for inflammatory 
markers, behavior tasks, diagnostic interviews, questionnaires, and phone-based 
EMA and sensor data collection activities. Phase 2 includes TBS and PA training. 
All participants will complete both phases. 
 
1. Eligibility - both Phases: 
At the eligibility visit for Phase 1, participants will complete written informed 
consent; the SCID-5 to diagnose DSM-5 disorders; the MADRS to assess depression 
severity; the SHAPS to assess anhedonia; a medical history form; and a treatment 

 
 
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history form. The eligibility visit may be broken into two or three parts as needed, 
and some procedures may be conducted virtually as appropriate. 
 
For Phase 2, participants will complete self-report measures of health relevant to 
TMS, a urine drug screen, and a urine pregnancy test (for those assigned female at 
birth). For Phase 2 participants, the visit to the M-CTRC lab at the time point after 
TMS will include vital signs, urine drug screen, urine pregnancy screen, and ECG. 
The PI or proxy (i.e., co-investigator or study physician) will review materials for 
eligibility and sign to confirm. Medical findings will be reviewed by a board-
certified physician co-investigator prior to the TMS procedures. 
 
Once informed consent for phase 2 has been completed, a consult with a study 
physician will occur, in which the physician will determine whether TMS treatment 
would be appropriate for the participant. If TMS is not deemed appropriate, the 
participant will not continue in the study. 
 
Eligibility procedures may be ended early if it is clear that a participant does not 
meet inclusion/exclusion criteria (eg., participant reports taking an exclusionary 
medication). 
 
2. Interview and Questionnaires - Phase 1: 
Participants will complete SCID diagnostic interviews at study entry. Also at study 
entry, the affect induction tasks will be completed (5-10 minutes) which involves a 
conversation with the participant and comparing vocal data. Participants will 
complete the MADRS interview on depressive severity and the SHAPS 
questionnaire on anhedonia severity at study entry, pre/post-TMS, and at 1 year. 
Interviews may be conducted in person or by HIPAA-compliant zoom virtual 
format. 
 
At 4 time points, participants will complete other self-report questionnaires. These 
time points are at entry, and approximately at month 2-4 (after TBS), month 4-6, and 
1 year. Questionnaires assess symptoms, demographic characteristics, and relevant 
experiences (e.g., trauma history). 
 
3. MRI - Phase 1: 
At the first 2 time points above, participants will complete a 1.5-hour (scan 1-2) or a 
1-hour scan (scan 3) at the CMU Bridge Center or Presby MRRC. The MRI visits 
will involve 2 resting state MRI scans, a guessing reward fMRI task in which 
participants can win money, scans to assess striatal tissue iron and midbrain 
neuromelanin, and a structural scan. Scans 1-2 will also include an fMRI task 

 
 
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involving effort to obtain reward, if participant interest and time limits allow. The 
tissue iron and neuromelanin scans will be used to compute proxy variables for 
dopamine availability, allowing measurement of dopamine function in reward 
circuitry. Participants can expect these visits to take approximately 1.5 hours (2.25 
hours if effort task is included). 
 
4. Inflammatory Markers - Phase 1: 
At the first 2 time points (described above), participants will complete a 30mL blood 
draw. Venipuncture will be conducted by a phlebotomist at the WPH phlebotomy 
lab. The venipuncture procedure will be billed to study accounts and not to 
participants or their insurance. 
 
5. Behavior - Phase 1: 
At the first two time points as above, participants will complete behavior tasks that 
are presented by computer and assess reward processing. 
 
6. Digital phenotyping - Phase 1: 
For approximately the first 6 and last 3 months of participation in the study, 
participants will complete an ecological momentary assessment (EMA) procedure 
with collection of self-reported mood, symptoms, and related experiences (e.g., sleep 
quality) for 7-day bursts, with one burst per month. EMA will occur by phone, using 
app, such as EARS or WDX, text, or browser, to present surveys and collect data. 
Data will be encrypted, protected, and stored using HIPAA-compliant techniques. 
 
For the entire year of participation in the study, the EARS app may collect data from 
phone sensors to determine variables related to anhedonia, such as motor activity 
(from accelerometer) and location (from GPS). Data will be encrypted, protected, 
and stored using HIPAA-compliant techniques. 
 
7. Computer Cognitive Tasks: 
After the first and second Phenotyping Visits, participants will complete computer 
tasks remotely (approx. 1 hour). They will receive a link by email and will complete 
the tasks when convenient for them. The tasks will include an effort-based reward 
task in which participants make decisions about pressing a button to obtain small or 
large rewards and a task in which participants go through learning and unlearning 
using aversive stimuli (a scream sound). A questionnaire will be in the middle of the 
two tasks. This questionnaire serves as a break to separate the acquisition and 
extinction phases, which is important for the task to be realistic and valid, and data 
will not be collected from the questionnaire. 
 

 
 
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8. Theta Burst Stimulation (TBS) - Phase 2: 
Participants in Phase II of the study will undergo 2 sessions of continuous TBS 
(cTBS) per day over 10 days (on weekdays, over 2 weeks; 20 sessions total). TBS is 
a form of TMS. TBS will be conducted by research personnel who have undergone 
comprehensive training according to the SOP previously provided to the IRB for 
STUDY20050081. 
 
TBS will be administered with the MagPro X100 Transcranial Magnetic Stimulation 
(TMS) system, which is FDA cleared for Theta Burst Stimulation (TBS) treatment 
of Major Depressive Disorder in adult patients who have failed to receive 
satisfactory improvement from prior antidepressant medication in the current 
episode (k170114, k150641, and k171481). Thus, the device is acceptable for use in 
this research context. 
 
The total time of each pair of sessions will be approximately 1 hour, with each 
administration of TBS lasting approximately 2 minutes. Before the first TBS session 
on each TBS session day (i.e., 10x during the study), participants will be asked 
"How well did you sleep last night?" Additionally on each TBS session day, 
participants will complete self-report forms on recent substance use and medical 
status. If drug use or change in medical status is reported, a team member will assess 
for such change and contact a study MD as needed (e.g., participant has started a 
new medication) to determine whether the participant can continue to receive TBS. 
At the beginning and end of each TBS visit (once for every pair of TBS sessions, or 
10x total), participants will rate their pain levels. After all TBS sessions have been 
completed, participants will complete an acceptability scale. Participants can miss 
up to two consecutive days of TMS as long as they come for the appropriate total 
number of visits. 
 
9. PA training - Phase 2: 
At each TBS visit, participants in Phase II will complete a positive affect (PA) 
training task (30-45 min per training session). The exercises in the PA training are 
designed to enhance reward processing and PA, and they will be adapted from 
Positive Affect Therapy, a psychosocial treatment targeting anhedonia and intended 
to improve disrupted frontostriatal function (Craske et al., 2016). This treatment 
reduces negative affect and enhances PA (Craske et al., 2018). PA training will be 
administered by trained research staff. 
 
10. Follow-up assessment - Phase 1: 
The follow-up assessment approximately 1 year after entering the study will include 

 
 
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the MADRS and questionnaires described above. The participant will also complete 
the study completion survey. 
 
 
 
Eligibility Criteria 
Inclusion criteria are as follows: 
Phase 1 (all participants) 
• Age 15-25  
• Current DSM-5 depressive disorder  
• Severity ≥ 12 on MADRS  
• Moderate-severe anhedonia (75% of sample) or low anhedonia (25% of 
sample)  
Phase 2 (for participants in TBS phase, in addition to above) 
• ≥ 1 failed antidepressant trial (for qualification for Phase 2 of study and 
definition of non-response to TMS to be eligible for ketamine) = Treatment for 
at least 6 weeks with an antidepressant medication reaching recommended 
dosage for adults for at least 3 weeks of the treatment (e.g., 20 mg fluoxetine)  
  
Exclusion criteria are as follows: 
Phase 1 (all participants)  
• Lifetime psychosis, bipolar disorder, autism spectrum disorder, or 
developmental disorder  
• Serious, unstable neurological disorder (e.g., seizure disorder)  
• Brain injury with loss of consciousness  
• Moderate-severe substance use disorder, past 6 mos.  
• MRI contraindications (e.g., claustrophobia or ferromagnetic objects that cannot 
be removed from the body, weight > 300 lbs)  
Phase 2 (for participants in TBS phase, in addition to above) 
• Serious, unstable respiratory or cardiovascular illness  
• Pre-TBS: Alcohol binge in past week, which is defined as the number of drinks 
over a two-hour period greater than or equal to: 4 drinks for women, 5 drinks 
for men, 3 drinks for girls (15-21) and 4 drinks for boys (ages 15-21).  
• Pre-TBS: Current illicit stimulant use  
• Pregnancy  
• High blood pressure 
• Lifetime recreational ketamine or PCP use 
• Lifetime history of seizure  
 

 
 
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Statistical Considerations 
 
Analyses will test pre-/post-treatment change in severity of depression symptoms 
(from MADRS) and anhedonia symptoms (from SHAPS) using repeated measures 
tests. Change in symptoms will be computed in separate models for TMS+PAT 
and for TMS+PAT, then ketamine, and for depression and anhedonia. Given the 
small  number of tests, there will not be additional correction for Type I error, and 
statistical threshold for each test will be set at p < .05. For statistical power, 
G*Power 3.1 tests indicate that for repeated measures models with the original 
target sample of 100 participants, we will have >95% power to detect change in 
symptoms with medium effect size of f=.0.2.